Chemical Safety Report s1

CHEMICAL SAFETY REPORT

Substance Name: cadmium sulphate

EC Number: 233-331-6

CAS Number: 10124-36-4

Registrant's Identity: EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4

Table of Contents Part A...... 1 1. SUMMARY OF RISK MANAGEMENT MEASURES...... 1 2. DECLARATION THAT RISK MANAGEMENT MEASURES ARE IMPLEMENTED...... 1 3. DECLARATION THAT RISK MANAGEMENT MEASURES ARE COMMUNICATED...... 1 Part B...... 2 1. IDENTITY OF THE SUBSTANCE AND PHYSICAL AND CHEMICAL PROPERTIES...... 2 1.1. Name and other identifiers of the substance...... 2 1.2. Composition of the substance...... 2 1.3. Physico-chemical properties...... 3 2. MANUFACTURE AND USES...... 5 2.1. Manufacture...... 5 2.2. Identified uses...... 5 2.3. Uses advised against...... 8 3. CLASSIFICATION AND LABELLING...... 8 3.1. Classification and labelling according to CLP / GHS...... 8 3.2. Classification and labelling according to DSD / DPD...... 11 3.2.1. Classification and labelling in Annex I of Directive 67/548/EEC...... 11 3.2.2. Self classification(s)...... 13 3.2.3. Other classification(s)...... 13 4. ENVIRONMENTAL FATE PROPERTIES...... 13 4.1. Degradation...... 15 4.1.1. Abiotic degradation...... 15 4.1.1.1. Hydrolysis...... 15 4.1.1.2. Phototransformation/photolysis...... 15 4.1.1.2.1. Phototransformation in air...... 15 4.1.1.2.2. Phototransformation in water...... 15 4.1.1.2.3. Phototransformation in soil...... 15 4.1.2. Biodegradation...... 15 4.1.2.1. Biodegradation in water...... 15 4.1.2.1.1. Estimated data...... 15 4.1.2.1.2. Screening tests...... 15 4.1.2.1.3. Simulation tests (water and sediments)...... 15 4.1.2.1.4. Summary and discussion of biodegradation in water and sediment...... 16 4.1.2.2. Biodegradation in soil...... 16 4.1.3. Summary and discussion of degradation...... 16 4.2. Environmental distribution...... 16 4.2.1. Adsorption/desorption...... 17 4.2.2. Volatilisation...... 18 4.2.3. Distribution modelling...... 18 4.2.4. Summary and discussion of environmental distribution...... 18 4.3. Bioaccumulation...... 18 4.3.1. Aquatic bioaccumulation...... 19 4.3.2. Terrestrial bioaccumulation...... 27 4.3.3. Summary and discussion of bioaccumulation...... 37 4.4. Secondary poisoning...... 39 4.5. Natural background...... 41 5. HUMAN HEALTH HAZARD ASSESSMENT...... 42 5.1. Toxicokinetics (absorption, metabolism, distribution and elimination)...... 42 5.2. Acute toxicity...... 44 5.2.1. Non-human information...... 44 5.2.1.1. Acute toxicity: oral...... 44 5.2.1.2. Acute toxicity: inhalation...... 45 5.2.1.3. Acute toxicity: dermal...... 47 5.2.1.4. Acute toxicity: other routes...... 47 5.2.2. Human information...... 47 5.2.3. Summary and discussion of acute toxicity...... 48

2010-09-03 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 2 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4

5.3. Irritation...... 49 5.3.1. Skin...... 49 5.3.1.1. Non-human information...... 49 5.3.1.2. Human information...... 49 5.3.2. Eye...... 49 5.3.3. Respiratory tract...... 49 5.3.4. Summary and discussion of irritation...... 49 5.4. Corrosivity...... 49 5.5. Sensitisation...... 49 5.5.1. Skin...... 49 5.5.1.1. Non-human information...... 50 5.5.1.2. Human information...... 50 5.5.2. Respiratory system...... 50 5.5.3. Summary and discussion of sensitisation...... 50 5.6. Repeated dose toxicity...... 51 5.6.1. Non-human information...... 51 5.6.1.1. Repeated dose toxicity: oral, inhalation and other...... 51 5.6.1.2. Repeated dose toxicity: dermal...... 58 5.6.2. Human information...... 58 5.6.3. Summary and discussion of repeated dose toxicity...... 62 5.7. Mutagenicity...... 63 5.7.1. Non-human information...... 63 5.7.1.1. In vitro data...... 63 5.7.1.2. In vivo data...... 66 5.7.2. Human information...... 66 5.7.3. Summary and discussion of mutagenicity...... 70 5.8. Carcinogenicity...... 71 5.8.1. Non-human information...... 71 5.8.1.1. Carcinogenicity: oral...... 71 5.8.1.2. Carcinogenicity: inhalation...... 72 5.8.1.3. Carcinogenicity: dermal...... 76 5.8.1.4. Carcinogenicity: other routes...... 76 5.8.2. Human information...... 78 5.8.3. Summary and discussion of carcinogenicity...... 90 5.9. Toxicity for reproduction...... 91 5.9.1. Effects on fertility...... 91 5.9.1.1. Non-human information...... 91 5.9.1.2. Human information...... 97 5.9.2. Developmental toxicity...... 100 5.9.2.1. Non-human information...... 101 5.9.2.2. Human information...... 103 5.9.3. Summary and discussion of reproductive toxicity...... 106 5.10. Other effects...... 107 5.10.1. Non-human information...... 107 5.10.1.1. Neurotoxicity...... 107 5.10.1.2. Immunotoxicity...... 107 5.10.1.3. Specific investigations: other studies...... 107 5.10.2. Human information...... 107 5.10.3. Summary and discussion of specific investigations...... 108 5.11. Derivation of DNEL(s) / DMEL(s)...... 109 5.11.1. Overview of typical dose descriptors for all endpoints...... 109 5.11.2. Correction of dose descriptors if needed (for example route-to-route extrapolation), application of assessment factors and derivation of the endpoint specific DN(M)EL...... 113 6. HUMAN HEALTH HAZARD ASSESSMENT OF PHYSICO-CHEMICAL PROPERTIES...... 116 6.1. Explosivity...... 116 6.2. Flammability...... 116 6.3. Oxidising potential...... 116 7. ENVIRONMENTAL HAZARD ASSESSMENT...... 117 7.1. Aquatic compartment (including sediment)...... 118 7.1.1. Toxicity test results...... 118

7.1.1.1. Fish...... 128 7.1.1.1.1. Short-term toxicity to fish...... 128 7.1.1.1.2. Long-term toxicity to fish...... 131 7.1.1.2. Aquatic invertebrates...... 137 7.1.1.2.1. Short-term toxicity to aquatic invertebrates...... 137 7.1.1.2.2. Long-term toxicity to aquatic invertebrates...... 140 7.1.1.3. Algae and aquatic plants...... 159 7.1.1.4. Sediment organisms...... 164 7.1.1.5. Other aquatic organisms...... 166 7.1.2. Calculation of Predicted No Effect Concentration (PNEC)...... 167 7.1.2.1. PNEC freshwater...... 168 7.1.2.2. PNEC water Marine...... 170 7.1.2.3. PNEC sediment...... 174 7.2. Terrestrial compartment...... 183 7.2.1. Toxicity test results...... 183 7.2.1.1. Toxicity to soil macro-organisms...... 187 7.2.1.2. Toxicity to terrestrial plants...... 192 7.2.1.3. Toxicity to soil micro-organisms...... 198 7.2.1.4. Toxicity to other terrestrial organisms...... 200 7.2.2. Calculation of Predicted No Effect Concentration (PNEC soil)...... 200 7.3. Atmospheric compartment...... 204 7.4. Microbiological activity in sewage treatment systems...... 204 7.4.1. Toxicity to aquatic micro-organisms...... 205 7.4.2. PNEC for sewage treatment plant...... 205 7.5. Non compartment specific effects relevant for the food chain (secondary poisoning)...... 206 7.5.1. Toxicity to birds...... 206 7.5.2. Toxicity to mammals...... 208 7.5.3. Calculation of PNECoral (secondary poisoning)...... 208 7.6. Conclusion on the environmental hazard assessment and on classification and labelling...... 208 8. PBT AND VPVB ASSESSMENT...... 209 8.1. Assessment of PBT/vPvB Properties...... 209 8.1.1. Summary and overall conclusions on PBT or vPvB properties...... 210 9. EXPOSURE ASSESSMENT...... 210 9.1. GES CdSO4 solution-0: Industrial isolation of the Intermediate Cadmium Sulphate solution (273-721- 3) from Cadmium and/or Cadmium compounds leaching, refining or extraction steps, by settling, filtering and other hydrometallurgical processes...... 210 9.1.1. Exposure scenario...... 210 9.1.2. Exposure estimation...... 217 9.2. GES CdSO4 solution-2: Industrial use of the Intermediate Cadmium Sulphate solution (273-721-3) in the ultimate manufacturing of Cadmium or Cadmium compounds by several metallurgical processes.....217 9.2.1. Exposure scenario...... 217 9.2.2. Exposure estimation...... 224 10. RISK CHARACTERISATION...... 224 10.1. (Title of exposure scenario 1)...... 224 10.1.1. Human health...... 224 10.1.1.1. Workers...... 224 10.1.1.2. Consumers...... 224 10.1.1.3. Indirect exposure of humans via the environment...... 224 10.1.2. Environment...... 224 10.1.2.1. Aquatic compartment (incl. sediment)...... 224 10.1.2.2. Terrestrial compartment...... 224 10.1.2.3. Atmospheric compartment...... 224 10.1.2.4. Microbiological activity in sewage treatment systems...... 224 10.2. (Title of exposure scenario 2)...... 224 10.3. Overall exposure (combined for all relevant emission/release sources)...... 224 10.3.1. Human health (combined for all exposure routes)...... 225 10.3.2. Environment (combined for all emission sources)...... 225 REFERENCES...... 226

List of Tables

Table 1. Substance identity...... 2

Table 2. Constituents...... 3

Table 3. Overview of physico-chemical properties...... 3

Table 4. Overview of quantities (in tonnes// year))...... 5

Table 5. Uses by workers in industrial settings...... 6

Table 6. Freshwater BCF (L kg-1) reported in the EU risk assessment (ECB 2008; ) Table 3.2.34a)...... 19

Table 7. BAF values for whole body vertebrates (L kg-1). (from the EU RA: Table 3.2.34b)...... 20

Table 8. BAF values of some benthic organisms (from EU RA; table 3.2.40)...... 21

Table 9. Overview of studies on aquatic bioaccumulation...... 21

Table 10. Bioaccumulation factors (BAF's) of soil dwelling organisms (from EU RA: table 3.2.37.)...... 27

Table 11. Overview of studies on terrestrial bioaccumulation...... 28

Table 12. Kidney concentration in mammals and predicted critical soil concentrations at which the renal threshold for toxicity may be exceeded (after linear extrapolation of the critical soil levels (values taken from the RA Cd, (ECB 2008))...... 40

Table 13. Ambient background concentrations in Europe according to FOREGS (2006)...... 41

Table 14. Water solubility of the eight cadmium compounds covered in this assessment...... 42

Table 15. Overview of selected experimental studies on acute toxicity after oral administration...... 44

Table 16. Overview of selected experimental studies on acute toxicity after inhalation exposure...... 46

Table 17. Overview of selected experimental studies on repeated dose toxicity after oral administration...... 51

Table 18. Overview of selected experimental studies on repeated dose toxicity after inhalation exposure...... 53

Table 19 . Overview of selected studies on repeated dose toxicity (other routes)...... 55

Table 20. Thresholds for renal effects in recent/relevant studies in occupational settings (inhalation exposure) (adapted from ‘Recommendation from the Scientific Expert Group on Occupational Exposure Limits for Cd and its inorganic compounds’ SCOEL/SUM/136)...... 59

Table 21. Overview of selected experimental in vitro genotoxicity studies...... 63

Table 22. Overview of selected exposure-related observations on genotoxicity in humans...... 66

Table 23. Overview of selected experimental studies on carcinogenicity after oral administration...... 72

Table 24. Overview of selected experimental studies on carcinogenicity after inhalation exposure...... 72

Table 25. Overview of selected experimental studies on carcinogenicity (other routes)...... 77

Table 26. Overview of selected exposure-related observations on carcinogenicity in humans...... 79

Table 27. Overview of selected experimental studies on male fertility and reproductive organs (oral route)...... 91

Table 28. Overview of selected experimental studies on female fertility and reproductive organs (oral route)...94

Table 29. Overview of selected exposure-related observations on toxicity to reproduction / fertility in humans 97

Table 30. Overview of selected experimental studies on developmental toxicity...... 101

Table 31. Overview of selected exposure-related observations developmental toxicity in humans...... 103

Table 32. Available dose-descriptor(s) per endpoint for water-soluble cadmium compounds (cadmium nitrate, chloride and sulphate)...... 109

Table 33. Available dose-descriptor(s) per endpoint for slightly soluble cadmium compounds (i.e. cadmium metal, oxide, hydroxide and carbonate)...... 111

Table 34. Derivation of cadmium DNEL biomonitoring for workers...... 113

Table 35. Derivation of cadmium DNEL general population based on animal data...... 115

Table 36. Derivation of cadmium DNEL general population based on general population monitoring data...... 115

Table 37. Acute aquatic toxicity of cadmium by species as a function of pH and hardness...... 119

Table 38. Lowest acute aquatic toxicity data observed for cadmium...... 119

Table 39. 'Case-by-case”- selected NOEC data of effects of Cd in freshwater and case-by-case calculation of 'geometric mean NOEC's. Bold, underlined data are selected for the HC5 calculation. (after table 3.2.9C of the EU risk assessment)...... 120

Table 40. Endpoints selected for use in SSD for the derivation of marine PNEC for Cd...... 125

Table 41. Summary statistics for the SSD on chronic NOEC values for cadmium in saltwater (n=50)...... 127

Table 42. Results of field experiments made on phytoplankton communities coming from various natural sea waters...... 128

Table 43. Overview of short-term effects on fish...... 128

Table 44. Overview of long-term effects on fish...... 131

Table 45. Overview of short-term effects on aquatic invertebrates...... 137

Table 46. Overview of long-term effects on aquatic invertebrates...... 140

Table 47. Overview of effects on algae and aquatic plants...... 159

Table 48. Overview of long-term effects on sediment organisms...... 164

Table 49. Overview of short-term effects on other aquatic organisms...... 166

Table 50. PNEC water...... 172

Table 51. PNEC sediment...... 182

Table 52. Summary table of species geometric mean NOECs for the most sensitive endpoints of plants and invertebrates used in the SSD. New species to the ones mentioned in the RA or species for which new information was found are highlighted in bold. The newly added individual NOECs are underlined in the last column...... 185

Table 53. Overview of effects on soil macro-organisms...... 187

Table 54. Overview of effects on terrestrial plants...... 192

Table 55. Overview of effects on soil micro-organisms...... 198

Table 56. Summary statistics for the SSD on chronic NOEC values for cadmium in soil...... 201

Table 57. Phytotoxicity of Cd salts in field trials (from Cd RA, 2008)...... 203

Table 58. Chronic long term field NOEC values taken from table 54...... 203

Table 59. PNEC soil...... 204

Table 60. Overview of effects on micro-organisms...... 205

Table 61. PNEC sewage treatment plant...... 205

Table 62. Overview of effects on birds...... 206

Table 63. PNEC oral...... 208

Table 64. GES CdSO4 solution-0...... 210

Table 65. GES CdSO4 solution-2...... 217

List of Figures

Figure 1. The BCF values (L kg-1) of fish or fish tissues as a function of the Cd concentration in water (µg L-1). Data collated from experiments where solution Cd was artificially increased (Figure 3.2.10 of the EU risk assessment, ECB 2008)...... 20

Figure 2. The bioaccumulation factors (BAF kg kg-1) of earthworms as a function of the Cd concentration in soil (mg kg-1)(taken from the EU RA, figure 3.2.11)...... 28

Figure 3. Cumulative frequency of the critical soil Cd concentration at which the critical kidney Cd concentration (400µg/gDW) may be exceeded in the average population of different wildlife species (log- logistic curve fitting)...... 41

Figure 4. Illustration of Eurometaux/ICdA medical supervision guidance (2006) (BI: biological indicators; C: creatinine)...... 114

Figure 5. Species sensitivity distribution of selected chronic marine Cd endpoints (n=47)...... 127

Figure 6. The cumulative frequency distribution of the NOEC values of Cd toxicity tests of data quality group and RI 1-3 used to calculate the HC5 (case-by-case geometric mean calculation; n = 44). Selected data and logistic distribution curve fitted on the data (figure taken from the RA Cd/CdO, ECB 2008)...... 168

Figure 7. Species diversity in the marine environment (from ECETOC 2001). The stars highlight taxonomic groups represented in the cadmium marine database...... 171

Part A 1. SUMMARY OF RISK MANAGEMENT MEASURES Under section 9, risk management measures and operational conditions are described in more detail.

2. DECLARATION THAT RISK MANAGEMENT MEASURES ARE IMPLEMENTED

“I, , declare hereby that risk management measures as described in this CSR are implemented.”

3. DECLARATION THAT RISK MANAGEMENT MEASURES ARE COMMUNICATED

“I, , declare hereby that risk management measures as described in this CSR are communicated to downstream users.”

Part B 1. IDENTITY OF THE SUBSTANCE AND PHYSICAL AND CHEMICAL PROPERTIES

1.1. Name and other identifiers of the substance

The substance cadmium sulphate is a mono constituent substance (origin: inorganic) having the following characteristics and physical–chemical properties (see the IUCLID dataset for further details).

The following public name is used: cadmium sulphate.

Table 1. Substance identity

EC number: 233-331-6 EC name: cadmium sulphate CAS number (EC inventory): 10124-36-4 IUPAC name: cadmium sulfate Annex I index number: 048-009-00-9 Molecular formula: CdSO4 Molecular weight range: 208.446

Structural formula:

1.2. Composition of the substance

Name: cadmium sulphate

Degree of purity: >= 80.0 — < 100.0 % (w/w)

Table 2. Constituents

Constituent Typical concentration Concentration range Remarks cadmium sulphate 96.3 % (w/w) >= 80.0 — < 100.0 % (w/w) EC no.: 233-331-6

1.3. Physico-chemical properties

Table 3. Overview of physico-chemical properties

Property Results Value used for CSA / Discussion Physical state at The physical state of the substance is Value used for CSA: liquid 20°C and 1013 hPa homogenous liquid, its colour is green, it is odourless (Outotec, 2010). Melting / freezing Freezing point is below 0°C point Boiling point Boiling point is ca. 100°C (IZA, pers. comm.) Relative density The density of the substance is 1.257 g/cm³ Value used for CSA: 1.257 at 20°C Vapour pressure The vapour pressure of the substance is of Value used for CSA: 2680 Pa at 25 °C 0.0268 and 0.0475 bar at 25 and 35°C, respectively. Viscosity Viscosity was measured experimentally and Value used for CSA: Viscosity at 20°C: resulted in a value of 2.41, 1.49 and 1.08 2.41 mPa · s (dynamic) mPa S at 20, 40 and 60°C, respectively.

Data waiving

Information requirement: Surface tension Reason: other justification Justification: surface activity is variable and is not a desired property of the material (criteria Column 2 of Annex VII of REACH regulation).

Information requirement: Water solubility Reason: other justification Justification: this parameter is not relevant for liquids

Information requirement: Partition coefficient n-octanol/water (log value) Reason: other justification

Justification: Not applicable to metal compounds; The study does not need to be conducted if the substance is inorganic (column 2 of Annex VII of the REACH regulation)

Information requirement: Flash point Reason: other justification Justification: not applicable. The study does not need to be conducted if the substance is inorganic (Column 2 of Annex VII of REACH regulation)

Information requirement: Flammability Reason: other justification Justification: The substance has no flammability, explosiveness or auto-flammability properties.

Information requirement: Explosive properties Reason: other justification Justification: The substance has no flammability, explosiveness or auto-flammability properties.

Information requirement: Self-ignition temperature Reason: other justification Justification: The substance has no flammability, explosiveness or auto-flammability properties.

Information requirement: Oxidising properties Reason: other justification Justification: the substance has no oxidizing properties

Information requirement: Granulometry Reason: other justification Justification: particle size distribution is not relevant for liquids

Information requirement: Stability in organic solvents and identity of relevant degradation products Reason: other justification Justification: Stability in organic solvents and identity of relevant degradation products is not an applicable endpoint for inorganic substances according to column 2 of Annex IX of the REACH Regulation.

Information requirement: Dissociation constant Reason: other justification Justification: The dissociation constant relating to the acidity constant, pKa, as required by the IUCLID database and REACH Guidance document, is not relevant for the substance.

Discussion of physico-chemical properties

For generating an updated, consistent and well-referenced database on the physico-chemical properties of the substance, a typical sample from the lead registrant was analysed for all parameters relevant for REACH at the Outotec Oy laboratories, Pori, Finland.

Outotec Research Oy has a certified Quality system ISO 9001:2000, Environmental system ISO14001 and Occupational Health and Safety system ISO18001. Laboratory accreditation according to ISO/IEC 17025 covers gas and emission measurements and metal analyses.

Inspecta Sertifiointi Oy evaluates the management systems and FINAS (Finnish Accreditation Service) evaluates the accredited methods. These audits are carried out annually. A couple of internal audits are also done every year, for instance laboratory functions are audited annually. Besides audits, Outotec Research Oy takes part in interlaboratory comparisons concerning metal analytics and emission measurements.

In 2008, Outotec Research Oy took part in the Finnish Excellence Quality Awards and received the prestigious award, "Recognised for Excellence". Outotec Research Oy achieved a score of over 500 points, which entitles the winner to use the five-star Recognised for Excellence, R4E emblem.

By this approach, a consistent, high quality and complete dataset on physicochemical properties of the substance has been established, using state-of-the-art anaylitical techniques. This updated information is encoded in the IUCLID V format.

2. MANUFACTURE AND USES

Quantities

Table 4. Overview of quantities (in tonnes// year))

Year Total tonnage Own use Used for article Used as intermediate Used for under strictly controlled research conditions purposes

2.1. Manufacture

Manufacturing process

- Primary Cd-material (Cd-metal cake and Cd-bearing recycled scrap) are fed into the mixing tank. The leaching reaction with sulphuric acid solutions is kept at the proper temperature and proper pH (~4.2). - Leach residue is filtered on pressfilters - Oxidation of some of the present elements may be necessary (Te > TeO2), followed by another filtration step, if necessary - Further transfer of the Cadmium sulphate solution by pipes or in specially designed transfer units

2.2. Identified uses

Table 5. Uses by workers in industrial settings

Confidential IU number Identified Use Substance Use descriptors (IU) name supplied to that use 1 Cadmium as such Process category (PROC): sulphate (substance itself) PROC 2: Use in closed, continuous process with occasional controlled exposure production - wet PROC 3: Use in closed batch process (synthesis or formulation) PROC 8b: Transfer of substance or preparation (charging/discharging) from/to vessels/large containers at dedicated facilities PROC 9: Transfer of substance or preparation into small containers (dedicated filling line, including weighing) PROC 22: Potentially closed processing operations with minerals/metals at elevated temperature. Industrial setting PROC 26: Handling of solid inorganic substances at ambient temperature

Market sector by type of chemical product: PC 20: Products such as ph-regulators, flocculants, precipitants, neutralisation agents

Environmental release category (ERC): ERC 1: Manufacture of substances

Sector of end use (SU): SU 8: Manufacture of bulk, large scale chemicals (including petroleum products) SU 9: Manufacture of fine chemicals

Subsequent service life relevant for that use?: yes 2 Use of Cadmium as such Process category (PROC): sulphate as (substance itself) PROC 2: Use in closed, continuous process with occasional controlled exposure component for PROC 3: Use in closed batch process (synthesis or formulation) in a mixture production of PROC 8b: Transfer of substance or preparation (charging/discharging) from/to vessels/large inorganic containers at dedicated facilities Cadmium PROC 9: Transfer of substance or preparation into small containers (dedicated filling line, including compounds weighing) PROC 15: Use as laboratory reagent

Confidential IU number Identified Use Substance Use descriptors (IU) name supplied to that use PROC 21: Low energy manipulation of substances bound in materials and/or articles PROC 22: Potentially closed processing operations with minerals/metals at elevated temperature. Industrial setting

Market sector by type of chemical product: PC 19: Intermediate PC 20: Products such as ph-regulators, flocculants, precipitants, neutralisation agents PC 21: Laboratory chemicals

Environmental release category (ERC): ERC 6a: Industrial use resulting in manufacture of another substance (use of intermediates)

Sector of end use (SU): SU 8: Manufacture of bulk, large scale chemicals (including petroleum products) SU 9: Manufacture of fine chemicals SU 10: Formulation [mixing] of preparations and/or re-packaging (excluding alloys)

Subsequent service life relevant for that use?: yes

Most common technical function of substance (what it does): Intermediates 2.3. Uses advised against

None 3. CLASSIFICATION AND LABELLING 3.1. Classification and labelling according to CLP / GHS

Name: cadmium sulphate

Implementation: EU

State/form of the substance: liquid

Related composition: cadmium sulphate

Classification

The substance is classified as follows:

←for physical-chemical properties:

Explosives: Reason for no classification: conclusive but not sufficient for classification

Flammable gases: Reason for no classification: conclusive but not sufficient for classification

Flammable aerosols: Reason for no classification: conclusive but not sufficient for classification

Oxidising gases: Reason for no classification: conclusive but not sufficient for classification

Gases under Reason for no classification: conclusive but not sufficient for classification pressure:

Flammable liquids: Reason for no classification: conclusive but not sufficient for classification

Flammable solids: Reason for no classification: conclusive but not sufficient for classification

Self-reacting Reason for no classification: conclusive but not sufficient for classification substances and mixtures:

Pyrophoric liquids: Reason for no classification: conclusive but not sufficient for classification

Pyrophoric solids: Reason for no classification: conclusive but not sufficient for classification

Self-heating Reason for no classification: conclusive but not sufficient for classification substances and mixtures:

Substances and Reason for no classification: conclusive but not sufficient for classification mixtures which in

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 8 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 contact with water emits flammable gases:

Oxidising liquids: Reason for no classification: conclusive but not sufficient for classification

Oxidising solids: Reason for no classification: conclusive but not sufficient for classification

Organic peroxides: Reason for no classification: conclusive but not sufficient for classification

Corrosive to metals: Reason for no classification: conclusive but not sufficient for classification

←for health hazards:

Acute toxicity - oral: Acute Tox. 3 (Hazard statement: H301: Toxic if swallowed.)

Acute toxicity - Reason for no classification: conclusive but not sufficient for classification dermal:

Acute toxicity - Acute Tox. 2 (Hazard statement: H330: Fatal if inhaled.) inhalation:

Skin Reason for no classification: conclusive but not sufficient for classification corrosion/irritation:

Serious damage/eye Reason for no classification: conclusive but not sufficient for classification irritation:

Respiration Reason for no classification: conclusive but not sufficient for classification sensitization:

Skin sensitation: Reason for no classification: conclusive but not sufficient for classification

Aspiration hazard: Reason for no classification: conclusive but not sufficient for classification

Reproductive Repr. 1B (Hazard statement: H360: May damage fertility or the unborn child .)

Reproductive Reason for no classification: conclusive but not sufficient for classification Toxicity: Effects on or via lactation:

Germ cell Muta. 1B (Hazard statement: H340: May cause genetic defects .)

Carcinogenicity: Carc. 1B (Hazard statement: H350: May cause cancer .)

Specific target organ Reason for no classification: conclusive but not sufficient for classification toxicity - single:

Specific target organ STOT Rep. Exp. 1 (Hazard statement: H372: Causes damage to organs through prolonged or repeated exposure .)

Specific concentration limits:

Concentration (%) Classification >= 7.0 STOT Rep. Exp. 1 >= 0.1 — < 7.0 STOT Rep. Exp. 2 >= 0.01 Carc. 1B

←for environmental hazards:

Hazards to the Aquatic Chronic 1 (Hazard statement: H410: Very toxic to aquatic life with long lasting aquatic environment: effects.)

Hazardous to the Reason for no classification: data lacking atmospheric environment: M-Factor: 10

Labelling

Signal word: Danger

Hazard pictogram:

GHS06: skull and crossbones

GHS08: health hazard

GHS09: environment

Hazard statements:

H350: May cause cancer . H340: May cause genetic defects . H360: May damage fertility or the unborn child . (H360FD is exact statement (translation

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 10 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 of R60-61)) H330: Fatal if inhaled. H301: Toxic if swallowed. H372: Causes damage to organs through prolonged or repeated exposure . H410: Very toxic to aquatic life with long lasting effects.

Precautionary statements:

P270: Do not eat, drink or smoke when using this product. P280: Wear protective gloves/protective clothing/eye protection/face protection. P308+P313: IF exposed or concerned: Get medical advice/attention. P273: Avoid release to the environment. P391: Collect spillage. P405: Store locked up. P501: Dispose of contents/container to... (text according to local/national law)

------3.2. Classification and labelling according to DSD / DPD 3.2.1. Classification and labelling in Annex I of Directive 67/548/EEC

Chemical name: cadmium sulphate

Related composition: cadmium sulphate

Classification

The substance is classified as follows:

←for health effects:

T+; R26 Very toxic; Very toxic by inhalation. T; R25 Toxic; Toxic if swallowed.

T; R48/23/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed.

Carc. Cat. 2; R45 May cause cancer.

Muta. Cat. 2; R46 May cause heritable genetic damage.

Repr. Cat. 2; R60 May impair fertility.

Repr. Cat. 2; R61 May cause harm to the unborn child.

←for the environment:

N; R50/53 Dangerous for the environment; Very toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment.

Labelling

Indication of danger:

T+ - very toxic N - dangerous for the environment

R-phrases:

R45 - may cause cancer R46 - may cause heritable genetic damage R60 - may impair fertility R61 - may cause harm to the unborn child R25 - toxic if swallowed R26 - very toxic by inhalation R48/23/25 - toxic: danger of serious damage to health by prolonged exposure through inhalation and if swallowed R50/53 - very toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment

S-phrases:

S36/37/39 - wear suitable protective clothing, gloves and eye/face protection S53 - avoid exposure - obtain special instructions before use S45 - in case of accident or if you feel unwell, seek medical advice immediately (show the lable where possible) S60 - this material and its container must be disposed of as hazardous waste S61 - avoid release to the environment. refer to special instructions/safety data sheets

Specific concentration limits:

Concentration (%) Classification >= 25.0 Carc. Cat. 2; R45 May cause cancer. Muta. Cat. 2; R46 May cause heritable genetic damage. Repr. Cat. 1; R60 May impair fertility. T; R25 Toxic; Toxic if swallowed. T+; R26 Very toxic; Very toxic by inhalation. T; R48/23/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed. N; R50/53 Dangerous for the environment; Very toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment. >= 10.0 — < 25.0 Carc. Cat. 2; R45 May cause cancer. Muta. Cat. 2; R46 May cause heritable genetic damage. Repr. Cat. 1; R60 May impair fertility. Repr. Cat. 2; R60 May impair fertility. T; R25 Toxic; Toxic if swallowed. T+; R26 Very toxic; Very toxic by inhalation. T; R48/23/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed. N; R51/53 Dangerous for the environment; Toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment. >= 7.0 — < 10.0 Carc. Cat. 1; R45 May cause cancer. Muta. Cat. 1; R46 May cause heritable genetic damage. Repr. Cat. 1; R60 May impair fertility. Repr. Cat. 2; R60 May impair fertility. Xn; R22 Harmful; Harmful if swallowed. T+; R26 Very toxic; Very toxic by inhalation. T; R48/23/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed. N; R51/53 Dangerous for the environment; Toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment.

Concentration (%) Classification >= 2.5 — < 7.0 Carc. Cat. 2; R45 May cause cancer. Muta. Cat. 2; R46 May cause heritable genetic damage. Repr. Cat. 1; R60 May impair fertility. Repr. Cat. 2; R60 May impair fertility. Xn; R22 Harmful; Harmful if swallowed. T; R23 Toxic; Toxic by inhalation. Xn; R48/20/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation and if swallowed. N; R51/53 Dangerous for the environment; Toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment. >= 1.0 — < 2.5 Carc. Cat. 2; R45 May cause cancer. Muta. Cat. 2; R46 May cause heritable genetic damage. Repr. Cat. 1; R60 May impair fertility. Repr. Cat. 2; R60 May impair fertility. Xn; R22 Harmful; Harmful if swallowed. T; R23 Toxic; Toxic by inhalation. Xn; R48/20/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation and if swallowed. R52/53 Dangerous for the environment; Harmful to aquatic organisms, may cause long-term adverse effects in the aquatic environment. >= 0.5 — < 1.0 Carc. Cat. 2; R45 May cause cancer. Muta. Cat. 2; R46 May cause heritable genetic damage. Repr. Cat. 1; R60 May impair fertility. Repr. Cat. 2; R60 May impair fertility. Xn; R20/22 Harmful; Harmful by inhalation and if swallowed. Xn; R48/20/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation and if swallowed. R52/53 Dangerous for the environment; Harmful to aquatic organisms, may cause long-term adverse effects in the aquatic environment. >= 0.25 — < 0.5 Carc. Cat. 2; R45 May cause cancer. Muta. Cat. 2; R46 May cause heritable genetic damage. Xn; R20/22 Harmful; Harmful by inhalation and if swallowed. Xn; R48/20/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation and if swallowed. R52/53 Dangerous for the environment; Harmful to aquatic organisms, may cause long-term adverse effects in the aquatic environment. >= 0.1 — < 0.25 Carc. Cat. 2; R45 May cause cancer. Muta. Cat. 2; R46 May cause heritable genetic damage. Xn; R20/22 Harmful; Harmful by inhalation and if swallowed. Xn; R48/20/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation and if swallowed. >= 0.01 — < 0.1 Carc. Cat. 2; R45 May cause cancer.

Notes:

Note E

3.2.2. Self classification(s)

3.2.3. Other classification(s)

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 13 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 4. ENVIRONMENTAL FATE PROPERTIES

General discussion of environmental fate and pathways:

The intermediates are as a principle not released in the environment. Still, if even minute, insignificant amounts of the main substance (cadmium) is released, some of the information on environmental distribution of cadmium is relevant and available. It is summarised in the IUCLID section 5.

General introduction to chapters 4, 5, 6 and 7.

Under Regulation 793/93/CEE, an extensive risk assessment on Cd metal and CdO has been recently prepared by the Belgian authorities for the EU. The risk assessment report (RAR) on these cadmium substances has been recently published (ECB 2008).

Since these RARs were the result of intensive discussions between all stakeholders, and were approved by experts from all the member states; since they provide a recent review of the available evidence on cadmium and cadmium compounds, they will be used as the main reference for this chemical safety report.

In this chemical safety report, the information, data and conclusions of the RAR will be summarised, focusing on the principles applied, the assumptions made and the conclusions. Where available and relevant, new information and data will be included and discussed.

General remarks on the chapter on environmental fate properties.

Cadmium is a natural element, which is present in all environmental compartments. It occurs in the metallic state, or as cadmium compound, with one valency state (Cd++). All environmental concentration data are expressed as “Cd”, while toxicity is caused by the Cd++ ion. For this reason, the sections on human toxicity and ecotoxicity are applicable to all cadmium compounds, from which Cd ions are released into the environment. Some compounds have however very low solubility and will therefore not release Cd ions, or to a lower extent; this strongly decreases their potential for (eco-)toxicity. As a consequence, distinction can be made between Cd compounds, as a function of their solubility (see chapters 5 and 7).

For checking the potential of metal substances to release ions in the environment, a specific test, the transformation/dissolution (T/D) test is used. For metallic Cd and some of the Cd compounds, this test has been performed. If applicable, the results of such T/D test are discussed in section 4.6. (data in IUCLID section 5.6.).

The issue of degradation (section 4.1.) is not applicable to inorganic compounds.

When Cd ions are present in the environment, they will further interact with the environmental matrix and biota. As such, the concentration of Cd ions that is available to organisms, the bioavailable fraction, will depend on processes like dissolution, absorption, precipitation, complexation, inclusion into (soil) matrix, etc. These processes are defining the fate of Cd in the environment and, ultimately, its ecotoxic potential.

In the water, the bioavailability of Cd through interaction with components of the water and biota has been discussed in the Cd RA (ECB 2008). This has resulted in an approach for quantifying Cd bioavailability into risk assessment, using hardness as a driver for ecotoxicity. When the information on hardness is available, the PNEC can be expressed on a water hardness basis (see chapter 7).

The ultimate fate of metals in water (in the water column) can be assessed via the “unit world model”, that can quantify the “removal from the water column” of the Cd species. This phenomenon was not yet studied for Cd, but can be considered for classification.

In sediment, Cd binds to the sulphide fraction to form insoluble CdS. As such, Cd is not bioavailable anymore to organisms. The sulfide fraction in sediment, as quantified by the AVS, is a reactive pool that binds metals, e.g. Cd and makes them unavailable for biota. The affinity for metal binding on the sulfide fraction in the sediment has been well established for the metals Cu, Cd, Pb, Zn and Ni. In that order, these metals will be bound on the sulfide present in the sediment and, as a consequence, will not be available anymore for uptake and possible toxicity. If the molar difference between SEM and AVS (i.e., SEM-AVS) is less than zero, no toxicity is

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 14 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 expected, while a molar difference greater than zero suggests that toxic effects may occur. Although the background and application of this method was described in detail in the Cd RAR (2008), the approach was not applied in the EU risk assessment on cadmium. However, it was fully worked out in the subsequent discussions on the Zn RA (ECB 2008), and applied for the risk characterisation. Because of the fact that Cd will bind to sulfide preferentially over zinc, it can be anticipated that the AVS/SEM concept applies also to cadmium. It is therefore considered possible to apply the concept on a local site-specific scale (Cd RAR, 2008) Due to the insolubility of the CdS (6 x 10-7 mg/l) Cd will be sequestered in the (anaerobioc) sediments, and the re- mobilisation of Cd ions into the water column will be prevented.

In soil, short-term interaction of Cd ions upon spiking, and long term interactions (“ageing”) have been discussed in the Cd RA (ECB 2008). The analysis was however based on the worst case of acid sandy soils, without making further refinements related to soil type or ageing.

4.1. Degradation 4.1.1. Abiotic degradation

4.1.1.1. Hydrolysis

Data waiving

Reason: study scientifically unjustified

Justification: Waived: According to Annex IX of REACH Regulation, information on hydrolysis is not required for inorganics

The following 4.1.-related endpoints are not relevant for inorganics:

4.1.1.2. Phototransformation/photolysis

4.1.1.2.1. Phototransformation in air

4.1.1.2.2. Phototransformation in water

4.1.1.2.3. Phototransformation in soil

4.1.2. Biodegradation

4.1.2.1. Biodegradation in water

4.1.2.1.1. Estimated data

4.1.2.1.2. Screening tests

Data waiving

Reason: other justification Justification: Biodegradation is not applicable to metals/inorganic substances; study does not need to be conducted if substance is inorganic (Annex VII of REACH regulation).

4.1.2.1.3. Simulation tests (water and sediments)

Data waiving

Reason: other justification

Justification: Biodegradation is not applicable to metals/inorganic substances; study does not need to be conducted if substance is inorganic (Annex VII of REACH regulation).

4.1.2.1.4. Summary and discussion of biodegradation in water and sediment

Discussion (screening testing)

Discussion (simulation testing)

4.1.2.2. Biodegradation in soil

Data waiving

Reason: other justification

Justification: Biodegradation is not applicable to metals/inorganic substances; study does not need to be conducted if substance is inorganic (Annex VII of REACH regulation).

4.1.3. Summary and discussion of degradation

Abiotic degradation

Biotic degradation

Biodegradation is not applicable to metals/inorganic substances. Tests are not to be conducted if the substance is inorganic (Column 2 of Annex VII of REACH regulation)

4.2. Environmental distribution

The environmental fate and release of Cd and Cd compounds has been discussed extensively in the RAR (ECB 2008).

Environmental distribution in water

Cd in freshwater or seawater can occur in both suspended and dissolved forms and is partitioned over a number of chemical species. Depending on the concentration of suspended matter, about 25-40% of the Cd entering the surface water is in dissolved form, the remaining part is bound to the suspended matter. For toxicity, only the fraction not bound is important.

Dissolved forms of Cd in freshwater are e.g.: hydrated Cd ions, Cd ions complexed by inorganic or organic ligands (humic and fulvic acids), Cd oxy ions and Cd adsorbed to solid matter.

The speciation of Cd in the aquatic compartment is of high complexity and depends highly on abiotic factors, such as pH, (dissolved) organic matter content, redox potential, etc. It is assumed that speciation is very relevant for the migration of Cd through sediment, for the distribution of Cd among its truly dissolved and non-dissolved forms, and for the uptake of Cd by some aquatic and sediment organisms. The relationship between the physicochemical factor hardness and the bioavailability, and consequently, the toxicity of Cd has been experimentally elucidated and has been quantified in the RA (see further).

Environmental distribution in soil; adsorption/desorption of Cd in soil

Speciation of Cd in soil

In soils, Cd interacts with various reactive soil surfaces. The most important in this respect are soil organic matter, amorphous soil oxides (Al, Fe, Mn) and clay minerals. The major process by which metals are bound to these surfaces is adsorption. Other processes including precipitation of carbonate type minerals can occur but are, in non- and moderately polluted soils, unlikely to control the solubility of metals in soils. An exception to this is the formation of sulphide minerals that are formed, in the presence of sulphate under reducing conditions. Cd in soil is distributed between the following fractions : 1. Dissolved in pore water (which includes many species) 2. Exchangeable, bound to soil particles 3. Exchangeable, bound to organic ligands (of which a small part in the dissolved fraction and the major part in the solid fraction) 4. Present in secondary clay minerals and metal oxides/hydroxides 5. Present in primary minerals

So, Cd is present in the soil in various forms, that have varying degree of extractability. The soil pH is an important parameter that affects the speciation and the distribution of the Cd species over the soil and the solution. Cd tends to be more sorbed and complexed at higher pH (pH > 7) than at lower pH. Below pH 7, the amount of Cd in solution was reported to be inversely related to soil pH (Janssen et al., 1997). The pH of the soil not only determines the degree of complexation and adsorption of Cd, but also the solubility of the various Cd minerals. The solubility of Cd in soil decreases with increasing pH (ECB 2008).

After addition of a metal to a soil, often a slow decrease in the soil solution concentration, or the available fraction as determined in an extraction solution (e.g. by CaCl2) decreases as a result of (presumably) slow diffusion processes of metals into the matrix of the reactive surfaces. It is this process, or sum of as of yet poorly defined slow processes, that can be defined as ‘ageing’.

The bioavailability of Cd has however not been worked out further in the RA or in this analysis.

4.2.1. Adsorption/desorption

Data waiving

Reason: study scientifically unjustified

Justification: For metals, adsorption/desorption translates in the distribution of the metals between the different fractions of the environmental compartment, e. g. the water (dissolved fraction, fraction bound to suspended matter), soil (fraction bound or complexed to the soil particles, fraction in the soil pore water...). This distribution between the different compartments is translated in the partition coefficients between these different fractions. Information on partition coefficients is given under IUCLID section 5.6.

Discussion

For metals, the transport and distribution over the different environmental compartments e. g. the water (dissolved fraction, fraction bound to suspended matter), soil (fraction bound or complexed to the soil particles, fraction in the soil pore water...) is described and quantified by the metal partition coefficients between these different fractions. The information on these partition coefficients is given under IUCLID section 5.6.

Partition coefficients for cadmium in freshwater have been reviewed in the EU risk assessment report (ECB 2008). Based on this experimental evidence, a partition coefficient for the distribution between solid particulate 3 matter and water (Kpsusp) of 130 x 10 l/kg has been defined for EU waters and was used throughout the RAR.

The Kp for the distribution between sediment and water (Kpsed) was estimated in the RAR from the ratio of the average sediment (1.32mg/kgDW) to average water Cd concentrations (0.14µg/l). This "best fit" Kd yields 10000L/kgDW (ECB 2008).

These partition coefficients have been used since then in other legislative processes in the EU (e. g. the water framework directive) and will also be used for REACH.

The marine Kd was derived based on data from several marine waters. The geomean value for cadmium in seawater is 617 l/kg

The following information is taken into account for any environmental exposure assessment:

Kp for solid particulate matter and water (Kpsusp): 130000 l/kg (log value: 5.1) Kp for water and sediment (Kpsed); 10000 l/kg (log value: 4) Kd for marine waters is 617 l/kg (log value: 2.79)

4.2.2. Volatilisation

4.2.3. Distribution modelling

4.2.4. Summary and discussion of environmental distribution

For metals, the transport and distribution over the different environmental compartments e. g. the water (dissolved fraction, fraction bound to suspended matter), soil (fraction bound or complexed to the soil particles, fraction in the soil pore water...) is described and quantified by the metal partition coefficients between these different fractions. The information on these partition coefficients is given under IUCLID section 5.6.

Partition coefficients for cadmium in freshwater have been reviewed in the EU risk assessment report (ECB 2008). Based on this experimental evidence, a partition coefficient for the distribution between solid particulate matter and water (Kpsusp) of 130 x 103 l/kg has been defined for EU waters and was used throughout the RAR.

The Kp for the distribution between sediment and water (Kpsed) was estimated in the RAR from the ratio of the average sediment (1.32mg/kgDW) to average water Cd concentrations (0.14µg/l). This "best fit" Kd yields 10000L/kgDW (ECB 2008).

These partition coefficients have been used since then in other legislative processes in the EU (e. g. the water framework directive) and will also be used for REACH.

For the marine water, a partition coefficient water/suspended matter of 617 l/kg has been derived.

The summary of these Kp values is given under 4.2.1..

4.3. Bioaccumulation

Numerous data on bioconcentration and bioaccumulation were reviewed in the Cd RA, and in McGeer et al (2003). Reviewed. For Cd (as for other metals), BCF and BAF values are not independent of exposure: the higher BCF/BAF factors are observed generally at the lower Cd exposure levels. In other words, the BCF/BAF will strongly decrease when exposure concentrations increase. This results in a general negative relationship between BCF and exposure, and has implications forn the interpretation of BCF/BAF for hazard identification and classification (McGeer et al 2003).

4.3.1. Aquatic bioaccumulation

Numerous data on BCFs for Cadmium and its compounds were reviewed in the EU risk assessment (ECB 2008). The analysis was based on BCF-values that are calculated on the basis of steady-state uptake and depuration rate constants. Data were considered adequate and relevant when based on measured concentrations in the water and the biota, when the experiments span a long-term exposure, steady state was reached and the test conditions are relevant for the real environment. Most of the BC values were calculated from the concentration ratio between water and biota. BCF's for cadmium are highest in algae and lowest in fish (see table below). In the RA, it was emphasised that a high BCF in algae does not necessarily reflect high bioconcentration, because a significant part of the Cd is absorbed to the outer side of the organisms, and not taken up. Another factor of error is the lack of gut clearance in invertebrates. Organs (kidney, liver) contain most Cd.

Table 6. Freshwater BCF (L kg-1) reported in the EU risk assessment (ECB 2008; ) Table 3.2.34a)

min max median algae wet weight 1636 23143 7535 dry weight 2222 310000 115116 invertebrates wet weight 396 17560 994 dry weight 546 33333 5000 vertebrates wet weight 0.51 684 229 dry weight 5 33333 233 vertebrates -total body content- wet weight 0.51 51 15 dry weight 5 1385 80

Main influencing factors for Cd BCF identified in the RA were hardness and Cd concentration in the water. Increasing water hardness reduces Cd uptake. BCF was also found to be inversely related to Cd concentration in water.

McGeer et al (2003) recently reviewed extensive evidence on bioconcentration and bioaccumulation of cadmium as a function of exposure concentration in a wide variety of taxonomic groups (algae, molluscs, arthropods, annelids, salmonid fish, cyprinid fish, and other fish). The data clearly illustrated that there is a significant degree of control by the organisms on their internal cadmium content. In general and for all taxonomic groups, BCF data showed an inverse relationship to exposure concentrations. In all cases, the relationship of BCF to exposure was significant and negative. The slopes of the BCF/BAF – exposure relations were: algae: -0.72, insects: -0.32, arthropods: -0.61, molluscs: -0.50, salmonids: -0.87, Centrarchids: -0.47, Killifish: -0.05, other fish: -0.72. Overall, species mean slope was -0.49 +/- 0.04 (McGeer et al 2003). This confirms the observation of the RA:, increasing water Cd-concentrations results in decreasing BCF. This is further illustrated by the BCF values of fish presented in figure below. The decreasing trend was observed in all tissues.

Figure 1. The BCF values (L kg-1) of fish or fish tissues as a function of the Cd concentration in water (µg L- 1). Data collated from experiments where solution Cd was artificially increased (Figure 3.2.10 of the EU risk assessment, ECB 2008)

For BAF, the data are more scarce. The risk assessment reported BAF from 4 up to 170000L/kgDW (for Hyallela azteca). BAF are much lower in fish (see table below). Comparison of bioaccumulation factors and bioconcentration factors of aquatic invertebrates reveals the latter to be significantly lower (EU RA).

Table 7. BAF values for whole body vertebrates (L kg-1). (from the EU RA: Table 3.2.34b) min max median vertebrates -total body– 4 2492 167 content- dry weight vertebrates -total body 1 623 42 content- wet weight* * calculated assuming a mean dry weight:wet weight ratio of 0.25 for whole fish

-1 Munger and Hare (1997) found a BAF of 1345 L kg dw for the insect Chaoborus punctipennis in a laboratory test. They also studied the relative importance of water and food as Cd sources to the insect. In artificial lake water, a food chain was simulated, composed of the larvae of the insect, its crustacean prey (Ceriodaphnia dubia), and the prey's algae food (Selenastrum capricornutum). Animals were exposed to a Cd concentration of 1.1 µg Cd2+ L-1. From this test it was possible to study the biomagnification. Selenastrum capricornutum 2+ -1 -1 exposed to 1.1 µg Cd L had a Cd content of 1110 g g dw and was the food for Ceriodaphnia dubia. Exposure of the latter to the same Cd2+ concentration in the water and to Cd-enriched algae resulted in a body -1 -1 burden of 77 g g dw. Chaoborus punctipennis contained 16 g Cd g dw when fed by Cd-enriched Ceriodaphnia in water containing 1.1 µg Cd L-1. The RA concluded that these results suggest no biomagnification of Cd in the lower aquatic food chain Munger and Hare, 1997). This was also observed in an experimental food chain study consisting of algae, zooplankton and fish, in which it was demonstrated that Cd concentrations decreased with increasing throphic level (Ferard et al 1983)

The EU risk assessment also discussed some data on bioaccumulation in sediment. In the sediment, BAFs are generally very low; most of the BAF’s of benthic organism are lower than 1 (either fresh weight based or dry weight based (see table below). The BAF’s are smaller for vertebrates than for invertebrates.

Table 8. BAF values of some benthic organisms (from EU RA; table 3.2.40) min max median invertebrates, wet weight 0.38 0.44 0.43 (kgdw/kgww) invertebrates, dry weight 0.01 1.15 0.28 (kgdw/kgdw) vertebrates, wet weight 0.006 0.18 0.07 (kgdw/kgww)

The body burden Cd generally increases with increasing Cd concentration in the sediment but levels off at higher Cd contents of the sediment. Low BAF values can therefore be found at high Cd concentrations in the sediment (EU RA, ECB 2008)

The studies on aquatic bioaccumulation are summarised in the following table:

Table 9. Overview of studies on aquatic bioaccumulation

Method Results Remarks Reference Chaereborus punctipennis BAF: 1345 (whole body d.w.) 2 (reliable with Munger C and Hare (steady state) restrictions) L (1997) aqueous (freshwater) key study semi-static read-across based on Total uptake duration: 14 d grouping of substances (category Details of method: measured approach) concentrations Test material Laboratory study; BAF (IUPAC name): calculation based on measured cadmium dichloride concentrations in the water and (See endpoint the exposed organisms summary for justification of read- across) Lepomis macrochirus BAF: 240 (whole body d.w.) 2 (reliable with Wiener JG and (steady state) restrictions) Giesy JP Jr. (1979) aqueous (freshwater) weight of evidence field study experimental result Total uptake duration: 499 d Test material Details of method: measured (IUPAC name): concentrations cadmium Field study; BAF calculation based on measured concentrations in the water and the exposed organisms Asellus aquaticus BAF: 65000 (whole body d.w.) 2 (reliable with Lithner G, Holm K (steady state) restrictions) and Borg H (1995) aqueous (freshwater) weight of evidence field study read-across based on Total uptake duration: d grouping of substances (category Details of method: measured approach)

Method Results Remarks Reference concentrations Test material (IUPAC name): Laboratory study; BAF cadmium (See calculation based on measured endpoint summary concentrations in the water and for justification of the exposed organisms read-across) Libellulidae BAF: 41000 (whole body d.w.) 2 (reliable with Lithner G, Holm K (steady state) restrictions) and Borg H (1995) aqueous (freshwater) weight of evidence field study read-across based on Total uptake duration: d grouping of substances (category Details of method: measured approach) concentrations Test material Laboratory study; BAF (IUPAC name): calculation based on measured cadmium (See concentrations in the water and endpoint summary the exposed organisms for justification of read-across) Sialis lutaria BAF: 27000 (whole body d.w.) 2 (reliable with Lithner G, Holm K (steady state) restrictions) and Borg H (1995) aqueous (freshwater) weight of evidence field study read-across based on Total uptake duration: d grouping of substances (category Details of method: measured approach) concentrations Test material Laboratory study; BAF (IUPAC name): calculation based on measured cadmium (See concentrations in the water and endpoint summary the exposed organisms for justification of read-across) periphyton BCF: 130000 (steady state) 2 (reliable with Stephenson M and restrictions) Turner MA (1993) aqueous (freshwater) supporting study field study read-across based on Total uptake duration: 116 d grouping of substances (category Field study; BCF calculation approach) based on measured concentrations in the water and Test material the exposed organisms (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Elodea sp. BCF: > 4560 — < 11400 (whole 2 (reliable with Van hattum B, de body w.w.) (steady state) restrictions) Voogt P, van den

Method Results Remarks Reference Bosch L, van aqueous (freshwater) BCF: > 6700 — < 22333 (whole supporting study Straalen NM and body w.w.) (steady state) Joosse ENG (1989) semi-static read-across based on BCF: > 7535 — < 23143 (whole grouping of Total uptake duration: >= 14 d body w.w.) (steady state) substances (category approach) Details of method: BCF based on BCF: 1636 (whole body w.w.) measured concnetrations (steady state) Test material (IUPAC name): Laboratory study; BCF cadmium dichloride calculation based on measured (See endpoint concentrations in the water and summary for the exposed organisms justification of read- across) Phytium sp. BCF: 44000 (whole body w.w.) 2 (reliable with Duddridge JE and (steady state) (5d test) restrictions) Wainwright M aqueous (freshwater) (1980) BCF: 38000 (whole body w.w.) supporting study static (steady state) (7d test) read-across based on Total uptake duration: > 5 — < 7 grouping of substances (category Details of method: based on approach) measured concentrations Test material Laboratory study; BCF (IUPAC name): calculation based on measured cadmium dichloride concentrations in the water and (See endpoint the exposed organisms summary for justification of read- across) Dictyuchus sterile BCF: 89000 (whole body w.w.) 2 (reliable with Duddridge JE and (steady state) (5d test) restrictions) Wainwright M aqueous (freshwater) (1980) BCF: 90000 (whole body w.w.) supporting study static (steady state) (7d test) read-across based on Total uptake duration: > 5 — < 7 grouping of substances (category Details of method: based on approach) measured concentrations Test material Laboratory study; BCF (IUPAC name): calculation based on measured cadmium dichloride concentrations in the water and (See endpoint the exposed organisms summary for justification of read- across) Scytalidium lignicola BCF: 50000 (whole body w.w.) 2 (reliable with Duddridge JE and (steady state) (5d test) restrictions) Wainwright M aqueous (freshwater) (1980) BCF: 48000 (whole body w.w.) supporting study static (steady state) (7d test) read-across based on Total uptake duration: > 5 — < 7 grouping of substances (category Details of method: based on approach) measured concentrations

Method Results Remarks Reference

Laboratory study; BCF Test material calculation based on measured (IUPAC name): concentrations in the water and cadmium dichloride the exposed organisms (See endpoint summary for justification of read- across) Pteronarcys dorsata BCF: 1000 (whole body w.w.) 2 (reliable with Spehar RL, (steady state) restrictions) Anderson RL and aqueous (freshwater) Fiandt JT (1978a) BCF: 2500 (whole body w.w.) supporting study semi-static (steady state) read-across based on Total uptake duration: 28 d BCF: 3614 (whole body w.w.) grouping of (steady state) substances (category Details of method: measured approach) concentrations were used for BCF: 1818 (whole body w.w.) calculations of BCF (steady state) Test material (IUPAC name): Laboratory study; BCF BCF: 546 (whole body w.w.) cadmium dichloride calculation based on measured (steady state) (See endpoint concentrations in the water and summary for the exposed organisms justification of read- across) Hydropsyche betteni BCF: 2000 (whole body w.w.) 2 (reliable with Spehar RL, (steady state) restrictions) Anderson RL and aqueous (freshwater) Fiandt JT (1978a) BCF: 33333 (whole body w.w.) supporting study semi-static (steady state) read-across based on Total uptake duration: 28 d BCF: 21084 (whole body w.w.) grouping of (steady state) substances (category Details of method: measured approach) concentrations were used for BCF: 7455 (whole body w.w.) calculations of BCF (steady state) Test material (IUPAC name): Laboratory study; BCF BCF: 798 (whole body w.w.) cadmium dichloride calculation based on measured (steady state) (See endpoint concentrations in the water and summary for the exposed organisms justification of read- across) Physa integra BCF: 9000 (whole body w.w.) 2 (reliable with Spehar RL, (steady state) restrictions) Anderson RL and aqueous (freshwater) Fiandt JT (1978a) BCF: 12333 (whole body w.w.) supporting study semi-static (steady state) read-across based on Total uptake duration: 28 d BCF: 5904 (whole body w.w.) grouping of (steady state) substances (category Details of method: measured approach) concentrations were used for BCF: 5818 (whole body w.w.) calculations of BCF (steady state) Test material (IUPAC name): Laboratory study; BCF BCF: 672 (whole body w.w.) cadmium dichloride calculation based on measured (steady state) (See endpoint concentrations in the water and summary for the exposed organisms justification of read-

across) Asellus aquaticus BCF: 17560 (whole body w.w.) 2 (reliable with Van Hattum B, de (steady state) restrictions) Voogt P, van den aqueous (freshwater) Bosch L, van supporting study Straalen NM and flow-through Joosse ENG (1989) read-across based on Total uptake duration: 30 d grouping of substances (category Details of method: BCF based on approach) measured concentrations Test material Laboratory study; BCF (IUPAC name): calculation based on measured cadmium dichloride concentrations in the water and (See endpoint the exposed organisms summary for justification of read- across) Gasterosteus aculeatus BCF: 511 (whole body w.w.) 2 (reliable with Pascoe D and (steady state) restrictions) Mattey DL (1977) aqueous (freshwater) BCF: 173 (whole body w.w.) supporting study semi-static (steady state) read-across based on Total uptake duration: > 0.3 d BCF: 216 (whole body w.w.) grouping of (steady state) substances (category Details of method: determined on approach) measured concentrations BCF: 101 (whole body w.w.) (steady state) Test material Laboratory study; BCF (IUPAC name): calculation based on measured BCF: 34 (whole body w.w.) cadmium dichloride concentrations in the water and (steady state) (See endpoint the exposed organisms summary for BCF: 23 (whole body w.w.) justification of read- (steady state) across) BCF: 14 (whole body w.w.) (steady state)

BCF: 15 (whole body w.w.) (steady state)

BCF: 5 (whole body w.w.) (steady state)

BCF: 3 (whole body w.w.) (steady state) Salmo salar BCF: 1385 (whole body d.w.) 2 (reliable with Rombough PJ and (steady state) restrictions) Garside ET (1982) aqueous (freshwater) BCF: 1277 (whole body d.w.) supporting study flow-through (steady state) read-across based on Total uptake duration: 92 d BCF: 1282 (whole body d.w.) grouping of (steady state) substances (category Details of method: determined on approach) measured concentrations BCF: 213 (whole body d.w.) (steady state) Test material

Laboratory study; BCF BCF: 213 (whole body d.w.) (IUPAC name): calculation based on measured (steady state) cadmium dichloride concentrations in the water and (See endpoint the exposed organisms BCF: 95 (whole body d.w.) summary for (steady state) justification of read- across) BCF: 60 (whole body d.w.) (steady state)

BCF: 5 (whole body d.w.) (steady state) Salvelinus fontinalis BCF: 33333 (organ d.w. (kidney)) 2 (reliable with Benoit DA, (steady state) (1st generation) restrictions) Leonard EN, aqueous (freshwater) Christensen GM BCF: 1166 (organ d.w. (Gill)) supporting study and Fiandt JT flow-through (steady state) (1st generation) (1976a) read-across based on Total uptake duration: >= 266 d BCF: 666 (organ d.w. (liver)) grouping of (steady state) (1st generation) substances (category Details of method: determined on approach) measured concentrations BCF: 24000 (organ d.w. (kidney)) (steady state) (1st generation) Test material Laboratory study; BCF (IUPAC name): calculation based on measured BCF: 11000 (organ d.w. (gill)) cadmium dichloride concentrations in the water and (steady state) (1st generation) (See endpoint the organs of the exposed summary for organisms BCF: 9000 (organ d.w. (liver)) justification of read- (steady state) (1st generation) across) BCF: 14118 (organ d.w. (kidney)) (steady state) (1st generation)

BCF: 2206 (organ d.w. (liver)) (steady state) (1st generation)

BCF: 2941 (organ d.w. (liver)) (steady state) (1st generation)

BCF: 1912 (organ d.w. (gonad)) (steady state) (1st generation) Salvelinus fontinalis BCF: 882 (organ d.w. (spleen)) 2 (reliable with Benoit DA, (steady state) (1st generation) restrictions) Leonard EN, aqueous (freshwater) Christensen GM BCF: 29.4 (organ d.w. (muscle)) supporting study and Fiandt JT flow-through (steady state) (1st generation) (1976a) read-across based on Total uptake duration: >= 266 d BCF: 29.4 (organ d.w. (red blood grouping of cells)) (steady state) (1st substances (category Details of method: determined on generation) approach) measured concentrations BCF: 12647 (organ d.w. (kidney)) Test material Laboratory study; BCF (steady state) (2nd generation) (IUPAC name): calculation based on measured cadmium dichloride concentrations in the water and BCF: 1765 (organ d.w. (gill)) (See endpoint the organs of the exposed (steady state) (2nd generation) summary for organisms justification of read- BCF: 4412 (organ d.w. (liver)) across) (steady state) (2nd generation)

Method Results Remarks Reference Hyalella azteca BAF: 170000 (whole body d.w.) 2 (reliable with Stephenson M and (steady state) restrictions) Turner MA (1993) aqueous (freshwater) supporting study field study read-across based on Total uptake duration: 116 d grouping of substances (category Details of method: measured approach) concentrations Test material Field study; BAF calculation (IUPAC name): based on measured cadmium dichloride concentrations in the water and (See endpoint the exposed organisms summary for justification of read- across)

4.3.2. Terrestrial bioaccumulation

The EU risk assessment defined bioconcentration of Cd in the terrestrial compartment as the net result of the Cd uptake, distribution and elimination in an organism due to exposure to Cd in soil only.

Results of cadmium bioaccumulation studies in soil were reviewed in the EU RA (see table below). The median BAF observed on earthworms (85 results) was 15; the median BAF observed on arthropods (45 results) was 1.4 (EU RA, ECB 2008). All BAF values were calculated from the soil:biota concentration ratio’s. Most organisms observed were earthworms.

Table 10. Bioaccumulation factors (BAF's) of soil dwelling organisms (from EU RA: table 3.2.37.). min max median 5th n percentile earthworms- wet weight basis 4 32 15 5 11 (kgdw/kgww) earthworms- dry weight basis 1.6 151 15 5 85 (kgdw/k–dw) arthropoda - dry weight basis 0.05 18.8 1.4 0.30 45 (kgdw/kgdw)

Overall, it was concluded that cadmium is concentrated from the soil into earthworms organisms (BAF values all higher than 1). Most important factors affecting the bioaccumulation of Cd by earthworms are the Cd concentration of the soil, soil type, pH, soil organic matter and CEC. The influence of the Cd content of the soil on the bioaccumulation of Cd is illustrated in most of the studies. Cadmium concentrations in earthworms increase with increasing Cd levels in a non-proportional way. As a result, the BAF decreases with increasing soil Cd, (see figure below). In other words, the BAF observed on soil containing higher Cd was lower than the BAF observed on control soils.

1000 BAF, fresh weight basis BAF, dry weight basis

100 ) 1 - g k

F A B 10

1 0.01 0.1 1 10 100 1000 Cd concentration in soil (mg kgdw-1)

Figure 2. The bioaccumulation factors (BAF kg kg-1) of earthworms as a function of the Cd concentration in soil (mg kg-1)(taken from the EU RA, figure 3.2.11)

The results of terrestrial bioaccumulation studies are summarised in the following table:

Table 11. Overview of studies on terrestrial bioaccumulation

Method Results Remarks Reference Lumbricus terrestris BSAF: 14.64 (whole body d.w.) 2 (reliable with Wright MA and (steady state) (control soil) restrictions) Stringer A (1980) Field study; BAF calculation based on measured BSAF: 5.58 (whole body d.w.) key study concentrations in the soil and the (steady state) (contaminated soil) exposed organisms read-across based on grouping of substances (category approach)

Test material (IUPAC name): cadmium (See endpoint summary for justification of read-across) Allobophora calluginosa BSAF: 32.45 (whole body d.w.) 2 (reliable with Wright MA and (steady state) (control soil) restrictions) Stringer A (1980) Field study; BAF calculation based on measured BSAF: 6.43 (whole body d.w.) key study concentrations in the soil and the (steady state) (contaminated soil) exposed organisms read-across based on grouping of substances (category

approach)

Test material (IUPAC name): cadmium (See endpoint summary for justification of read-across) Allolobophora chlorotica BSAF: 14.91 (whole body d.w.) 2 (reliable with Wright MA and (steady state) (control soil) restrictions) Stringer A (1980) Field study; BAF calculation based on measured BSAF: 5.56 (whole body d.w.) key study concentrations in the soil and the (steady state) (contaminated soil) exposed organisms read-across based on grouping of substances (category approach)

Test material (IUPAC name): cadmium (See endpoint summary for justification of read-across) Allolobophora tuberculata BSAF: 17.55 (whole body d.w.) 2 (reliable with Wright MA and (steady state) (control soil) restrictions) Stringer A (1980) Field study; BAF calculation based on measured key study concentrations in the soil and the exposed organisms read-across based on grouping of substances (category approach)

Test material (IUPAC name): cadmium (See endpoint summary for justification of read-across) Allolobophora longa BSAF: 16.01 (whole body d.w.) 2 (reliable with Wright MA and (steady state) (control soil) restrictions) Stringer A (1980) Field study; BAF calculation based on measured BSAF: 3.99 (whole body d.w.) key study concentrations in the soil and the (steady state) (contaminated soil) exposed organisms read-across based on grouping of substances (category approach)

Test material (IUPAC name): cadmium (See endpoint summary for justification of read-across) Allolobophora rosea BSAF: 16.27 (whole body d.w.) 2 (reliable with Wright MA and

Method Results Remarks Reference (steady state) (control soil) restrictions) Stringer A (1980) Field study; BAF calculation based on measured BSAF: 6.06 (whole body d.w.) key study concentrations in the soil and the (steady state) (contaminated soil) exposed organisms read-across based on grouping of substances (category approach)

Test material (IUPAC name): cadmium (See endpoint summary for justification of read-across) Lumbricus terrestris BSAF: 40 (whole body d.w.) 2 (reliable with Beyer WN, Chaney (steady state) (control soil d)) restrictions) RL and Mulhern Field study; BAF calculation BM (1982) based on measured BSAF: 62 (whole body d.w.) key study concentrations in the soil and the (steady state) (control soil c)) exposed organisms read-across based on BSAF: 14 (whole body d.w.) grouping of (steady state) (sludge amended substances (category soil d)) approach)

BSAF: 54 (whole body d.w.) Test material (steady state) (sludge amended (IUPAC name): soil c)) cadmium (See endpoint summary BSAF: 13 (whole body d.w.) for justification of (steady state) (sludge amended read-across) soil a)) Aporrectodea turgida BSAF: 62 (whole body d.w.) 2 (reliable with Beyer WN, Chaney (steady state) (control soil c)) restrictions) RL and Mulhern Field study; BAF calculation BM (1982) based on measured BSAF: 54 (whole body d.w.) key study concentrations in the soil and the (steady state) (sludge amended exposed organisms soil c)) read-across based on grouping of substances (category approach)

Test material (IUPAC name): cadmium (See endpoint summary for justification of read-across) Aporrectodea Tuberculata BSAF: 66 (whole body d.w.) 2 (reliable with Beyer WN, Chaney (steady state) (control soil a)) restrictions) RL and Mulhern Field study; BAF calculation BM (1982) based on measured BSAF: 30 (whole body d.w.) key study concentrations in the soil and the (steady state) (control soil b)) exposed organisms read-across based on grouping of substances (category approach)

Test material

(IUPAC name): cadmium (See endpoint summary for justification of read-across) Aporrectodea longa BSAF: 20 (whole body d.w.) 2 (reliable with Beyer WN, Chaney (steady state) (sludge amended restrictions) RL and Mulhern Field study; BAF calculation soil b)) BM (1982) based on measured key study concentrations in the soil and the BSAF: 30 (whole body d.w.) exposed organisms (steady state) (control soil b)) read-across based on grouping of substances (category approach)

Test material (IUPAC name): cadmium (See endpoint summary for justification of read-across) pasture BCF: 0.8 (plant dry weight) 2 (reliable with Ma WC (1987) (steady state) (site 1) restrictions) field study with measurement of Cd and other metals in soil BCF: 0.35 (plant dry weight) key study (contaminated and control) , (steady state) (site 2) plants and animals. read-across based on BCF: 0.22 (plant dry weight) grouping of (steady state) (site 3) substances (category approach) BCF: 5.3 (plant dry weight) (steady state) (site 4) Test material (CAS name): cadmium BCF: 21 (plant dry weight) (See endpoint (steady state) (site 5 (control)) summary for justification of read- across) Lumbricus rubellus BSAF: 13 (whole body d.w.) 2 (reliable with Ma WC (1987) (steady state) (site 2) restrictions) field study with measurement of Cd and other metals in soil BSAF: 12.4 (whole body d.w.) key study (contaminated and control) , (steady state) (site 3) plants and animals. read-across based on BSAF: 190 (whole body d.w.) grouping of (steady state) (site 5 (control)) substances (category approach)

Test material (CAS name): cadmium (See endpoint summary for justification of read- across) Talpa europea BSAF: 62 (organ d.w. (kidney)) 2 (reliable with Ma WC (1987) (steady state) (site 1) restrictions) field study with measurement of Cd and other metals in soil BSAF: 37 (organ d.w. (kidney)) key study

(contaminated and control) , (steady state) (site 2) read-across based on plants and animals. grouping of BSAF: 24 (organ d.w. (kidney)) substances (category (steady state) (site 3) approach)

BSAF: 620 (organ d.w. (kidney)) Test material (CAS (steady state) (site 4) name): cadmium (See endpoint BSAF: 590 (organ d.w. (kidney)) summary for (steady state) (site 5 (control)) justification of read- across) BSAF: 52 (organ d.w. (liver)) (steady state) (site 1)

BSAF: 38 (organ d.w. (liver)) (steady state) (site 2)

BSAF: 300 (organ d.w. (liver)) (steady state) (site 5 (control)) Microtus agrestis BSAF: 0.4 (organ d.w. (kidney)) 2 (reliable with Ma WC, Denneman (steady state) (Budel soil, Feb- restrictions) W and Faber J field study with measurement of March) (1991) Cd and lead in soil (contaminated key study and control) , plants and animals. BSAF: 0.18 (organ d.w. (kidney)) (steady state) (Budel soil, May- read-across based on June) grouping of substances (category BSAF: 0.5 (organ d.w. (kidney)) approach) (steady state) (Budel soil, Oct- Nov) Test material (CAS name): cadmium BSAF: 0.23 (organ d.w. (kidney)) (See endpoint (steady state) (Arnhem soil, feb- summary for March) justification of read- across) BSAF: 0.08 (organ d.w. (kidney)) (steady state) (Arnhem soil, May- June)

BSAF: 0.18 (organ d.w. (kidney)) (steady state) (Arnhem soil, Oct- Nov)

BSAF: 0.06 (organ d.w. (liver)) (steady state) (Budel soil, Feb- March)

BSAF: 0.034 (organ d.w. (liver)) (steady state) (Budel soil, May- June)

BSAF: 0.1 (organ d.w. (liver)) (steady state) (Budel soil Oct-

BSAF: 0.08 (organ d.w. (liver)) (steady state) (Arnhem soil, Feb- March)

BSAF: 0.1 (organ d.w. (liver)) (steady state) (Arnhem soil, May- June)

BSAF: 0.11 (organ d.w. (liver)) (steady state) (Arnhem soil, Oct- Nov) Sorex araneus BSAF: 36 (organ d.w. (kidney)) 2 (reliable with Ma WC, Denneman (steady state) (Budel soil, Feb- restrictions) W and Faber J field study with measurement of March) (1991) Cd and lead in soil (contaminated key study and control) , plants and animals. BSAF: 15 (organ d.w. (kidney)) (steady state) (Budel soil, May- read-across based on June) grouping of substances (category BSAF: 23 (organ d.w. (kidney)) approach) (steady state) (Budel soil, Oct- Nov) Test material (CAS name): cadmium BSAF: 43 (organ d.w. (kidney)) (See endpoint (steady state) (Arnhem soil, feb- summary for March) justification of read- across) BSAF: 12 (organ d.w. (kidney)) (steady state) (Arnhem soil, May- June)

BSAF: 26 (organ d.w. (kidney)) (steady state) (Arnhem soil, Oct- Nov)

BSAF: 49 (organ d.w. (liver)) (steady state) (Budel soil, Feb- March)

BSAF: 14 (organ d.w. (liver)) (steady state) (Budel soil, May- June)

BSAF: 33 (organ d.w. (liver)) (steady state) (Budel soil Oct- Nov)

BSAF: 38 (organ d.w. (liver)) (steady state) (Arnhem soil, Feb- March)

BSAF: 8 (organ d.w. (liver)) (steady state) (Arnhem soil, May- June)

BSAF: 25 (organ d.w. (liver)) (steady state) (Arnhem soil, Oct-

Nov) Castor fiber BSAF: 4.7 (organ d.w. (kidney)) 2 (reliable with Nolet BA, Dijkstra (steady state) restrictions) VAA and Heidecke Field study on the D (1994) bioaccumulation of Cd in kidney supporting study of local animals through environmental exposure read-across based on grouping of substances (category approach)

Test material (CAS name): cadmium (See endpoint summary for justification of read- across) Sorex araneus BSAF: 47 (organ d.w.) (steady 2 (reliable with Read HJ and Martin state) restrictions) MH (1993) Field study on the bioaccumulation of Cd in kidney supporting study of local animals through environmental exposure read-across based on grouping of substances (category approach)

Test material (CAS name): cadmium (See endpoint summary for justification of read- across) Sorex minutus BSAF: 13 (organ d.w.) (steady 2 (reliable with Read HJ and Martin state) restrictions) MH (1993) Field study on the bioaccumulation of Cd in kidney supporting study of local animals through environmental exposure read-across based on grouping of substances (category approach)

Test material (CAS name): cadmium (See endpoint summary for justification of read- across) Sorex araneus BSAF: 26 (organ d.w.) (steady 2 (reliable with Hunter BA, state) restrictions) Johnson MS and Field study on the Thompson DJ bioaccumulation of Cd in kidney supporting study (1989) of local animals through environmental exposure read-across based on grouping of substances (category

approach)

Test material (CAS name): cadmium (See endpoint summary for justification of read- across) Microtus agrestis BSAF: 6 (organ d.w.) (steady 2 (reliable with Hunter BA, state) restrictions) Johnson MS and Field study on the Thompson DJ bioaccumulation of Cd in kidney supporting study (1989) of local animals through environmental exposure read-across based on grouping of substances (category approach)

Test material (CAS name): cadmium (See endpoint summary for justification of read- across) Apodemus sylvaticus BSAF: 3 (organ d.w.) (steady 2 (reliable with Hunter BA, state) restrictions) Johnson MS and Field study on the Thompson DJ bioaccumulation of Cd in kidney supporting study (1989) of local animals through environmental exposure read-across based on grouping of substances (category approach)

Test material (CAS name): cadmium (See endpoint summary for justification of read- across) Sorex araneus BSAF: 45 (organ d.w.) (steady 2 (reliable with Hunter BA and state) restrictions) Johnson MS (1982) Field study on the bioaccumulation of Cd in kidney supporting study of local animals through environmental exposure read-across based on grouping of substances (category approach)

Test material (CAS name): cadmium (See endpoint summary for justification of read- across) Microtus agrestis BSAF: 3 (organ d.w.) (steady 2 (reliable with Hunter BA and

Method Results Remarks Reference state) restrictions) Johnson MS (1982) Field study on the bioaccumulation of Cd in kidney supporting study of local animals through environmental exposure read-across based on grouping of substances (category approach)

Test material (CAS name): cadmium (See endpoint summary for justification of read- across) Apodemus sylvaticus BSAF: 2 (organ d.w.) (steady 2 (reliable with Hunter BA and state) restrictions) Johnson MS (1982) Field study on the bioaccumulation of Cd in kidney supporting study of local animals through environmental exposure read-across based on grouping of substances (category approach)

Test material (CAS name): cadmium (See endpoint summary for justification of read- across) Sorex araneus BSAF: 6 (organ d.w.) (steady 2 (reliable with Hendriks AJ, Ma state) restrictions) W-C, Brouns JJ, Field study on the Deruiterdijkman bioaccumulation of Cd in kidney supporting study EM and Gast R of local animals through (1995) environmental exposure read-across based on grouping of substances (category approach)

Test material (CAS name): cadmium (See endpoint summary for justification of read- across) Sylvilagus floridanus BSAF: 28 (organ d.w. (kidney)) 2 (reliable with Storm GL, Fosmire (steady state) restrictions) GJ and Bellis ED Field study on the (1994) bioaccumulation of Cd in kidney supporting study of local animals through environmental exposure read-across based on grouping of substances (category approach)

Test material (CAS name): cadmium

(See endpoint summary for justification of read- across) Odocoileus virginianus BSAF: 12 (organ d.w. (kidney)) 2 (reliable with Storm GL, Fosmire (steady state) restrictions) GJ and Bellis ED Field study on the (1994) bioaccumulation of Cd in kidney supporting study of local animals through environmental exposure read-across based on grouping of substances (category approach)

Test material (CAS name): cadmium (See endpoint summary for justification of read- across) Sylvilagus floridanus BSAF: 53 (organ d.w. (kidney)) 2 (reliable with Dressler RL, Storm (steady state) restrictions) GL, Tzilkowski Field study on the WM and Sopper bioaccumulation of Cd in kidney supporting study WE (1986) of local animals through environmental exposure read-across based on grouping of substances (category approach)

Test material (CAS name): cadmium (See endpoint summary for justification of read- across)

4.3.3. Summary and discussion of bioaccumulation

Aquatic bioaccumulation

BCF's for cadmium are highest in algae and lowest in fish; High BCF in algae does not necessarily reflect high bioconcentration, because a significant part of the Cd is absorbed to the outer side of the organisms, and not taken up. Another factor of error is the lack of gut clearance in invertebrates. Organs (kidney, liver) contain most Cd.

Main influencing factors for Cd BCF are hardness and Cd concentration in the water. Increasing water hardness reduces Cd uptake. BCF is also inversely related to Cd concentration in water.

McGeer et al (2003) recently extensively reviewed the evidence on bioconcentration and bioaccumulation of cadmium as a function of exposure concentration in a number of taxonomic groups (algae, molluscs, arthropods, annelids, salmonid fish, cyprinid fish, and other fish). The data clearly illustrated that there is a significant degree of control on internal cadmium content. In general, BCF data showed an inverse relationship to exposure concentrations. In all cases, the relationship of BCF to exposure was significant and negative. The slopes of the BCF/BAF – exposure relations were: algae: -0.72, insects: -0.32, arthropods: -0.61, molluscs: -0.50, salmonids: -0.87, Centrarchids: -0.47, Killifish: -0.05, other fish: -0.72. Overall, species mean slope was -0.49 +/- 0.04 (McGeer et al 2003. Environm. Toxicology & Chemistry, vol 22, nr 5, 1017 -1037).

The following information is taken into account for any hazard / risk / bioaccumulation assessment:

In general, BCF and BAF data show an inverse relationship to exposure concentrations. BCF's for cadmium are highest in algae and lowest in fish. In algae, external adsorption of Cd is one of the reasons for high BCF. Hardness and Cd concentration in the water are inversely related to BCF. Median BCF (per dry weight) reported in the EU risk assessment (ECB 2008) are: 115116 (algae), 5000 (invertebrates), 233 (vertebrates) The risk assessment mentions a median BAF for vertebrates of 167. Highest BAF is observed for the invertebrate Hyalella (170000), at a very low Cd concentration.

Terrestrial bioaccumulation

The EU Risk assessment (ECB 2008) presents BAF values that were calculated from the soil: biota concentration ratio’s. Most organisms are earthworms and the Cd levels were expressed on dry or wet weight basis. All the data on earthworms were obtained from specimens with guts voided prior to analysis.

Cadmium is concentrated from the soil into earthworms organisms (BAF values are all higher than 1). Most important factors affecting the bioaccumulation of Cd by earthworms are the Cd concentration of the soil, soil type, pH, soil organic matter and CEC.

The influence of the Cd content of the soil on the bioaccumulation of Cd is illustrated in most of the studies. Cadmium concentrations in earthworms increase with increasing Cd levels in a non-proportional way. As a result, the BAF observed in Cd-contaminated or Cd-enriched soils is lower than the BAF observed in control soils.

The following information is taken into account for any hazard / risk / bioaccumulation assessment:

Median BAF observed on earthworms is 15 (expressed on a dry weight basis). For arthropoda, the median BAF is 1.4 (summary from the EU risk assessment, ECB 2008). The BAF observed in Cd-contaminated or Cd- enriched soils is lower than the BAF observed in control soils. In a field study, the BAF observed under contaminated conditions on Lumbricus rubellus was 12-123, under control conditions it was 190.

General conclusion

The available evidence makes it difficult to decide whether or not Cd is to be considered as a bioaccumulative substance in the environment. The high BCF /BAF factors observed in the lower levels of the food chain (algae notably) would suggest Cd is to be considered as bioaccumulative. However, there are some uncertainties with the data: the high BCF/BAF factors observed in the algae are (at least partly) due to external absorption, not to uptake; the higher levels in invertebrates maybe related to lack of gut clearance of the organisms studied. BCF in fish are generally below the criterion for considering a substance bioaccumulative.

In terms of hazard identification/classification, several considerations speak against a conclusion of considering Cd as bioaccumulative substance:

-the BCF/BAF values observed with Cd consistently decrease with increasing exposure, which clearly shows some level of physiological regulation of uptake. One of the key theoretical conditions of the BCF model in terms of its relevance for chronic toxicity and applicability to the hazard identification/classification of chemicals is that the BCF/BAF should be independent of exposure. BCF/BAF values should in other words remain fairly constant over a range of exposures, which is clearly not the case for Cd.

-Evidence related to biomagnification in the aquatic food chain consistently shows that Cd is not biomagnifying.

Based on an extensive review of evidence on a wide variability of taxonomic groups, McGeer et al (2003) concluded that the BCF/BAF criteria, as conceived for organic substances, are inappropriate for the hazard identification and classification of metals, including Cd. They highlighted the inconsistency between BCF/BAF values and toxicological data, as BCF values are highest (suggesting hazard) at low exposure concentrations and are lowest (indicating no hazard) at the highest exposure concentrations, were toxicity is likely.

So the case on Cd bioaccumulation for hazard identification/classification is inconclusive. In any case, the main

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 38 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 question to pose in this respect is on secondary poisoning. This aspect is discussed in the next section.

4.4. Secondary poisoning

Secondary poisoning will be evaluated based on the interpretation of the available data with regard to the potential to bio-accumulate in the food chain, presented in the EU RA (ECB 2008).

The EU RA assessed the toxicity of Cd through secondary poisoning based on laboratory studies where organisms are exposed to variable Cd concentrations in their prey. The PNECoral following fom such studies was combined with the bioconcentration factors (BCF’s) or bioaccumulation factors (BAF’s) of the prey to assess risks of secondary poisoning of the predator by Cd originating from soil, freshwater or sediment. The risk of secondary poisoning in the RA was focussed on mammals and birds and not on lower organisms, because no or little data were found to calculate the PNECoral for fish or aquatic invertebrates, benthic organisms or lower terrestrial organisms. A short discussion was however, given about secondary poisoning in fish or lower terrestrial organisms.

The importance of the bioconcentration factors soil-plant (the soil-plant transfer factors) for Cd exposure to the general population is noted.

The following assessment is based on the EU RA.

In the freshwater compartment, BCFs can be high for primary producers, but they decrease significantly further up the food chain. Bioconcentration and bio-accumulation are also inversely related to Cd-concentration or Cd- exposure; in other words, BCF and BAF are lower when exposure to Cd is higher. Finally, there is evidence that Cd is not biomagnifying in the (lower) aquatic food chain, where the observed BCFs (e.g. with the authotrophic organisms) are highest. The risk of secondary poisoning of fish eating birds by Cd is predicted to be smaller than the direct effects of Cd in the aquatic environment. The RA demonstrated, using BCF’s of fish (mentioned in section 4.3) that the Cd concentration in whole fish at the PNECwater of 0.19 µg Cd/l (section 7.) could be predicted to range between 0.0001 and 0.13 mg Cd/kg fresh weight using the whole range of BCF’s (0.5-684 l/kg fresh weight). It was concluded that these Cd concentrations were below the PNECoral for birds or birds+mammals (ECB 2008).

In the terrestrial compartment, a PNEC for secondary poisoning was calculated from the lowest observed PNECoral for mammals and birds, which was derived from feeding studies with Cd salt spiked diets. Nine feeding studies were selected (sub-chronic and chronic studies), four studies with birds and 5 studies with mammals. The PNECoral was calculated from the lowest NOEC using an assessment factor, (see section 7).

In the RA, the risk for secondary poisoning in a soil-worm-bird/mammal system was discussed in great detail. Using the range of BCFs/BAFs, reported in section 4.3., exposure above the PNEC oral for birds in the soil- worm-bird system were calculated starting from the PNEC soil of 2.3mg/kg soil. This model was however questioned because a) a mean BAF would overestimate earthworm concentrations at more contaminated sites because the BAF decreases with soil Cd and b) higher availability of Cd in metal salt spiked meals in the laboratory tests than Cd in worms (EU RA, ECB 2008). This was confirmed by the observation that concentrations of Cd in terrestrial birds (kidney and liver concentrations) did not indicate Cd-poisoning, even in contaminated areas and in top-predators (EU RA, ECB 2008).

Several factors can explain this. In studies with shrew, it was demonstrated that Cd intake in the field is 4-times less than under laboratory conditions. In general, it was observed that Cd is more available in laboratory spiked meals than in the diet of field-exposed animals. These arguments were seen as suggesting that risk of secondary poisoning by Cd may be overestimated when based on Cd salt feeding studies. Therefore, the risk assessment developed an alternative approach for estimating risks from secondary poisoning, based on renal thresholds (EU-RA, ECB 2008).

The alternative method used kidney Cd concentrations of wildlife as an indicator of Cd exposure and risk. The kidney is regarded as the critical organ in chronic Cd toxicity. With continued exposure, there is a continued increase in Cd concentration in the renal cortex until a critical value is reached and symptoms of renal

dysfunction are found (proximal tubular cell necrosis, proteinuria and glycosuria). This critical value is to be regarded as a sublethal endpoint. The risk of secondary poisoning was assessed by calculating the exposure at which this critical value was not exceeded for wildlife. The proposed approach could overcome the uncertainties in the traditional approach which uses food chain modelling (i.e. soil-worm-mammal modelling) because the proposed approach did not require assumptions about the diet (e.g. 100% earthworms) and about Cd bioavailability during transfer soil-food-wildlife (i.e. the BAF value and assumption of equal exposure at equal diet Cd between spiked meals and environmental Cd).

The ecological relevance of kidney damage as the critical endpoint in the assessment of the Cd RA deviated from traditional endpoints such as growth or reproduction which have obvious ecological relevance. Indeed, the relationship between ecological fitness and kidney damage is unknown which is the major difficulty in understanding effects of Cd in wildlife (Cooke and Johnson, 1996). The kidney has spare functional capacity and proteinuria or calciuria might be tolerated without progression to renal failure. Several field observations were discussed in the EU RA leading to the conclusion “that renal dysfunction could be used as an endpoint with ecological relevance, realising that this endpoint leads to a more conservative approach than traditional endpoints in most conditions” (EU RA , ECB 2008). As critical concentration of Cd in the kidney, the lower limit of the critical range for mammals, as set by WHO (IPCS 1992), was used, i.e. 400µg Cd/g DW kidney (range: 400-800 µg Cd/g DW; EU RA, ECB 2008).

The critical soil Cd concentration for secondary poisoning was defined as that concentration at which a critical kidney Cd concentration of 400 g/g dw (whole kidney) could be predicted using a proportional extrapolation from each paired soil/kidney Cd concentration set (often from only 1 point at lower concentration). It was noted that the proportional extrapolation assumed full linearity, which was indicated not to be the case as Cd uptake levels at higher concentrations would be lower. So the RA emphasised that using this proportional extrapolation was an important element of conservatism in the approach used.

Table 12. Kidney concentration in mammals and predicted critical soil concentrations at which the renal threshold for toxicity may be exceeded (after linear extrapolation of the critical soil levels (values taken from the RA Cd, (ECB 2008)) species Soil Cd Measured Calculated critical soil Cd reference (µg/gDW) kidney Cd (µg/g DW) to reach (µg/g DW) 400µg/g DW in kidney beaver 24 113 85 Nolet et al 1994 Common shrew 3.3 154 8.6 Read and Martin, 1993 0.8 15.6 15.6 Hunter et al 1989 3.1 139 8.9 Hunter & Johnson 1982 2.9 126-200 5.8 Ma et al 1991 0.3 14-51 2.4 1.8 11 65.5 Hendriks et al 1995 Cottontail rabbit ~10 284 14.1 Storm et al 1994 0.1 5.3 7.5 Dressler eta l 1986 Field vole 15.4 88.8 69.4 Hunter et al 1989 8.5 23.3 145.9 Hunter & Johnson 1982 2.9 1-3 368.7 Ma et al 1991 0.3 0.1-0.3 400 mole 1.7 112 6.1 Ma 1987 0.3 186 0.6 0.1 59 0.7 Pygmy shrew 0.6 7.9 30.4 Read & Martin 1993 White tailed deer 6-100 70 30.4 Storm et al 1994 Woud mouse 15.4 41.7 147.7 Hunter et al 1989 0.75 1.46 205.5 Hunter & Johnson 1982

In total, 20 critical concentrations could be calculated in the RA for 8 mammal species (see table above). The frequency distribution of these 20 values allowed for a statistical extrapolation to an “HC5” value, conceptually equal to the HC5 derived from ecotoxicity studies. This HC5, derived from all 20 data on critical concentrations, was 0.9 µg Cd/g DW soil (log-logistic extrapolation, see figure below).

Figure 3. Cumulative frequency of the critical soil Cd concentration at which the critical kidney Cd concentration (400µg/gDW) may be exceeded in the average population of different wildlife species (log- logistic curve fitting)

This HC5 for protecting mammals is about twofold below the PNECsoil derived for protecting plants, soil fauna and microflora (see chapter 7), effectively suggesting that biotransfer of Cd from soil to higher trophic levels is the most critical pathway for Cd.

It is emphasised that this PNEC level has several elements of conservatism built-in, as indicated above (for details see EU RA, section 3.2.6.5.1. (ECB 2008)).

According to the EU risk assessment, the PNEC soil based on protecting mammals is carried forward to the risk characterisation in the present analysis. Since this PNEC is the most critical for soil, and more critical than direct effects of Cd on higher plants, soil fauna or soil microbial processes, secondary poisoning and direct effects are both integrated in the risk characterisations that use this most critical PNECof 0.9 µg Cd/g DW soil.

The PNECoral is 0.16 mg/kg food (see CSR chapter 7.5.3 "Calculation of PNECoral (secondary poisoning)".

4.5. Natural background

The natural background of cadmium in the different environmental compartments can vary with e.g. underlying soil type, local geological conditions, etc.

FOREGS (2006) reported the following 10P, 50P and 90P values for Europe, based on a systematical analysis of a 70X70km grid covering the whole of the EU. Sampling points were chosen to avoid local influences, so concentrations are “ambient” background.

Table 13. Ambient background concentrations in Europe according to FOREGS (2006) Compartment 10P 50P 90P Freshwater (µg/l dissolved) 0.002 0.01 0.077 Topsoil (mg / kgDW) 0.03 0.14 0.83 Stream sediment (mg / kgDW) 0.09 0.29 1.39

Floodplain sediment (mg / 0.06 0.3 1.46 kgDW)

5. HUMAN HEALTH HAZARD ASSESSMENT General considerations

The present human health hazard assessment covers cadmium metal and 7 cadmium compounds, i.e. cadmium oxide - CdO; cadmium hydroxide - Cd(OH)2; cadmium chloride - CdCl2; cadmium nitrate - Cd(NO3)2; cadmium carbonate - CdCO3; cadmium sulphide - CdS and cadmium sulphate - CdSO4. The cadmium compounds have been grouped into three categories on the basis of their water solubility, as shown in Table 14.

Table 14. Water solubility of the eight cadmium compounds covered in this assessment Cadmium compound Water solubility (mg/L)1 Ranking of solubility Cadmium nitrate 507.103 Cadmium sulphate 540.103 Very soluble Cadmium chloride 457.103 Cadmium metal 2.3 Cadmium oxide 2.1 Slightly soluble Cadmium hydroxide 69.5 Cadmium carbonate 3.2 Cadmium sulphide 6.10-7 Insoluble 1Values are taken from section 4 of the IUCLID files on the respective substances. Data by Outotec Research Oy, Pori, Finland.

There is a wealth of information available in the public domain regarding the effects of cadmium compounds on human health. This data has been carefully reviewed and scrutinised in the framework of the discussions on the EU Risk Assessment Report (RAR) developed according to EU Regulation 793/93/EEC, with a focus on cadmium metal and cadmium oxide (JRC, 2007). Occupational exposure aspects have recently been assessed by the Scientific Committee on Occupational Exposure Limits (SCOEL, 2009). The US Department of Health and Human Services, Agency for Toxic Substances and Disease Registry also recently published a comprehensive revised draft toxicological profile for cadmium (ATSDR, 2008). The EU RAR, SCOEL recommendations and ATSDR profile are the main data source for this chapter. Given the substantial amount of data, only selected studies have been included in the IUCLID5 files and the present Chemical Safety Report (CSR).

Assumptions For cadmium metal and the various cadmium compounds, systemic toxicity is attributed to the cadmium ion and differences in toxicity are principally linked to bioavailability. Although several factors influence bioavailability, the main physico-chemical property of importance is solubility in water or biological fluids. Substances with higher solubility are expected to penetrate more easily into the organism and therefore generally show higher toxicity. A large amount of data is available on the effects of cadmium in humans and animals, but most of the studies have been conducted using cadmium metal (powder or dust), chloride or oxide and information on other cadmium compounds is limited. However, for the reasons presented above, read-across of toxicity data within solubility groups can be conducted. In certain cases, it is also possible to read-across from one solubility group to another.

As such, this section in the CSR makes an integrated case on the cadmium compounds mentioned above and is relevant for all of them. For reasons of consistency, it was decided not to develop partial cases on separate cadmium substances. 5.1. Toxicokinetics (absorption, metabolism, distribution and

elimination) Uptake of cadmium can occur in humans via the inhalation of polluted air, the ingestion of contaminated food or drinking water and, to a minor extent, through exposure of the skin to dusts or liquids contaminated by the element (JRC, 2008; SCOEL, 2009). In occupational settings, mainly inhalation exposure occurs although the dermal route may also play a role when metal, powder or dust is handled or during maintenance of machinery. Additional uptake is possible through food and tobacco (for example in workers who eat or smoke at the workplace). For the general population, uptake of cadmium occurs principally via the ingestion of food or, to a lesser extent, of contaminated drinking water. In industrial sites polluted by cadmium, inhalation of air and/or ingestion of soil or dusts may contribute to significant exposure. Tobacco is an important additional source of cadmium uptake in smokers. Finally, the consumer could be exposed (skin, inhalation or oral) through the use of consumption products. Absorption Gastrointestinal absorption of cadmium is usually less than 5% but varies with the form of cadmium present, the composition of the diet, age and the individual iron status. High gastrointestinal absorption rates (up to 20%) have been observed for example in women with lowered iron stores (serum ferritin <20 μg/L) (Sasser and Jarboe, 1977; Weigel et al., 1984; JRC, 2007). Cadmium is absorbed by the respiratory route at rates varying between 2 and 50% depending on the cadmium compound involved (water soluble or insoluble), the size of the particles (dusts or fumes), the deposition pattern in the respiratory tract and the ventilation rate. Values of 10 to 30% for dusts and 25-50% for fumes are cited in the EU Summary Risk Assessment Report (RAR) (JRC, 2007) and various publications (Boisset et al., 1978; Glaser et al., 1986; Oberdörster et al., 1979; Oberdörster and Cox, 1989; Oberdörster, 1992; Dill et al., 1994; Hadley et al., 1980). The results from studies in mouse, rat, rabbit and in vitro human skin models suggest that, although cadmium may penetrate through skin, absorption of soluble and less soluble compounds is generally lower than 1% (Kimura and Otaki, 1972; Lansdown and Sampson, 1996; Wester et al., 1992; JRC, 2008). Distribution Following absorption, the biodisposition of cadmium (Cd2+) is assumed to be independent of the chemical form to which exposure occured (JRC, 2007). Cadmium is a cumulative toxicant. It is transported from its absorption site (lungs or gut) to the liver, where it induces the synthesis of metallothionein which sequestrates cadmium. The cadmium-metallothionein complex is then slowly released from the liver and transported in the blood to the kidneys, filtrated through the glomerulus and reabsorbed in the proximal tubule where it may dissociate intracellularly (Chan and Cherian, 1993). There, free cadmium again induces the synthesis of metallothionein, which protects against cellular toxicity until saturation. In non-occupationally exposed individuals, cadmium concentrations in kidney is generally between 10 and 50 mg/kg wet weight, with smokers showing 2 to 5-fold higher values than non-smokers (Nilsson et al., 1995). After long-term low level exposure, approximately half the cadmium body burden is stored in the liver and kidneys, one third being in the kidney where the major part is located in the cortex (Kjellström et al., 1979). The kidney:liver concentration ratio decreases with the intensity of exposure and is, for instance, lower in occupationally exposed workers (7 to 8-fold ratio) (Ellis et al., 1981; Roels et al., 1981) than in the general population (10 to 30-fold ratio) (Elinder et al., 1985). The distribution of cadmium in the kidney is important as this organ is one of the critical targets after long-term exposure. In blood, most cadmium is localised in erythrocytes (90%) and values measured in adult subjects with no occupational exposure are generally lower than 1 μg/L in non-smokers. Blood cadmium (Cd-B) values are 2 to 5-fold higher in smokers than in non-smokers (Staessen et al., 1990; Järup et al., 1998; Ollson, 2002). In the absence of occupational exposure, the mean urinary cadmium concentration (Cd-U) is generally below 1 to 2 μg/g creatinine in adults. While Cd-B is influenced by both recent exposure and cadmium body burden, Cd-U is mainly related to the body burden (Lauwerys and Hoet, 2001). Smokers excrete more cadmium than non- smokers and their Cd-U is on average 1.5-fold higher than for non-smokers. The placenta provides a relative barrier, protecting the foetus against cadmium exposure. Cadmium can cross the placenta but at a low rate (Trottier et al., 2002; Lauwerys et al., 1978; Lagerkvist et al., 1992). Metabolism Cadmium is not known to undergo any direct metabolic conversion such as oxidation, reduction or alkylation. The cadmium (Cd2+) ion does bind to anionic groups (especially sulfhydryl groups) in proteins and other molecules (Nordberg et al., 1985). Plasma cadmium circulates primarily bound to metallothionein and albumin (Foulkes and Blanck, 1990; Roberts and Clark, 1988). Excretion Absorbed cadmium is excreted very slowly, with urinary and fecal pathways being approximately equal in quantity (< 0.02% of the total body burden per day) (Kjellström et al., 1985). It accumulates over many years,

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 43 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 mainly in the renal cortex and to a smaller extent in the liver and lung. The biologic half-life of cadmium has been estimated to be between 10 to 30 years in kidney and 4.7 to 9.7 years in liver (Ellis et al., 1985). The half- life in both organs is markedly reduced with the onset of renal toxicity when tubule loss of cadmium is accelerated. The total cadmium body burden reaches about 30 mg by the age of 30. Biomonitoring Biomonitoring methods for either Cd-B or Cd-U are often used rather than airborne measurements because they integrate all possible sources of occupational and environmental exposures (e.g. digestive exposure at the workplace, tobacco smoking and diet). In addition, since cadmium is a cumulative toxicant, a measure of the body burden (i.e. Cd-U) is the most appropriate exposure parameter for conducting risk assessments. In workers with substantial cadmium exposure (i.e. Cd-U > 3 μg/g creatinine), 30 years exposure to 50 μg/m³ of cadmium would lead to a Cd-U of 3 μg/g creatinine (SCOEL, 2009). 5.2. Acute toxicity 5.2.1. Non-human information

5.2.1.1. Acute toxicity: oral Acute oral toxicity studies have been conducted in mouse and rat with cadmium chloride, oxide and metal powder. The results of experimental studies are summarised in the following table. No data was found for other cadmium compounds.

Table 15. Overview of selected experimental studies on acute toxicity after oral administration Method LD50 (mg Cd/kg bw) Remarks Reference Cadmium chloride Mouse > 60.2 - < 89.9 2 (reliable with Andersen O, Oral: gavage restrictions) Nielsen JB and Observation 10 days key study Svendsen P (1988) experimental result Rat 29 - 147 2 (reliable with Kostial K, Kello D, Oral: gavage restrictions) Jugo S, Rabar I and Observation for 8 d key study Maljkovic T (1978) experimental result Rat 225 2 (reliable with Kotsonis FN and Oral: gavage restrictions) Klaassen CD (1977) Observation for 14 d key study experimental result

Rat 107 (24 h fasted rats) 2 (reliable with Shimizu M and Oral: gavage 327 (fed rats) restrictions) Morita S (1990) Observation for 24 h key study experimental result Cadmium oxide Mouse 63 2 (reliable with JRC, 2007 Oral: gavage restrictions) weight of evidence experimental result Rat 63-259 2 (reliable with JRC, 2007 Oral: gavage restrictions) weight of evidence experimental result Cadmium metal powder Mouse 890 2 (reliable with JRC, 2007

Method LD50 (mg Cd/kg bw) Remarks Reference Oral: gavage restrictions) weight of evidence experimental result Rat 2,330 2 (reliable with JRC, 2007 Oral: gavage restrictions) weight of evidence experimental result Reported acute oral LD50 values for the water-soluble cadmium chloride range from 29 to 327 mg Cd/kg bodyweight (bw), with higher toxicity in fasted than in fed animals. The range of LD50 values for slightly soluble cadmium oxide and cadmium metal powder is wider (63 to 2,330 mg/kg bw). This data suggest that slightly soluble or insoluble cadmium compounds may be less acutely toxic. However, it should be noted that no data on the original studies was available. Where present, toxicity is generally characterized by lesions of the proximal sections of the intestinal tract (Andersen et al., 1988).

5.2.1.2. Acute toxicity: inhalation Acute inhalation toxicity studies have been conducted in multiple species using cadmium chloride, oxide and carbonate. Results are presented in the following table. No data was found for cadmium metal or other cadmium compounds. To allow comparison across studies of different duration, LC50 values were converted to a 4 h value according to the method of Health Canada (http://www.hc-sc.gc.ca/): LC50 at 4 hours= LC50 at Y hours x (Y hours)/4; Y= actual number of hours of exposure duration, for a dust, mist or fume. The formula assumes a simple linear relationship between time of exposure and concentration in the animal chamber for dust, mist and fume. It is only valid for LC50 values obtained for exposure durations of 1 hour or longer.

Table 16. Overview of selected experimental studies on acute toxicity after inhalation exposure Method LC50 4 h LC50 Remarks Reference (mg Cd/m3) (10-3 mg Cd/L)1 Cadmium chloride Rat and rabbit > 4.5 (2h) > 2.3 2 (reliable with Grose EC, Richards Inhalation: aerosol restrictions) JH, Jaskot RH, Observation for 72 h key study Ménache MG, experimental result Graham JA and Dauterman WC (1987) Cadmium oxide Mouse > 9 (15 min) - 2 (reliable with Chaumard C, Quero Inhalation: fumes (nose restrictions) AM, Bouley G, only) key study Girard F, Boudene Observation for 17 d experimental result C and German A (1983) Rat and mouse > 1 (3 h) > 0.8 2 (reliable with McKenna IM, Inhalation: vapour (fumes) restrictions) Waalkes M, Chen (nose only) key study LC and Gordon T experimental result (1997)

Rat > 8.4 (3 h) > 6.3 2 (reliable with Hart BA, Voss GW Inhalation: aerosol (dust) restrictions) and Willean CL Observation for 7 d key study (1989) experimental result Rat > 8.63 (30 min) - 2 (reliable with Boisset M and Inhalation: aerosol (fumes) restrictions) Boudene C (1981) (whole body) key study Observation for 72 h experimental result Rat > 4.6 (3 h) > 3.5 2 (reliable with Buckley BJ and Inhalation: aerosol restrictions) Bassett DJ (1987) Observation for 15 d key study experimental result Rat and mouse > 10 (15 min) - 3 (not reliable) Bouley G, Dubreuil Inhalation: dust (nose only) supporting study A, Despaux N and Observation for 24 h experimental result Boudène C (1977) Rat 60 (30 min) - 3 (not reliable) Hadley JG, Conklin Inhalation: aerosol supporting study AW and Sanders Observation for up to 1 y experimental result CL (1979)

Rat 25 (30 min) - 4 (not assignable) Yoshikawa H and Inhalation: fumes supporting study Homma K (1974) Observation for 7 d experimental result Rat < 112 (2 h) < 56 2 (reliable with Rusch GM, Inhalation: aerosol (fumes) restrictions) O'Grodnick J and key study Rinehart WE (1986) experimental result Rat and rabbit > 4.5 (2 h) > 2.3 2 (reliable with Grose EC, Richards Inhalation: aerosol (dust) restrictions) JH, Jaskot RH, Observation for 72 h key study Ménache MG, experimental result Graham JA and

1 The conversion to a 4 h value was only made for LC50 values obtained for exposure durations of 1 hour or more.

Method LC50 4 h LC50 Remarks Reference (mg Cd/m3) (10-3 mg Cd/L) Dauterman WC (1987) Rabbit > 22.4 (15 min) - 2 (reliable with Fukuhara M, Inhalation: fumes restrictions) Bouley G, Godin J, key study Girard F, Boisset M experimental result and Boudene C (1981) Rabbit - 28.4 4 (not assignable) Friberg L (1950) Inhalation: dust supporting study experimental result Various species 41 (mouse); - 4 (not assignable) Barrett HM, Irwin Inhalation: fumes 30 (rat); supporting study DA and Semmons 204 (guinea-pig); experimental result E (1947) 940 (monkey); 230 (dog) (15 min) Cadmium carbonate Rat <132 (2h) <66 2 (reliable with Rusch GM Inhalation: aerosol restrictions) O'Grodnick J and Observation for 30 d key study Rinehart WE (1986) experimental result The acute inhalation 4 h LC50 values for cadmium chloride, oxide and carbonate range from > 0.8 x 10-3 to <66 x 10-3 mg Cd/L. No information is available for insoluble cadmium compounds. Upon inhalation of high doses, cadmium causes severe pulmonary lesions. Several biochemical changes have been show to parallel the morphological alterations (JRC, 2008).

5.2.1.3. Acute toxicity: dermal No reliable studies were located regarding acute effects after dermal exposure to cadmium metal or cadmium compounds. In a study by Wahlberg (1965), 9/20 guinea pigs died several weeks after being exposed to cadmium chloride applied dermally (0.14 mg/kg bw). However, it was difficult to attribute these deaths to cadmium exposure due to the low dose compared to oral LD50 values and to the fact that no necropsy was done to determine whether the exposed guinea pigs might have died from pneumonia (which killed some control animals) (ATSDR, 2008; JRC, 2007).

5.2.1.4. Acute toxicity: other routes As discussed in Section 5.1, there are no other relevant routes of exposure to cadmium metal and cadmium compounds. 5.2.2. Human information Reports of effects from oral and inhalatory exposure to cadmium in humans can be found in the literature. Acute gastrointestinal symptoms have been recorded after ingestion of food or beverages contaminated with high amounts of cadmium. Intoxication has also resulted in workers exposed to cadmium dust that ate their meals with dirty hands, smoked or bit their fingernails at the workplace. In two recorded suicide attempts, mortality occurred within 7 days and 33 hours of ingestion of 25 mg Cd/kg bw in the form of cadmium iodide (Wisniewska-Knypl et al., 1971) and 1,840 mg Cd/kg bw in the form of cadmium chloride (Buckler et al., 1986), respectively. The cause of death was massive fluid loss, oedema and widespread organ failure. As summarised in Bernard and Lauwerys (1986)2, the no observed effect level (NOEL) of a single oral dose is estimated to be equivalent to 3 mg Cd/person and the lethal dose is estimated to range from 350 to 8,900 mg Cd/person. Acute cadmium poisoning and in some cases death have been reported among workers shortly after inhalatory exposure to fumes when cadmium metal or cadmium-containing materials were heated to high temperatures. Cadmium metal fumes are reported to be instantly transformed into cadmium oxide when entering in contact with air. Case reports after accidents and following short-term exposure of users extend over more than half a century, as summarized in the European Risk Assessment Report (RAR) (JRC, 2007). During the acute

2 These values are reported in several reviews without further evaluation. Primary studies are unavailable.

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 47 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 exposure phase, the general symptoms are relatively mild but, within a few days, severe pulmonary edema and chemical pneumonitis develop, leading to death due to respiratory failure. The dose sufficient to cause pulmonary edema is not exactly known. In one fatal case the average airborne concentration was estimated to be 8.6 mg/m³ during 5 hours, or approximately an 8-hour time-weighted average (TWA) of 5 mg/m³ (Beton et al., 1966; Barrett et al., 1947). This estimate was based on lung Cd content at post-mortem examination, which may have been greater than the dose necessary to cause death. The atmospheric concentration necessary to cause pneumonitis may therefore be considerably less. It has been estimated that an 8 hour exposure to 1 mg Cd/m³ is immediately dangerous for life (CRC, 1986). 5.2.3. Summary and discussion of acute toxicity When administered orally, the water soluble cadmium chloride caused mortality at relatively low doses, with LD50s in mouse and rat ranging from 29 to 327 mg Cd/kg bw. On this basis, cadmium chloride has been classified as T; R25 (toxic if swallowed) in Annex I of Directive 67/548/EEC. Under GHS-CLP, the corresponding classification would be ‘Acute toxicity (oral) category 3; H301’. Although no animal studies are available, cadmium sulphate is also classified in Annex I as T; R25, which is justified given its comparable solubility to cadmium chloride. Cadmium nitrate, also highly water soluble, is at present not classified for acute oral toxicity but a similar classification should be considered. Although original studies were not available, data for cadmium oxide and cadmium metal powder suggest that the slightly soluble or insoluble forms of cadmium (like also cadmium hydroxide and cadmium carbonate) may present lower oral acute toxicity. To date, they are not classified for this endpoint. The only exception is cadmium sulphide which, despite being insoluble, carries an Xn; R22 (harmful if swallowed) in Annex I of Directive 67/548/EEC (the corresponding GHS-CLP classification would be ‘Acute toxicity (oral) category 4; H302). Given that there are no studies to support this classification, a revision of this classification may be appropriate based on solubility properties. In humans, the no observed effect level (NOEL) of a single oral dose is estimated to be equivalent to 3 mg Cd/person (i.e. 0.05 mg/kg bw for a 60 kg person) and the lethal dose is estimated to range from 350 to 8,900 mg Cd/person (i.e. 5.8 to 148 mg/kg bw for a 60 kg person). Cadmium chloride, oxide, carbonate and metal have a high acute toxicity by the inhalation route (0.8 x 10-3 < 4h LC50 < 66 x 10-3 mg Cd/L). Cadmium chloride, sulphate, oxide and metal have been classified as T+; R26 (Very toxic by inhalation) in Annex I of Directive 67/548/EEC (the corresponding GHS-CLP classification is ‘Acute toxicity (inhalation) category 2; H330). Based on comparable toxicity and/or solubility / bioavailability, all other highly and slightly soluble cadmium forms, i.e. cadmium nitrate, hydroxide and carbonate should carry a comparable classification. The insoluble cadmium compound cadmium sulphide is however not expected to cause significant adverse effects via this route and is currently not classified for acute inhalatory toxicity. For human health, observations indicate that an 8 hour inhalatory exposure to 5 mg Cd/m3 is lethal and 1 mg Cd/m³ is immediately dangerous for life. No information was located regarding effects in humans after dermal exposure to cadmium. However, acute toxicity via the dermal route is not expected to be significant as uptake of soluble and less-soluble cadmium compounds applied onto the skin of animals appears to be low (<1%) (see Section 5.1.1). Also in view of the risk reduction measures which need to be taken as a result of the carcinogenicity of cadmium metal and some of the cadmium compounds, acute dermal toxicity is not likely to pose an issue for human health. No corresponding classification is therefore required.

5.3. Irritation 5.3.1. Skin

5.3.1.1. Non-human information No studies were located regarding the skin irritation potential of cadmium metal and cadmium compounds to animals. However, given the carcinogenic properties of cadmium metal and some of the cadmium compounds, risk reduction measures are in place at the workplace to prevent contact. Therefore, skin irritation is not expected to be an issue for human health and further testing is not considered necessary for this endpoint, in accordance with Annex XI (3) of the REACH directive.

5.3.1.2. Human information Wahlberg (1977) reported that, among eczema patients routinely patch-tested with 2% cadmium chloride, 25 out of 1,502 (1.7%) showed some reaction. Since no effects were seen at lower dilutions, toxicity was likely due to direct irritation of the skin and was considered to be a LOAEL. No information was located on cadmium metal or other cadmium compounds. 5.3.2. Eye No studies were located regarding the eye irritation potential for humans or animals. However, given the carcinogenic properties of cadmium metal and some of the cadmium compounds, risk reduction measures are in place at the workplace to prevent contact. Therefore, eye irritation is not expected to be an issue for human health and further testing is not considered necessary for this endpoint, in accordance with Annex XI (3) of the REACH directive. 5.3.3. Respiratory tract No studies were located regarding the respiratory tract irritation potential of cadmium metal or cadmium compounds to humans or animals. According to the EU RAR (JRC, 2007), it may be appropriate to consider cadmium oxide (fumes, dust) as an irritant to the respiratory tract after inhalatory exposure, based on results from single and repeated inhalation exposure studies (see Sections 5.2 and 5.6). In animals, the lowest dose reported to cause mild pulmonary damage (hypercellularity indicative of hyperplasia) after single exposure was 0.5 mg Cd/m3 (3 h) as cadmium oxide fumes. The lowest dose reported to cause lung changes after repeated exposure to cadmium oxide fumes was 50 µg CdO/m3 in rats for 13 weeks and 10 µg CdO/m3 in hamster for 14 months (Dunnick, 1995; Aufderheide et al., 1989; JRC, 2007). 5.3.4. Summary and discussion of irritation Limited information is available on the skin, eye and respiratory tract irritation potential of cadmium metal and cadmium compounds. In a study on patients with eczema, cadmium chloride caused skin irritation in 1.7% of the volunteers when applied at 2%. Based on single and repeated inhalation exposure studies, cadmium oxide fumes may be considered irritating to the respiratory tract. However, given the carcinogenic properties of cadmium metal and some of the cadmium compounds, risk reduction measures are in place at the workplace to prevent contact. Therefore, neither skin, eye nor respiratory tract irritation are expected to be an issue for human health and further testing is not considered necessary for these endpoints, in accordance with Annex XI (3) of the REACH directive. This is in line with the conclusions of the EU RAR (JRC, 2007). At present, none of the cadmium substances covered in the present assessment is classified for irritation according to Directive 67/548/EEC. 5.4. Corrosivity No studies were located regarding corrosivity for humans or animals. However, if at all, significant exposure is expected to occur principally in occupational settings. Given the carcinogen properties of cadmium metal and some of the cadmium compounds, risk reduction measures are in place to prevent contact. Therefore, corrosivity is not expected to be an issue for human health and further testing is not considered necessary, in accordance with Annex XI (3) of the REACH directive. This is in line with the conclusions of the EU RAR (JRC, 2007). At present, none of the cadmium substances covered in the present assessment is classified for corrosivity in Annex I of Directive 67/548/EEC. 5.5. Sensitisation 5.5.1. Skin

5.5.1.1. Non-human information The only skin sensitization study that could be found was a guinea-pig maximization test (GMPT) conducted with water soluble cadmium chloride, which indicated no contact sensitisation following epicutaneous exposure at concentrations up to 0.5% after intradermal or topical sensitisation (Wahlberg and Boman, 1979). However, due to incomplete reporting and deviations from the current regulatory test protocols, the study was considered unreliable. No skin sensitization studies were located on cadmium metal or any of the other cadmium compounds.

5.5.1.2. Human information Positive patch-test reactions to cadmium chloride and sulphate in human volunteers are summarised by Wahlberg (1977). The results are not consistent and, according to the authors, the percentage of positive reactions may have varied with the vehicle used for the cadmium solution (ethanol or water) or with possible impurities contained in the test substance. No clear conclusion could therefore be drawn on the skin sensitization potential of the substances (JRC, 2007). With regard to cadmium metal and cadmium oxide, the accumulated experience in occupational practice over decades does not indicate any sensitizing potential (JRC, 2007). No further human information was located on cadmium metal or the other cadmium compounds. 5.5.2. Respiratory system No studies were located on respiratory sensitisation in humans or animals. However, given the carcinogen properties of cadmium metal and some of the cadmium compounds, risk reduction measures are in place at the workplace to prevent contact. Therefore, respiratory sensitization is not expected to be an issue for human health and further testing is not considered necessary, in accordance with Annex XI (3) of the REACH directive. 5.5.3. Summary and discussion of sensitisation Only limited data were available on the skin or respiratory sensitization potential of cadmium metal and cadmium compounds. Cadmium chloride did not show any skin sensitization effects at 0.5% in a GMPT test. Cadmium chloride and sulphate were patch-tested in human volunteers but, across several studies, the evidence remained inconclusive. If at all, significant exposure is expected to occur principally in occupational settings. Given the carcinogen properties of cadmium metal and some of the cadmium compounds, risk reduction measures are in place to prevent contact. Therefore, neither skin nor respiratory tract sensitization are expected to be an issue for human health and further testing is not considered necessary, in accordance with Annex XI (3) of the REACH directive. This is in line with the conclusions of the EU RAR (JRC, 2007). At present, none of the cadmium substances covered in the present assessment is classified for sensitization in Annex I of Directive 67/548/EEC.

5.6. Repeated dose toxicity 5.6.1. Non-human information

5.6.1.1. Repeated dose toxicity: oral, inhalation and other Studies in various animal species using different cadmium substances (i.e. cadmium chloride and oxide) demonstrate that repeated exposure via both the oral and inhalation routes can cause damage to kidney and bone. Inhalatory exposure may additionally result in toxicity to the lung. The kidney (and possibly bone) is the most sensitive target organ (JRC, 2008). The type of effects and the underlying mechanisms have been analysed in more detail in testing conducted using other routes of administration (i.e. intravenous, intraperitoneal or subcutaneous). Selected studies are presented in the following tables. Results are then discussed by target organ rather than by exposure route, as this is more relevant given the similarity of the effects observed. Table 17. Overview of selected experimental studies on repeated dose toxicity after oral administration Method Results Remarks Reference Cadmium chloride Mouse (CF-1) female no NOAEL identified. 1 (reliable without Whelton BD, chronic (oral: feed) (limited role of Cd alone in restriction) Peterson DP, 0.25, 5 or 50 ppm Cd decreasing body mass during supporting study Moretti ES, Dare H Vehicle: none the post-reproductive period experimental result and Bhattacharyya Exposure: > 600 d (continuous) but combined Cd and dietary MH (1997) A study was conducted to determine nutrient deficiencies showed the effect of Cd on body mass and this effect. 50 ppm Cd calcium levels in the post- depressed Ca levels in femur reproductive period. Confounding and vertebrae. Skeletal effect of nutrient deficient diet, degeneration characteristic of multiparity and ovariectomy were Itai-Itai syndrome not considered; the calcium-depleting reproduced, suggesting that the effect of each factor was evaluated full-blown disease requires by determining calcium levels in primary and profound skeletal femur and lumbar vertebrae. demineralisation secondarily supported and enhanced by renal dysfunction) Rat (SPF-Wistar) male/female NOAEL: 30 ppm ( i.e. ca. 3 2 (reliable with Loeser E and Lorke chronic (oral: feed) mg Cd/kg bw/d) restrictions) D (1977a) 0, 1, 3, 10 and 30 ppm Cd (no effects on any parameters key study Vehicle: none followed but Cd accumulated experimental result Exposure: 3 months dose-dependently in the A study was conducted to determine kidneys and liver the repeated dose oral toxicity of cadmium in rat. Clinical signs, bodyweight, food consumption, hematology were followed. Histology was conducted at study end. Rat (Wistar) male NOAEL: 0.2 mg Cd/kg bw/d 2 (reliable with Brzoska MM and Chronic (oral: water) (increased lumbar spine restrictions) Moniuszko- Drinking water: 0, 1, 5 and 50 mg deformities, decreased lumbar key study Jakoniuk J (2005a Cd/L spine mineralization, altered experimental result and 2005b) Exposure: 12 months bone turnover parameters)

Dog (Beagle) male/female NOAEL: 30 ppm (i.e. ca. 0.75 2 (reliable with Loeser E and Lorke chronic (oral: feed) mg Cd/kg bw/d) restrictions) D (1977b) 0, 1, 3, 10 and 30 ppm Cd (no effects on any parameters key study

Method Results Remarks Reference Vehicle: none followed but Cd accumulated experimental result Exposure: 3 months dose-dependently above all in A study was conducted to determine kidney and liver) the repeated dose oral toxicity of cadmium in dog. Clinical signs, bodyweight, food consumption, hematology were followed. Histology was conducted at study end. Dog (Beagle) female no NOAEL identified. 2 (reliable with Sacco-Gibson N, subchronic (diet (capsules), drinking (Cd increased bone resorption restrictions) Chaudhry S, Brock water) (skeletal 45Ca release) in supporting study A et al. (1992) Diet: increasing doses of 1, 5, 15 and ovariectomized and sham- experimental result 50 ppm. Drinking water: 15 ppm operated dogs without renal Vehicle: none dysfunction or calcitropic Exposure: capsules in diet: 1 month, hormone interaction. Cd drinking water: 6 months appears to be an exogenous A repeated exposure study was factor exacerbating bone conducted to determine the effects of mineral loss in post- oral Cd on calcium release from menopausal osteoporosis) bone tissues. Skeletons of ovariectomised dogs were prelabelled with 45Ca and Cd was administered through capsules and in drinking water. The release of 45Ca from bone was observed. Monkey (Macaca mulatta) male NOAEL: 3 ppm Cd (i.e. ca. 2 (reliable with Masoaka T, chronic (oral: feed) 0.12 mg/kg bw/d) restrictions) Akahori F, Arai S 0.27 (controls), 3, 10, 30 and 100 (reduced bodyweight and body supporting study et al. (1994) ppm Cd length as of 10 ppm. Early experimental result Vehicle: none effects on renal function at 100 Exposure: 462 wks (9 y) ppm but no aggravated renal A study was conducted to determine dysfunction or renal failure the repeated dose oral toxicity of during the 9 years of the study) cadmium in monkey. General health parameters were followed.

Table 18. Overview of selected experimental studies on repeated dose toxicity after inhalation exposure Method Results Remarks Reference Cadmium oxide Mouse (B6C3F1) male/female No NOAEL identified. 1 (reliable without Dunnick JK (1995) subchronic (inhalation: aerosol) LOAEL: 0.025 mg CdO (0.022restriction) (whole body) mg Cd)/m3/6h key study 0, 0.025, 0.05, 0.1, 0.25 or 1 mg (lung effects) experimental result CdO/m3 (nominal conc.) Vehicle: unchanged (no vehicle) Exposure: 13 wk (6 h and 20 min/d; 5 d/wk) equivalent or similar to OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-day) Rat (Fischer 344) male/female NOAEL: 0.025 mg 1 (reliable without Dunnick JK (1995) subchronic (inhalation: aerosol) CdO/m³/6h (male/female) restriction) (whole body) (lung effects) key study 0, 0.025, 0.05, 0.1, 0.25 or 1 mg LOAEL: 0.05 mg CdO/m³/6h experimental result CdO/m3 (nominal conc.) (male/female) (lung effects) Vehicle: unchanged (no vehicle) Exposure: 13 wk (6 h and 20 min/d; 5 d/wk) equivalent or similar to OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-day) Rat (Wistar) female LOAEL: 0.025 mg Cd/m3/24h 2 (reliable with Prigge E (1978) subchronic (inhalation: aerosol) (female) (cell proliferations of restrictions) 25, 50, 100 µg Cd/m3 (nominal the bronchi, bronchioli and key study conc.) alveoli, indicating hyperplasia experimental result Vehicle: unchanged (no vehicle) of the lungs; histiocytic cell Exposure: 90 d at 25 and 50 µg granulomas) Cd/m3; 63 d at 100 µg Cd/m3 (24 h/d) A repeated dose inhalation exposure study was conducted to determine the effects of the test material on lungs. Female rats were exposed to CdO for 90 d at 25 and 50 μg Cd/m3, and for 63 d at 100 µg Cd/m3. Rat (Lewis) male no NOAEL identified. 3 (not reliable) Hart BA (1986) subchronic (inhalation: aerosol) LOAEL: 1.6 mg Cd/m³/3h supporting study (nose only) (male) (interstitial experimental result 1.6 +/- 0.03 mg cadmium/m3 pneumonitis) Vehicle: unchanged (no vehicle) Exposure: 1-6 wk (3 h/d; 5 d/wk) A study was conducted to determine the effects of the test material in the lungs of male Lewis rats. Groups of rats were exposed to an atmosphere of 1.6 mg Cd/m3 for several weeks (as CdO for 80 ± 5%, 3 h/d, 5 d/wk, 1 to 6 wk). Histopathological examination was then performed on the lungs.

Method Results Remarks Reference Rat (Wistar) male no NOAEL identified. 3 (not reliable) Glaser U, Klöppel subchronic (inhalation: aerosol) LOAEL: 0.1 mg CdO/m³/22 h supporting study K and Hochrainer D 0.1 mg Cd/m3 (nominal conc.) (male) (increased total (1986) Vehicle: unchanged (no vehicle) bronchoalvelolar macrophage Exposure: 30 d (22 h/d; 7 d/wk) numbers, leukocytes, and A study was conducted to determine macrophage cytotoxicity) the effects of subchronic exposure in rat lungs. Wistar rats were exposed to an aerosol of CdO (0.1 mg/m3, 22 h/d, 7 d/wk for 30 d), and evaluation of clinical signs, bodyweight, heamotological and clinical parameters were performed. Lung lavage and histopathology of the lungs were carried out at termination. Rat (Wistar) female NOAEL: 0.16 mg Cd/m³/ 5 3 (not reliable) Baranski B, Opacka subchronic (inhalation: aerosol) h(female) (absence of effects supporting study J and Wronska- 0.02, 0.16 and 1.0 mg Cd/m3 on bodyweight, clinical signs experimental result Nofer TL et al. (nominal conc.) and blood pressure) (1983) Exposure: 6 months (15 wk for the LOAEL: 1.0 mg Cd/m³/5 h high-exposed group) (5 h/d; 5 d/wk) (female) (decrease of systolic A study was conducted to examine blood pressure + mortality) the effecs of the test material on arterial blood pressure, lipid content in serum and some organs, cadmium level in blood, aorta wall, lung and liver in rats. The rats were repeatedly exposed to CdO fume 5 h daily, 5 d/wk, for 6 months. Measurement of blood pressure was carried out before exposure and at the end of 6, 12, 15, 22 and 27 wk. Clinical biochemical examinations and determination of the cadmium content in different organs such as lungs, kidneys and aorta wall were also carried out at termination. Rat (Wistar) female no NOAEL identified. 3 (not reliable) Kolakowski J, subchronic (inhalation: aerosol) (differences in ultrastructure of supporting study Baranski B and 0.16-1.0 mg CdO/m3 (nominal intercalated discs in cardiac experimental result Opalska B (1983) conc.) papillary muscle compared to Exposure: 3 and 6 months at 0.16 controls) mg/m3; 3 and 4 months at 1.0 mg/m3 (5 h/d; 5 d/wk) A study was conducted to evaluate the effects of the test material on the ultra structure of the cardiac muscle in rats. The experimental rats were exposed by inhalation to CdO fumes (0.16 and 1.0 mg/m³ 5 h daily, 5 d/wk for 3 and 6, 3 and 4 months respectively) was evaluated. Microscopic and macroscopic examination of the cardiac papillary muscles (left ventricle) and arterioles were performed at termination.

Rat (Sprague-Dawley) LOAEL: 0.1 mg Cd/m³/6 h 4 (not assignable) Yoshikawa H, subchronic (inhalation) (lung fibrosis and first-stage supporting study Kawai K, Suzuki Y 0, 0.1 and 1.0 mg/m3 emphysema at high doses) experimental result and Nozaki K, Exposure: 12 wk (6 h/d; 5 d/wk) Ohsawa M (1975) A study was conducted to determine the pulmonary effects of the test material in rats. The experimental rats were exposed to CdO fumes (0.1 or 1.0 mg Cd/m³) for up to three months. Hamster (Syrian (SxHU)) male NOAEL: 0.01 mg Cd/m3/8 h 2 (reliable with Aufderheide M, subchronic (inhalation: aerosol) (i.e. ca. 0.013 mg Cd/m3/6h) restrictions) Thiedemann KU, 0.01, 0.09, 0.27 mg Cd/m3 (nominal (hyperplasia in peribronchiolar key study Riebe M and conc.) region) experimental result Kohler M (1989) Exposure: 16 months (8 h/d; 5 d/wk) A study was conducted to determine the chronic exposure effects of the test material in hamster lungs. Syrian Golden hamsters were exposed to aerosols of CdO, followed by microscopic examination of the lungs.

Table 19 . Overview of selected studies on repeated dose toxicity (other routes) Method Results Remarks Reference Cadmium chloride Mouse (Metallothionein (MT) no NOAEL identified. 2 (reliable with Habeebu SS, Liu J, knock-out mice (129/SvPCJ (male/female) restrictions) Liu Y and Klaassen background) and LOAEL: 0.0125 mg Cd/kg bw key study CD (2000) 129/Sv+P+C+MGFSLJ)) (total dose) (male/female) experimental result male/female (LO(A)EL bone damage: in subchronic (subcutaneous) MT-null mice: 0.0125 mg wild-type mice: 0.05-0.8 mg Cd/kg Cd/kg bw) bw LOAEL: 0.1 mg Cd/kg bw MT-null mice: 0.0125-0.1 mg Cd/kg (total dose) (male/female) bw (LO(A)EL bone damage: in Vehicle: physiol. saline wild-type mice: 0.1 mg Cd/kg Exposure: 10 wk (6 d/wk) bw) A study was conducted to determine the repeated dose effect of the test material on the bone tissue of wild- type and MT-knockout mice and the protective effect of MT on bone. Repeated sc injections of CdCl2 over a wide range of doses for 10 weeks. Rat (Sprague-Dawley) female no NOAEL identified. 2 (reliable with Katsuta O, subchronic (intravenous) (bone toxicity at high doses; restrictions) Hiratsuka H, 1 and 2 mg CdCl2/kg bw/d results do not allow key study Matsumoto J et al. Vehicle: physiol. saline discrimination of whether boneexperimental result (1994) Exposure: 13 wk (5 d/wk) effects are due to direct action The repeated exposure effect of the of Cd or are a consequence of test material on bone was kidney damage). determined. Young, ovariectomised, female rats were administered CdCl2 intravenously (1.0 or 2.0 mg

Method Results Remarks Reference CdCl2/kg bw, 5 d/wk during 13 wk). General clinical observations, bodyweights and relevant serum levels were measured. Femurs and humerus were examined upon autopsy. Rat (Sprague-Dawley) male/female no NOAEL identified. 2 (reliable with Li J P, Akiba T and subchronic (intraperitoneal) (severe pathological and restrictions) Marumo F (1997) 0.228 mg/rat functional renal toxicity. Bone key study Vehicle: physiol. saline calcium content significantly experimental result Exposure: 16 months (3 times/wk) affected by Cd treatment) A repeated dose exposure study was conducted to determine the effects of the test material to the bone and kidney. Males and females (42 females underwent bilateral ovariectomy at 11 wk of age) were used. CdCl2 was administered i.v. for 16 months. Bodyweights were measured and urinalysis for females was performed before sacrifice. Macroscopic and microscopic analysis were performed on bone, kidney, liver and spleen. Rat (Sprague-Dawley) female no NOAEL identified. 2 (reliable with Uriu K, Morimoto subchronic (intraperitoneal) LOAEL: 0.18 mg CdCl2/rat restrictions) I, Kai K, Okazaki 0.18 mg CdCl2/rat (female) key study Y, Okada Y et al. Vehicle: water (severe renal toxicity, experimental result (2000) Exposure: 28 wk (3 times/wk) decreased bone mineral A study was conducted to determine content in lumbar vertebral the repeated dose exposure effects of body and femur, resulting in the test material on bone metabolism reduced mechanical strength) and kidneys of ovariectomised rats.0.18 mg CdCl2 was administered intraperitoneally 3 times/wk for 28 weeks in ovariectomised Sprague-Dawley rats (15 rats treated with cadmium and 10 controls). Urinalysis and examination of the femur and vertebrae were performed at termination. Rat and monkey (Sprague-Dawley No NOAEL identified 2 (reliable with Umemura T (2000) and Macaca fascicularis) female (tubular nephropathy, anemia restrictions) subchronic (intravenous) and bone changes; not clear key study 4 experiments: doses ranged from whether bone changes were a experimental result 0.05 to 3.0 mg Cd/kg bw result of direct action of Cd or Vehicle: physiol. saline a secondary effect linked to Exposure: 14days up to 13-15 kidney toxicity) months (see table 1 IUCLID entry) Four repeated dose studies were conducted to explore the pathological mechanism of Itai- Itaidisease in rat and monkey. Toxic effects of different doses of cadmium were assessed in ovariectomised and non-

Method Results Remarks Reference ovariectomised rats and in monkeys after repeated i.v. injection of CdCl2. Kidney Numerous studies indicate that oral exposure to cadmium compounds causes kidney toxicity (Loeser and Lorke, 1979a and b; Masoaka, 1994; ATSDR, 2008; JRC, 2007). ATSDR (2008) also notes that other studies showed no effect on renal function, which illustrates the existence of a critical cumulative dose. Oral cadmium exposure in animals has been shown to increase or decrease relative kidney weight and cause histological (necrosis of the proximal tubules, interstitial fibrosis) and functional (reduced glomerular filtration rate, proteinuria) changes. There is no good agreement about the cadmium dose necessary to bring about these effects in animals. Critical tissue concentrations reported in the literature vary between 50 and 300 µg Cd/g renal cortex. Most authors agree however that a mean critical concentration of approximately 200 µg Cd/g renal cortex must be reached in order to observe tubular proteinuria, which is the most sensitive indicator of cadmium-induced renal toxicity. At these doses, the amount of free cadmium in the kidney (not bound to metallothionein) becomes sufficiently high to cause tubular damage. The health significance of tubular proteinuria and its predictive value for the development of end-stage renal failure is however not answered by experimental data (JRC, 2007). Early animal studies confirmed that renal damage occurs also following inhalation exposure to cadmium (ATSDR, 2008). Moderate proteinuria was seen in rabbit exposed to cadmium oxide dust at 8 mg Cd/m3 for 4 months. After 7 to 9 months, histopathological examination of the kidneys revealed interstitial infiltration of leucocytes in the majority of the exposed animals (Friberg, 1950). Most subsequent experimental studies using inhalation exposure have not found proteinuria (Glaser et al., 1986; Prigge, 1978) but these were limited by the fact that the level of exposure and duration of follow-up that cause serious respiratory effects were not sufficient to produce critical concentrations of cadmium in the kidney (ATSDR, 2008; JRC, 2007). Bone In vitro studies have demonstrated that cadmium compounds exert a direct effect on bone metabolism, affecting both bone resorption and formation, and inducing calcium release (JRC, 2007). In animals, cadmium has been shown to affect bone metabolism, manifested as osteopetrosis, osteosclerosis, osteomalacia and/or osteoporosis after oral (Whelton et al., 1997; Brzoska and Moniuszko-Jakoniuk, 2005a and 2005b; Sacco-Gibson et al., 1992), subcutaneous (Habeebu et al., 2000) or intraperitoneal (Li et al., 1997) exposure. In most experimental studies, bone effects were accompanied or preceded by renal damage induced by cadmium treatment; these studies therefore do not allow to determine whether cadmium bone toxicity occurs in parallel to or as a consequence of nephrotoxicity (Katsuta et al., 1994; Umemura, 2000). Young age (growing bones), gestation, lactation and ovariectomy (used as an animal model of menopause) appeared to exacerbate this toxicity. A clear NOAEL/LOAEL for bone damage can therefore not be extrapolated from the studies (JRC, 2007). Lung Some lung effects have been observed after oral administration of cadmium compounds in rat for several weeks (Petering et al., 1979) but no effects were seen in monkey exposed to higher doses for several years (Masoaka et al., 1994). It has been suggested that the observed lung effects are related to liver or kidney damage and subsequent changes in cellular metabolism (JRC, 2007). Long-term inhalatory exposure to cadmium oxide in animals resulted in similar effects as seen in acute studies, i.e. pneumonia and emphysema accompanied by histopathological alterations and changes in the cellular and enzymatic composition of the bronchoalveolar fluid (Dunnick, 1995; Prigge, 1978; Hart, 1986; Glaser et al., 1986; Yoshikawa et al., 1975; Aufderheide et al., 1989). Differences in metallothionein metabolism could be noted as an explanation for differences (Habbeebu et al., 2000; JRC, 2007). Some tolerance to cadmium appears to develop with duration so that lung lesions developed after a few weeks of exposure do not progress, and may even regress after long exposure. Multiple mechanisms could explain this tolerance, including the synthesis of lung metallothionein and proliferation of Type II cells (ATSDR, 2008). Identified NOAELS are 0.025 mg CdO/m3 in F344/N rats exposed for 13 weeks (Dunnick, 1995) and 0.01 mg Cd/m3 in hamster exposed for 16 months (Aufderheide et al., 1989). Other Contradictory findings have been reported in studies investigating effects on blood pressure after oral administration of cadmium in animals. Inhalation exposure to cadmium oxide was not associated with an increase in blood pressure (Baranski et al., 1983). In one study, exposure was reported to have induced ultrastructural changes in the cardiac papillary muscle of rats at 0.16 mg Cd/m3 (Kolakowski et al., 1983). Overall, evidence for cardiovascular toxicity resulting from oral and inhalatory exposure in animals is suggestive of a slight effect. Conflicting results have been reported about the haematological effects of cadmium after long-term exposure. In the studies where such alterations (e.g. anemia) were seen, several mechanisms have been postulated, including impaired iron absorption, direct cytotoxicity to bone marrow, inhibition of the heme system or

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 57 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 hypoproduction of erythropein (ATSDR, 2008; JRC, 2007). Certain experimental studies using cadmium soluble compounds have reported morphological and metabolic changes in the liver but this is not a universal finding. Inhalation studies show conflicting results; even when signs of cadmium toxicity were seen, they were usually mild (ATSRD, 2008; JRC, 2007). Potential effects on the neurological or immunological systems are discussed in Section 5.10.

5.6.1.2. Repeated dose toxicity: dermal No studies were located regarding chronic effects after dermal exposure to cadmium metal or cadmium compounds. However, repeated dose toxicity via the dermal route is not expected to be significant as uptake of soluble and less-soluble cadmium compounds applied onto the skin of animals appears to be low (<1%) (see Section 5.1.1). Also in view of the risk reduction measures which need to be taken as a result of the carcinogenicity of cadmium metal and some of the cadmium compounds, dermal toxicity is not likely to pose an issue for human health. 5.6.2. Human information Numerous studies have looked into the effects of cadmium exposure both in the general population and at the workplace. In the general environment and in occupational settings, the main target organs are kidney and bone. For workers, the lungs may also be affected. The following section presents some of the main human information, by target organ, as summarized in SCOEL (2009). Kidneys In occupationally exposed subjects, the first manifestation of cadmium nephrotoxicity is usually tubular dysfunction resulting in a reabsorption defect and, hence, an increased urinary excretion of low molecular weight proteins such as the human complex protein (also called α1-microglobulin, ß2-microglobulin and/or retinol-binding protein) but also calcium and amino-acids (Lauwerys et al., 1979; Elinder et al., 1985; Jakubowski et al., 1987; Mason et al., 1988; Chia et al., 1989; Roels et al., 1993; Järup and Elinder, 1994). Other biomarkers of tubular toxicity such as urinary alanine aminopeptidase, gamma-glutamyltranspeptidase and the lysosomal enzyme N-acetyl-beta-Dglucosaminidase have also been used to demonstrate the tubular effects associated with occupational exposure to cadmium (Mueller et al., 1989; Bernard et al., 1995). Studies conducted in the 1980s on active workers in the cadmium industry have demonstrated that low molecular weight (tubular) proteinuria is likely to occur in approximately 10% of workers when the cadmium concentration in kidney cortex exceeds about 200 ppm (μg Cd/g wet weight of renal cortex) (Nordberg et al., 2007; Bernard, 2008; Roels et al., 1981; Roels et al, 1983). These studies have also shown that, before renal dysfunction develops, the amount of cadmium stored in the kidneys can be assessed non-invasively by measuring the concentration of the metal in urine (Cd-U) (Norberg et al., 2007). On the basis of the relationship between cadmium concentrations in urine and in kidney cortex in workers with no renal dysfunction, the Cd-U value corresponding to the critical level of 200 ppm in kidney cortex was estimated at 10 μg Cd/g creatinine (Norberg et al., 2007; Roels et al., 1981), a value that was in concordance with that derived from the relationships between ß2-microglobulin urine concentration and Cd-U (Bernard et al, 1979; Roels et al., 1993). Since then, a number of studies have further explored the dose-effect/response relationships for cadmium- induced renal dysfunction in industrial workers, with threshold values ranging between 1.5 and 15 µg Cd/g creatinine, as shown in Table 20.

Table 20. Thresholds for renal effects in recent/relevant studies in occupational settings (inhalation exposure) (adapted from ‘Recommendation from the Scientific Expert Group on Occupational Exposure Limits for Cd and its inorganic compounds’ SCOEL/SUM/136) Type of n Glomerular Tubular Threshold Reference industry effects effects Electronic - HMW proteins, ß2-M Cd-U : 10 µg/g Lauwerys et al. (1979) workshop serum ß2-M creatinine Ni-Cd storage and creatinine (G and T) battery factory Cd-producing plants Alkaline battery 102 ß2-M, RBP Cd-U : 10-15 µg/g Jakubowski et al. (1987) factory creatinine Cd smelter 53 ß2-M Cd-U : 13.3 µg/g Shaikh et al. (1987) creatinine Secondary Cd 26 ß2-M, RBP, Cd-U : 5.6 µg/L Verschoor et al. (1987) users NAG Cd pigment 29 ß2-M, NAG Cd-U : < 10 µg/g Kawada et al. (1989) factory creatinine (NAG) Non-ferrous 58 Albumin, ß2-M, RBP, Cd-U : 10 µg/g Bernard et al. (1990) smelter transferrin, protein-1, creatinine serum ß2-M NAG Zn-Cd smelter 108 GFR decline Cd-U : 10 µg/g Roels et al. (1991) creatinine Cd alloy factory 105 ß2-M Cd-U : 10 µg/g Toffoletto et al. (1992) creatinine Zn-Cd smelter 37 Albumin, ß2-M, RBP Cd-U : 4 µg/g Roels et al. (1993) transferrin and other creatinine (G) markers Cd-U : 10 µg/g creatinine (T) Zn-Cd refinery 14 ß2-M Cd-U : 7 µg/g van Sittert et al. (1993) creatinine Battery factory 561 ß2-M Cd-U : 1.5 µg/g Järup and Elinder (1994) creatinine (> 60 y) Cd-U : 5 µg/g creatinine (< 60 y) Cadmium 85 β2-M, NAG Cd-U : 5–10 μ g/g Chen et al. (2006) smelter creatinine HMW: High Molecular Weight protein; ß2-M: ß2-microglobulin; RBP: Retinol Binding Protein; NAG: N-acetyl-beta- Dglucosaminidase; G: glomerular effects; T: tubular effects Recently, a study by Chaumont et al. (2010) reassessed the somewhat contradictory findings reported for industrial settings. The studied population was a cohort of 599 occupationally exposed workers from four Ni-Cd manufacturing plants located in France, Sweden and the United States. The study focused on never smokers and used as critical effect an increased urinary excretion of retinol-binding protein (RBP-U) or β 2-microglobulin ( β 2m-U). The Cd-U threshold for these two proteins to exceed the 95th percentile value was constructed using as a reference those workers with Cd-U < 1 µg Cd/g creatinine. For never smokers, the odds of abnormal RBP-U and β 2-m-U were increased only among workers with Cd-U > 10 µg Cd/g creatinine. Benchmark dose (BMD5) and benchmark dose lower limit (BMDL5) for the two proteins were estimated at 12.6/6.6 and 12.5/5.5 µg Cd/g creatinine. The reason for removing smokers is because it is now established that, beyond the direct effect of cadmium originating from tobacco (which accumulates in the body along with cadmium coming from occupational exposure and is consolidated in the Cd-U of individuals, irrespective of its source), smoking is detrimental to the renal function, even in subjects without hypertension or abnormal glucose metabolism. This effect, although distinct from those induced by cadmium, is likely to distort the dose-response relation between low molecular weight proteins and cadmium in urine. Indeed, chronic smoking, even when moderate, is associated with a marked increase of albuminuria, reflecting damage to the glomerular filter (which is most likely due to the cardiovascular toxicity of tobacco smoke). As glomerular proteinuria is frequently associated with a certain degree of tubular dysfunction, confounding is likely to arise from the co-excretion of cadmium with both albumin (the main cadmium-binding protein in plasma) and low molecular weight proteins induced by this tubular dysfunction.

In other terms, because of these co-excretion mechanisms, the high albumin excretion associated with tobacco smoking may be a so far unsuspected cause of secondary association between cadmium and low molecular weight proteins in urine. This is confirmed by the fact that when including ever smokers in the statistics, BMD5 and BMDL5 decrease substantially and are estimated at 6.2/4.9 and 4.3/3.5 µg Cd/g creatinine respectively. Additionally and interestingly, no BMD value could be derived in ever smokers when considered separately. These findings thus mean that, when smokers are included in the analysis of the renal effects of cadmium, the dose-response relationships are artificially shifted to the left since the renal effects of tobacco smoke are unavoidably associated with a moderate increase of urinary cadmium. This study suggests that when sources of bias (like tobacco smoke, age, sex and residual influence of diuresis) are avoided, the LOAEL or BMD for urinary Cd are estimated around 12.0g/g creatinine and the corresponding NOAEL or BMDL can be reliably estimated between 5.5 and 6.6 µg/g creatinine. On the basis of studies conducted in Europe (Buchet et al., 1990; Hotz et al., 1999; Järup et al., 2000), the United States (Noonan et al., 2002) and Asia (Jin et al., 2002), it appears that renal effects can be detected in the general population for Cd-U below 5 μg Cd/g creatinine and even from 2 μg Cd/g creatinine or below. These studies show associations between Cd-U and markers of tubular effect. The largest studies were conducted in Belgium (Cadmibel study) in a population exclusively exposed via the environment (n=1700; geometric mean Cd-U, 0.84 μg/24 h) (Buchet et al., 1990) and in Sweden (OSCAR study) in subjects with environmental and/or occupational exposure (n=1021; Cd-U, 0.18-1.8 μg/g creatinine) (Järup et al., 2000). Both studies had a cross- sectional design so that it cannot be excluded that some of the tubular effects observed in these cohorts are the results of previous much higher exposures (particularly in occupationally exposed subjects included in the OSCAR study) which may have contributed to shift the dose-effect/response relationship to the left. In the Cadmibel study, it was found that, after adjustment for age, gender, smoking, use of medications and urinary tract disease, tubular effects (mainly increased urinary calcium excretion) occurred in the general population at Cd-U levels ≥ 2 μg/24 h (roughly equivalent to 2 μg/g creatinine according to SCOEL, 2009). Recently, de Burbure et al. (2006) and Suwazono et al. (2006) have reported effects even at the environmentally relevant concentration of 1 µg Cd/g creatinine in children and elderly populations. The association between renal parameters and cadmium exposure has been further confirmed in a study in the most exposed subgroup of the Cadmibel study (Pheecad study) (Hotz et al., 1999). In the OSCAR study, excretion of protein HC (alpha-1-microglobulin) was found associated with Cd-U (0.18-1.8 μg/g creatinine) and the prevalence of elevated values (> 95th percentile in a Swedish reference population) increased with Cd-U. The exact health significance of tubular changes observed at Cd-U levels < 5 μg/ g creatinine is, however, uncertain and subject to contrasting scientific opinions. Some authors believe that these changes represent the earliest dysfunction of the renal tubular cells and should be considered as an adverse effect because the aim of public health is to detect and prevent effects at their earliest stage in the most sensitive groups of the population (Järup et al., 1998). Others believe that these changes most likely reflect benign, non-adverse responses (Hotz et al., 1999; Bernard, 2004). While mortality studies were not able to detect an excess of end-stage renal diseases in populations environmentally exposed to cadmium compounds, an ecological study conducted in Sweden indicated that cadmium exposure was a determinant of the incidence of renal replacement therapy in a population with occupational/environmental exposure to cadmium (Hellström et al., 2001). Cadmium may also potentiate diabetes-induced effects on kidney (Buchet et al., 1990, Akesson et al., 2005, Chen et al., 2006, reviewed in Edwards and Prozialeck, 2009). A recent large cross-sectional study using US NHANES data showed that urinary cadmium levels are significantly and dose-dependently associated with both impaired fasting glucose and diabetes, suggesting that cadmium may be a cause of prediabetes and diabetes in humans (Schwartz et al., 2003). Renal damage could cause cadmium to leak into urine, potentially leading to a (noncausal) association between cadmium and diabetes. The investigators therefore restricted the analysis to persons without evidence of renal damage, but this restriction did not appreciably affect their findings. There were clear dose-response relationships between U-Cd and fasting glucose as well as diabetes. However, the pathogenesis remains to be explored. Finally, an additional effect on the kidney seen in workers with high cadmium exposures is an increased frequency of kidney stone formation (Järup et al., 1997; JRC, 2007).

Bone In humans, the mechanism of bone toxicity is not fully elucidated and types of bone lesions associated with cadmium exposure are not clearly identified. One likely mechanism is direct disturbance of bone metabolism but another explanation is that cadmium-induced kidney damage and/or hypercalciuria might promote osteoporosis and associated fractures. The most severe form of bone disease caused by cadmium intoxication is Itai-Itai disease which led to kidney and bone lesions in aged Japanese women in the past (CRC 1986; Tsuchiya, 1992). A follow-up of the population examined in the Cadmibel study (mean Cd-U, approx. 0.5 and 0.8 μg/g creatinine in men and women, respectively) has shown that Cd-U was linked to an increased risk of fracture in women and, possibly, an increased risk of height loss in men. The decline of bone mineral density in post-menopausal women was significantly aggravated by cadmium exposure (Staessen et al., 1999). In the OSCAR study, bone mineral density has been measured in the forearm of more than 1000 individuals with occupational (Cd-U, 0.06- 4.7 μg/g creatinine) and/or environmental (Cd-U, 0.06-3.7 μg/g creatinine) exposure to cadmium. An association between Cd-U and decreased bone mineral density was found in older men, and an increased risk of osteoporosis was noted in men > 60 years with a similar tendency in women > 60 years. The threshold for these effects was about 3 μg/g creatinine (Alfven et al., 2000). It has also been shown in the OSCAR cohort that cadmium exposure was associated with increased risk of forearm fractures in people over 50 years of age (Alfven et al., 2004). The association between cadmium exposure, tubular effects and osteoporosis has been confirmed in a large cross-sectional study in a Chinese population with environmental exposure to cadmium (mean Cd-U in the group with the highest exposure, 11.18 μg/g creatinine) (Jin et al., 2004). In a population- based health survey conducted in southern Sweden among women with no known historical cadmium contamination (Women's Health in the Lund Area (WHILA)), negative effects of low-level cadmium exposure (median Cd-U = 0.67 μg/g creatinine) on bone, possibly exerted via increased bone resorption, seemed to be intensified after menopause (Akesson et al., 2006). More recent Belgian data on 294 women from a Flemish population with environmental cadmium exposure (PheeCad study) confirmed the negative effects of low-level cadmium exposure (mean Cd-B = 7 - 10 nmol/L = 0.79 - 1.1 μ g/L)) on bone mineral density. Even in the absence of cadmium-induced renal tubular dysfunction, low-level environmental exposure to cadmium increases calciuria with reactive changes in calciotropic hormones (Schutte et al., 2008). A very recent US study using NHANES data reported an increased risk in 3207 women aged 50 years and older for osteoporosis in the hip at Cd-U levels between 0.5 and 1.0 μ g/g creatinine and 1.4 for Cd-U > 1.0 μ g/g creatinine as compared to the reference (< 0.5 μ g/g creatinine) (Gallagher et al., 2008). In workers exposed to cadmium compounds, clinical bone disease has been described but the number of cases is limited. One cross-sectional study reported results compatible with a role of cadmium in the genesis of osteoporosis in exposed workers who were also included in the OSCAR study mentioned above (Jarüp et al. 1998). The dose-effect/response relationship between cadmium body burden and bone effects has not been defined. Lung Early reports indicated that anosmia was a common finding in workers often exposed to high airborne cadmium levels (Friberg, 1950; Adams et al., 1961). A recent study in workers exposed to lower levels (mean Cd-B = 3.7 μg/L and Cd-U = 4.4 μg/g creatinine) confirmed that olfactory neurons are sensitive to cadmium, as demonstrated by an elevation of the olfactory threshold in these workers (Mascagni et al., 2003). Similar olfactory alterations have been reported among Polish workers from a nickel-cadmium production plant, although with much higher exposure (mean Cd-B = 35 μg/L and Cd-U = 86 μg/g creatinine) (Rydzewski et al., 1998). Long-term inhalation exposure to cadmium and cadmium compounds may also affect lung function and is associated with the development of emphysema. Surveys of workforces exposed to cadmium published in the 1950s already indicated that protracted occupational exposure to cadmium could cause emphysema (Friberg, 1950; Lane et al., 1954). Mortality studies in cadmium workers in the United Kingdom found that those who had experienced high exposure had an increased mortality rate from “bronchitis” (Armstrong et al., 1983). In copper-cadmium alloy producers, a marked excess of deaths from chronic non-malignant respiratory diseases has also been found related to cadmium exposure (Sorahan et al., 1995). The respiratory impact of occupational cadmium exposure has also been reported in more recent studies that were able to collect detailed lung function measurements, good exposure assessment and to control for confounding such as other industrial exposures and tobacco smoking. In a copper-cadmium alloy factory, it was found that the cadmium-exposed workforce had evidence of airflow limitation (reduced FEV1 and Tiffeneau ratio), hyperinflated lungs (increased RV and TLC) and reduced gas transfer (reduced DLCO and KCO), an overall pattern of functional abnormalities consistent with emphysema. Regression analysis identified a significant relationship between the reduction in FEV1, FEV1/FVC ratio, DLCO, and KCO, and both estimated cumulative cadmium exposure (years x μg/m³) and liver cadmium content measured by neutron activation analysis (Davison et al., 1988). A moderate increase in residual volume (+7% compared to controls matched for smoking habits) has also been reported in workers

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 61 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 exposed to cadmium fumes in a factory producing silver-cadmium-copper alloys for brazing, already at cumulative exposure levels below 500 years x μg Cd/m3 (mean Cd-U = 3.1 μg Cd/L) (Cortona et al., 1992). Other studies have shown no cadmium-related impairment of respiratory function (Stanescu et al., 1977; Edling et al., 1986) presumably because of differences in the intensity of exposure, the species of Cd involved, variable diagnostic criteria or incomplete control for confounding factors, including tobacco smoking. Other While some studies reported an association between environmental exposure to cadmium and increased risks of cardiovascular diseases (Everett and Frithsen, 2008; Schutte et al. 2008; Tellez-Plaza et al., 2008), other studies did not detect such an increased risk (Staessen et al., 1991). Studies on the cardiovascular effects of occupational exposure were not located. No major effects of cadmium on the liver have been reported. Furthermore, cadmium-induced anemia is not likely to be of concern for occupational or general population exposure (JRC, 2007). Potential effects on the neurological or immunological systems are discussed in Section 5.10. 5.6.3. Summary and discussion of repeated dose toxicity Results from studies in animals and observations in humans indicate that the sensitive targets of cadmium toxicity are kidney and bone following oral exposure and kidney and lungs following inhalation exposure (ATSDR, 2008). Cadmium being a cumulative toxicant, the systemic manifestations associated with chronic exposure are related to the body burden of the element (liver and kidney content), assessed with biomarkers such as urinary concentration (Cd-U). In workers exposed to cadmium, a body burden corresponding to 200 ppm in kidney cortex, ie ca. 10 μg Cd/g creatinine is considered to represent a critical level based on the occurrence of low molecular weight proteinuria. SCOEL (2009) recommends an Occupational Exposure Level (OEL) equivalent to 4 µg Cd/m3 (respirable fraction) as protective against long-term local effects (respiratory effects, including lung cancer). This is based on human data that shows changes in residual volume of the lung for a cumulative exposure to CdO fumes of 500 µg Cd/m3 x years, corresponding to 40 years exposure to 12.5 µg Cd/m3 (LOAEL) (Cortona et al., 1992). Applying an uncertainty factor of 3 (LOAEL to NOAEL) leads to a value of 4 µg/m3. Based on the most recent studies, it seems that renal effects can be detected in the general European population (mainly exposed by the oral route) for cadmium body burdens at or even below 2 μg Cd/g creatinine. There is, however, a scientific debate about the health significance of these early changes. This lower value in the general population compared to that identified in workers is thought to reflect, among other parameters, an interaction of cadmium exposure with pre-existing, concurrent or subsequent renal diseases (mainly renal complications of diabetes) that are less prevalent in healthy young individuals in occupational settings. As workers exposed to cadmium may, however, suffer from such diseases during or most often after their occupational career, and considering the long half-life of cadmium in humans and its accumulation with age, it is considered prudent to recommend a Biological Limit Value (BLV) that would provide a sufficient degree of protection in this respect (SCOEL, 2009). Available NOAELs from repeated dose oral and inhalation studies range between 0.12 - 3 mg/kg bw/day and 0.013. 10-3 - 0.022 x 10-3 mg/L, respectively. This data supports a classification as T; R48/23/25 (Toxic: danger of serious damage to health by prolonged exposure through inhalation and if swallowed), which has been attributed to cadmium chloride, sulphate, oxide and metal in Annex I of Directive 67/548/EC (the corresponding GHS-CLP classification would be STOT category 1; H372). By analogy, the other highly and slightly soluble forms of cadmium (i.e. cadmium nitrate, hydroxide and carbonate) warrant comparable classifications. Apart from cadmium sulphide, no other insoluble cadmium compounds (e.g. cadmium sulfoselenide, cadmium zinc sulphide or cadmium telluride), not expected to penetrate easily into the organisms, are classified for repeated dose toxicity. Cadmium sulphide is an exception. As there is no data to support its T; R48/23/25 classification, a revision of this classification may be appropriate based on solubility properties. Repeated dose toxicity of cadmium via the dermal route is not expected given the relatively low skin penetration of all forms of this metal. Also in view of the risk reduction measures which need to be taken as a result of the carcinogenicity of cadmium metal and some of the cadmium compounds, chronic dermal toxicity is not expected to be an issue for human health. No corresponding classification is therefore required.

5.7. Mutagenicity 5.7.1. Non-human information Numerous in vitro and in vivo studies have been conducted on cadmium compounds, mostly with cadmium chloride. An extensive review is available in the EU Risk Assessment Report (RAR) (JRC, 2007). The following section presents the main results, as discussed in CSTEE (2004), JRC (2007) and SCOEL (2009).

5.7.1.1. In vitro data Various cadmium compounds (in particular water soluble forms) have been tested in vitro for direct DNA damage, oxidative damage and inhibition of DNA repair in bacterial (e.g. S. typhymurium and E. coli), rodent (e.g. mouse spleen, Chinese hamster V19 and V79, Chinese Hamster ovary, rat liver and rat myoblast) and human (e.g. human lymphocyte, HSBP fibroblast and human diploids fibroblasts) cell lines. A detailed list of experiments can be found in IARC (1993) and JRC (2007). Selected studies are summarised in the following table:

Table 21. Overview of selected experimental in vitro genotoxicity studies Method Results Remarks Reference Cadmium chloride Bacterial gene mutation assay Negative (gene mutation) 2 (reliable with Bruce WR and S. typhimurium TA 1535, TA met. act.: with and without; restrictions) Heddle JA (1979) 1537, TA 98 and TA 100 (met. cytotoxicity: no, but tested up to key study act.: with and without) limit concentrations experimental result 0,05; 0,5; 5; 50; 500 µg/plate The Ames Salmonella test was used to test cadmium chloride for reversion of his- auxotrophs of S. typhimurium in the strains TA1535, TA1537, TA98 and TA100 in vitro mammalian chromosome Positive (CA and SCE) 2 (reliable with Fahmy MA and Aly aberrations test and sister restrictions) FA (2000) chromatid exchange assay in key study mammalian cells experimental result mouse spleen cells 10, 15, 20 µg/ml CA:  incubation time: 48 hours  number of cells observed: 100 metaphases per culture  staining: Giemsa in phosphate buffer (pH 6.8) SCE:  incubation time: 24 hours  number of cells observed: 30 metaphases per culture  staining: fluorescence dye 33258 Hoechst plus Giemsa Single cell gel/comet assay in Positive (DNA damage and SCE) 2 (reliable with Mourón SA, Grillo mammalian cells for detection of Weak positive (gene mutation K- restrictions) CA, Dulout FN, DNA damage, sister chromatid ras) key study Golijow CD (2004) exchange assay in mammalian experimental result cells and mammalian cell gene mutation assay (gene mutation (K-ras)) human lung fibroblast cell line

Method Results Remarks Reference MRC-5 1, 2 and 4µM SCE: Number of cells observed: 50 metaphases per culture Comet: According to the method of Singh et al., 1988 Point mutations in codon12 of the K-ras protooncogene: PCR-SSCP and RFLP enriched PCR methods Cadmium oxide bacterial gene mutation assay Negative (gene mutation) 2 (reliable with Mortelmans K, S. typhimurium TA 1535, TA met. act.: with and without; restrictions) Haworth S, 1537, TA 98 and TA 100 (met. cytotoxicity: no, but tested up key study Lawlor T, Speck act.: with and without) to limit concentrations experimental result W, Tainer B and Doses: 0, 3.3, 10.0, 33.0, 100.0, Zeiger E (1986) 333.0, 1000.0, 3333.0 µg/plate 3 plates per dose level equivalent or similar to OECD Guideline 471 (Bacterial Reverse Mutation Assay) equivalent or similar to EU Method B.13/14 (Mutagenicity - Reverse Mutation Test Using Bacteria) in vitro mammalian CA: positive and SCE: negative 2 (reliable with Wang TC and chromosome aberrations test restrictions) Lee ML (2001) and sister chromatid exchange key study assay in mammalian cells experimental result Chinese hamster Ovary (CHO) Doses: CA: 0, 12.5, 25.0, 50.0, 100.0 µM SCE: 0, 13.0, 25.0, 50.0, 100.0 µM CA: -incubation time: 20 hours -number of cells observed: 100 metaphases per culture -staining: 3% Giemsa SCE: -incubation time: 24 hours -number of cells observed: 50 metaphases per culture -staining: fluorescence dye 33258 Hoechst plus Giemsa Cadmium sulphide in vitro mammalian chromosome Positive (CA) 2 (reliable with Shiraishi Y, aberration test restrictions) Kurahashi H and lymphocytesDoses: 6.2x10-2 key study Yoshida TW (1972) µg/ml experimental result CA: -incubation time: 72 hours -number of cells observed: 50 metaphases per culture -staining: Giemsa

Method Results Remarks Reference DNA damage and repair assay, Positive (DNA damage) 2 (reliable with Robison SH, unscheduled DNA synthesis in restrictions) Cantoni O, Costa mammalian cells in vitro Chinese key study M. (1982) hamster Ovary (CHO) Doses: experimental result 10µg/ml -Analysis of DNA by alkaline sucrose gradients -DNA molecular weight calculations Cadmium sulphate Single cell gel/comet assay in Positive (DNA damage and SCE) 2 (reliable with Mourón SA, Grillo mammalian cells for detection of Weak positive (gene mutation K- restrictions) CA, Dulout FN, DNA damage, sister chromatid ras) key study Golijow CD (2004) exchange assay in mammalian experimental result cells and mammalian cell gene mutation assay (gene mutation (K-ras)) human lung fibroblast cell line MRC-5 0.033, 0.067 and 0.13µM SCE: Number of cells observed: 50 metaphases per culture Comet: according to the method of Singh et al., 1988 Point mutations in codon12 of the K-ras protooncogene: PCR-SSCP and RFLP enriched PCR methods Cadmium carbonate in vitro mammalian chromosome CA: positive and SCE: negative 2 (reliable with Wang TC and Lee aberrations test and sister restrictions) ML (2001) chromatid exchange assay in key study mammalian cells Chinese experimental result hamster Ovary (CHO) Doses: CA: 0, 12.5, 25.0, 50.0, 100.0 µM SCE: 0, 13.0, 25.0, 50.0, 100.0 µM CA: -incubation time: 20 hours -number of cells observed: 100 metaphases per culture -staining: 3% Giemsa SCE: -incubation time: 24 hours -number of cells observed: 50 metaphases per culture -staining: fluorescence dye 33258 Hoechst plus Giemsa Overall, in vitro mutagenicity studies of cadmium give conflicting results. While some (especially in bacterial systems) are negative, others (including those in mammalian cells) have yielded positive results for the induction of DNA strand breaks, protein-DNA crosslinks, chromosome aberrations and other markers of mutagenicity (Bruce and Heddle, 1979; Fahmy and Aly, 2000; Mouron et al., 2004; Mortelmans et al., 1986; Wang and Lee, 2001; Shiraishi et al., 1972; Robison et al., 1982). According to several reviews, differences between treatments as well as between the cells used may play a role in explaining the variability in findings (IARC, 1992; ATSDR, 2008 and 1999; WHO, 1992).

With regard to mechanism of action, the data suggests that cadmium ions accumulated in cells may cause genetic damage directly or indirectly by:

 Interacting with chromatin to generate strand break, cross links or structural alterations in DNA,

 Depleting antioxidant levels and thereby increasing intracellular hydrogen peroxide and other oxidants, or

 Interacting at metal-binding sites of proteins involved in transcription, DNA replication or DNA repair. According to JRC (2007), the various mechanisms of action described above are not mutually exclusive; their relevance to in vivo situations may nevertheless be questioned since in vitro studies are conducted at concentrations well above physiologically relevant levels.

5.7.1.2. In vivo data Inhalation exposure for 13 weeks to cadmium oxide did not result in increased frequency of micronucleated erythrocytes in peripheral blood of male or female B6C3F1 mice (McGregor et al., 1990; Dunnick, 1995). However, this result should be interpreted with caution due to the absence of sufficient bioavailability to the bone marrow and the fact that the most relevant target cells (lung) were not examined. Several experiments using cadmium water-soluble compounds were identified and summarized by IARC (1993). Results were judged conflicting (JRC, 2007). More recently, Fahmy and Aly (2000) found induction of micronuclei, increased sister chromatid exchange in bone marrow and chromosomal aberration after a single intraperitoneal treatment with cadmium chloride. Single strand breaks were observed after acute treatment of male albino rats with cadmium chloride injected intraperitoneally. Cadmium also increased the amount of single strand breaks in kidney (Saplakoglu et al., 1997). Forni (1992) suggested that cadmium ions may act as co-mutagens rather than mutagens. Indeed, cadmium appears to inhibit the repair of DNA damaged by other agents. For example, cadmium chloride given to mice at 300 ppm in water for 7 days enhanced the frequency of micronuclei resulting from dimethylnitrosamine, thereby enhancing its mutagenicity (Watanabe, 1982; IARC, 1993). Overall, although the results for the various cadmium substances are conflicting, it cannot be excluded that cadmium exerts a mutagenic effect in vivo (JRC, 2007). 5.7.2. Human information Mutagenicity studies of cadmium in humans have been reviewed by several organisations (CRC, 1986; IARC, 1992 and 1993; WHO, 1992 and ATSDR, 2008) and are summarised in JRC (2007). Both oral and inhalation routes have been considered and endpoints include chromosomal aberration, sister chromatid exchange and micronucleus. Selected data is presented in the table below, then discussed by type of population considered. Table 22. Overview of selected exposure-related observations on genotoxicity in humans Method Results Remarks Reference Cadmium oxide Study type: cross sectional study Non significantly increased 2 (reliable with Deknudt G, Type of population: occupational incidences of observed restrictions) Léonard A and Subjects: aberrations in exposed groups key study Ivanov B (1973) -Final population: compared to control group E: 14 (M) classified into 3 groups but significantly increased  Group I: high level of Zn, low prevalence of "more complex levels of Cd and Pb (N=5) aberrations"  Group II: high levels of Zn, Cd, Pb (N=5)  Group III: high levels of Cd and Pb, no Zn (N=4) Age: 27-56 y. C: 5; Age: 31-55 y. - Selected from : E: "workers in a Zn industry classified into 3 groups according to the type and duration of exposure” C: N.I. Study type: cross sectional study Non significantly increased 2 (reliable with Deknudt G and

Method Results Remarks Reference Type of population: occupational incidences of observed restrictions) Léonard A (1975) Subjects: aberrations in exposed groups key study -Final population: compared to control group E: 35 (M only?) classified into 2 but significantly increased groups: prevalence of "more complex  "Cd-service": high levels of Pb aberrations" and Cd, no Zn (N=23)  "Rolling-mill": exposed mostly to Zn, lower levels of Pb and Cd (N=12) Age (mean): "Cd-service": 40.2 y. "Rolling-mill": 34.8 y. C: 12 (M only?) Age (mean): 32.2 y. -Selected from : E: "workers in a Cd plant classified into 2 groups according to the type & duration of exposure” C: "people from the administration department of the same plant” Study type: cross sectional study - Significantly increased 2 (reliable with Bauchinger M, Type of population: occupational incidences of structural restrictions) Schmid E, Einbrodt Subjects: chromosome aberrations in the key study HJ and Dresp J -Final population: exposed group compared to the (1976) E: 24 (M only) control group Age: 25-53 y. - No relationship detected C: 15 (11M/4F) between the prevalence of Age: 26-60 y. aberrations per person and Cd-B -Selected from: or Pb-B or length of exposure E: “Workers at a smelting plant” C: “Unexposed, healthy controls from the general population” Study type: cross sectional study - The 22 workers with Cd-U >10 2 (reliable with Forni A, Toffoletto Type of population: occupational µg/l had significantly higher restrictions) F, Ortisi E, and Subjects: rates of abnormal metaphases key study Alessio L (1990) -Final population: (excluding gaps) and E: 40 (M only) chromosome type aberrations Age: 23 – 58 y. than the controls and the 18 other C: 40 (M only) workers. Age: 23 –63 y. - No increase in chromosome- -Selected from: type aberrations was detectable E: “workers in a single factory in the group of subjects with producing cadmium, zinc, copper and mean Cd-U levels lower than 10 silver alloys” µg/l, the biological exposure C: “ matched for age, sex and limit value at the time of the smoking” study (Forni et al., 1990, Forni, 1992). -long-term exposure associated with significant increase in frequency of chromosome-type aberrations (2.37% in workers with CEI>1000 vs. 0.8 in workers with CEI<100, vs.0.5% in controls . Cadmium metal

Method Results Remarks Reference Study type: cross sectional study - Significant difference in 1 (reliable without Fu JY, Huang XS Type of population: general chromosome aberration rates restriction) and Zhu XQ (1999) Subjects: between the exposed and the key study -Final population: control group E: 56 (26M/ 30 F); Age: 36.8 ± 17.6 - Micronucleus rates are y. significantly elevated in all C: 10 (4M/ 6 F); Age: 41.0 ± 10.6 y. exposed subgroups when -Selected from: compared with controls, except E: "people environmentally exposed when Cd-U was <2.5 µg/l to Cd and in Suichang county of - Prevalence of aneuploidy: Zhejiang province" differences in numerical C: “living in areas known to be aberrations were not significant uncontaminated by Cd” Study type: cross sectional study - Increased prevalence of 2 (reliable with Shiraishi Y and Type of population: general chromosomal aberrations in Itai- restrictions) Yosida TH (1972) Subjects: Itai patients compared with the key study -Final population: results in control subjects E: 7- 12 (F only) ; Age: 52-73 y - Frequency of aneuploidy also C: 6 (F) - 9 (6F/3M) ; Age: 58-78 y significantly higher than in the -Selected from: controls E:” Itai-Itai patients”

Study type: cross sectional study No differences in chromosome 2 (reliable with Bui TH, Lindsten J Type of population: general aberration frequencies between restrictions) and Nordberg GF Subjects: exposed and controls key study (1975) - Final population: E: 4 (F only); Age: 55-71 y. C: 4 (3F, 1M); Age: 65-94 y. - Selected from: E:” Itai-Itaipatients from Fuchu (endemic cadmium-polluted area)” C: “Living in an area known not to be contaminated by cadmium” -Lost subjects: 2 Study type: cross sectional study - Significantly higher increase of 2 (reliable with Tang XM, Chen Type of population: general chromosome aberrations in restrictions) XQ, Zhang JX and Subjects: cadmium-polluted groups versus key study Qin WQ (1990) -Final population: controls E: 40 (21M/ 19 F); Age: 36.8 ± 17.6 - Significant correlations y. between urinary cadmium C: 11 (9M/ 2 F); Age: 41.9 ± 14.5 y. content and chromosome -Selected from: aberration frequencies E: "lived in Cd-polluted area of - More aneuploidy and cells with Suichang (China) (Cd-soil : 1.103 complex structural chromosome ppm)” aberrations in the exposed groups C: “lived in unpolluted region of the same general area (Cd-soil: 0.20 ppm)” -Lost subjects: 7 Study type: cross sectional study - No increased frequency of 2 (reliable with Bui TH, Lindsten J Type of population: occupational chromosome aberrations in the restrictions) and Nordberg GF Subjects: exposed group versus control key study (1975) -Final population: group E: 5 (M only); Age: 44-57 y. C: 3 (M only); Age: 52-54 y. -Selected from: E: “electrode department of an

Method Results Remarks Reference alkaline battery factory” C: "office workers of about the same age, from the same factory” Study type: cross sectional study -Statistically significant increases2 (reliable with Palus J, Rydzynski Type of population: occupational compared to the control restrictions) K, Dziubaltowska Subjects: population in micronuclei rates key study E, Wyszynska K, -Final population: and sister chromatid exchanges Natarajan AT E: 22 (7M+15F) Cd-exposed; 44(M) as well as evidence of an (2003) Pb-exposed ; Age: 44-57 y. increased incidence of C: 52 (35M+17F); Age: 52-54 y. leukocytes with DNA -Selected from: fragmentation. E: battery plant located in the north- western part of Poland where acid and alkaline batteries were produced and where occupational exposure to respectively lead or cadmium by inhalation was found. C: the same battery plant but recruited from departments with no occupational exposure to lead and cadmium, as well as health service and office workers.

Oral route (general population) Overall, mutagenicity studies on the general population yield conflicting results (Fu et al, 1999; Shiraishi and Yoshida, 1972; Bui et al., 1975; Tang et al., 1990). The main features common to the selected studies are:

 Cross-sectional design (apart from Shiraishi (1972) in which part of the population was re-examined several months later);

 Small population sizes so that false negative findings may be due to chance and lack of statistical power;

 Many endpoints and inter-group comparisons used but independence of the endpoints not clearly stated; chance findings may have occurred;

 Lack of consistency regarding endpoints affected by cadmium;

 Incomplete or missing data on cadmium blood or urine values or their quality control;

 Not clear whether higher cadmium body burden is the cause of cytogenetic change or only a marker of exposure to other variables (e.g. Itai-Itai disease, smoking, nutrition pattern, etc.). Lack of attention in the selection procedures, use of small groups, different technical procedures and gaps in information about exposure and confounding factors may contribute to explain most of the conflicting results (JRC, 2007). Nevertheless, based on available data, it cannot be excluded that cadmium may exert mutagenic effects in populations exposed via the oral route. Inhalation route (workers) Again, a consistent pattern of mutagenic effects associated with occupational exposure cannot be deduced from the inhalation exposure studies (Deknudt et al., 1973; Deknudt and Léonard, 1975; Bauchinger et al., 1976; Bui et al., 1975; Forni et al., 1990; Palus et al., 2003). The main features common to the selected studies are:

 Cross-sectional design;

 Many endpoints and inter-group comparisons used but independence of the endpoints not clearly stated; chance findings may have occurred;

 Lack of consistency regarding endpoints affected by cadmium;

 Incomplete or missing data on cadmium blood or urine values or their quality control;

 Cadmium compound not always clearly defined. Definition of population size, exposure characteristics and outcome, as well as incomplete analysis of confounding factors may in part explain conflicting results. Overall, it cannot be excluded that cadmium may exert mutagenic effects in populations exposed via inhalation. 5.7.3. Summary and discussion of mutagenicity Data from in vitro and in vivo experimental systems are not consistent but suggests that cadmium, in certain forms, has mutagenic properties. With regard to human exposure, data are also conflicting but again a mutagenic potential both via oral and inhalation exposure routes cannot be excluded. Different possible non-mutually exclusive direct and indirect mechanisms of mutagenicity have been identified in vitro, although their relevance to in vivo situations is not clearly established. A recent review by Parry and Parry (2009) (available in IUCLID 5 under ‘7.12 Additional toxicological information’) concluded that there is considerable evidence to suggest that the primary mechanism of genotoxicity is the production of oxidative lesions. In this case, there could be a threshold at low doses where the DNA repair enzymes remove the lesions, thus reducing the potential for genetic changes in cells. The EU Risk Assessment Report (RAR) (JRC, 2007) states that most of the mechanisms proposed to explain the mutagenicity of cadmium ions are dose-dependent and support the possibility of a threshold for mutagenic effects (Madle et al., 2000; Kirsch-Volders et al., 2000). Further research may be able to determine No Adverse Effect Levels (NOAEL) and generate dose-response curves. It should however be noted that cadmium has also been suggested to act as a co-mutagen rather than as a mutagen, e.g. by decreasing fidelity in DNA synthesis or interfering with DNA repair mechanisms (Schwerdtle et al., 2010). In this case, repair activity within a potential thresholded region of the dose-response-curve would be limited (Parry and Parry, 2009). If cadmium inhibits the repair of DNA damage induced by other agents, this could explain some of the

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 70 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 differences in the results of cytogenetic studies in human populations. Indeed, chromosome aberrations might be increased in the different populations/subjects with different additional occupational/environmental exposures as a result of unrepaired damage (Forni, 1992). Recently, SCOEL cited in his DRAFT NOTE on the 76th MEETING (March 2010) the study of Forni et al. 1990 for referring to the 10 µg/g creatinin in Cd/urine as a threshold for genotoxicity. SCOEL also published that ‘having defined a threshold for genotoxicity, it was shown that renal and respiratory effects are more sensitive than genotoxicity, in turn thought to be a pre-requisite for carcinogenicity’.

Based upon the available evidence at present it is concluded that cadmium has a threshold for genotoxicity. A second important conclusion is that the renal respiratory effects are more sensitive than the genotoxic effects. The risk management for cadmium consequently is based on the protection for renal and inhalatory effects.

Based on available data and read-across, cadmium chloride and sulphate are currently classified as Muta. Cat. 2; R46 (may cause heritable genetic damage) in Annex I of Directive 67/548/EC (the corresponding GHS-CLP classification would be Mutagenic category 1B; H340). By analogy, the other highly soluble forms of cadmium (i.e. cadmium nitrate) warrant comparable classifications. At present, the slightly soluble cadmium metal and oxide are classified as Muta. Cat. 3; R68 (possible risk of irreversible effects) in Annex I of Directive 67/548/EC (the corresponding GHS-CLP classification would be Mutagenic category 2; H341). A similar classification for cadmium hydroxide and carbonate may therefore be considered. Apart from cadmium sulphide, none of the insoluble cadmium compounds (e.g. cadmium sulfoselenide, cadmium zinc sulphide or cadmium telluride), not expected to penetrate easily into the organisms, are classified for mutagenicity. Cadmium sulphide (Muta. Cat. 3; R68 or Mutagenic category 2; H341 under GHS-CLP) is an exception for which a revision of the classification could be considered based on solubility properties. 5.8. Carcinogenicity 5.8.1. Non-human information

5.8.1.1. Carcinogenicity: oral Numerous studies have been conducted in mice and rat to determine whether cadmium (mainly in the form of water-soluble compounds such as cadmium sulphate, chloride and acetate) causes carcinogenicity in animals when administered via gastric instillation, food or drinking water. These are summarised in JRC (2007). Most early studies have not reported an increased overall cancer incidence or an increased incidence of specific tumour types. However, the sensitivity was limited because the maximum doses used were clearly below the maximum tolerated dose or exposure was too brief. Also, in some cases, histopathological examination was only conducted on a restricted number of animals and tissues. Waalkes and Rehm (1992) reported an oral study using cadmium chloride suggestive of carcinogenic activity (see Table). Cadmium chloride, given to rats in the diet, was associated with large granular lymphocyte leukemia and proliferative lesions of the prostate. Another neoplastic, albeit benign, effect was associated with dietary cadmium: interstitial cell adenomas in the testes.

Table 23. Overview of selected experimental studies on carcinogenicity after oral administration Method Results Remarks Reference Cadmium chloride Rat (Wistar) male LOAEL (carcinogenicity): 3.5 2 (reliable with Waalkes MP and oral: feed mg/kg bw/d (male) (increased restrictions) Rehm S (1992) 0, 25, 50, 100, 200 ppm (nominal rates of prostatic adenomas) key study conc. (equivalent to 0, 1.75, 3.5, 7 Neoplastic effects observed in experimental result and 14 mg Cd/ kg bw/d)) any test group: yes Exposure: 77 wk A study was conducted to determine the effect of chronic dietary zinc deficiency on the carcinogenic potential of dietary cadmium in rat. Rats were exposed to cadmium (0, 25, 50, 100, 200 ppm), given as cadmium chloride and mixed with diets either adequate or marginally deficient in zinc. Necropsy was performed on all animals.

5.8.1.2. Carcinogenicity: inhalation Carcinogenicity via the inhalation route has been studied in rat, mouse and hamster with various cadmium compounds. The results of selected experimental studies are summarised in the following table. Table 24. Overview of selected experimental studies on carcinogenicity after inhalation exposure Method Results Remarks Reference Cadmium chloride Rat (Wistar) male/female LOAEL (carcinogenicity): 2 (reliable with Glaser U, inhalation: aerosol 0.03 mg Cd/m³ (male/female) restrictions) Hochrainer D, Otto 30 and 90 µg Cd/m3 (nominal conc.) (lung bronchioalveolar key study FJ and Oldiges H Vehicle: none adenomas, adenocarcinomas, experimental result (1990) (update of Exposure: max 18 months (22 h/d x and squamous cell carcinomas) Oldiges,1989) 7 d/wk; 40 h/wk x 6 months) Neoplastic effects observed in A study was conducted to evaluate any test group: yes the carcinogenic potential of the test material in rats. Rats were exposed to the aerosols of the test material at 30 and 90 µg Cd/m3 continuously for a maximum period of 18 months followed by a treatment-free observation for 29 - 31 months. Bodyweight, clinical signs, hematological and clinical chemistry examinations were performed throughout the study. Cadmium contents of lung, liver and kidneys were determined along with the histopathological examination of the lungs.

Method Results Remarks Reference Rat (Wistar) male LOAEL (carcinogenicity): 2 (reliable with Takenaka S, inhalation: aerosol 0.0125 mg Cd/m³ (nominal) restrictions) Oldiges H, König 12.5, 25 and 50 µg Cd/m3 (nominal (male) (lung epidermoid key study H, Hochrainer D conc.) carcinomas, adenocarcinomas experimental result and Oberdörster G Exposure: 18 months (continuously and mucoepidermoid (1983) (23 h/d, 7 d/wk)) carcinomas) A study was conducted to evaluate Neoplastic effects observed in the carcinogenic potential of the test any test group: yes material in rats. Rats were continuously exposed (23 h/d, 7 d/wk) to the test material aerosols at 12.5, 25 and 50 µg/m3 for 18 months and then observed for 13 months. Clinical signs and mortality were observed in the treated groups throughout the exposure period and during the post-exposure observation period. Histopathology of the lungs was carried out to evaluate the incidence of lung carcinomas. Rat / mouse (Fisher 344 / Balb-c) NOAEL (rat) 3 (not reliable) Oberdörster G, male (carcinogenicity): 0.1 mg/m³ supporting study Cherian MG and 100 µg Cd/m3 (nominal conc.) (male) experimental result Baggs RB (1994) Groups of rats and mice were LOAEL (mouse) exposed to the test material at 100 (carcinogenicity): 0.1 mg/m³ μg Cd/m³ in a subchronic inhalation air (male) (increased study (6 h/d, 5 d/wk for a total of 4 neutrophils, LDH and beta- wk). Following exposure, evaluation glucuronidase; pulmonary of pulmonary inflammatory changes, inflammation) determination of metallothionein levels and cadmium content in lungs in both the species were conducted. NMRI mice and Syrian golden no NOAEL identified for 3 (not reliable) Heinrich U, Peters hamsters (male/female) mouse or hamster supporting study L, Ernst He, 30 and 90 µg Cd/m3 (nominal conc.) (carcinogenicity) experimental result Rittinghausen S, Vehicle: none (lung tumours) Dasenbrock C and Exposure: Up to 14 months (19 h or König H (1989) 8 h/d, 5 d/wk) A study was conducted to evaluate the possible carcinogenic effects of the test material in hamster and mouse. Animals were exposed to the test material aerosols at 30 and 90 µg Cd/m3 for 19 h or 8 h/d, 5 d/wk for up to 14 months. Following exposure distribution of cadmium in the lungs and histopathology of the lungs were carried out.

Method Results Remarks Reference Cadmium sulphate Rat (Wistar) male/female LOAEL (carcinogenicity): 2 (reliable with Glaser U, inhalation: aerosol 0.09 mg Cd/m³ (male/female) restrictions) Hochrainer D, Otto 90µg Cd/m3 (nominal conc.) (lung bronchioalveolar key study FJ and Oldiges H Vehicle: unchanged (no vehicle) adenomas, adenocarcinomas, experimental result (1990) (update of Exposure: max 18 months (22 h/d x and squamous cell carcinomas) Oldiges,1989) 7 d/wk; 40 h/wk x 6 months) Neoplastic effects observed in A study was conducted to evaluate any test group: yes the carcinogenic potential of the test material in rats. Rats were exposed to the aerosols of the test material at 90 µg Cd/m3 continuously for a maximum period of 18 months followed by a treatment-free observation for 29 - 31 months. Bodyweight, clinical signs, hematological and clinical chemistry examinations were performed throughout the study. Cadmium contents of lung, liver and kidneys were determined along with the histopathological examination of the lungs. NMRI mice and Syrian golden no NOAEL identified for 3 (not reliable) Heinrich U, Peters hamsters (male/female) mouse or hamster supporting study L, Ernst He, 30 and 90 µg Cd/m3 (nominal conc.) (carcinogenicity) experimental result Rittinghausen S, Vehicle: none (lung tumours) Dasenbrock C and Exposure: Up to 14 months (19 h or König H (1989) 8 h/d, 5 d/wk) A study was conducted to evaluate the possible carcinogenic effects of the test material in hamster and mouse. Animals were exposed to the test material aerosols at 30 and 90 µg Cd/m3 for 19 h or 8 h/d, 5 d/wk for up to 14 months. Following exposure distribution of cadmium in the lungs and histopathology of the lungs were carried out. Cadmium oxide Rat (Wistar) male/female LOAEL (CdO dust) 2 (reliable with Glaser U, inhalation: aerosol (carcinogenicity): 0.03 mg restrictions) Hochrainer D, Otto CdO fumes: 10 and 30 µg Cd/m3; Cd/m³ (male/female) (lung key study FJ and Oldiges H CdO dust: 30 and 90 µg Cd/m³ bronchioalveolar adenomas, experimental result (1990) (update of (nominal conc.) adenocarcinomas, and Oldiges,1989) Vehicle: unchanged (no vehicle) squamous cell carcinomas) Exposure: max 18 months (22 h/d x LOAEL (CdO fume) 7 d/wk; 40 h/wk x 6 months) (carcinogenicity): 0.03 mg A study was conducted to evaluate Cd/m³ (male) (lung the carcinogenic potential of the test bronchioalveolar adenomas, material aerosols in rats. Groups of adenocarcinomas, and rats were exposed to the aerosols of squamous cell carcinomas) the test material at 10 and 30 (CdO Neoplastic effects observed in fume) and 30 and 90 (CdO dust) µg any test group: yes Cd/m3 continuously for a maximum 18 months followed by a treatment- free observation period of 29 - 31

Method Results Remarks Reference months. Bodyweight, clinical signs, hematological and clinical chemistry examinations were performed throughout the study. Cadmium contents of lung, liver and kidneys were determined along with the histopathology of the lungs. Rat (Wistar-SPF) male Effect level (carcinogenicity): 4 (not assignable) Hadley JG, Conklin inhalation: aerosol (male/female) (No dose- supporting study AW and Sanders 60 µg/L air (nominal conc.) response as a single dose with experimental result CL (1979) Vehicle: none a single exposure was used. No Exposure: 30 min (single exposure) relevance to carcinogenicity) Rats exposed to single dose of an Neoplastic effects observed in aerosol of cadmium oxide (60 µg/L any test group: yes for 30 min) were observed for up to 1 year post-exposure. Hamster and mouse (Syrian golden NOAEL (carcinogenicity): ca. 3 (not reliable) Heinrich U, Peters hamsters (Hoe: SYHK (SPF Ars) 0.01 mg/m³ (nominal) (mouse, supporting study L, Ernst He, and NMRI Mice) male/female female) (CdO fumes) experimental result Rittinghausen S, CdO dust: 30, 90 and 270 µg Cd/m3; (lung tumours) Dasenbrock C and CdO-fumes: 10, 30 and 90 µg Cd/m3 König H (1989) (nominal conc.) No NOAEL identified for CdO Vehicle: none dust in mouse or for any form Exposure: Up to 14 months (19 h or of CdO in hamster 8 h/d, 5 d/wk) (carcinogenicity) A study was conducted to evaluate (lung tumours) the possible carcinogenic effects of the test material in hamster and mouse. Animals were exposed to the test material aerosols at 30, 90 and 270 (CdO dust) and 10, 30 and 90 (CdO fumes) µg Cd/m3for 19 h or 8 h/d, 5 d/wk for up to 14 months. Distribution of Cd and histopathology of the lungs analysed. Cadmium sulphide Rat (Wistar) male/female LOAEL (carcinogenicity): 2 (reliable with Glaser U, inhalation: aerosol 0.09 mg Cd/m³ (male/female) restrictions) Hochrainer D, Otto 90, 270, 810 and 2430 µg Cd/m3 (lung bronchioalveolar key study FJ and Oldiges H (nominal conc.) adenomas, adenocarcinomas, experimental result (1990) (update of Vehicle: unchanged (no vehicle) and squamous cell carcinomas) Oldiges,1989) Exposure: max 18 months (22 h/d x Neoplastic effects observed in 7 d/wk; 40 h/wk x 6 months) any test group: yes A study was conducted to evaluate the carcinogenic potential of the test material in rats. Rats were exposed to the aerosols of the test material at 90, 270, 810 and 2430 µg Cd/m3 continuously for a maximum period of 18 months followed by a treatment-free observation for 29 - 31 months. Bodyweight, clinical signs, hematological and clinical chemistry examinations were performed throughout the study. Cadmium contents of lung, liver and kidneys were determined along with

Method Results Remarks Reference the histopathological examination of the lungs. Hamster and mouse (Syrian golden no NOAEL identified for 3 (not reliable) Heinrich U, Peters hamsters (Hoe: SYHK (SPF Ars) mouse or hamster. supporting study L, Ernst H, and NMRI Mice) male/female experimental result Rittinghausen S, 90, 270 and 1000 µg Cd/m3 Dasenbrock C and (nominal conc.) König H (1989) Vehicle: unchanged (no vehicle) Exposure: Up to 14 months (19 h or 8 h/d, 5 d/wk) A study was conducted to evaluate the possible carcinogenic effects of the test material in hamster and mouse. Animals were exposed to the test material aerosols at 90, 270 and 1000 µg Cd/m3 for 19 h or 8 h/d, 5 d/wk for up to 14 months. Distribution of Cd and histopathology of the lungs analysed. An unequivocal relationship between cadmium exposure and lung cancer incidence was demonstrated in chronic inhalation studies in Wistar rat exposed to CdCl2, CdO fumes and CdO dust. In certain studies, malignant lung tumours were produced by cadmium oxide dust and fumes at low levels of exposure for short duration (JRC, 2007). The lowest dose to produce carcinogenic effects was 30 µg Cd/m3 as cadmium oxide dust and fumes (Glaser et al., 1990). For cadmium chloride, the lowest dose to produce lung tumours in rats was 12.5 µg/m3 (Takenaka et al., 1983). In mice, some groups exposed to cadmium oxide fumes or dust had increased incidences of lung tumours, but the spontaneous rate of the tumours was high and variable. No increased incidence of lung tumours was seen in hamsters exposed to cadmium oxide fumes and dust. This may have been linked to lung damage and subsequent decreased survival at high doses. Some authors hypothesized that expression of metallothionein protein in the lung after inhalation of cadmium differs between species, therefore providing varying degrees of cadmium sequestration and protection from its carcinogenic effects (JRC, 2007).

5.8.1.3. Carcinogenicity: dermal No studies were located regarding carcinogenicity after dermal exposure to cadmium metal or cadmium compounds. However, toxicity via the dermal route is not expected to be significant as uptake of soluble and less-soluble cadmium compounds applied onto the skin of animals appears to be low (<1%) (see Section 5.1.1). Also in view of the risk reduction measures which need to be taken as a result of the carcinogenicity of cadmium metal and some of the cadmium compounds via the inhalatory route, dermal carcinogenicity is not likely to pose an issue for human health.

5.8.1.4. Carcinogenicity: other routes A number of experiments were conducted looking into the carcinogenic potential of various cadmium compounds when administered intrathoracically, intratracheally and subcutaneously (see following Table). Although these routes of exposure are not relevant for the present risk assessment, the studies are presented as supporting data.

Table 25. Overview of selected experimental studies on carcinogenicity (other routes) Method Results Remarks Reference Cadmium metal Rat (hooded) No NOAEL identified. 3 (not reliable) Heath JC and (intramuscular) (severe inflammation 3 days supporting study Daniels MR (1964) 14 or 28 mg Cd/rat after injection; tumours in all experimental result Vehicle: fowl serum but 3 rats, principally Exposure: Single rhabdomyosarcomata)

Neoplastic effects observed in any test group: yes Rat (Fischer 344) male/female no NOAEL identified. 3 (not reliable) Furst A, Cassetta (intrathoracic injection) supporting study DM and Sasmore 3 mg Cd/rat or 3 mg Cd + 6 mg Neoplastic effects observed in experimental result DP (1973) Zn/rat (nominal conc.) any test group: yes Vehicle: physiol. saline Exposure: 5 administrations, 1 per month A study was conducted to evaluate the carcinogenic potential of the test material in rats through intrathoracic administration. Rats were administered test material at a dose of 3 mg Cd or 3 mg Cd plus 6 mg Zn through intrathoracic injection, a total of 5 administrations once per month. The animals were observed for 10 months thereafter. Cadmium oxide Rat (Fischer 344) male no NOAEL identified. 3 (not reliable) Sanders CL and (intratracheal) supporting study Mahaffey JA (1984) 25 µg CdO (nominal conc.) Neoplastic effects observed in experimental result Vehicle: physiol. saline any test group: yes Exposure: 30 days interval for all three groups. Group 1 = single exposure, Group 2 = two times exposure and Group 3 = thrice) A study was conducted to evaluate the carcinogenic effect of single or multiple intrathoracic administrations of the test material in rats. Animals were divided in 4 groups: a control group and three groups with one, two or three instillations of 25 µg CdO, respectively, at an interval of 30 d. Animals were observed for up to 880 days and all were examined histologically. Rat (Wistar) male/female no NOAEL identified. 3 (not reliable) Kazantzis G and (subcutaneous) supporting study Hanbury WJ (1966) 25 µg CdO (nominal conc.) Neoplastic effects observed in experimental result Vehicle: physiol. saline any test group: yes Exposure: single

Method Results Remarks Reference This study was conducted to examine the carcinogenic potential of the test material in rats, when administered via the subcutaneous route. Rats were administered a single subcutaneous dose of the test material and thereafter observed for a period of one year. Rat (Fischer 344) male no NOAEL identified. 3 (not reliable) Pott F, Ziem U, (intraperitoneal) (peritoneal cavity tumours) supporting study Reiffer FJ, Huth F, 25 µg CdO in saline experimental result Ernst H and Mohr U (1987) Cadmium sulphide Rat (Wistar) male/female no NOAEL identified. 3 (not reliable) Kazantzis G and (subcutaneous) supporting study Hanbury WJ (1966) 25 µg CdS in 0.25 ml saline Neoplastic effects observed in experimental result (nominal conc. (subcutaneous any test group: yes injection)); 50 µg CdS in 0.50 ml saline (nominal conc. (intramuscular injection)) Vehicle: physiol. saline Exposure: single This study was conducted to examine the carcinogenic potential of the test material in rats, when administered through the subcutaneous and intramuscular routes. Rats were administered a single subcutaneous/intramuscular dose of the test material and thereafter observed for a period of one year. Cadmium metal powder produced local sarcomas in rats following intramuscular administration, including some fibrosarcomas which metastasised (Heath and Daniels, 1964). An inthratoracic injection of cadmium metal associated with zinc metal induced pleural cavity tumours (Furst et al., 1973). An intraperitoneal injection of cadmium oxide induced peritoneal cavity tumours (Pott et al., 1987). Single or multiple subcutaneous injections of cadmium oxide or sulphide were observed to cause local sarcomas in rat (Kazantzis and Hanbury, 1966). 5.8.2. Human information Food-borne cadmium is the major source of exposure for most of the non-smoking general population. Occupational exposure to cadmium is mainly by inhalation but includes additional intakes through food and tobacco. A review of cadmium carcinogenicity to humans has been conducted in the EU Risk Assessment Report (RAR) (JRC, 2007). Selected exposure-related observations in humans are summarised by cadmium compound in the following table, then commented according to the type of population considered.

Table 26. Overview of selected exposure-related observations on carcinogenicity in humans Method Results Remarks Reference Cadmium metal Study type: cohort study Prostate cancer (o/e): 4/3.09 1 (reliable Andersson K, (prospective) SMR (95% CI) prostate: 130 without Elinder C, Hogstedt Type of population: occupational Lung cancer (o/e): 6/5.03 restriction) C, Kjellström T and HYPOTHESIS TESTED (if cohort or SMR (95% CI) lung: 119 key study Spang G (1984) case control study): Cancer mortality →non-significant increase in among cadmium-nickel exposed deaths due to prostate and lung workers cancer STUDY PERIOD: 1951-1980 STUDY POPULATION - E: 528 (M only) - S: “at least one year of cadmium exposure” Exposure to Cd, Ni Study type: cohort study Prostate cancer (o/e): 4/1.15 2 (reliable with Lemen R, Lee JS, (prospective) SMR (95% CI) prostate: 348 (94- restrictions) Wagoner JK and Type of population: occupational 891) key study Blejer HP (1976) HYPOTHESIS TESTED (if cohort or Lung cancer (o/e) : 12/5.11 case control study): Cancer mortality SMR (95% CI) lung: 235 (121- among cadmium production workers 410)* STUDY PERIOD: 1940-1973 *p<0.05 STUDY POPULATION: → Significantly increased risk - E: 292 ( white M only) for lung cancer - S: “who had achieved 2 years of employment between 01.01.1940 and 31.12.1969” - Lost cases: 20 Exposure to Cd fumes & dust Cadmium hydroxide Study type: cohort study -overall: 1 (reliable Sorahan T and (prospective) prostate cancer (o/e) : 9/7.5 without Esmen NA (2004) Type of population: occupational SMR (95% CI) prostate: 116 (53- restriction) HYPOTHESIS TESTED (if cohort or 221) key study case control study): Association Lung cancer (o/e) : 45/40.7 between the risk of dying from lung SMR (95% CI) lung: 111(81-148) cancer and occupational cadmium → Non significantly increases in exposure lung/ prostate cancer deaths STUDY PERIOD: 1947-2000 STUDY POPULATION E: 926 (M) S: “workers first employed in the period 1947-1975 and having min of 12 months of employment at the factory” Lost cases: 26 emigrated, 4 untraced Exposure to Cd(OH)2, nickel hydroxide, cobalt, graphite, iron oxide, potassium hydroxide Study type: cohort study -Overall: 1 (reliable Sorahan T and (prospective) Prostate cancer (o/e): 8/6.6 without Waterhouse JA Type of population: occupational SMR (95% CI) prostate: 121 (52- restriction) (1983) HYPOTHESIS TESTED (if cohort or 239) key study

Method Results Remarks Reference case control study): Association Lung cancer (o/e) : 89/70.2 between the risk of dying from SMR (95% CI) lung: 127 cancer and occupational cadmium → Significant increase in cancer exposure of the respiratory tract STUDY POPULATION E: 3025 (2559 men) S: “had a minimum period of employment of one month between 1923 and 1975” Exposure to CdO, Cd(OH)2 dust, nickel hydroxide, oxyacetylene fumes Study type: cohort study -Overall: 1 (reliable Sorahan T (1987) (prospective) Lung cancer (o/e) : 110/84.5 without Type of population: occupational SMR (95% CI) lung: 130 (107- restriction) HYPOTHESIS TESTED (if cohort or 157) key study case control study): Association → Increase in lung cancer between the risk of dying from lung deaths among workers with the cancer and occupational cadmium highest exposure first employed exposure between 1926 and 1946 STUDY PERIOD: 1946-1984 STUDY POPULATION E: 3025 (2559 men) S: “minimum period of employment of 1 month who started employment between 1923 and 1975” Lost cases: 78 Exposure to CdO, Cd(OH)2 dust, nickel hydroxide Cadmium oxide Study type: cohort study -Overall: 1 (reliable Armstrong BG and (retrospective) Prostate cancer (o/e): 23/23.3 without Kazantzis G. (1983) Type of population: occupational SMR (95% CI) prostate: 99 (63- restriction) HYPOTHESIS TESTED (if cohort or 148) key study case control study): Association Lung cancer (o/e) : 199/185.6 between the risk of cancer and SMR (95% CI) lung: 107 (92-122) occupational cadmium exposure -ever high (N=3%): STUDY POPULATION Prostate cancer (o/e): 0/0.4 E: 6995 (M only) SMR (95% CI) prostate: 0 (0-962) S: "exposed for more than 1 year Lung cancer (o/e) : 5/4.4 between 1942 and 1970" SMR (95% CI) lung: 113 (37-263) Lost cases: 90 -ever medium (N=17%): Exposure to CdO dust & fumes, CdS, Prostate cancer (o/e): 0/2.5 dust from Cd stabilisers, silver, SMR (95% CI) prostate: 0 (0-147) copper + beryllium, nickel, Lung cancer (o/e) : 27/24.2 mineral oils, arsenic, lead SMR (95% CI) lung: 112 (74-163) -always low (N=80%): Prostate cancer (o/e): 23/20.4 SMR (95% CI) prostate: 113(72- 170) Lung cancer (o/e) : 167/157.0 SMR (95% CI) lung: 106 (90-123) → No statistically significant excess of lung/prostate cancer Study type: cohort study -all workers: 1 (reliable Elinder CG, (prospective) Prostate cancer (o/e): 4/3.7 without Kjellström T, Type of population: occupational SMR (95% CI) prostate: 108 (29- restriction) Hogstedt C, HYPOTHESIS TESTED (if cohort or 277) key study Andersson K and

Method Results Remarks Reference case control study): Association Lung cancer (o/e): 8/6.01 Spang G (1985) between the risk of cancer and SMR (95% CI) lung: 133 (57-262) occupational cadmium exposure - ≥ 5 years of exposure, 20 years STUDY POPULATION latency E: 522 (M only) Prostate cancer (o/e): 4/N.I. S: “exposed to cadmium for at least SMR (95% CI) prostate: 148/N.I. one year” Lung cancer (o/e): 7/4.0 Lost cases: 3 (+ 17 emigrated) SMR (95% CI) lung: 175(70-361) Exposure to CdO dust, nickel - ≥ 5 years of exposure, 10 years hydroxide, asbestos latency Prostate cancer (o/e): 4/N.I. SMR (95% CI) prostate: 125/N.I. Lung cancer (o/e): 8/N.I. SMR (95% CI) lung: 163/N.I. → Lung, prostate cancer: SMR was increased but did not reach statistical significance, even in the high exposure group (20 years latency, at last 5 years of exposure) Study type: cohort study Prostate cancer (o/e): 1/1.58 2 (reliable with Holden H (1980a) (prospective) SMR (95% CI) prostate: 63 (1- restrictions) Type of population: occupational 352) key study HYPOTHESIS TESTED (if cohort or Lung cancer (o/e) : 10/12.35 case control study): Association SMR (95% CI) lung: 81 (N.I.) between the risk of cancer and -> Mortality slightly increased occupational cadmium exposure from respiratory disease in STUDY POPULATION workers exposed to cadmium; E: 347 (M only) statistically significant positive D: “who had been employed for at association with prostate cancer least 12 months between 1922 and 1978” Lost cases: E: 13 (+ 4 emigrated) Exposure to CdO fumes, copper Study type: cohort study cadmium workers: 2 (reliable with Holden H (1980b) (prospective) Prostate cancer (o/e): 1/1.58 restrictions) Type of population: occupational SMR (95% CI) prostate: 63 (1- key study HYPOTHESIS TESTED (if cohort or 352) case control study): Association Lung cancer (o/e) : 10/13.14 between the risk of cancer and SMR (95% CI) lung: 76 (N.I.) occupational cadmium exposure Vicinity workers: STUDY POPULATION Prostate cancer (o/e): 8/3.0 E: 347 (M only) SMR (95% CI) prostate: 267 (115- S: ”who had been employed for at 526) least 12 months between 1922 and Lung cancer (o/e) : 36/26.08 1978” + 624 vicinity workers (M SMR (95% CI) lung: 138 (97-191) only) -> Mortality slightly increased Lost cases: 25 (+ 27 emigrated) from respiratory disease in Exposure to CdO fumes, copper workers exposed to cadmium; vicinity workers: arsenical copper, statistically significant positive silver, nickel association with prostate cancer

Study type: cohort study total (male only): 1 (reliable Järup L, Bellander (prospective) Prostate cancer (o/e): 11/9 without T, Hogstedt C and Type of population: occupational SMR (95% CI) prostate: 122 restriction) Spang G (1998) HYPOTHESIS TESTED (if cohort or (61.1-219) key study case control study): Association Lung cancer (o/e): 16/9.1

Method Results Remarks Reference between the risk of cancer and SMR (95% CI) lung: 176 (101- occupational cadmium exposure 287) STUDY POPULATION → Significant increase in lung E: 869 (M and F) cancer mortality, however no S: "employed at least one year relationship between cumulative between 1940 and 1980" cadmium exposure and lung Lost cases: 31 cancer deaths Exposure to CdO dust, nickel hydroxide Study type: cohort study -Overall: 1 (reliable Kazantzis G, (prospective) Prostate cancer (o/e): 37/49.5 without Blanks R and Type of population: occupational SMR (95% CI) prostate: 75 (53- restriction) Sullivan K (1992); HYPOTHESIS TESTED (if cohort or 103) key study Kazantzis G and case control study): Association Lung cancer (o/e) : 339/304.1 Blanks R (1992) between the risk of cancer and SMR (95% CI) lung: 112 (100- occupational cadmium exposure 124) STUDY POPULATION -ever high (N=3%): E: 6910 (M only) Prostate cancer (o/e): 1/1.0 S: "exposed for more than 1 year SMR (95% CI) prostate: 97 (1- between 1942 and 1970" 540) Exposure to CdO dust and fumes, Lung cancer (o/e) : 14/8.6 CdS, dust from Cd stabilisers, silver, SMR (95% CI) lung: 162 (89-273) copper + beryllium, nickel, mineral -ever medium (N=17%): oils, arsenic, lead Prostate cancer (o/e): 0/6.2 SMR (95% CI) prostate: 0 (0-59) Lung cancer (o/e) : 55/45.6 SMR (95% CI) lung: 121 (91-157) -always low (N=80%): Prostate cancer (o/e): 36/42.3 SMR (95% CI) prostate: 85 (60- 118) Lung cancer (o/e) : 270/249.9 SMR (95% CI) lung: 108 (96-122) → Absence of an increased risk from prostate cancer → Significant excess mortality for lung cancer Study type: cohort study -Overall: 1 (reliable Kazantzis G, Lam (retrospective) Prostate cancer (o/e): 30/33.2 without TH and Sullivan Type of population: occupational SMR (95% CI) prostate: 90 (61- restriction) KR (1988) HYPOTHESIS TESTED (if cohort or 129) key study case control study): Association Lung cancer (o/e) : 277/240.9 between the risk of cancer and SMR (95% CI) lung: 115 (101- occupational cadmium exposure 129) STUDY POPULATION -ever high (N=3%): E: 6958 (M only) Prostate cancer (o/e): 0/0.6 S: "exposed for more than 1 year SMR (95% CI) prostate: 0 (0-615) between 1942 and 1970" Lung cancer (o/e) : 12/6.2 Lost cases: 67 + 184 emigrated SMR (95% CI) lung: 194 (100- Exposure to CdO dust & fumes, CdS, 339) dust from Cd stabilisers, silver, -ever medium (N=17%): copper + beryllium, nickel, mineral Prostate cancer (o/e): 0/4.0 oils, arsenic, lead SMR (95% CI) prostate: 0 (0-92) Lung cancer (o/e) : 41/34.0 SMR (95% CI) lung: 121 (84-158) -always low (N=80%): Prostate cancer (o/e): 30/28.6

Method Results Remarks Reference SMR (95% CI) prostate: 105 (71- 150) Lung cancer (o/e) : 224/200.7 SMR (95% CI) lung: 112 (97-126) → No excess risk from prostate cancer → Significant increase in lung cancer deaths in the cohort as a whole and also in the high exposure group Study type: cohort study -Overall: 2 (reliable with Kipling MD and (prospective) Prostate cancer (o/e): 4/0.58 restrictions) Waterhouse JAH Type of population: occupational SMR (95% CI) prostate: 690 (186- key study (1967) Subjects: E: 248 (M only) 1766) (SIR) S: “at least one year of exposure” Lung cancer (o/e) : 5/4.4 Lost cases: N.I. SMR (95% CI) lung: 114 (0.37- Exposure to CdO dust 265) (SIR) → Indication of elevation of prostate cancer: 4 fatalities Study type: cohort study Prostate cancer (o/e): 4/2.69 1 (reliable Kjellström T, (prospective) SMR (95% CI) prostate: 149 (40- without Friberg L and Type of population: occupational 381) restriction) Rahnster B (1979) HYPOTHESIS TESTED (if cohort or → Mortality from prostate key study case control study): Association cancer was above the expected between the risk of cancer and from national rates occupational cadmium exposure STUDY POPULATION E: 94 S: “all workers with a 5 years or longer exposure to cadmium since the factory started (1930’s)” Exposure to CdO fumes Study type: cohort study -Overall: 2 (reliable with Potts CL (1965) (prospective) Prostate cancer (o/e): 3/N.I. restrictions) Type of population: occupational SMR (95% CI) prostate: N.I. key study HYPOTHESIS TESTED (if cohort or Lung cancer (o/e) : 1/N.I. case control study): Association SMR (95% CI) lung: N.I. between the risk of dying from → Indication of elevation of cancer and occupational cadmium prostate cancer: 3 fatalities exposure STUDY POPULATION E: 74 S: “at least ten years of exposure” Exposure to CdO dust Study type: cohort study Lung cancer (o/e) : 1 (reliable Sorahan T and (retrospective) < 400 mg Cd.d/m³: 6/N.I. without Lancashire R Type of population: occupational 400 – 999 mg Cd.d/m³: 6/N.I. restriction) (1997) Subjects: 1,000- 1,999 mg Cd.d/m³: 4/N.I. key study E: 571 (M only) ≥ 2,000 mg Cd.d/m³: 5/N.I. S: ”employed for at least 6 months as SMR (95% CI) lung: plant production workers between < 400 mg Cd.d/m³: 100 1940 and 1969 and first employed 400 – 999 mg Cd.d/m³: 225 (72- after 1.1.1926” 702) Exposure to CdO fumes & dust, 1,000- 1,999 mg Cd.d/m³: 341 (66- CdSO4, CdS, arsenic 872) ≥ 2,000 mg Cd.d/m³: 413 (121- 1403)*

Method Results Remarks Reference trend: 156 (1.06-2.28)* *p<0.05 → Significant positive trend between cumulative exposure to cadmium and risks of mortality from lung cancer only in the presence of concomitant exposure to As Study type: cohort study - Overall: 1 (reliable Sorahan T and (prospective) Prostate cancer (o/e): 8/6.6 without Waterhouse JA Type of population: occupational SMR (95% CI) prostate: 121 (52- restriction) (1983) HYPOTHESIS TESTED (if cohort or 239) key study case control study): Association Lung cancer (o/e) : 89/70.2 between the risk of dying from SMR (95% CI) lung: 127 cancer and occupational cadmium → Significant increase in cancer exposure of the respiratory tract STUDY POPULATION E: 3025 (2559 men) S: “had a minimum period of employment of one month between 1923 and 1975” Exposure to CdO, Cd(OH)2 dust, nickel hydroxide, oxyacetylene fumes Study type: cohort study cadmium workers: 1 (reliable Sorahan T, Lister (prospective) Prostate cancer (o/e): 2/2.83 without A, Gilthorpe MS Type of population: occupational SMR (95% CI) prostate: 71 (9- restriction) and Harrington JM HYPOTHESIS TESTED (if cohort or 255) key study (1995) case control study): Association Lung cancer (o/e) : 18/17.8 between the risk of cancer and SMR (95% CI) lung: 101 (60-159) occupational cadmium exposure Vicinity workers: STUDY POPULATION Prostate cancer (o/e): N.I. E: 347 (M only) SMR (95% CI) prostate: N.I. S: “who had been employed for at Lung cancer (o/e) : 55/34.3 least 12 months between 1922 and SMR (95% CI) lung: 160 (N.I.) 1978” + 624 vicinity workers (M Iron and brass foundry workers: only) Prostate cancer (o/e): N.I. Lost cases: 26 (+ 27 emigrated) SMR (95% CI) prostate: N.I. Exposure to CdO fumes, copper Lung cancer (o/e) : 19/17.8 vicinity workers: arsenical copper, SMR (95% CI) lung: 107(N.I.) phosphor bronze, other copper alloys → No significant increases in lung cancer deaths Study type: cohort study -Overall: 1 (reliable Sorahan T (1987) (prospective) Lung cancer (o/e) : 110/84.5 without Type of population: occupational SMR (95% CI) lung: 130 (107- restriction) HYPOTHESIS TESTED (if cohort or 157) key study case control study): Association → Increase in lung cancer between the risk of dying from lung deaths among workers with the cancer and occupational cadmium highest exposure first employed exposure between 1926 and 1946 STUDY PERIOD: 1946-1984 STUDY POPULATION E: 3025 (2559 men) S: ”minimum period of employment of 1 month who started employment between 1923 and 1975” Lost cases: 78 Exposure to CdO, Cd(OH)2 dust,

Method Results Remarks Reference nickel hydroxide Study type: cohort study Lung cancer (o/e) : 2 (reliable with Stayner L, Smith R, (prospective) Overall: 24/16.07 restrictions) Thun M, Schnorr T Type of population: occupational ≤584 mg Cd.d/m³: 2/5.73 key study and Lemen R HYPOTHESIS TESTED (if cohort or 585-2,920 mg Cd.d/m³: 7/4.28 (1992) case control study): Association 1,461-2,920: 6/2.75 between the risk of cancer and ≥ 2,921 mg Cd.d/m³: 9/3.30 occupational cadmium exposure SMR (95% CI) lung: STUDY POPULATION Overall: 149 (95-222) E: 606 (white M only) ≤584 mg Cd.d/m³: 34 S: “all hourly employees and 585-2,920 mg Cd.d/m³: 163 foremen who had worked for at least 1,461-2,920: 217 6 months in a production area of the ≥ 2,921 mg Cd.d/m³: 272 (123- facility between 01.01.1940 and 513)* 31.12.1969…and first employed at p<0.05 the facility on or after 1.1.1926” →Significant dose response Lost cases: 12 relationship for lung cancer Exposure to CdO fumes & dust, CdSO4, CdS, arsenic Study type: cohort study Prostate cancer (o/e): 2 (reliable with Thun MJ, Schnorr (prospective) Overall: 3/2.2 restrictions) TM, Blair SA, Type of population: occupational SMR (95% CI) prostate: key study Halperin W and Subjects: E: 602 (white M only) Overall: 136 Lemen RA (1985) S: ”who had worked more than 6 Lung cancer (o/e) : months between 01.01.1940 and Overall: 20/12.15 31.12.1969” Hired before 1926: 4/0.56 Lost cases: 12 Hired on or after 01.1926: Exposure to CdO fumes & dust, ≤584 mg Cd.d/m³: 2/N.I. CdSO4, CdS, arsenic 585-2,920 mg Cd.d/m³: 7/N.I. ≥ 2,921 mg Cd.d/m³: 7/N.I. SMR (95% CI) lung: Overall: 165 (101-254)* Hired before 1926: Hired on or after 01.1926: ≤584 mg Cd.d/m³: 53 585-2,920 mg Cd.d/m³: 152 ≥ 2,921 mg Cd.d/m³: 280 (113- 577)* *p<0.05 → Dose response relationship between lung mortality and cumulative exposure to cadmium Cadmium sulphate Study type: cohort study Lung cancer (o/e) : 1 (reliable Sorahan T and (retrospective) < 400 mg Cd.d/m³: 6/N.I. without Lancashire R Type of population: occupational 400 – 999 mg Cd.d/m³: 6/N.I. restriction) (1997) HYPOTHESIS TESTED (if cohort or 1,000- 1,999 mg Cd.d/m³: 4/N.I. key study case control study): Association ≥ 2,000 mg Cd.d/m³: 5/N.I. between the risk of cancer and SMR (95% CI) lung: occupational cadmium exposure < 400 mg Cd.d/m³: 100 STUDY POPULATION 400 – 999 mg Cd.d/m³: 225 (72- E: 571 (M only) 702) S: ”employed for at least 6 months 1,000- 1,999 mg Cd.d/m³: 341 (66- between 1940 and 1969 and first 872) employed after 1.1.1926” ≥ 2,000 mg Cd.d/m³: 413 (121- Exposure to CdO fumes & dust, 1403)* CdSO4, CdS, arsenic trend: 156 (1.06-2.28)*

Method Results Remarks Reference *p<0.05 → Significant positive trend between cumulative exposure to cadmium and risks of mortality from lung cancer only in the presence of concomitant exposure to As Study type: cohort study Lung cancer (o/e) : 2 (reliable with Stayner L, Smith R, (prospective) Overall: 24/16.07 restrictions) Thun M, Schnorr T Type of population: occupational ≤584 mg Cd.d/m³: 2/5.73 key study and Lemen R HYPOTHESIS TESTED (if cohort or 585-2,920 mg Cd.d/m³: 7/4.28 (1992) case control study): Association 1,461-2,920: 6/2.75 between the risk of cancer and ≥ 2,921 mg Cd.d/m³: 9/3.30 occupational cadmium exposure SMR (95% CI) lung: STUDY POPULATION Overall: 149 (95-222) E: 606 (white M only) ≤584 mg Cd.d/m³: 34 S: “all hourly employees and 585-2,920 mg Cd.d/m³: 163 foremen who had worked for at least 1,461-2,920: 217 6 months in a production area of the ≥ 2,921 mg Cd.d/m³: 272 (123- facility between 01.01.1940 and 513)* 31.12.1969…and first employed at p<0.05 the facility on or after 1.1.1926” →Significant dose response Lost cases: 12 relationship for lung cancer Exposure to CdO fumes & dust, CdSO4, CdS, arsenic Study type: cohort study Prostate cancer (o/e): 2 (reliable with Thun MJ, Schnorr (prospective) Overall: 3/2.2 restrictions) TM, Blair SA, Type of population: occupational SMR (95% CI) prostate: key study Halperin W and Subjects: E: 602 (white M only) Overall: 136 Lemen RA (1985) S: ”who had worked more than 6 Lung cancer (o/e) : months between 01.01.1940 and Overall: 20/12.15 31.12.1969” Hired before 1926: 4/0.56 Lost cases: 12 Hired on or after 01.1926: Exposure to CdO fumes & dust, ≤584 mg Cd.d/m³: 2/N.I. CdSO4, CdS, arsenic 585-2,920 mg Cd.d/m³: 7/N.I. ≥ 2,921 mg Cd.d/m³: 7/N.I. SMR (95% CI) lung: Overall: 165 (101-254)* Hired before 1926: Hired on or after 01.1926: ≤584 mg Cd.d/m³: 53 585-2,920 mg Cd.d/m³: 152 ≥ 2,921 mg Cd.d/m³: 280 (113- 577)* *p<0.05 → Dose response relationship between lung mortality and cumulative exposure to cadmium Cadmium sulphide Study type: cohort study -Overall: 1 (reliable Armstrong BG and (prospective) Prostate cancer (o/e): 23/23.3 without Kazantzis G (1983) Type of population: occupational SMR (95% CI) prostate: 99 (63- restriction) HYPOTHESIS TESTED (if cohort or 148) key study case control study): Association Lung cancer (o/e) : 199/185.6 between the risk of cancer and SMR (95% CI) lung: 107 (92-122) occupational cadmium exposure -ever high (N=3%): STUDY POPULATION Prostate cancer (o/e): 0/0.4

Method Results Remarks Reference E: 6995 (M only) SMR (95% CI) prostate: 0 (0-962) S: "exposed for more than 1 year Lung cancer (o/e) : 5/4.4 between 1942 and 1970" SMR (95% CI) lung: 113 (37-263) Lost cases: 90 -ever medium (N=17%): Exposure to CdO dust & fumes, CdS, Prostate cancer (o/e): 0/2.5 dust from Cd stabilisers, silver, SMR (95% CI) prostate: 0 (0-147) copper + beryllium, nickel, Lung cancer (o/e) : 27/24.2 mineral oils, arsenic, lead SMR (95% CI) lung: 112 (74-163) -always low (N=80%): Prostate cancer (o/e): 23/20.4 SMR (95% CI) prostate: 113(72- 170) Lung cancer (o/e) : 167/157.0 SMR (95% CI) lung: 106 (90-123) → No statistically significant excess of lung/prostate cancer Study type: cohort study -Overall: 1 (reliable Kazantzis G, (prospective) Prostate cancer (o/e): 37/49.5 without Blanks R and Type of population: occupational SMR (95% CI) prostate: 75 (53- restriction) Sullivan K (1992); HYPOTHESIS TESTED (if cohort or 103) key study Kazantzis G and case control study): Association Lung cancer (o/e) : 339/304.1 Blanks R (1992) between the risk of cancer and SMR (95% CI) lung: 112 (100- occupational cadmium exposure 124) STUDY POPULATION -ever high (N=3%): E: 6910 (M only) Prostate cancer (o/e): 1/1.0 S: "exposed for more than 1 year SMR (95% CI) prostate: 97 (1- between 1942 and 1970" 540) Exposure to CdO dust and fumes, Lung cancer (o/e) : 14/8.6 CdS, dust from Cd stabilisers, silver, SMR (95% CI) lung: 162 (89-273) copper + beryllium, nickel, mineral -ever medium (N=17%): oils, arsenic, lead Prostate cancer (o/e): 0/6.2 SMR (95% CI) prostate: 0 (0-59) Lung cancer (o/e) : 55/45.6 SMR (95% CI) lung: 121 (91-157) -always low (N=80%): Prostate cancer (o/e): 36/42.3 SMR (95% CI) prostate: 85 (60- 118) Lung cancer (o/e) : 270/249.9 SMR (95% CI) lung: 108 (96-122) → Absence of an increased risk from prostate cancer → Significant excess mortality for lung cancer Study type: cohort study -Overall: 1 (reliable Kazantzis G, Lam (prospective) Prostate cancer (o/e): 30/33.2 without TH and Sullivan Type of population: occupational SMR (95% CI) prostate: 90 (61- restriction) KR (1988) HYPOTHESIS TESTED (if cohort or 129) key study case control study): Association Lung cancer (o/e) : 277/240.9 between the risk of cancer and SMR (95% CI) lung: 115 (101- occupational cadmium exposure 129) STUDY POPULATION -ever high (N=3%): E: 6958 (M only) Prostate cancer (o/e): 0/0.6 S: "exposed for more than 1 year SMR (95% CI) prostate: 0 (0-615)

Method Results Remarks Reference between 1942 and 1970" Lung cancer (o/e) : 12/6.2 Lost cases: 67 + 184 emigrated SMR (95% CI) lung: 194 (100- Exposure to CdO dust & fumes, CdS, 339) dust from Cd stabilisers, silver, -ever medium (N=17%): copper + beryllium, nickel, mineral Prostate cancer (o/e): 0/4.0 oils, arsenic, lead SMR (95% CI) prostate: 0 (0-92) Lung cancer (o/e) : 41/34.0 SMR (95% CI) lung: 121 (84-158) -always low (N=80%): Prostate cancer (o/e): 30/28.6 SMR (95% CI) prostate: 105 (71- 150) Lung cancer (o/e) : 224/200.7 SMR (95% CI) lung: 112 (97-126) → No excess risk from prostate cancer → Significant increase in lung cancer deaths in the cohort as a whole and also in the high exposure group Study type: cohort study Lung cancer (o/e) : 1 (reliable Sorahan T and (prospective) < 400 mg Cd.d/m³: 6/N.I. without Lancashire R Type of population: occupational 400 – 999 mg Cd.d/m³: 6/N.I. restriction) (1997) HYPOTHESIS TESTED (if cohort or 1,000- 1,999 mg Cd.d/m³: 4/N.I. key study case control study): Association ≥ 2,000 mg Cd.d/m³: 5/N.I. between the risk of cancer and SMR (95% CI) lung: occupational cadmium exposure < 400 mg Cd.d/m³: 100 STUDY POPULATION 400 – 999 mg Cd.d/m³: 225 (72- E: 571 (M only) 702) S: ”employed for at least 6 months 1,000- 1,999 mg Cd.d/m³: 341 (66- between 1940 and 1969 and first 872) employed after 1.1.1926” ≥ 2,000 mg Cd.d/m³: 413 (121- Exposure to CdO fumes & dust, 1403)* CdSO4, CdS, arsenic trend: 156( 1.06-2.28)* *p<0.05 → Significant positive trend between cumulative exposure to cadmium and risks of mortality from lung cancer only in the presence of concomitant exposure to As Study type: cohort study Lung cancer (o/e) : 2 (reliable with Stayner L, Smith R, (prospective) Overall: 24/16.07 restrictions) Thun M, Schnorr T Type of population: occupational ≤584 mg Cd.d/m³: 2/5.73 key study and Lemen R HYPOTHESIS TESTED (if cohort or 585-2,920 mg Cd.d/m³: 7/4.28 (1992) case control study): Association 1,461-2,920: 6/2.75 between the risk of cancer and ≥ 2,921 mg Cd.d/m³: 9/3.30 occupational cadmium exposure SMR (95% CI) lung: STUDY PERIOD: 1940-1984 Overall: 149 (95-222) STUDY POPULATIONE: 606 ≤584 mg Cd.d/m³: 34 (white M only) 585-2,920 mg Cd.d/m³: 163 S: “all hourly employees and 1,461-2,920: 217

Method Results Remarks Reference foremen who had worked for at least ≥ 2,921 mg Cd.d/m³: 272 (123- 6 months in a production area of the 513)* facility between 01.01.1940 and p<0.05 31.12.1969…and first employed at →Significant dose response the facility on or after 1.1.1926” relationship for lung cancer Lost cases: 12 Exposure to CdO fumes & dust, CdSO4, CdS, arsenic Study type: cohort study Prostate cancer (o/e): 2 (reliable with Thun MJ, Schnorr (prospective) Overall: 3/2.2 restrictions) TM, Blair SA, Type of population: occupational SMR (95% CI) prostate: key study Halperin W and HYPOTHESIS TESTED (if cohort or Overall: 136 Lemen RA (1985) case control study): Association Lung cancer (o/e) : between the risk of cancer and Overall: 20/12.15 occupational cadmium exposure Hired before 1926: 4/0.56 STUDY PERIOD: 1940-1978 Hired on or after 01.1926: STUDY POPULATION ≤584 mg Cd.d/m³: 2/N.I. E: 602 (white M only) 585-2,920 mg Cd.d/m³: 7/N.I. S: ”who had worked more than 6 ≥ 2,921 mg Cd.d/m³: 7/N.I. months between 01.01.1940 and SMR (95% CI) lung: 31.12.1969” Overall: 165 (101-254)* Lost cases: 12 Hired before 1926: Exposure to CdO fumes & dust, Hired on or after 01.1926: CdSO4, CdS, arsenic ≤584 mg Cd.d/m³: 53 585-2,920 mg Cd.d/m³: 152 ≥ 2,921 mg Cd.d/m³: 280 (113- 577)* *p<0.05 → Dose response relationship between lung mortality and cumulative exposure to cadmium General population (oral route) Information on the oral carcinogenic potential of cadmium may be derived from: 1) mortality studies in populations considered to be exposed to high concentrations of cadmium, and 2) the comparison of cadmium values measured in the tissue of healthy subjects with those obtained in tumour tissue of cancer patients (JRC, 2007). Available epidemiological studies do not report reliable estimates of individual dose and therefore have limited sensitivity to detect a possible carcinogenic effect. Classification of exposure and selection of appropriate control groups are two methodological problems encountered after analysis of these studies. Elevated cadmium levels were found in malignant prostate tissue of cancer patients compared to healthy subjects. Other authors have reported elevated levels of cadmium in other neoplastic tissues but differences with healthy subjects failed to reach statistical significance or were attributed to other factors, e.g. smoking. A prospective study conducted in a region of Belgium with historical industrial pollution by heavy metals found an excess of lung cancer cases. The risk of lung cancer was positively associated with Cd-U measured during the Cadmibel study (1985-89), suggesting a possible impact of inhalation exposure to Cd, but the role of other associated pollutants cannot be excluded (Nawrot et al., 2006). A statistically significant association between dietary cadmium intake (calculated from a food frequency questionnaire) and the risk of endometrial cancer has been reported in a cohort of post-menopausal women in Sweden followed during 16.0 years (484,274 person-years) (Akesson et al., 2008). Overall, there is currently no conclusive evidence that cadmium acts as a carcinogen following oral exposure (JRC, 2007). Workers (inhalation route) The concern that cadmium might cause cancer in humans was raised in the 1960s, before any experimental evidence of carcinogenicity in laboratory animals was available. The first suspicion started with four men who had worked in a factory of cadmium-nickel battery in UK who were reported to have died from prostate cancer although, compared to national rates, less than one case would have been expected (Potts, 1965). Subsequently, three additional studies conducted in small cohorts of workers employed in the production of batteries (Kipling et al., 1967), alloys (Kjellström et al., 1979) and cadmium metal (Lemen et al., 1976) reported an association

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 89 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 between Cd exposure and an increased mortality from prostate cancer. However, later studies (Sorahan et al., 1983; Thun et al., 1985; Kazantzis et al., 1988) failed to confirm this hypothesis. In humans, a statistically significant increase in mortality from lung cancer has initially been reported in studies involving cadmium recovery (Lemen et al., 1976; Thun et al., 1985), nickel cadmium battery (Sorahan, 1987) and cadmium processing workers (Ades et al., 1988; Kazantzis et al., 1992). Based on these studies, IARC (1993) concluded that there was sufficient evidence to classify cadmium and its compounds as human carcinogens (category 1). However, the epidemiological data that have been used to support this classification have been criticised because of the lack of control for confounding exposures (mainly arsenic) and smoking habits. Studies conducted after this IARC evaluation, have tried to address these difficulties. In particular, the dose-response relationship between Cd exposure and lung cancer mortality rates, previously reported by Thun et al. (1985) and Stayner et al. (1992), has not been confirmed with a refined exposure assessment methodology. A significant positive trend between cumulative exposure to cadmium and mortality from lung cancer was found after adjustment for age, year of hiring and ethnicity but only in the presence of concomitant exposure to arsenic (Sorahan et al., 1997). In two recent cohorts of workers from a nickel-cadmium battery plant (where arsenic is not a confounder), a globally increased mortality from lung cancer was observed but the dose-response relationships were not consistent with a causal role of cadmium (Järup et al., 1998; Sorahan et al., 2004). In the latter cohort, 926 male workers from a nickel-cadmium battery factory were followed up for a very long period of time (1947- 2000). Significantly increased mortality was obtained for pharynx cancer, diseases of respiratory system and diseases of genitourinary system. For lung cancer, the mortality was modestly increased and without any definite pattern or trend by time variables and cumulative exposure to cadmium. Interestingly, indications exist in this cohort of increased risks from other known adverse effects associated with exposure to cadmium compounds, specifically, a significantly increased mortality (although without dose-response trend) from non- malignant respiratory diseases, and an increase of diseases of the genitourinary system possibly reflecting late effects of kidney toxicity. If this were true, it could be assumed that measures protecting against renal/respiratory effects should also be protective against lung cancer risk. In a cohort of copper-cadmium alloy workers for whom individual cumulative exposure indexes were estimated, a non significant, negative trend between cumulative cadmium exposure and risks of lung cancer was reported. The dose-response trend was, however, significant for non-malignant diseases of the respiratory system (Sorahan et al., 1995). The most recent studies therefore do not support the hypothesis that Cd compounds act as lung carcinogens in humans (Verougstraete et al., 2003). Some epidemiological studies suggest an association between occupational exposure to Cd and the occurrence of renal cancer (reviewed by Il’yasova and Schwartz, 2005). 5.8.3. Summary and discussion of carcinogenicity Data from experimental studies clearly indicates that cadmium is an animal carcinogen. Only one study reported an increase in cancer after oral exposure to soluble cadmium compounds. However, strong evidence exists that inhalation of cadmium oxide dust and fumes or cadmium chloride causes lung cancer in rat. Mice exposed to equivalent levels of cadmium oxide had only marginally significant elevations in lung cancer and no evidence for lung carcinogenicity was found in hamster, so that it has been suggested that interspecies and also inter- strain differences may play a role in the sensitivity to cadmium-induced carcinogenesis. Intrathoracic, intratracheal and subcutaneous exposure to cadmium compounds have also been shown to produce carcinogenic responses in rat. Overall, there is currently no conclusive evidence from human studies that cadmium acts as a carcinogen following oral exposure. In worker populations exposed via inhalation, a statistically significant increase in mortality from lung cancer was initially reported but this has not been supported in later studies. More recent analyses suggest that measures protecting against renal/respiratory effects should also be protective of lung cancer. Conclusive data is not available for all forms of cadmium but the weight of evidence collected from mutagenicity tests, long-term animal studies and epidemiological studies leads to conclude that cadmium oxide should be considered at least as a suspected human carcinogen (lung cancer). Cadmium metal is a carcinogen when injected in experimental animals. No studies exist for the metal in humans or animals, which does not allow to sufficiently document its carcinogenic potential. Following long discussions, cadmium oxide was classified by the CMR Working Group as Carc. Cat. 2; R45 (may cause cancer), i.e. carcinogenic potential irrespective of the exposure route3 and appears as such in Annex I of Directive 67/548/EC (the corresponding GHS-CLP classification would be Carcinogenic category 1B; H350). Cadmium sulphate, cadmium chloride and cadmium metal have been granted the same

3 Although there is evidence that cadmium may cause lung cancer after inhalation exposure, there is no indication for a carcinogenic potential in the general population after oral exposure. A classification as Carc. Cat. 2: R49, i.e. may cause cancer by inhalation, could have been envisaged.

classification, based on weight of evidence and read-across. By analogy, a comparable classification could be considered for the other highly and slightly soluble cadmium compounds (e.g. cadmium nitrate, hydroxide and carbonate). Apart from cadmium sulphide, none of the insoluble cadmium compounds (e.g. cadmium sulfoselenide, cadmium zinc sulphide or cadmium telluride), not expected to penetrate easily into the organisms, are classified for carcinogenicity. Cadmium sulphide is an exception. As there is no strong evidence to specifically support its Carc. Cat. 2; R45 classification, a revision of the classification may be appropriate based on solubility properties.

5.9. Toxicity for reproduction 5.9.1. Effects on fertility

5.9.1.1. Non-human information Numerous studies have been conducted to assess the effects of cadmium on fertility, most of them with soluble compounds such as cadmium chloride. A complete review is available in the EU Risk Assessment Report (RAR) (JRC, 2007). The following section presents main findings by route of administration and type of compound. Effects on male and female reproductive organs/fertility and multigeneration experiments are considered separately. Oral route Effects on male organs and male fertility The acute and chronic toxicity of cadmium via the oral route on the testis have been investigated in several experiments. The results of selected studies, as summarised in the European Risk Assessment Report (RAR) (JRC, 2007) are summarised in the following table:

Table 27. Overview of selected experimental studies on male fertility and reproductive organs (oral route)4 Method Results (reproductive NOAEL/LOAEL) Remarks Reference Cadmium chloride Mouse NOAEL: 270 µmol/kg (30.4 mg Cd/kg bw) - Andersen et Exposure: gavage LOAEL: 59.6 mg Cd/kg bw al.(1988) 0-270-530-790 µmol Cd/kg (relative testicular deposition of cadmium, (as CdCl2) nearly constant at doses not inducing testicular Exposure: single damage but decreased at doses inducing necrosis of tubules and interstitial tissue (60-90 mg Cd/kg bw). Decrease attributed to cadmium-induced vascular damage and reduced circulation. At this dose, tissular damage also observed in the gastro-intestinal tract and in the liver) Rat NOAEL: 25 mg CdCl2 (15 mg Cd/kg bw) Only abstract Dixon et al. Oral: drinking water (no effects on bodyweight, weight of testis, available (1976) 0-6.25-12.5-25 mg CdCl2/ prostate and seminal vesicles. No change in cited in kg bw testis histopathology. No effect on clinical ATSDR Exposure: single dose parameters or serum hormone levels) (2008)

Rat NOAEL: 50 mg CdCl2/ kg bw (30.6 mg Cd/kg - Kotsonis, Oral: gavage bw) Klaassen 0-25-50-100-150 mg CdCl2/ LOAEL: 61.2 Cd/kg bw (1977) kg bw (focal testicular necrosis and reduced Exposure: single dose spermatogenesis at 100 and 150 mg/kg bw. Concentrations of cadmium in testicles ca. 0.35 μg/g for the two highest dose groups 2 days after dosing and decreased 20-35% after 14 days)

4 For many of these studies, only abstracts were available therefore IUCLID datasets were not produced.

Method Results (reproductive NOAEL/LOAEL) Remarks Reference Rat (male) NOAEL: 50 mg CdCl2/ kg bw (30.6 mg Cd/kg - Bomhard et Oral: gavage bw) al. (1987) 0-50-100-200 mg CdCl2/ kg LOAEL: 61.2 Cd/kg bw bw (at 100 and 200 mg CdCl2/kg bw, severe Exposure: single dose lesions of the whole testicular parenchyma with 25 males treated once with massive calcification of the necrotic tubuli and 200 mg CdCl2/kg bw and 35 pronounced fibrosis of the interstitium) males with 100 mg CdCl2/kg. Observation for 6 months Rat NOAEL: 51 mg CdCl2/ kg bw (31.3 mg Cd/kg - Borzelleca et Oral: gavage bw/d) al. (1989) 0-25-51-107-225 mg LOAEL: 65.6 mg Cd/kg bw/d CdCl2/kg (testicular atrophy and loss of spermatogenic Exposure: 10 days element at 107 mg CdCl2/kg bw as well as dose-dependent increase in mortality, kidney and hepatic changes) Rat NOAEL: 323 mg CdCl2/L (24.7 mg Cd/kg - Borzelleca et Oral: drinking water bw/d*) al. (1989) 13-323 mg CdCl2/L (W) (dose-dependent effects on bodyweight and Exposure: 10 days organ weights but no effect on testes) Rat (Wistar) male NOAEL: 5 mg CdCl2/ kg (3.6 mg Cd/kg bw) - Bomhard et Oral: gavage (no effects on testes of mature animals) al. (1987) 0-5 mg CdCl2 /kg bw Exposure: 10 weekly doses Animals necropsied after 12 and 18 months, or kept up to 30 months Rat NOAEL : 5 mg Cd/kg bw/d Only abstract Dixon et al. Oral: drinking water (no effects on testis histopathology, clinical available; (1976) 0-0.001-0.01-0.1 mg parameters or hormone levels) details of docing cited in CdCl2/L not available ATSDR Exposure: 30-90 days (2008) Rat NOAEL: 34.4 mg Cd/L (4.64 mg Cd/kg bw/d) - Zenick et al. Oral: drinking water (no effects on reproductive parameters) (1982) 0-17.2-34.4-68.8 mg Cd/L (as CdCl2) Exposure: 70-80 days Rat LOAEL: 8.58 mg Cd/kg bw/d Only abstract Cha et al. Oral: drinking water (atrophy of seminiferous tubule epithelium) available; (1987) cited Dosing with CdCl2, details details of dosing in ATSDR not available not available (1998) Exposure: 10 weeks

Rat NOAEL: 5 mg CdCl2/kg bw/d (2.9 mg Cd/kg Only abstract Pleasants et Oral: drinking water bw/d) available; al. (1992 and Dosing details not available LOAEL: 5.8 mg Cd/kg bw/d details of dosing 1993) cited Exposure: 14 weeks (cadmium-related increase in testis weight, not available in ATSDR reduced by simultaneous administration of (1998) vitamins A and D3) Rat LOAEL: 3 mg Cd/kg bw/d Only abstract Krasovskii et Oral: drinking water (significant reductions in sperm number and available; al. (1976) Dosing details not available motility and significant desquamation of details of dosing Exposure: 6 months spermatogenic epithelium; gonadotoxic effect not available manifested on the same level as general toxic effect 3 mg/kg bw)

Method Results (reproductive NOAEL/LOAEL) Remarks Reference Rat NOAEL: 100 mg Cd/L (12.5 mg Cd/kg bw/d*) - Kotsonis, Oral: drinking water (no altered testicular function; testicular tissue Klaassen 0-10-30-100 mg Cd/L (as within normal limits although concentration of (1978) CdCl2) cadmium in the testes after 12 weeks was Exposure: 24 weeks greater (± 0.9 μ g Cd/g) than that which caused testicular injury in previous acute study) Rat NOAEL: 10 mg CdCl2/L 3 (not reliable) Saygi S, Oral: drinking water LOAEL: ca. 0.8 mg Cd/kg bw/d* supporting Deniz, G, 10 mg CdCl2/L (necrosis of spermatogonia, spermatocyte and study Kutsal O and Exposure: 52 weeks (13 spermatid in some tubuli seminiferi after 10 experimental Vural, N months) months. Some tubuli showed atrophy, oedema result (1991) At the end of the treatment, and vascular hyperaemia in the interstitium. animals were kept for After 13 months, also slight atrophy of the mating for an additional testis and hyperaemia in the tunica vaginalis period of 30 days and serosal vessels of the interstitium. Some tubuli had no spermatozoa. Kidney alterations also observed. Some rats reported to have “lost their reproduction capacities”; however, test report incomplete and no indication of whether these rats were those in which histopathological anomalies were observed) Cadmium acetate Rat LOAEL: 12.6 mg Cd/kg bw/d Only abstract Saxena et al. Oral: drinking water (significantly increased relative testis weight, available; (1989) cited 50 ppm (as Cd acetate) decreased sperm count and motility, decreased details of dosing in ATSDR Exposure: 120 days seminiferous tubular diameter and seminiferous not available (1998) tubular damage) * Estimated consumption of water: 25 ml/day; Estimated weight of the rat: 200 g (Derelanko, 2000) The above studies suggest an effect of cadmium on fertility, including testicular aprophy, necrosis and decreased fertility. Additionally, Sutou et al. (1980) noted that a dose of 10 mg Cd/kg bw/d (as CdCl2) for 9 weeks did not affect fertility of male rats in a dominant-lethal test. All analysed fertility indices did not reveal a difference with control rats when males were mated with untreated females. When treated males were mated with females having undergone the same cadmium exposure, adverse effects were observed at 10 mg/kg bw/d on number of copulation and pregnancies as well as number of implants and live fetuses (NOAEL: 1 mg Cd/kg bw/d). This study appears to be the most critical with regard to effects on fertility.

Effects on female fertility and reproductive organs

Table 28. Overview of selected experimental studies on female fertility and reproductive organs (oral route) Method Results Remarks Reference Cadmium chloride Mouse (CF-1) female NOAEL (P): 5 ppm Cd 2 (reliable with Whelton B (1988) oral: feed (female) restrictions) Multigeneration study LOAEL (P): 50 ppm Cd + key study 0, 0.25, 5.0 and 50 ppm Cd (as deficient diet (female) experimental result CdCl2) (nominal conc.) (decreased fertility and litter Exposure: continuously during 6 size) generations (No decrease in fertility for For each cadmium concentration, mice on sufficient diet. diets were either sufficient in all Combined exposure to dietary constituents or deficient in cadmium and nutritional certain minerals, vitamins and fat. deficiencies had synergistic Dose of 5 ppm cadmium combined effect on fertility and litter with a deficient diet designed to size, statistically significant at simulate conditions of Itai-Itai 50 ppm. Low calcium content disease of deficient diet possibly allowed cadmium to interfere with calcium pathways important to maintain fertility. Increases with time in the extent of dietary deficiencies and in cadmium burdens of maternal organs had no measurable effect on reproduction) Mouse (Charles River CD) LOAEL (F1): 2.5 mg/kg bw/d 3 (not reliable) Schroeder HA and male/female (male/female) (low mating supporting study Mitchener M (1971) three-generation study index) experimental result oral: drinking water 0 and 10 mg/L = 0 and 2.5 mg/kg bw/day (nominal conc.) Exposure: Exposure period: up to 6 months (continuously) Method: other, no information Rat (Wistar) female NOAEL (P): 4 mg Cd/kg bw/d 2 (reliable with Baranski B and fertility (female) restrictions) Sitarek K (1987) oral: gavage LOAEL (P): 40 mg Cd/kg key study 0.04, 0.4, 4 and 40 mg Cd/kg bw/d bw/d (female) (length of experimental result (nominal conc.) oestrous cycle twice as in Vehicle: water control rats) Exposure: 14 wk (5 d/wk) (cadmium did not affect the A study was conducted to evaluate sexual cycle unless other overt the effects of the test material on the signs of Cd toxicity were estrus cycle of female rats. Animals induced) received0, 0.04, 0.4, 4 and 40 mg Cd/kg bw/d through oral gavage for 14 wk. Vaginal smears were taken daily for 14 days before the onset of cadmium exposure and then at 6 wk intervals during exposure.

Rat (Sprague-Dawley) male/female NOAEL (P): ca. 1 mg Cd/kg 2 (reliable with Sutou S, Yamamoto Single generation bw/d (female) restrictions) K, Sendota H and

Method Results Remarks Reference fertility/developmental test NOAEL (reproductive) (P): key study Sugiyama M (1980) combined with a dominant lethal 1 mg Cd/kg bw/d (female) experimental result assay LOAEL (reproductive) (P): 10 oral: gavage mg Cd/kg bw/d (female) 0, 0.1, 1.0 and 10.0 mg Cd/kg bw/d (>50% fewer copulating and Exposure: Exposure period: 6 wk pregnant females) prior to mating + 3 wk mating period NOAEL (F1): ca. 1 mg Cd/kg Premating exposure period (males bw/d (male/female) and females): 6 wk LOAEL (F1): 10 mg Cd/kg Method: males and females within bw/day (male/female) (delayed each treatment group (+ control) ossification, decreased were mated 6 d/wk for 3 wk bodyweight) changing partners every week if needed. Cadmium was administered during the mating period. Pregnant females were administered cadmium during gestation and killed on GD20 for developmental test (fetal examination). Non-pregnant females were killed after 13 wk. Additionally: After 9 wk, males were mated with 2 virgin females per male per week for 6 wk. Pregnant females were killed on GD13 for dominant lethal tests (examination of the numbers of corpora lutea, live fetuses, early deaths (no remnants of fetuses), and late deaths (remnants of fetuses)). One week after the cessation of dominant lethal tests, which represents a recovery period of 50 d, male rats were killed and examined. Cadmium oxide Rat (Wistar) female LOAEL (P): 1 mg Cd/m³ air 2 (reliable with Baranski B and fertility (female) (increased duration of restrictions) Sitarek K (1987) inhalation: dust oestrous cycle key study 0 and 0.02, 0.16, 1 mg Cd/m3 (CdO inhalation) experimental result (nominal conc.) (cadmium did not affect the Exposure: 20 wk (5 h/d, 5 d/wk) sexual cycle unless other overt A study was conducted to evaluate signs of Cd toxicity were the effects of the test material on the induced) estrus cycle of female rats. Animals were exposed to the test material at doses of 0 and 0.02, 0.16, 1 mg Cd/m3 for 20 wk. Vaginal smears were taken daily through 14 consecutive days before the onset of cadmium exposure and then at 6 wk intervals during exposure. Additionally to the experiments summarised above, Kreis et al. (1993) conducted a historic follow-up study that addressed the possibility of diminished fertility, decreased twinning rate and other developmental effects (increased foetal death) in cattle. The results suggest that long-term exposure to low levels of cadmium in soil, grass and food is associated with impaired reproduction in cows. However, confounding exposures to other chemicals might have been possible and this is not precisely documented in the study. Overall, evidence from experimental studies indicates that higher doses of cadmium compounds are needed to elicit a reproductive toxic response in females compared to the males (ATSDR, 2008). Effects included

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 95 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 decreased percentage of fertilised females and percentage of pregnancies, and increased duration of the oestrus cycle. Multigeneration studies Both female and male mice were treated over two generations with 2.5 mg CdCl2/kg bw/d via the drinking water. Five pairs of mice were given cadmium from weaning and allowed to breed freely up to 6 months of age. In the F1 litters, average litter size at birth was normal. Three of five pairs failed to breed in the second generation (Schroeder and Mitchener, 1971; cited in Barlow and Sullivan, 1982). The effects of a low-level exposure to cadmium (0, 0.1, 1.0 and 5.0 ppm) on reproduction and growth were evaluated in rats by Laskey et al. (1980). Exposure started with conception of the first generation and continued throughout the experiment (130 days). According to the water consumption data, the F1 rats received approximately 1.3 mg Cd/kg bw/d as young animals. This decreased to 0.5 mg Cd/kg bw/d as they reached adulthood. No gross testicular pathology or depression in fertility was observed. Epididymal sperm count at 130 days was reduced approximately 20% in the 5.0 ppm cadmium group but not at 50 days. No increase in serum FSH accompanied this reduced sperm count. Liver weight was decreased in the 5.0 ppm group. Three consecutive generations of Wistar rats were treated by gavage with 3.5, 7.0 or 14.0 mg/kg bw Cd/d (as cadmium chloride) over the period of pregnancy, lactation and 8 weeks after weaning in a study carried out by Nagymajtenyi et al. (1997). Aim of the study was to investigate possible behavioural and functional neurotoxicological changes caused by cadmium. However, the effects on the reproductive function were not assessed. Inhalation route Effects on male fertility and reproductive organs Male rats were exposed for 13 weeks to 0, 0.025, 0.05, 0.1, 0.25 and 1 mg CdO/m³ (as CdO aerosol) to assess effects on reproductive function at the end of the study (Dunnick, 1995). The number of spermatids per testis was reduced at 1 mg CdO/m3 but no histopathological changes in the reproductive system were seen, suggesting that the changes may have been related to other effects of cadmium, such as hormonal modifications. The LOAEL for the study was 1 mg CdO/m3 (ca. 0.09 mg Cd/m3) and the NOAEL was 0.25 mg CdO/m3 (ca. 0.23 mg Cd/m3). In male mice exposed to same concentrations of CdO, no reproductive toxicity was observed at any dose (NOAEL: 1 mg CdO/m3) (Dunnick, 1995). Effects on female fertility and reproductive organs Female rats were exposed by inhalation to CdO for 20 weeks (5 h/d, 5 d/wk) at concentrations of 0.02, 0.16 and 1 mg Cd/m3 (Baranski and Sitarek, 1987). In the high dose group, a pronounced increase in the main duration of the oestrous cycle was observed 7-8 weeks after exposure. Bodyweight gain of the females was significantly decreased and lethality was significantly higher in this group compared to the other experimental groups and increased with duration of exposure. At lower exposure levels, no changes in the main duration of the oestrous cycle were found when compared with that of controls, although at the end of exposure it was significantly longer than before the onset of treatment. During the last 2 weeks of exposure, the percentage of females (93%) with prolonged cycle (> 6 days) in the group exposed to 0.16 mg Cd/m³ group was significantly higher than in the control group but mean duration of the cycle was not reported to be significantly different from that in the non-exposed group (LOAEL: 1 mg Cd/m3). Bodyweight gain of females exposed to 0.02 and 0.16 mg Cd/m3 remained unchanged. Authors concluded that alterations of the oestrous cycle evoked by repeated exposure to Cd appeared only in female rats exhibiting other signs of intoxication (reduced bodyweight gain, increased lethality). In a further study, a significant increase in the length of the oestrous cycle was observed in female rats exposed to 1.0 mg CdO/m3 (LOAEL) (Dunnick, 1995). However, there were no histopathologic lesions indicative of toxicity of the reproductive system, suggesting that reproductive effects at the highest exposure level in rats may be related to other effects of cadmium such as hormonal changes. In female B6C3F1 mice exposed for 13 weeks to CdO (0, 0.025, 0.05, 0.1, 0.25 and 1 mg CdO/m3) (Dunnick 1995), no indication for reproductive toxicity was reported at any dose (NOAEL: 1 mg CdO/m3).

Toxicity to reproduction: other studies Effects on male and female reproductive organs have been observed after subcutaneous, intratesticular or intraperitoneal administration. Martin and colleagues found that cadmium administered by single intraperitoneal injection mimics oestrogen activity in breast cancer cells and that cadmium binds to and activates oestrogen receptor-α (Martin et al., 2003; Stoica et al., 2000). Recently, they reported vaginal epithelial cornification and increased uterine weight after a single dose of cadmium (5μ g/kg bw) in ovariectomised rats and these effects did not occur in the presence of anti-oestrogenic drugs (Johnson et al., 2003). While these studies may help to understand how cadmium may cause adverse effects on reproduction, their relevance for humans has not yet been explored; however, these routes are not considered to be relevant for a

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 96 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 human risk assessment (JRC, 2007). Summary Effects of cadmium treatment on male and female reproductive organs have been observed after oral administration of cadmium compounds in rats and mice. In several studies, effects were detected at dose levels which caused also general toxicity. In male rats and mice, acute exposure to cadmium compounds at doses higher than 50 mg/kg bw was shown to cause testicular atrophy and necrosis and concomitant decreased fertility. In females, effects on length of oestrous cycle after administration of cadmium compounds by gavage were observed at a dose of 40 mg/kg bw/d. Fertility was however reported to be affected at doses of 10 mg/kg bw/d. Overall, the lowest concentration (LOAEL) of cadmium reported to affect fertility in male and female rats upon oral administration was 10 mg Cd/kg bw/d (Sutou et al., 1980). In male rats exposed by inhalation to 1 mg CdO/m3 for 13 weeks (Dunnick, 1995), the number of spermatids per testis, as evaluated at necropsy, was reduced compared to controls. No histopathological changes of the reproductive system were observed (reproductive LOAEL: 1 mg CdO/m3 ca. 0.9 mg Cd/m3). This effect on the number of spermatids was not observed in mice (Dunnick, 1995). Exposure to cadmium oxide at a concentration of 1 mg/m3 (for more than 10 weeks) has been associated with an increase in oestrous cycle length in rats in two studies. It has been suggested that the effects on the oestrous cycle occur only when other signs of cadmium intoxication are present and might be related to other cadmium-induced effects such as hormonal changes; however, current data do not allow to definitely draw this conclusion. The reproductive

LOAEL for inhalation is therefore considered to be 1 mg CdO/m3 (ca. 0.9 mg Cd/m3), derived from the

13-week rat study. The corresponding NOAEL is 0.25 mg CdO/m³ (ca. 0.23 mg Cd/m³).

5.9.1.2. Human information A review of the fertility effects of cadmium to human has been conducted in the EU Risk Assessment Report (RAR) (JRC, 2007). Selected exposure studies are summarised by cadmium compound in the following table, then commented according to the type of population considered (general population or workers, with smokers considered apart).

Table 29. Overview of selected exposure-related observations on toxicity to reproduction / fertility in humans Method Results Remarks Reference Cadmium metal Study type: case control study No significant reduction in fertility 1 (reliable without Gennart JP, Buchet (prospective) was detected in the exposed group restriction) JP, Roels H, Type of population: occupational compared with the unexposed key study Ghyselen P, Subjects: HYPOTHESIS TESTED population. Ceulemans E and (if cohort or case-control study): Lauwerys R (1992) Effect of exposure to cadmium on the reproductive function. METHOD OF DATA COLLECTION - Type: By questionnaire, information was gathered on age, residence, educational level, occupational and health history, actual and previous occupations, smoking, coffee and alcohol consumption. The fertility section of the questionnaire contained the questions proposed by Levine et al. for the monitoring of the fertility of workers (Levine et al., 1980 cited by Gennart et al., 1992). STUDY POPULATION - Final population: E: 83 (M only), Age: 23.4-72.2 y

Method Results Remarks Reference C: 138 (M only), Age: 19.9-71.9 y - Selected from: E: “workers from two primary cadmium smelters, exposed uninterruptedly to cadmium for at least 1 y before the study and at the time of the study: Cd-U>2µg/g creatinine, Pb-B <30 µg/100mL” C: “workers from factories located in the same area, never occupationally exposed to heavy metals, at the time of the survey: Cd-U<2µg/g creatinine, Pb-B <20µg/100mL” For E and C, no pathologic conditions which might interfere with reproductive function, Belgian nationality and married at least once” - Lost subjects: 29 in E, 127 in C Endpoint addressed: toxicity to reproduction / fertility Study type: case control study - Mean cadmium concentrations in 1 (reliable without Keck C, Bramkamp (prospective) seminal plasma did not differ restriction) G, Behre HM, Type of population: general significantly for groups I (fertility key study Müller C, Subjects: HYPOTHESIS TESTED proven men), II (normozoospermic Jockenhövel F and (if cohort or case control study): patients), III (unselected patients) Nieschlag E (1995) Relationship between cadmium - There was no significant concentrations with parameters of correlation between seminal conventional semen analysis and cadmium concentrations and fertility assessment & the effect of conventional semen parameters or cigarette smoking on cadmium between cadmium concentrations concentrations in seminal plasma and the fertility status of the STUDY POPULATION patients. - Final population: - In normozoospermic patients, Cases: 44 (group II) + 118 (group seminal plasma cadmium III), Age: 35-36 y concentrations were significantly Controls: 12 (group I), Age: no higher in the group of smokers, information compared with the group of non- - Selected from: smokers (0.55 ± 0.81 versus 0.42 ± Cases: Group II: patients (of the 0.67 µg/L) infertility clinic) with unexplained infertility whose semen analysis revealed normozoospermia; Group III: “consecutive patients attended the infertility clinic due to barenness - Selection procedure: known - Lost subjects: no information Endpoint addressed: toxicity to reproduction / fertility Study type: cohort study - Extremely high within-subject 2 (reliable with Noack-Fuller G, De (prospective) variations were observed for the restrictions) Beer C and Seibert

Method Results Remarks Reference Type of population: general concentrations of cadmium and Pb key study H (1993) Subjects: HYPOTHESIS TESTED in semen (if cohort or case-control study): - No correlation was found Association between element between cadmium concentration in concentrations and semen semen and sperm density characteristics and sperm motion - Positive correlation between parameters. cadmium concentration in semen STUDY PERIOD: no information and sperm motility (r = 0.53, STUDY POPULATION p<0.05), linear (r = 0.757, - Final population: E: 22 (M); C: 0 p<0.001) and curvilinear velocity - Age: 21 – 50 y (r = 0.643 p<0.002) - Selected from: E: occupationally unexposed volunteers; C: 0 - Selection procedure: no information - Lost subjects: no information Endpoint addressed: toxicity to reproduction / fertility Study type: case control study - The volume of semen was 1 (reliable without Xu B, Chia SE, (prospective) inversely proportional to the restriction) Tsakok M and Ong Type of population: general cadmium concentration in seminal key study CN (1993) Subjects: HYPOTHESIS TESTED plasma (r = -0.29; p<0.05). (if cohort or case-control study): - Cadmium levels in blood had a Relationships between the significant inverse relationship concentrations of cadmium, Pb, Se with sperm density (r = -0.23, and Zn in blood and seminal p<0.05) in oligospermic (sperm plasma, and sperm quality. density below 20 million/mL) but METHOD OF DATA not in normospermic men. There COLLECTION was a significant reduction in - Type: subjects were interviewed sperm density in men with blood using a questionnaire to obtain cadmium of >1.5µg/L (7.8 ± 7.1 information on occupational million/mL versus 17.8 ± 4.5 exposure, general health, living million for men with Cd-B<1 habits, including cigarette smoking µg /L). and alcohol drinking and medical - No differences were observed in history sperm quality (density, motility, STUDY POPULATION morphology, volume and viability) - Final population: in the cohort when compared to 38 cases: 221 (M), Age: 24-54 y fertility proven men. controls: 38 (M), Age: no information - Selected from: cases: subjects who were undergoing initial screening for infertility in the Andrology Clinic at the Singapore General Hospital from January 1990 to June 1992 controls: cohort of fertility proven males (wives had recently conceived) analysed during same study period - Selection procedure: known for “E”, exclusion of individuals with

Method Results Remarks Reference significant past medical history, and/or signs of defective androgenisation or abnormal testicular examinations, and occupational exposure to metals - Lost cases: no information Endpoint addressed: toxicity to reproduction / fertility Cadmium oxide Study type: case control study - no change in testicular endocrine 1 (reliable without Mason HJ (1990) (prospective) function (as measured by serum restriction) Type of population: occupational levels of testosterone, luteinising key study Subjects: HYPOTHESIS TESTED hormone, and follicle-stimulating (if cohort or case control study): hormone) was observed in men Effects of occupational cadmium exposed to cadmium at levels exposure on testicular endocrine causing dose-related changes in function glomerular and tubular function in STUDY POPULATION the same population. - Final population: E: 77 (M), Age: 54 ± 13 y (mean ± SD) C: 101 (M), Age: 56 ± 12 y (mean ± SD) - Selected from: E: “all male current and ex-workers who had produced copper-cadmium alloy for one or more years since the factory opened in 1926” C: “from the current or past workforce of the same company, hourly paid workers without occupational exposure to cadmium” - Selection procedure: known - Lost subjects: 26 Endpoint addressed: toxicity to reproduction / fertility General population (oral route) In studies conducted by one group of authors, a significant inverse correlation was noted between semen volume and the concentration of cadmium in seminal plasma (Xu et al., 1993). In their conclusion, they suggested that cadmium may have a possible adverse effect on the prostate gland, as a significant amount of seminal plasma is derived from this gland. However, no clear prostate-specific cadmium accumulation could be demonstrated by Oldereid et al. (1993). They determined the tissular concentration of cadmium in various reproductive organs removed at necropsy from men who had died suddenly. The epididymis, and to a lesser extent the simal vesicles, appeared to be more efficient than both the prostate gland and the testis in their capacity to accumulate cadmium. The age-related rise in tissue cadmium in the testes and other organs was more apparent after the fourth decade. Amount of cadmium in the tissues was not influenced by the rural or urban backgrounds or occupations of the subjects. Xu et al. (1993) reported also a significant reduction in sperm density in men with blood cadmium of > 1.5 µg/L but no differences were observed in sperm quality in the whole group compared to controls. One group of authors reported a positive correlation between cadmium concentrations in semen and some parameters of sperm motility (Noack-Füller et al., 1993). However, to draw some conclusions and assess the clinical relevance of the modifications in seminal parameters, further studies would be required. Keck et al. (1995) did not find a correlation between cadmium levels in seminal plasma and semen parameters and fertility in 12 men with proven fertility and 44 normozoospermic patients as well as 118 unselected patients of an infertility clinic in Germany. Overall, the epidemiological evidence of clinically-relevant reproductive effects of cadmium in humans exposed by the oral route is weak.

Workers (inhalation route) In male workers exposed to cadmium by inhalation, studies dealing with endocrine and gonadal function found no effects that may be attributed to cadmium (Mason et al., 1990; Gennart et al., 1992). Fertility was not significantly different in exposed workers compared to unexposed subjects (Gennart et al., 1992). Overall, available evidence is insufficient to determine an association between occupational inhalation exposure to cadmium and effects on fertility or sex organs. Smokers In humans, cigarette smoke is an important source of cadmium and various studies have shown that there is no apparent barrier to prevent cadmium from entering the male reproductive system from the circulation. Nevertheless, the epidemiological evidence of an association between cadmium exposure through tobacco smoking and reduction of reproductive function is weak (JRC, 2007). 5.9.2. Developmental toxicity

5.9.2.1. Non-human information Several studies have been conducted to assess the effects of cadmium (mainly cadmium chloride and oxide) on developmental toxicity. A detailed review is available in the EU Risk Assessment Report (RAR) (JRC, 2007). Selected studies are summarised below and main results are then discussed by route of exposure. Table 30. Overview of selected experimental studies on developmental toxicity Method Results Remarks Reference Cadmium chloride Rat (Wistar) LOAEL (developmental 2 (reliable with Baranski B, oral: gavage toxicity): 0.04 mg Cd/kg restrictions) Stetkiewicz I, 0.04, 0.4, 4 mg Cd/kg bw/d bw/d key study Sitarek K and (nominal conc.) NOAEL (maternal toxicity): experimental result Szymczak W Exposure: 5 weeks before mating, 4 mg/kg bw/d (1983) during mating and gestation periods: 11 weeks (5 d/wk) Vehicle: water A study was conducted to evaluate the effects of the test material on the fertility of parental rats and fetal development / locomotor activity of offsprings. After 5 wk treatment, females were mated with untreated 4-month-old males for a maximum of 3 wk. Administration of Cd was continued throughout mating and gestation. Each group was further divided into 2. Females from the first subgroup, on Day 21 of gestation, were sacrificed and subjected to autopsy. The assessment of fetotoxic and structural teratogenic effects and the determination of Cd concentration in the fetuses were performed. Female rats from the other subgroup were allowed to deliver and feed their progeny. The number of living and dead pups and the bodyweight of offspring were noted. Viability, lactation and mortality were determined. At 2 months, spontaneous locomotor activity and locomotor coordination of movements were assessed Rat (Wistar) no NOAEL for maternal or 4 (not assignable) Baranski B (1985)5

Method Results Remarks Reference oral: gavage developmental toxicity Supporting study 2, 12 and 40 mg Cd/kg bw/d identified (data insufficient for experimental result (nominal conc.) assessment) Vehicle: water (Congenital defects and raised Exposure: GD 7 - 16 cadmium levels in tissues at 40 A study was conducted to evaluate mg Cd/kg bw/d. Retardation of the developmental and teratogenic intra-uterine development in effects of the test material on rats. the other groups. Cadmium The test material was administered concentration increase not in doses of 2, 12 and 40 mg Cd/kg found in the tissues of the bw/d by gavage to pregnant rats on young so that postnatal GD 7 - 16. At study end, the fetuses development changes may be were examined. associated with a higher Cd consumption with the milk of exposed females or with a lowered content of iron, zinc and copper) Rat (Sprague-Dawley) NOAEL (maternal and 2 (reliable with Sorell TL and oral: drinking water developmental toxicity): restrictions) Graziano JH (1990) 0, 5, 50 and 100 ppm (nominal 5 ppm (= 0.63 mg Cd/kg key study conc.) bw/d) experimental result Exposure: GD 6 - 20 LOAEL (maternal and To examine the effect of cadmium developmental toxicity): exposure on maternal and foetal zinc 50 ppm (= 4.7 mg Cd/kg metabolism, rats were exposed to bw/d) cadmium chloride in drinking water on GD 6 - 20. Cadmium oxide Mouse (Swiss) NOAEL (maternal and 1 (reliable without Dunnick JK (1995) inhalation (whole body) developmental toxicity): 0.05 restriction) 0, 0.05, 0.5 or 2 mg CdO/m3 mg CdO/m³ air key study (nominal conc.) LOAEL (maternal and experimental result Exposure: GD 4 - 17 (6h and 16 developmental toxicity): 0.5 min/d; 7 d/wk) mg CdO/m³ air OECD Guideline 414 (Prenatal Developmental Toxicity Study) equivalent or similar to EC TM B31 Dir. 87/302/EEC 30/05/88 Rat (Sprague-Dawley) NOAEL (maternal and 1 (reliable without Dunnick JK (1995) inhalation (whole body) developmental toxicity): restriction) 0, 0.05, 0.5 or 2 mg CdO/m3 0.5 mg CdO/m³ air key study (nominal conc.) LOAEL (maternal and experimental result Exposure: GD 4 - 19 (6h and 16 developmental toxicity): min/d; 7 d/wk) 2 mg CdO/m³ air OECD Guideline 414 (Prenatal Developmental Toxicity Study) equivalent or similar to EC TM B31 Dir. 87/302/EEC 30/05/88

5 It should be noted that the EU Risk Assessment Report (RAR (JRC, 2007) questions the robustness of the observations in Baranski 1984 and 1985 in view of: 1) high and unexplained mortality in certain groups, 2) apparent inconsistencies in the dose-effect relationship in a singme test (e.g. locomotor activity at 0.02 and 0.16 mg/m3), and 3) apparent inconsistencies in the response between tests (e.g. locomotor activity and rearing).

Method Results Remarks Reference Rat (Wistar) NOAEL (developmental 4 (not assignable) Baranski B (1984)6 inhalation toxicity): 0.02 mg Cd/m³ air Supporting study 0.02 and 0.16 mg Cd/m3 air LOAEL (developmental experimental result (nominal conc.) toxicity): 0.16 mg Cd/m³ air Exposure: 5 months before mating, (reduced viability) then for a maximum period of 3 wk LOAEL (pup behavioural of mating and from GD 1 - 20 alterations): 0.02 mg Cd/m3 (5 d/wk; 5 h/d) A study was conducted to evaluate the effects of the test material on the behavioural development of the progeny in Wistar rats. Groups of female rats were exposed to the test material at 0.02 and 0.16 mg Cd/m3 air for 5 months before mating, then for a maximum period of 3 wk of mating and from GD 1 - 20. Rat (Wistar) NOAEL (developmental 4 (not assignable) Baranski B (1985)6 inhalation: aerosol toxicity): 0.02 mg Cd/m³ air Supporting study 0.02, 0.16 and 1 mg Cd/m3 air LOAEL (developmental experimental result (nominal conc.) toxicity): 0.16 mg Cd/m³ air Exposure: 5 months before mating (increased number of foetuses for the two low concentrations and 4 with retarded development) months for the high concentration, then during mating and from GD 1 - 20 (5 d/wk; 5 h/d) A study was conducted to evaluate the effect of the test material on the development of the progeny in Wistar rats. Female rats were exposed to cadmium oxide at 0.02 mg Cd/m3 or 0.16 mg Cd/m3 for 5 h/d and 5 d/wk for a period of 5 months or 1 mg Cd/m3 for 4 months. The exposure was then continued during mating and from GD 1 - 20 Oral route Cadmium compounds have been reported to induce reduced bodyweight and malformations (primarily of the skeleton) in offspring of animals exposed via gavage or diet at doses that produced maternal toxicity. In some studies, information on maternal toxicity is lacking, but cross-reading with studies that provide this information indicates that the reported developmental effects occur at doses levels expected to cause maternal toxicity (overall > 5 ppm or ca. 0.6 mg CdCl2/kg bw/d) ( Sorell and Graziano, 1990; Baranski, 1985; JRC, 2007). Neurobehavioral effects or changes in electrophysiological parameters were reported to occur at doses that did not induce maternal toxicity. The lowest dose reported to generate behavioural changes in pups was 0.04 mg Cd/kg bw/day (LOAEL) (Baranski et al., 1983). The significance of these changes and underlying mechanisms for the observed effects on behavioural endpoints are not completely elucidated yet; some authors suggested that the toxic effects might be mediated by placental toxicity or by interference with the normal foetal metabolism of zinc and/or copper. Several other mechanisms of action (e.g. neurotransporters or ions channels) were suggested to explain the neurobehavioral changes in the pups of exposed dams. There is a need for further studies to better describe the effects of cadmium on the developing brain. Inhalation route Decreased foetal weight and a significant increase in retarded ossification frequency were reported in offsprings of rats and mice exposed to CdO by inhalation at levels that produced maternal toxicity (0.5 and 2 mg CdO/m3

6 It should be noted that the EU Risk Assessment Report (RAR) (JRC, 2007) questions the robustness of the observations in Baranski 1984 and 1985 in view of: 1) high and unexplained mortality in certain groups, 2) apparent inconsistencies in the dose-effect relationship in a single test (e.g. locomotor activity at 0.02 and 0.16 mg/m3), and 3) apparent inconsistencies in the response between tests (e.g. locomotor activity and rearing).

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 103 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 in mouse and rat, respectively) (Dunnick, 1995). Neurobehavioural changes were reported in young rats from dams exposed to CdO (0.02 mg Cd/m3) in a single experiment (Baranski, 1984) but observations should be confirmed in an independent study (JRC, 2007). Taken together, these results indicate a potential for developmental toxicity.

5.9.2.2. Human information A review of the developmental neurotoxicity effects of cadmium to human has been conducted in the EU Risk Assessment Report (RAR) (JRC, 2007). Selected exposure studies are summarised by cadmium compound in the following table, then commented according to the type of population considered (general population or workers, with smokers considered apart).

Table 31. Overview of selected exposure-related observations developmental toxicity in humans Method Results Remarks Reference Cadmium metal Study type: cohort study - With the exception of verbal or 3 (not reliable) Bonithon-Kopp C, (prospective) memory scores, other scores of the supporting study Huel G, Moreau T Type of population: general used McCarthy scales correlated and Wendling R HYPOTHESIS TESTED: significantly with cadmium hair levels (1986) Effects of maternal occupational in mothers cadmium exposure on child - With regard to cadmium hair levels development. in children (at birth), there was a STUDY POPULATION significant negative correlation with - Final population: the perceptual and motor scores E: 26 children; Age: 6 y. - Decreased mean general cognitive C: 0 index in children whose degree of - Selected from: exposure levels (cadmium hair) falls E: new-born babies, samples of above the third quartile hair were taken in 1977 in the Hagenau Maternity” - Lost subjects: no information

Study type: cohort study - A relationship was reported between 3 (not reliable) Fréry N, Nessmann (prospective) a decrease in birth weight (mean ± supporting study C, Girard F et al. Type of population: general SD) and an increase of cadmium (for (1993) HYPOTHESIS TESTED: The the first and last quartiles) in newborn effect of low levels of cadmium hair, depending on the presence or on the human placenta and the absence of placental calcifications consequences on birthweight - Other placental parameters not STUDY POPULATION significantly related to placental - Final population: cadmium concentrations E: 102 C: 0 - Selected from: E: "attending an obstetrical care unit" Study type: cohort study - A correlation was observed between 3 (not reliable) Huel G, Boudene C (prospective) cadmium-hair of mother and infant supporting study and Ibrahim MA Type of population: general - Higher levels of cadmium were (1981) HYPOTHESIS TESTED: found in infant's hair of hypertensive Effects of maternal occupational mothers compared to the infants of cadmium exposure on child normotensive mothers. Authors development. attributed this to a preferential STUDY POPULATION accumulation in the infants of

Method Results Remarks Reference - Final population: hypertensive mothers E: 108 F, Age: 25.4 y. (mean); 105 newborns C: 0 - Selected from: E: “110 births that occurred during the spring of 1978 in Hagenau Maternity” Study type: case control study - Lower number of women with three 3 (not reliable) Laudanski T, (prospective) or more pregnancies and deliveries at supporting study Sipowicz M, Type of population: general full term in the exposed group Modzelewski P, HYPOTHESIS TESTED: compared to the control group Bolinski J and Influence of lead and cadmium - Correlation between cadmium levels Szamatowicz J on human reproductive outcome and number of preterm labours (1991) STUDY POPULATION (r=0.17, p<0.05) - Final population: E: 136 (F), Age: 20 - >80 y C: 264 (F), Age: 20 - 79 y -Selected from: “405 of the total of 814 women aged 17-75 y. and living in the rural area of Suwalki” E: “136 came from villages where the soil…has approximately twice the normal content of lead and cadmium…” C: “nearby villages with no increased soil content” Study type: case control study - No association was detected between 3 (not reliable) Loiacono NJ, (prospective) placental cadmium and birth weight or supporting study Graziano JH, Kline Type of population: general gestational age at delivery JK et al. (1992) HYPOTHESIS TESTED (if cohort or case control study): The accumulation of tobacco- derived cadmium in the placenta is responsible for the adverse effect of cigarette smoking on infant birthweight -Final population: E: 136 (F); Age: 20 - >80 y. C: 264 (F); Age: 20 – 79 Y. -Selected from: “405 of the total of 814 women aged 17-75 y. and living in the rural area of Suwalki” E: “136 came from villages where the soil…has approximately twice the normal content of lead and cadmium…” C: “nearby villages with no increased soil content” -Selection procedure: partially known (positive response to a written invitation) -Lost subjects: no information

Method Results Remarks Reference -Final population: E: 106 (F only); Age (mean ± SD, years): 26.8 ± 5.0 C: 55 (F only); Age (mean ± SD): 27.0 ± 4.8 - Selected from: E and C:”1502 women from areas in and around the Yugoslavian cities of T.Mitrovica and Pristina, attending a single-out patient clinic, who were in approximately 12 to 20 weeks of gestation, during the period from May 1985 through December 1986” - Selection procedure: known -Lost subjects: 1341 Endpoint addressed: dev toxicity / teratogenicity Study type: case control study - Cadmium-hair values for both 2 (reliable with Huel G, Everson (prospective) mothers and newborns were twice as restrictions) RB and Menger I Type of population: high as the values for the matched key study (1984) occupational controls, suggesting that women HYPOTHESIS TESTED: whose occupations involved heavy Effects of maternal occupational metals passed substantially more cadmium exposure on child cadmium to their offspring than development. controls. STUDY POPULATION - A non-significant decrease in birth - Final population: weight of exposed newborns was E: 26 (F), Age: no information observed (250 g less when compared C: 26 (F), Age: no information to controls) - Selected from: - No other adverse effects (by the E: “women whose occupations clinical parameters measured) involved heavy metals, seeking documented in newborns obstetrical care at the Hagenau Maternal Hospital” C: “unexposed women who delivered at the (same) hospital” - Lost cases: 53/105 General population (oral route) Several studies addressing developmental effects in humans exposed to cadmium via the oral route were located (Bonithon-Kopp et al., 1986; Fréry et al., 1993; Huel et al., 1981; Laudanski et al., 1991; Loiacono et al., 1992). However, study populations were mostly exposed to different pollutants and no study specifically addressed the effects of an environmental exposure to cadmium. Moreover, several of these studies are of limited value for hazard assessment due to significant drawbacks, i.e. in the definition of the study endpoints, selection of population and assessment of exposure. Decreased birth weight (or small-for-date) was reported in the studies of Huel et al., 1981 and Fréry et al., 1993, related to concentration of cadmium in infant’s hair, which is however not a robust estimate of exposure. No other major morphologic alterations of the placenta were evidenced in the studies that could explain an adverse effect on the foetus (possibly due to the relatively low levels of cadmium compared to other studies and experimental systems). Overall, the epidemiological evidence for a developmental effect (on birth weight, malformations, neurobehavioral performances) of cadmium compounds in the general population mainly exposed by the oral route appears weak. Workers (inhalation route) One study was located regarding developmental effects in humans after inhalation exposure to cadmium (Huel et al., 1984). A non-significant decrease in birth weight was found in offspring of women with some occupational exposure to cadmium in France; however, no adverse effects were documented in these newborns.

The authors used hair samples to estimate exposure and this method is limited without controls to distinguish between exogenous and endogenous sources. Smokers It is well-known that babies of mothers who are cigarette smokers are smaller at birth than those of non-smokers and that smoking increases the uptake of cadmium. Some authors have suggested that in pregnant smokers, a cadmium-zinc interaction takes place in the maternal-foetal-placental unit and results in zinc deficiency in the foetus. A trapping of the zinc in the placenta would result in less zinc in the foetus’s red blood cells and theoretically less zinc to grow (JRC, 2007). The weight of evidence to attribute these developmental effects to cadmium from tobacco smoke is insufficient. 5.9.3. Summary and discussion of reproductive toxicity Effects on fertility and sex organs have been noted in experimental studies at high doses of cadmium which generally caused other manifestations of toxicity (e.g. changes in body or organ weights and/or lethality). The lowest NOAELs correspond to 1 mg Cd/kg bw/d via the oral route and ca. 0.23 mg Cd/ m³ after inhalatory exposure. Only a few publications on the effects on human fertility were found. Overall, epidemiological evidence does not speak for an association between exposure to cadmium and relevant effects on fertility or sex organs. In studies with mouse and rat, effects on development were observed after oral and inhalatory exposure to cadmium compounds. Neurobehavioural changes were reported in the absence of maternal toxicity but the robustness of these observations was not sufficient to derive an appropriate NOAEL. It is suggested that further studies are needed to better document the possible effects of cadmium on the developing brain (JRC, 2007). No clear evidence indicates that cadmium has adverse effects on the development of offprings from women exposed indirectly via the environment or occupationally. Effects on birth weight, motor and perceptual abilities of offsprings have been reported by some authors. However, these studies suffer from drawbacks either in the definition of the study postulation, the definition of the effects, or in the assessment of exposure. Moreover, it is not clear whether the effects on psychomotor development were related to cadmium or to a simultaneous exposure to other substances such as lead. This aspect is not considered to have received enough attention in humans and follow-up with a well designed epidemiology study has been proposed (JRC, 2007). Water-soluble cadmium chloride and sulphate are currently classified as Repr. Cat. 2; R60-61 (May impair fertility, may cause damage to unborn child) in Annex I of Directive 67/548 (the corresponding GHS-CLP classification would be Reproduction category 1B; H360). By analogy, a similar classification for cadmium nitrate could be considered. Slightly soluble cadmium metal and oxide have been granted the classification Repr. Cat. 3; R62-63 (Possible risk of impaired fertility, possible harm to unborn child) in Annex I of Directive 67/548 (the corresponding GHS-CLP classification would be Reproduction category 2; H361). Other cadmium compounds in this solubility class (e.g. cadmium hydroxide and carbonate) may warrant this classification as well. Apart from cadmium sulphide, none of the insoluble cadmium compounds (e.g. cadmium sulfoselenide, cadmium zinc sulphide or cadmium telluride), not expected to penetrate easily into the organisms, are classified for reproductive toxicity. Cadmium sulphide is an exception. As there is no data to support its Repr. Cat. 3; R62-63 classification, a revision of the classification may be appropriate based on solubility properties. 5.10. Other effects 5.10.1. Non-human information

5.10.1.1. Neurotoxicity In rats, cadmium carbonate has been reported to produce tremors from exposure to 132 mg Cd/m3 for 2 h, and cadmium fumes produced reduced activity at 112 mg Cd/m3 for 2 h (Rusch et al., 1986). Studies on continuous exposure to cadmium for 30 d have shown no neurological effects at 0.105 mg Cd/m3 for cadmium chloride, 0.098 mg Cd/m3 for cadmium dusts or 1.034 mg Cd/m3 for cadmium sulphide (Glaser et al., 1986). Cadmium chloride had no neurological effects at 0.33 mg Cd/m3 for 5 d/wk, 6 h/d for a total of 62 daily exposures, but did significantly increase relative brain weight at 1.034 mg Cd/m3 (Kutzman et al., 1986). No other studies were located regarding neurological effects in adult animals after inhalation exposure to cadmium.

5.10.1.2. Immunotoxicity An effect of cadmium on the immune function has been reported in mice exposed to 0.190 mg Cd/m 3 (as cadmium chloride, 2 h) which showed suppression of the primary humoral immune response (Graham et al., 1978). The NOAEL for immunological effects from this study was 0.11 mg Cd/m3 (ATSDR, 2008). Krzystyniak et al. (1987) observed a reduction in spleen lymphocyte viability and humoral response at 0.88 mg Cd/m3 in mice exposed to cadmium chloride for 60 minutes.

Prigge (1978) also observed increased relative spleen weights in pregnant females at 0.394 mg Cd/m3 for an exposure of 24 h/d for 21 d during gestation. Oldiges and Glaser (1986) noted enlarged thoracic lymph nodes in dead animals in a chronic-exposure study with cadmium sulphate at 0.092 mg Cd/m3 for 22 h/d, 7 d/wk for 413–455 d and in an intermediate study with cadmium oxide dust at 0.090 mg Cd/m3 for 22 h/d, 7 d/wk for 218 d. However, other studies have found no effect on natural killer cell activity or viral induction of interferon in mice (Daniels et al., 1987). Evidence concerning the effect of inhalation exposure to cadmium on resistance to infection is conflicting, because the same exposure decreases resistance to bacterial infection while increasing resistance to viral infection (Bouley et al., 1982).

5.10.1.3. Specific investigations: other studies There are no other relevant specific investigations. 5.10.2. Human information Neurotoxicity A few studies have reported an association between environmental cadmium exposure and neuropsychological functioning. These studies used hair cadmium as an index of exposure. Endpoints that were affected included verbal IQ in rural Maryland children (Thatcher et al., 1982), acting-out and distractibility in rural Wyoming children (Marlowe et al., 1985) and disruptive behavior in Navy recruits (Struempler et al., 1985). The usefulness of the data from these studies is limited because of the potential confounding effects of lead exposure, lack of control for other possible confounders (including home environment, caregiving and parental IQ levels) and an inadequate quantification of cadmium exposure. Neurotoxicity is not generally associated with inhalation exposure to cadmium, although a few studies have specifically looked for neurological effects. Hart et al. (1989) reported that in a group of 31 men occupationally exposed to cadmium in a refrigerator coil manufacturing plant (average exposure = 14.5 years) there was a modest correlation between cadmium exposure and decreased performance on neuropsychological tests for attention, psychomotor speed and memory. The limited number of men studied makes it difficult to evaluate the significance of this effect. Rose et al. (1992) studied the presence and severity of olfactory impairment in 55 workers chronically exposed to cadmium fumes generated during a brazing operation. A significant olfactory impairment was observed in the workers compared to the reference group. The workers with both higher urinary cadmium levels and tubular proteinuria had the most significant olfactory dysfunction, with a selective defect in odor threshold. The results suggest that chronic occupational cadmium exposure sufficient to cause renal damage is also associated with impairment in olfactory function. Some limitations of the study are that historical exposure to other confounders cannot be ruled out, the classification for nephrotoxicity is based on a single 24 h urine β 2-microglobulin level and the smoking history of the reference group was unknown. No other human neurological studies from inhaled cadmium were found. Immunotoxicity There is limited evidence for immunological effects following inhalation exposure to cadmium. The blood of workers exposed to cadmium for 1–14 years had a slight but statistically significant decrease in the generation of reactive oxygen species by leukocytes compared to unexposed controls (Guillard and Lauwerys, 1989). The toxicological significance of this effect is unclear. Karakaya et al. (1994) measured blood and urine concentrations of cadmium and serum IgG, IgM and IgA in a group of 37 males employed in zinc-cadmium smelters and a small cadmium-electroplating plant. Blood cadmium concentrations were significantly higher in exposed workers compared to controls in both urine and blood. No differences between the exposed and control serum concentrations of IgG, IgM and IgA populations were observed. No changes in blood counts of white blood cells (lymphocyte, neutrophil and eosinophil) were found between exposed and control populations, except for significantly increased monocyte counts. No other studies were located regarding immunological effects in humans following inhalation exposure to cadmium. 5.10.3. Summary and discussion of specific investigations Evidence from experimental systems indicates a potential neurotoxic hazard for cadmium in adult rats. In humans, heavy occupational exposure to cadmium dust has been associated with olfactory impairment and studies performed on a limited number of occupationally-exposed subjects are suggestive of an effect of cadmium on the peripheral and central nervous system but these findings should be confirmed by independent investigators before firm conclusions can be drawn. In the young age, there is some evidence that cadmium exposure may affect the developing brain. This aspect warrants further attention (JRC, 2007). There are some indications of immunotoxicity in animal studies and limited evidence for immunological effects following inhalation exposure to cadmium in humans. The toxicological significance of these effects is unclear.

5.11. Derivation of DNEL(s) / DMEL(s) 5.11.1. Overview of typical dose descriptors for all endpoints The following section summarises available dose descriptors for cadmium metal and cadmium compounds by solubility classes. Separate tables are presented for the water-soluble cadmium nitrate, chloride and sulphate and the slightly soluble cadmium hydroxide, oxide, metal and carbonate. Practically no data is available for the insoluble cadmium sulphide, therefore no dose descriptor summary is given. Based on its low bioavailability, this subtance is expected to present lower toxicity than the more soluble forms of cadmium. Table 32. Available dose-descriptor(s) per endpoint for water-soluble cadmium compounds (cadmium nitrate, chloride and sulphate) Endpoint Quantitative dose descriptor Associated Remarks (appropriate unit) or qualitative relevant effect on study assessment7, 8 Local Systemic Acute toxicity oral NA LD50 = Mortality; lesions Acute LD50 studies 29 - 327 of the proximal (mouse and rat); mg Cd/kg bw section of the qualify for intestinal tract classification as T; R25 / Acute toxicity (oral) Category 2 or 3 dermal NA NA Not expected to - be an issue for human health inhalation NA 0.8 < 4h LC50 ≤ Mortality; Acute LC50 studies 66 x 10-3 mg Cd/L pulmonary lesions (various species); qualify for classification as T+; R26 / Acute toxicity (inhalation) Category 1 Inhalation of 1 mg Toxicity; Observations in Cd/m3 immediately mortality humans dangerous to life; 8h inhalation of 5 mg Cd/m3 lethal Irritation / skin Not expected to - corrosivity eye - NA be an issue for respiratory tract human health Sensitization skin Not expected to - - NA be an issue for respiratory tract human health Repeated dose oral NA NOAEL = 0.12 - 3 Effects in kidney toxicity (sub- mg/kg Cd bw/day and bone Repeated-dose toxicity acute / sub- dermal NA - Not expected to studies in rat, hamster chronic / be an issue for and monkey; qualify chronic) human health for classification as T, inhalation NA NOAEL = Effects in lung, R48/23/25 / STOT 0.013 - 0.022 x 10-3 kidney and bone Category 1 mg Cd/L

7 Pooled results from studies conducted on one or several forms of cadmium

8 A large proportion of the inhalation data comes from studies with cadmium oxide. Cadmium oxide is considered to be ‘slightly’ and not ‘highly’ soluble but data was used to read-across to the highly soluble forms for classification and labelling purposes.

Endpoint Quantitative dose descriptor Associated Remarks (appropriate unit) or qualitative relevant effect on study assessment9 Local Systemic Mutagenicity in vitro - - Conflicting results: negative In vitro and in vivo in bacterial mutagenicity cannot systems, positive be excluded; possible in some threshold for mammalian cell mutagenic effects; systems considered to qualify for classification as in vivo - - Conflicting Muta. Cat. 2: R46 / results; negative Mutagenic Category in certain studies, 1B positive in others Carcinogenicity oral - - Evidence for Animal potential carcinogenicity and carcinogenicity in human epidemiology animals (rat) and studies; considered to general qualify for population classification as dermal - - Not expected to suspected human be an issue for carcinogens (lung human health cancer); attributed inhalation - - Evidence of classification as Carc. carcinogenicity Cat. 2; R45 (lung) in rat and (irrespective of workers route) / Carcinogenic Category 1B Reproductive oral NA NOAEL = Effects on male toxicity 1 mg Cd/kg bw/d and female (fertility reproductive impairment) parameters dermal NA - Not expected to be an issue for human health inhalation NA - No inhalation Oral: one generation studies available fertility/developmental Reproductive oral NA - Evidence of test in rat; toxicity potential developmental toxicity (developmental developmental studies in rat; tox.) effects in rat; considered to qualify considered to for classification as require follow-up Repr. Cat 2: R60-61 / dermal NA - Not expected to Reproduction be an issue for Category 1B human health inhalation NA - Evidence of potential developmental effects in rat; considered to require follow-up

9 Pooled results from studies conducted on one or several forms of cadmium.

Table 33. Available dose-descriptor(s) per endpoint for slightly soluble cadmium compounds (i.e. cadmium metal, oxide, hydroxide and carbonate) Endpoint Quantitative dose descriptor Associated Remarks (appropriate unit) or relevant effect on study qualitative assessment10 Local Systemic Acute toxicity oral NA LD50 = 63 - Mortality Acute LD50 study 2,330 (rat); no classification mg Cd/kg bw dermal NA NA Not expected to be - an issue for human health inhalation NA 0.8 < 4h LC50 ≤ Mortality; Acute LC50 studies 66 x 10-3 mg pulmonary lesions (various species); Cd/L qualify for classification as T+; R26 / Acute toxicity (inhalation) Category 1 Inhalation of 1 Toxicity; mortality Observations in mg Cd/m3 humans immediately dangerous to life; 8h inhalation of 5 mg Cd/m3 lethal Irritation / skin Not expected to be - corrosivity eye - NA an issue for human respiratory tract health Sensitization skin Not expected to be - - NA an issue for human respiratory tract health Repeated dose oral NA NOAEL = 0.12 - Effects in kidney toxicity (sub- 3 mg/kg Cd and bone Repeated-dose acute / sub- bw/day11 toxicity studies in rat, chronic / dermal NA - Not expected to be hamster and monkey; chronic) an issue for human qualify for health classification as T, inhalation NA NOAEL = Effects in lung, R48/23/25 / STOT 0.013 - 0.022 x kidney and bone Category 1 10-3 mg Cd/L Mutagenicity in vitro - - Conflicting results: In vitro and in vivo negative in mutagenicity cannot bacterial systems, be excluded; possible positive in some threshold for mammalian cell mutagenic effects; systems considered to qualify in vivo - - Conflicting results; for classification as negative in certain Muta. Cat. 3: R68 / studies, positive in Mutagenic Category others 2

Carcinogenicity oral - - Evidence for Animal

10 Results from studies conducted on one or several forms of cadmium.

11 Read across from studies with cadmium chloride.

Endpoint Quantitative dose descriptor Associated Remarks (appropriate unit) or relevant effect on study qualitative assessment Local Systemic potential carcinogenicity and carcinogenicity in human epidemiology animals (rat) and studies; considered to general population qualify for dermal - - Not expected to be classification as an issue for human supected human health carcinogens (lung inhalation - - Evidence of cancer); attributed carcinogenicity classification as Carc. (lung) in rat and Cat. 2; R45 workers (irrespective of route) / Carcinogenic Category 1B Reproductive oral NA - No oral toxicity toxicity studies available (fertility dermal NA - Not expected to be impairment) an issue for human health inhalation NA NOAEL = Effects on number 0.25 mg of spermatids in CdO/m3 , male rats ca. 0.23 mg Inhalation: 13 week Cd/m3 inhalation study in Reproductive oral NA - Evidence of rat/ developmental toxicity potential toxicity studies in rat; (developmental developmental considered to qualify tox.) effects in rat; for classification as considered to Repr. Cat 2: R62-63 / require follow-up Reproduction dermal NA - Not expected to be Category 2 an issue for human health inhalation NA - Evidence of potential developmental effects in rat; considered to require follow-up

5.11.2. Correction of dose descriptors if needed (for example route-to-route extrapolation), application of assessment factors and derivation of the endpoint specific DN(M)EL As presented in Section 5.1, uptake of cadmium can occur in humans via the inhalation of polluted air, the ingestion of contaminated food or drinking water and, to a minor extent, through exposure of the skin to dusts or liquids contaminated by the element. The critical routes of exposure are considered to be inhalation in occupational settings and ingestion for the general population. Tobacco is an important additional source of cadmium uptake in smokers. On this basis, DNELS were derived for both workers and general populations. Long-term exposure was considered, in accordance with Section R.8.1.2.5 of the ‘REACH guidance on information requirements and chemical safety assessment, Chapter R.8’. In general, the water soluble cadmium compounds show more toxicity due to their higher bioavailability. Where possible, dose descriptors for these forms are therefore used for calculating DNELS. Much of the inhalation data is however derived from CdO, so that data for that compound forms the basis for the inhalatory DNEL extrapolations.

Workers In worker populations exposed via inhalation, a statistically significant increase in mortality from lung cancer was reported in early studies, but this has not been supported in later work. More recent analyses suggest that, in occupational settings, measures protecting against renal/respiratory effects should also be protective of lung cancer (see Section 5.8.2). SCOEL (2009) recommends an Occupational Exposure Level (OEL) equivalent to 4 µg Cd/m3 (respirable fraction) as protective against long-term local effects (respiratory effects, including lung cancer). This is based on human data that shows changes in residual volume of the lung for a cumulative exposure to CdO fumes of 500 µg Cd/m3 x years, corresponding to 40 years exposure to 12.5 µg Cd/m3 (LOAEL) (Cortona et al., 1992). Applying an uncertainty factor of 3 (LOAEL to NOAEL) leads to a value of 4 µg/m3. Using this OEL value as a starting point and applying the default assessment factors proposed in Table R.8-6 of the ‘REACH guidance on information requirements and chemical safety assessment, Chapter R.8’ yields the following results:

Table 34. Derivation of cadmium DNEL biomonitoring for workers Value Comment Starting point 4 µg Cd/m3 OEL calculated based on critical levels producing lung effects in worker populations Assessment factor 1 Interspecies difference 1 Intraspecies variation 1 Exposure duration 1 Dose-response 1 Quality of whole database

DNEL workers, biomonitoring 4 µg Cd/m3 All assessments factors are equivalent to 1 as actual biomonitoring data was used to derive the OEL, which already integrates inter-individual variation. The proposed DNEL workers, biomonitoring is therefore equivalent to 4 µg Cd/m3. Protection of workers based on this proposed DNEL is recommended to be done according to the Eurometaux/ICdA medical supervision guidance (2006), complementary to all risk reductions measures already in place. This management scheme has been derived from Swedish regulations and the medical part is very similar to the official Guidelines for Occupational Medical examinations of the German Social Accident Insurance. Nowadays it is applied throughout the cadmium-related industry in Europe. The scheme integrates exposure through all possible routes by assessing the Cd-body burden and early biological indicators (BI’s) of sub-clinical effect. It ensures that the risk to Cd-exposed workers is controlled. The medical supervision system is based on measurement of:

 Markers for integrated exposure: Cd-urine (Cd-U; indicator of life-long exposure) and Cd-blood (Cd- B; indicator of present-day or recent exposure)

 Early biological indicators of renal dysfunction

It is designed to be applied in a progressive way, as follows (see also Figure below):

 Cd-U ≤ 2 µg Cd/g creatinine, a conservative threshold based on general population studies, as described in Section 5.6.2 (green zone): general medical follow-up (complementary indicator: Cd-B < 5 µg Cd/L)

 2 < Cd-U ≤ 5 µg Cd /g creatinine, a threshold based on studies at the workplace, as described in Section 5.6.2 (orange zone): biological indicators (BI’s) of early renal dysfunction are being measured on a regular basis (e.g. beta-2 microglobuline (B2-M) or retinol-binding protein (RBP); complementary analysis: Cd-B).

 If the BI’s remain stable and below the reference value (300 µg/g creatinine, the generally applied standard for evaluating renal tubular function), the worker is kept at the workplace, and the reason for the increased exposure is determined (e.g. due to current or previous exposure, due to personal hygiene behavior), followed by additional hygiene measures, if appropriate.

 If the BI’s are exceeding the reference values or showing a consistent pattern of increase, which may lead to approaching the reference values, the worker is removed from cadmium exposure.

 Cd-U > 5 µg Cd/g creatinine (red zone): worker is removed from exposure.

Figure 4. Illustration of Eurometaux/ICdA medical supervision guidance (2006) (BI: biological indicators; C: creatinine)

General population Given the wealth of available animal and human data, the calculation of DNELs for general population can be done using different approaches. In the following section, DNELs are derived based on the results of 1) long- term animal testing and 2) monitoring data. The resulting values are then compared and discussed. DNEL general population derived from animal data As there is currently no conclusive evidence from human studies that cadmium acts as a carcinogen following oral exposure, DNELs for the general population can be calculated based on data from repeated-dose toxicity studies in animals. The lowest oral NOAEL presented in Section 5.11.1 corresponds to 0.12 mg Cd/kg bw/day from a 9 year study in monkey (Masoaka et al., 1994). Using this value as a starting point and applying the default assessment factors proposed in Table R.8-6 of the ‘REACH guidance on information requirements and chemical safety assessment, Chapter R.8’ yields the following results:

Table 35. Derivation of cadmium DNEL general population based on animal data Value Comment Starting point 0.12 mg/kg bw/day NOAEL from a 9 year repeated dose oral toxicity study in monkey Assessment factor 2 Interspecies difference, allometric scaling monkey - human 2.5 Interspecies difference - remaining differences 10 Intraspecies variation, general population 1 Exposure duration (9 years; chronic) 1 Dose-response 1 Quality of whole database

DNEL general population 0.0024 mg Cd/kg bw/day

The resulting DNEL general population is therefore equivalent to 0.0024 mg (2.4 µg) Cd/kg bw/day. DNEL general population derived from general population monitoring As discussed in Section 5.6.2, data from several large general population studies indicate that early renal effects (urinary excretion of low molecular weight proteins, occuring before the onset of overt clinical manifestations of kidney disease) can be detected in the general population for Cd-U around 2 μg Cd/g creatinine. In the Belgian Cadmibel study (Buchet et al., 1990), a urinary excretion of 2 µg/24 h (i.e. roughly 2 µg/g creatinine according to SCOEL, 2009) is estimated to correspond to a mean renal cortex concentration of 50 ppm (wet weight), which in non-smokers would be reached after 50 years of oral ingestion of approximately 1 µg Cd/kg bw/day. This value of 1 µg Cd/kg bw/day can be used as the starting point for estimation of the DNEL general population. As above, applying the default assessment factors proposed in Table R.8-6 of the ‘REACH guidance on information requirements and chemical safety assessment, Chapter R.8’ yields the following results:

Table 36. Derivation of cadmium DNEL general population based on general population monitoring data Value Comment Starting point 1 µg Cd/kg bw/day Estimated lifetime oral ingestion from general (i.e. 2 µg Cd/g creatinine) population studies Assessment factor 1 Interspecies difference 1 Interspecies difference - remaining differences 1 Intraspecies variation 1 Exposure duration 1 Dose-response 1 Quality of whole database

DNEL general population 1 µg Cd/kg bw/day (i.e. 2 µg Cd/g creatinine)

All assessments factors are equivalent to 1 as actual biomonitoring data was used to derive the starting point, which already integrates inter-individual variation and accounts for lifetime exposure.The resulting DNEL general population is therefore equivalent to 1 µg Cd/kg bw/day (i.e. ca. 2 µg Cd/g creatinine).

Discussion The DNELgeneral population derived using either animal or human monitoring data are in good accordance (i.e. 2.4 and

1 µg Cd/kg bw/day, respectively), with the second approach yielding a slightly lower value. As a comparison, the WHO calculate that, in order that levels of cadmium do not exceed 50 µg/g in renal cortex, assuming an absorption rate of 5% and a daily excretion of 0.005% of body burden, total intake should not exceed about 1 µg/kg bw/day continuously for 50 years (WHO, 1987).

6. HUMAN HEALTH HAZARD ASSESSMENT OF PHYSICO-CHEMICAL PROPERTIES 6.1. Explosivity

Data waiving: see CSR section 1.3 Physico-chemical properties.

Classification according to GHS

Name: cadmium sulphate Related composition: cadmium sulphate State/form of the substance: liquid Reason for no classification: conclusive but not sufficient for classification

Classification according to DSD / DPD

6.2. Flammability

Name: cadmium sulphate Related composition: cadmium sulphate State/form of the substance: liquid Reason for no classification (Flammable gases): conclusive but not sufficient for classification Reason for no classification (Flammable aerosols): conclusive but not sufficient for classification Reason for no classification (Flammable liquids): conclusive but not sufficient for classification Reason for no classification (Flammable solids): conclusive but not sufficient for classification

6.3. Oxidising potential

Name: cadmium sulphate Related composition: cadmium sulphate

State/form of the substance: liquid Reason for no classification (Oxidising gases): conclusive but not sufficient for classification Reason for no classification (Oxidising liquids): conclusive but not sufficient for classification Reason for no classification (Oxidising solids): conclusive but not sufficient for classification

7. ENVIRONMENTAL HAZARD ASSESSMENT

General considerations

Cadmium and cadmium compounds form a “data rich” substance group: a vast volume of information is available on the effect of cadmium on the different ecotoxicity endpoints in the open scientific literature. This vast volume of ecotoxicological information was carefully scrutinised by the Rapporteur (Belgium) in the framework of the discussions on the EU risk assessment report (RAR) made under EU Regulation 793/93/EEC. In that process, the Rapporteur’s analysis of the available ecotoxicity data was extensively discussed by the experts from member states and other stakeholders during the meetings of the “Technical committee on new and existing substances” (TCNES), where the data sets to be used for setting ecotoxicity reference values for classification and for PNEC derivation were officially approved.

For this reason, we will use the data used in the RAR as the main data source for the environmental hazard assessment. We will not come back to the decisions on data quality and relevancy that were approved by TCNES, but use the data as they were qualified and used in the RA process. Consequently, we will use for the current analysis the data that were considered useful in the RAR as such. Likewise, we will not use the data that were found not useful in the RA process for the current analysis. Given the vast amount of data, we have only reported the useful data in the IUCLID V file; the data not considered useful in the RA process have been summarised in the RAR (ECB 2008).

For some endpoints, the extensive datasets from the RAR will be updated with significant and reliable information that became available after the closure of the RA databases. These data are also reported under IUCLID V and used for the present hazard assessments. There are two exceptions to this general approach: 1) Setting of the PNEC for marine waters. In the RAR, no analysis was made for Cd toxicity to aquatic marine organisms. Therefore a detailed literature search was made for marine ecotoxicity data on cadmium, the information was scrutinised for quality and relevancy, and a PNEC for Cd in marine waters was subsequently derived.

2) Setting of a PNEC for Cd in marine sediments, which was not done in the RAR either. For this endpoint also, a detailed literature search was made for ecotoxicity data on the effect of cadmium in marine sediments. The information was scrutinised for quality and relevancy, and a PNEC for Cd in marine sediments was subsequently derived.

In the RAR, the datasets on freshwater ecotoxicity have resulted in derivation of a hardness-related PNEC, that has been used afterwards for setting the water quality standard for Cd in EU waters (according to directive 2008/105/EC). Considering on one hand that the PNEC was defined in the risk assessment based on an extensive database covering a broad spectrum of taxonomic groups and, on the other hand, that the EQS have been confirmed in EU legislation, we have not further updated the aquatic database from the risk assessment.

In accordance to the scientific approach followed in the EU RA process, two assumptions are the key to the cadmium environmental hazard assessment: 1) The basic assumption made in this hazard assessment and throughout this CSR is that the ecotoxicity of cadmium and cadmium compounds is due to the Cd++ ion. Consequently, all aquatic and terrestrial toxicity data in this report are expressed as “cadmium”, not as the different cadmium compounds that were used for the testing, because ionic cadmium is considered to be the causative factor for toxicity. Hence, all ecotoxicity data obtained on different (soluble) cadmium compounds are mutually relevant for each other. For that reason, the considered ecotoxicity data related to cadmium and the different cadmium compounds are combined before calculating the PNECs. The only way cadmium compounds can differ in this respect is in their capacity to release cadmium ions into (environmental) solution. That

capacity is checked eventually in the transformation/dissolution tests and may result in different classifications. But in principle, this section 7 of the CSR is the same for all soluble cadmium substances.

2) Cadmium is a natural component of the earth’s crust and present in natural background concentration in all environmental compartments. The natural cadmium background is rather low. To avoid acclimation to elevated Cd levels prior to testing, only test results obtained under Cd-background in test and/or nutrient solution were used e.g. for aquatic toxicity tests, only tests performed at Cd Background <1µg Cd/l were used according to the RAR. The Cd-background was not further considered in the derivation of the PNECs, except in the case of the sediments. Hence, most of the PNECs are “total” PNECs, integrating the full concentration of cadmium, of both natural and anthropogenic origin combined. Exception are the sediment PNECs, which are “added” PNECs, i.e. the background concentration in sediment needs to be considered in the assessment.

7.1. Aquatic compartment (including sediment) 7.1.1. Toxicity test results

1. Aquatic toxicity: freshwater, short-term

Acute data- establishing the dataset

Numerous data are available on acute toxicity of cadmium to aquatic organisms. The quality and relevancy of the unique data is of great importance because, in contrast to the PNEC derivation (where all the chronic data are used in a species sensitivity distribution), one single value defines the ecotoxicity reference value for classification. Therefore, for setting the reference value for acute aquatic toxicity (and classification), only data from standardised test protocols and standardized test organisms were considered in the analysis.

The RAR made an in-depth analysis of the reliability of the acute toxicity data and assigned a “reliability index” (RI) to each data point. For setting the reference value for acute aquatic ecotoxicity, only the results qualified as RI 1 (standard tests) were used, complemented for the fish and invertebrates with RI 2 qualified data (not standard test but from a similar protocol and with a complete background information on test conditions).

In the RAR, acute ecotoxicity reference values were specifically set for Cd (metal) and CdO. These values were based on high quality (Q1=RI 1) test results. Since these data are expressed on basis of a measured cadmium (ion) concentration, they were pooled with the data obtained on other Cd-compounds, also mentioned in the RAR.

This strict selection of the highest quality data is possible because the high number of acute data that are available. It ensures that the tests were performed under well defined and/or standard conditions, and provide a sound basis for classification.

The acute aquatic ecotoxicity data base for cadmium was reviewed further according to the following principles:

←the data assigned RI 1 and RI 2 in the acute aquatic toxicity database of the RAR (ECB 2008, tables 3.2.2., 3.2.4., and 3.2.6.) were used as such. Prescriptions from standard protocols were strictly followed, e. g. duration for acute test: fish 96 hrs, daphnids 48 hrs, algae 72 hrs.

←Data that were assigned RI 3 (not reliable) and RI 4 (not assignable) in the RAR were not used for setting the reference value for acute aquatic toxicity.

Hardness is the main determining factor for Cd toxicity to aquatic organisms (RAR 2008). Cd-toxicity is more important under conditions of low hardness. Therefore, in the review of the acute data, special attention was paid to considering and selecting data obtained under low hardness conditions. Only tests performed at Cd background <1µg Cd/l were used, according to the RAR.

If 4 or more data points were available on a same species, and the data were obtained under similar conditions, the geomean was calculated and used for the analysis.

Acute data - results

The short-term acute aquatic toxicity data on cadmium for all species (1 algae species, 2 invertebrate species, and 7 fish species) are summarised in the CSR.

The short-term acute aquatic toxicity data on cadmium for all species (algae, invertebrates, and fish) are summarised per species and group in table below.

The full set of EC50 values are presented under sections 7.1.1.1.1.(fish), 7.1.1.2.1. (invertebrates) and 7.1.1.3. (algae and plants). In the table below, the data are summarised together with the pH and hardness of the test media. A significant number of data are available at both low and neutral/high pH.

Table 37. Acute aquatic toxicity of cadmium by species as a function of pH and hardness. species RI pH Hardness E(L, I)C50 reference (mg value (µg CaCO3/l) Cd/l) Algae (cfr RAR CdO, table 3.2.6.) Selenastrum capricornutum 1 7.7-10.4 49 23 LISEC 1998a Selenastrum capricornutum 1 7-10 49 18 LISEC 1998b Selenastrum capricornutum 1 7-9 23 70 Janssen Pharmaceutica 1993a Selenastrum capricornutum 1 7-8 23 120 Janssen Pharmaceutica 1993b Daphnids Daphnia magna 1 7.76 247 110 Janssen Pharmaceutica 1993c 2 8.0 11 1900 Kühn et al. 1989 2 8.05 226 750 Janssen Pharmaceutica 1993d 2 6.95 130 58 Attar and Maly 1982 2 8-8.5 160-180 38 Lewis and Horning 1991 2 6.6-7.8 26-32 36 (static) Schuytema et al, 1984 49 (continuous) Daphnia pulex 2 8.8.5 80-100 42 Lewis and Horning 1991 Fish Pimephales promelas 2 7.1-7.8 44 1500 Phipps and Holcombe 1985 Salmo Salar 2 6.5-7.3 19-28 34 Rombough and Garside 1982 Jordanella floridae 2 7.1-7.8 44 2500 Spehar 1976 Lepomis macrochirus 2 7.4-7.7 18 2300 Bishop and McIntosh 1981 L. macrochirus (juv) 2 7.1-7.8 44 6470 Phipps and Holcombe 1985 Carassius auratus 2 7.1-7.8 44 748 Phipps and Holcombe 1985 Ictalurus punctatus 2 7.1-7.8 44 4480 Phipps and Holcombe 1985

The lowest species values (µg Cd/l) are summarised in table below

Table 38. Lowest acute aquatic toxicity data observed for cadmium species Hardness <100mg Hardness >100mg CaCO3/l CaCO3/l algae Selenastrum 18 / capricornutum

Daphnids Daphnia magna 36 38 Daphnia pulex 42 / fish Salmo Salar 34 /

Discussion/conclusion: reference value for short term aquatic ecotoxicity

The data span for all groups a variety of hardnesses, from very low to high. Low hardness data are available for all 3 taxonomic groups. Most data are obtained at neutral to higher pH (7-8.5).

The EC50 values show strong variability, but the lowest values observed at low hardness are of the same order of magnitude for all 3 taxonomic groups.

In conclusion, the data set covers the 3 taxonomic groups (algae, daphnids and fish) and allows to set the reference value for acute aquatic toxicity for Cd (dissolved, ionic form). The lowest value is obtained on the algae Selenastrum capricornutum under low hardness conditions: 18 µg Cd/l. This value was also used as reference value for acute aquatic toxicity in the RAR on CdO (ECB 2008), for both low and neutral/high pH, and for low and high hardness.

2. Aquatic chronic toxicity: freshwater

Chronic data - establishing the dataset

As for the acute toxicity, numerous data are available on the chronic toxicity of cadmium to aquatic organisms. The quality and relevancy of the data has been reviewed in detail by the Belgian rapporteur for the EU risk assessment (RA; ECB 2008). Data categorised as RI 3 are less reliable: they may lack key information to assess the quality and relevancy of the test result, e. g. information on test conditions like pH may lack, there may be no information on measured Cd concentrations or no indication that nominal Cd levels were close to measured levels, there may be no information that Cd concentrations during testing were maintained, there may be no statistics on the dose response relationship, no information on the origin of the test organisms or the tested concentration range. In spite of those shortcomings, the RI 3 data are also considered for inclusion in the species sensitivity distribution, because it was done as such in the EU risk assessment. The RA combined all 3 groups of data because the species sensitivity distribution covers the sensitivity of all the species included and the RI 3 data also contribute to the weight of evidence on the sensitivity of aquatic organisms to Cd. To avoid effects of acclimation, only tests performed at Cd background <1µg Cd/l were used, according to the RAR.

Chronic data results

The dataset on chronic aquatic toxicity is presented in detail under sections 7.1.1.1.2. (long-term fish), 7.1.1.2.1. (invertebrates), and 7.1.1.3. (algae and plants).

The chronic aquatic toxicity data (NOECs) that are used for PNEC derivation in the EU RA, are summarised in table below. Chronic NOECs categorised RI 1 and RI 2 are combined with data categorised RI 3. According to the EU RA, no species geomean was made for some species, because tests were done in different medium or different endpoint was mentioned. Such “case-by-case” approach as it was called in the RA deviates from the one generally used in statistical extrapolation; still, it was used in the EU risk assessment and therefore taken over in the present analysis.

Table 39. 'Case-by-case”- selected NOEC data of effects of Cd in freshwater and case-by-case calculation of 'geometric mean NOEC's. Bold, underlined data are selected for the HC5 calculation. (after table 3.2.9C of the EU risk assessment).

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 120 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 organism medium H endpoint NOEC references (µg L-1)

Salmo gairdneri aerated well water; T 10; O2 7.5; pH 375-390 mortality 12 Lowe-Jinde and Niimi, 8-8.6 1984

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 121 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 organism medium H endpoint NOEC references (µg L-1) Salmo gairdneri synthetic water (ISO 1977) ; T 25; pH 100 median survival time 4 Dave et al., 1981 no geometric mean 8.3 calculation: different test (no medium geomean) Oncorhynchus kisutch sand filtered Lake Superior Water; 45 biomass 1.3 Eaton et al., 1978 continuous flow; DO 10.3; Al 41; Ac 3; pH 7.6 Salvelinus fontinalis sand filtered Lake Superior Water; 45 biomass 1.1 Eaton et al., 1978 continuous flow; DO 10.3; Al 41; Ac 3; pH 7.6 Salvelinus fontinalis sterilised Lake Superior water; pH 7- 42-47 total weight of young 0.9 Benoit et al, 1976 geometric mean 8; Al 38-46; Ac 1-10; DO 4-12; T 9- /female of the 2nd geomean calculation: same test 15 generation = 1.0 medium, same endpoint (biomass) Salvelinus fontinalis reconstituted soft water: T 14-16°C; 20 survival 8 Jop et al., 1995 DO 9.3-11.4 mg/L; Cd(BG) <0.2 µg/L; pH 6.3-7.6; H 20 Salvelinus fontinalis river water: T 14-16°C; DO 8.7-12.2 16-28 survival 62 Jop et al., 1995 geometric mean mg/L; Cd(BG) <4 µg/L; pH 6.6-7.4; geomean calculation: similar test H 16-28 = 22 medium, same endpoint (survival) Salmo salar municipal water charcoal filtered and 19-28 total biomass 0.47 Rombough and Garside, UV sterilised; BC 0.13 µg Cd/L; pH 1982 6.5-7.3; T 5-10; DO 11.1-12.5; Al 14- 17 Catostomus commersoni sand filtered Lake Superior Water; 45 standing crop (biomass) 4.2 Eaton et al., 1978 Esox lucius continuous flow; DO 10.3; Al 41; Ac biomass 4.2 Salvelinus namaycush 3; pH 7.6 4.4 Salmo trutta (late eyed 1.1 eggs) Jordanella floridae untreated Lake Superior water; T 25; 44 reproduction 4.1 Spehar, 1976 DO 8.3; Al 42; Ac 2.4; pH 7.1-7.8 Brachydanio rerio synthetic water (changed ISO) ; T 24; 100 reproduction 1 Bresch ., 1982 DO >80%; pH 7.2 Oryzias latipes tap water; continuous flow; T 20 200 mortality and 6 Canton and Slooff, 1982 no geometric mean 100 abn. behaviour 3 calculation: different test medium Xenopus laevis tap water; continuous flow; T 20 170 inhibition of larvae 9 Canton and Slooff, 1982 development Pimephaless promelas pond water diluted with carbon 201-204 reproduction (pond fish) 13 Pickering and Gast, geometric mean filtered demineralised tap water; DO reproduction (laboratory 1972 calculation: same test 6.5-6.6; pH 7.6-7.7; Al 145-161; Ac fry) 14 medium, same endpoint 8-12; T 16-27 geomean (reproduction) = 13.5 Daphnia magna 50 µm filtered and sterilised Lake 224 intrinsic rate of natural 3.2 Van Leeuwen et al., IJssel water; pH 8.1; T 20; H 224 increase 1985 Daphnia magna NPR synthetic water; pH 8.4; T 20 200 mortality 1 Van Leeuwen et al., no geometric mean 1985 calculation: different endpoints Daphnia magna synthetic water; T 25; pH 8; DO 69% 11 reproduction 0.6 Kühn et al., 1989 different medium

Daphnia magna Synthetic water; Al 65; T 25 90 reproduction 2 Winner, 1988 D. magna: well water: T 202°C; DO 4.9-7.9; 103 reproduction 0.16 Chapman et al., 1980 geometric mean Cd(BG) 0.08; pH 7.9 geomean calculation: similar = 0.6 medium, same endpoint) well water: T 202°C; DO 4.9-7.9; 209 reproduction 0.21 Chapman et al., 1980t Cd(BG) 0.08; pH 8.2 Daphnia magna unchlorinated, carbon filtered well 240 reproductive impairment 2.5 Elnabarawy et al., 1986 water, aerated to saturation; Al 230; pH 8; DO >5; T 23; Cd < 0.01 µg Cd/L Daphnia magna aerated well water; DO >70%; pH 8; 300 reproduction 0.8 Knowles and McKee, no geometric mean T 22; Al 250 1987 calculation: different medium Daphnia magna culture medium; pH8.4; T 20 150 biomass 2.5 Bodar et al., 1988a

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 122 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 organism medium H endpoint NOEC references (µg L-1) production/female Daphnia magna 20 µm cloth filtered Lake Superior 45.3 weight/animal 1 Biesinger and no geometric mean water; pH 7.7; Al 42.3; DO 9; T 18 Christensen, 1972 calculation: different medium Daphnia pulex Whatman N° 1 filtered Lake 65 longevity 1 Bertram and Hart, 1979 Champlain water; pH 7.7; Al 42.4; Cd < 1µg L-1 Daphnia pulex unchlorinated, carbon filtered well 240 reproductive impairment 7.5 Elnabarawy et al., 1986 water, aerated to saturation; Al 230; pH 8; DO >5; T 23; Cd < 0.01 µg Cd/L Aplexa hypnorum: Lake Superior water; DO 7.5; T 24 growth 4.41 Holcombe et al., 1984 immature Physa integra untreated Lake Superior water; pH 44-48 mortality 8.3 Spehar et al., 1978 7.1-7.7; T 15; DO 10-11; Al 40-44; Ac 1.9-3 Daphnia galeata mendotae 10 µm filtered Lake Michigan water; 120 number of individuals 2 Marshall, 1978 T 18.5 Ceriodaphnia reticulata unfiltered river water; static; Ac 2- 55-79 reproduction 3.4 Spehar and Carlson, 4.2; Al 41-65; pH 7.2-7.8 1984 Ceriodaphnia reticulata unchlorinated, carbon filtered well 240 reproductive impairment 0.25 Elnabarawy et al., 1986 no geometric mean water, aerated to saturation; Al 230; calculation: different pH 8; DO >5; T 23; Cd < 0.01 µg/L medium Ceriodaphnia dubia Synthetic water; Al 65; T 25 90 mortality 1.5 Winner, 1988 no geometric mean calculation: different medium, different endpoint Ceriodaphnia dubia reconstituted soft water: T 14-16°C; 20 reproduction 10 Jop et al., 1995 DO 9.3-11.4 mg/L; Cd(BG) <0.2 µg/L; pH 6.3-7.6; H 20 Ceriodaphnia dubia river water: T 14-16°C; DO 8.7-12.2 16-28 reproduction 11 Jop et al., 1995 geometric mean mg/L; Cd(BG) <4 µg/L; pH 6.6-7.4; geomean calculation: similar H 16-28 = 10.5 medium, same endpoint (reproduction) Hyalella azteca well water: T 23; pH 7.8 280 Survival 0.51 Ingersoll and Kemble, 2000 Chironomus tentans well water: T 23; pH 7.8 280 weight 5.8 Ingersoll and Kemble, 2000 Selenastrum modified ISO 6341 medium; 0.2 µm 49 cell number 2.4 LISEC, 1998a capricornutum filtered; T 20.3-25.6; pH 7.7-10.4 Coelastrum proboscideum AM;T 31;pH 5.3; 32 biomass 6.3 Müller and Payer 1979 Asterionella formosa AM; pH 8 121 growth rate 0.85 Conway and Williams 1979 Chlamydomonas reinhardii AM; pH 6.7; T 20 42 steady state cell number 7.5 Lawrence et al. 1989 Scenedesmus quadricauda AM; pH 7 biomass (OD) 31 Bringmann and Kühn, 1980 Lemna paucicostata AM; T 25 number of fronds Nasu and Kugimoto, no geometric mean pH>6 120 5 1981 calculation: different pH 5.1 120 10 medium pH 5.1 700 10

T = temperature (°C); H = hardness (as mg CaCO3/L); DO = dissolved oxygen (mg O2/L); Al = alkalinity (mg CaCO3/L); Ac = acidity (mg CaCO3/L); AM, artificial medium.

For classification purposes, the following lowest NOECs (µgCd/l) per taxonomic group can be identified (when values are not grouped for the SSD, they are also not grouped for the chronic ecotoxicity reference value): fish Salmo salar 0.47 invertebrates Daphnia magna 0.21 algae Asterionella formosa 0.85

So, the lowest chronic NOEC for use as reference value in classification is 0.21 µg Cd/l (Daphnia magna)

Results' extensive table "Case-by-case"- selected NOEC data of effects of Cd in freshwater and case-by-case calculation of 'geometric mean NOEC's can be found in the CMR (after table 3.2.9C of the EU risk assessment).

3. Aquatic chronic toxicity: marine waters

Chronic data - establishing the dataset

The Cd Risk Assessment has not carried out an effect assessment on the aquatic marine environment, while REACH requires protection of this environmental compartment, i. e. the derivation of a saltwater PNEC for Cd. The saltwater PNEC derived in this section covers truly marine conditions. It is derived based on chronic toxicity data from the literature. The available chronic cadmium toxicity data were derived from original papers, published in peer-reviewed international journals. Literature and environmental databases, including AQUIRE (US EPA), MARITOX, ECETOC, and BIOSIS, as well as review articles covering cadmium in marine waters were searched and reviewed for sources of relevant and reliable chronic toxicity data on cadmium. Only original literature was used.

Data reliability and relevance Selection of ecotoxicity data for quality was done according to a systematic approach as presented by Klimisch et al. 1997. Standardized tests, as prescribed by organizations such as ASTM, OECD and US EPA, are used as a reference when test methodology, performance and data treatment/reporting are considered. A detailed description of methods and conditions employed in the study should be provided. The thorough description of key requirements guarantees the high reliability (Q1) of the reported ecotoxicity data. Non-standardized test data, may also have a high reliability, but required a more thorough check on their compliance with reliability criteria before being used for deriving a PNEC. As for data relevancy, tests should be performed in media that reflect natural environmental conditions (e.g. salinity and other abiotic conditions). A set of criteria for checking reliability and relevancy has been defined in this work and is presented here below. Those criteria were used to discriminate between data accepted with restrictions (Q2) and unreliable data (Q3).

Test medium Both natural sea water and artificial sea water were accepted as test medium. In case EDTA is present in the test medium, the study is considered not reliable. Chelators other than EDTA (e.g. NTA, citrate,…) can be added. In this case, the data were considered reliable. Only the results of tests with soluble cadmium salts were used. Data where information on the salt used was not available were regarded as reliable with restrictions (Q2). In the reported data, cadmium has been used as the test material with several salts being used. As with other risk assessments on metals, it is generally recognized that under laboratory conditions almost all the cadmium is present in the dissolved fraction, therefore these results can be regarded as being dissolved cadmium concentrations. Tests with metal mixtures were not considered for this evaluation.

Salinity The TGD does not define the salinity range of sea water. The Water Framework Directive allows for using the saltwater EQS at salinities ≥ 5‰, which sets the limit between freshwater and brackish waters. Therefore, tests performed at salinity levels down to a value of 5 g/kg were accepted for this marine dataset.

Measured versus nominal concentrations The results of marine aquatic toxicity studies are expressed either as measured concentration, or usually as nominal concentration. The measured concentrations include the background concentration. However, most of the publications do not report Cd background concentrations as they are usually very minor compared to the no effect or lowest effect levels. A total risk approach was then considered in this assessment without correcting for background values. That is, no correction for background was applied to measured concentrations which were used together with nominal concentrations to derive the PNEC. Highly reliable data supported by nominal concentrations were regarded as Q2 data. If it is not mentioned whether the NOEC/L(E)C10 values are based on measured or nominal concentrations, they were considered as nominal concentrations.

Control data Tests were rated as not reliable if control data was not provided. Effect levels derived from toxicity tests using only one test concentration always result in unbounded values and therefore not assignable data. Therefore, only the results from toxicity tests using one control and at least two cadmium concentrations were retained for this evaluation. Data reporting mortality rates higher than 20% in the control were not used in this assessment.

Test statistics Because effect concentrations are statistically derived values, information concerning the statistics was used as a criterion for data selection. Studies that do not report test statistics but present trust-worthy data are rated as reliable with restrictions (Q2). Studies that do not report test statistics and do not present a dose-response analysis are rated as unreliable (Q3).

Test design Data without treatment replication or with pseudo-replication were not used (Q3).

Type of test (duration, endpoints covered) Only reliable endpoints from properly conducted chronic tests were considered. Toxicological (sub)lethal endpoints which affect the species at population level were taken into account (i.e. survival, development, reproduction and growth). Historically, chronic exposure has been defined as > 4 days for all invertebrates and fish. With respect to this assessment, the arbitrary selection of this exposure period has been reviewed in light of the sensitivity of the endpoint and the duration of the life stage under assessment. For example, early life stages tests (embryos, larvae) of 24-48 hours have been included in this assessment because of their expected higher sensitivity towards pollutants. Sperm cells and fertilized eggs tests of a few hours were also considered as chronic data. Indeed, abnormal development can be observed within this time frame (e.g. in molluscs, echinoderms), and the continuation of these tests would derive no additional information which could provide protection for the environment. For algae, and according to ASTM guidelines, data reporting growth rates < 1 in the control were not used.

Origin of test species: The culture and test conditions are considered more relevant than the geographical origin of the species and the OECD guidelines recommend the use of a number of “standard” species which do not have a world-wide distribution. Moreover, using the origin of species as criterion would considerably reduce the dataset and limit the data to only a few species / taxa, which may obscure variation in sensitivity. Therefore, the geographical origin of the test species has not been used as selection criterion. Organisms collected at contaminated sites were not used in the analysis. Only results from unpolluted test media were used.

Derivation of NOEC/LOEC values (methods) The toxicological variables are estimated based on NOECs or EC 10 values coming from concentration-effect relationship. In the past, the NOEC was determined directly from the concentration-effect curve by consideration of the deviation from the control (e.g. 10%) or it was derived on the basis of ANOVA (analysis of variance) and a subordinate test (e.g. Dunett's). This method to derive the NOEC with the ANOVA is criticized. Pack et al., 1993 recommends the calculation of the ECX point as a preferable alternative. In older investigations, it may be difficult to find out how the NOEC was generated unless test reports or raw data are available. NOEC values without any information about the concentration-dependent response were excluded from PNEC analysis.

Unbounded NOEC values (i.e. no effect was found at the highest concentration tested) were not used in this analysis in accordance to previous risk assessments on metals.

In a few cases, no NOEC or LOEC value was provided, but raw data were reported. When possible, the raw data were used to derive an EC10 using the Toxicity Relationship Analysis Program (TRAP) from the US EPA National Health and Environmental Effects Research Laboratory (NHEERL) or using a simple linear interpolation. The recalculated EC10 values were used with restrictions.

In case only a LOEC is given in the report, it was used to derive a NOEC with the following procedure (in accordance to the approach taken in the EU Risk Assessment Report on Zn metal, ECB 2008): - LOEC ≥ 10 and < 20% effect: NOEC can be calculated as LOEC/2. - LOEC ≥ 20 and < 30% effect: NOEC can be calculated as LOEC/3. - If the effect percentage of the LOEC is higher than 30% or if it is unknown, no NOEC can be derived.

In aquatic toxicity the MATC (maximal acceptable toxicant concentration) is often calculated. This is the geometric mean of the NOEC and the LOEC. If in the test report only the MATC is presented, the MATC can be divided by √ 2 to derive a NOEC.

If for one species, several chronic NOEC values (from different tests) based on the same endpoint are available, these values are averaged by calculating the geometric mean, resulting in a “species mean NOEC”. If several toxicity endpoints are reported for the same species, the most sensitive endpoint, so the lowest NOEC value is selected for PNEC derivation. The lowest value is determined on the basis of the geometric mean if more than one value for the same endpoint exists.

Chronic toxicity of Cd in saltwater

Aquatic marine ecotoxicity database for cadmium

The marine cadmium database largely fulfils the species and taxonomic requirements for input chronic toxicity data as explained in the RIP R. 10 guidance (at least 10 species NOECs and 8 taxonomic groups). Indeed, 48 species mean NOECs based on 62 NOEC values, coming from 39 families and from 9 taxonomic groups covering three trophic levels were found to fulfil the relevancy and reliability requirements as explained by Klimisch et al. 1997. The marine Cd database includes 1 micro- and 1 macro-algae species, 4 annelid species, 11 crustacean species, 7 echinoderm species, 13 mollusc species, 3 nematod species, 2 cnidarian species, 1 ascidian species and 6 fish species.

The geometric mean values of the species NOECs together with their reliability scoring are presented in Table below. Most of the effects data are ranked as reliability 2 (Q2). Data are either reported as nominal or measured concentrations.

Table 40. Endpoints selected for use in SSD for the derivation of marine PNEC for Cd. Cadmium aquatic marine database (chronic toxicity data)

Taxonomic Species name Family Geomean NOECadd Reliability group value (µg Cddiss/L) Micro-Algae - Chaetoceros compressum Chaetocerotacae 18.3 2 (1) Macro-Algae - Ulva pertusa Ulvaceae 63 2 (1) Annelids - Capitella capitata Capitellidae 126.5 2 (4) - Ctenodrilus serratus Ctenodrilidae 320.9 2 - Neanthes arenaceadontata Nereididae 126.5 2 - Ophryotrocha diadema Dorvilleidae 100 2 Cnidarians - Eirene viridula Eirenidae 100 2 (2) - Campanularia flexuosa Campanulariidae 87.7 2 Crustaceans - Artemia franciscana Artemiidae 39.3 2 (11) - Artemia parthenogenetica Artemiidae 106.1 2 - Artemia persimilis Artemiidae 99.5 2 - Artemia salina Artemiidae 56.7 2 - Balanus Amphitrite Balanidae 5 2 - Elminius modestus Archaeobalanidae 316 2 - Mysidopsis bahia Mysidae 2.2 2 - Paragraspus Grapsidae 105 2 quadridentatus Penaeidae 33.3 2 - Penaeus monodon Harpacticidae 36.7 2 - Tigriopus brevicornis Moiniidae 1.8 1 - Moina monogolica Echinoderms - Arbacia lixula Arbaciidae 357 2 (7) - Asterias amurensis Asteriidae 10000 2 - Echinometra mathaei Echinometridae 10 2

Cadmium aquatic marine database (chronic toxicity data)

Taxonomic Species name Family Geomean NOECadd Reliability group value (µg Cddiss/L) - Lytechinus pictus Toxopneustidae 4.2 2 - Paracentrotus lividus Echinidae 35.5 2 - Sphaerechinus granularis Toxopneustidae 623 2 - Strongylocentrotus Strongylocentrotidae 12.5 2 droebachiensis Molluscs - Crassostrea cucullata Ostreidae 7.1 2 (13) - Crassostrea gigas Ostreidae 13 2 - Crassostrea margaritacea Ostreidae 12.6 2 - Haliotis rubra Haliotidae 520 2 - Ilyanassa obsolete Nassariidae 112.4 2 - Isognomon californicum Isognomonidae 0.3 2 - Meretrix lusoria Veneridae 33.3 2 - Mya arenaria Myidae 50 2 - Mytilus edulis Mytilidae 480 2 - Mytilus galloprovincialis Mytilidae 119.8 2 and 1 - Perna viridis Mytilidae 345.8 2 and 1 - Ruditapes decussatus Veneridae 265 2 - Tresus nuttalli Mactridae 42 2 Nematods - Monhystera disjuncta Monhysteridae 3333 2 (3) - Monhysteramicrophthalma Monhysteridae 1000 2 - Pellioditis marina Rhabditidae 25000 2 Ascidians (1) - Ciona intestinalis Ascidiaceae 430.5 1 and 2 Fish - Atherinops affinis Atherinidae 10 1 (6) - Epinephelus coioides Serranidae 33.3 2 - Lates calcarifer Centropomidae 794 2 - Menidia menidia Atherinidae 259.8 2 - Mugil cephalus Mugilidae 20 2 - Pseudopleuronectes Pleuronectidae 283.7 2 americanus TOTAL: 10 Tax. gps 48 species 39 families 48 species mean NOECs

Statistics on Species sensitivity distribution

Given the multitude of relevant high quality ecotoxicity data, species mean NOECs were plotted in a species sensitivity distribution (SSD) and statistical extrapolation was used for PNEC determination. No alternative method i. e. assessment factor approach was applied for the PNEC determination. Following the RIP R. 10 guidance, different distributions may be used for the SSD. But according to the rules established in previous Risk Assessments for metals, and given the significance levels are accepted, the use of a log-normal distribution is preferred over other statistical distributions (Cd RAR 2007). Based on the 48 species geometric mean NOECs presented in Table above and use of the program ETX 2.0 (Van Vlaardingen et al. 2004) for deriving an SSD (Figure below), the median 5th percentile value of 2.28 µg/L is calculated with a lower 95 per cent confidence interval of 0.93 µg/L and an upper 95 per cent confidence interval of 4.64 µg/L. The assumption that the input data are normally distributed is accepted at the highest significance level (P = 0.01) using the Anderson-Darling Goodness-of-Fit, the Kolmogorov-Smirnov and the Cramer von Mises tests for normality. Other statistical distributions were calculated using the software “@risk” (Palisade Inc.). The Logistic distribution on the log-transformed data turned out to be the best fit with an HC5-50 value of 2.54 µg Cd/L (Table below). The difference between both distributions is however minimal. The statistics of the curve-fitting on the chronic NOEC data are summarized in the table below.

Table 41. Summary statistics for the SSD on chronic NOEC values for cadmium in saltwater (n=50).

Distribution Media Lower Median A-D A-D K-S K-S Acceptance n HC5 estimate HC5/lower statistic significance statistic significance for PNEC on HC5 95% C. I. level level setting Lognormal 2.28 0.93 2.45 0.35 P > 0.1 0.66 P > 0.1 Accepted (ETX) Lognormal 2.33 / / 0.35 P > 0.25 0.09 P > 0.15 Accepted (@risk) Best fit 2.54 / / 0.21 P > 0.25 0.07 P > 0.1 Accepted (Logistic; @risk)

The observed high quality data are presented as log-scale together with their fitted normal distribution curve in figure below:

Figure 5. Species sensitivity distribution of selected chronic marine Cd endpoints (n=47)

The 5th percentile value of the SSD (the HC5), set at 50% confidence value, using the lognormal distribution (ETX 2.0) function, results in a value of 2.28 µg cadmium/L. This value is taken forward for the PNEC derivation.

Mesocosm studies A study on phytoplankton communities from three different areas was carried out by Wolter et al. (1984). Influence of metal to carbon fixation rate of phytoplankton and to glucose incorporation by bacteria was

determined. Water samples coming from Kiel Fjord, North Sea and a coastal area of the North Atlantic Ocean were investigated after addition of varying concentrations of metals including cadmium. Surface samples were taken in Kiel Fjord during the spring and autumn plankton bloom. Cadmium was added to subsamples to give concentrations in the range of 0.08 to 20.08 µg/L. Samples from the North Sea and Atlantic were collected. The added cadmium concentrations were 0.5 to 2.5 µg/L. The added metal concentrations were lower than in the Kiel Fjord experiments due to lower concentrations in the water compared to Baltic Sea water. In all cases the samples contained mixed phytoplankton populations which were dominated by diatoms. From the graph, cadmium did not reduce plankton activity in the Kiel Fjord samples at a concentration of 1.5 µg/L. However, carbon fixation measurements carried out four and 24 hours after metal addition to the North Sea and Atlantic samples were not reduced at any test concentration, which then gives unbounded values (see table below for summary of results). The same was true for bacterial glucose incorporation.

Table 42. Results of field experiments made on phytoplankton communities coming from various natural sea waters   Location  Endpoint   Kiel Fjord  North Sea  Atlantic   NOEC (µg  1.5 (from  2.5  2.5  C fixation rate Cd/L) after 4 or graph) (unbounded) (unbounded) 24 hours exposure  NOEC (µg  /  2.5  2.5  Bacterial Cd/L) after 4 or (unbounded) (unbounded) glucose 24 hours incorporation exposure

Although this study has nothing inherently wrong in the design, but some important details are lacking (no accurate information about test organisms and test conditions, no information on statistics and on control data, …). The results should thus be handled with care .

7.1.1.1. Fish

7.1.1.1.1. Short-term toxicity to fish

The results are summarised in the following table:

Table 43. Overview of short-term effects on fish

Method Results Remarks Reference Pimephales promelas LC50 (4 d): 1500 µg/L 2 (reliable with Phipps & Holcombe dissolved (nominal) restrictions) (1985) freshwater key study flow-through read-across based on 4 days acute fish test, flow-through grouping of system, natural water substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Carassius auratus LC50 (4 d): 748 µg/L 2 (reliable with Phipps & Holcombe

Method Results Remarks Reference dissolved (nominal) restrictions) (1985) freshwater key study flow-through read-across based on 4 days acute fish test, flow-through grouping of system, natural water substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Ictalurus punctatus LC50 (4 d): 4480 µg/L 2 (reliable with Phipps & Holcombe dissolved (nominal) restrictions) (1985) freshwater key study flow-through read-across based on 4 days acute fish test, flow-through grouping of system, natural water substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Lepomis macrochirus LC50 (4 d): 6470 µg/L 2 (reliable with Phipps & Holcombe dissolved (nominal) restrictions) (1985) freshwater key study flow-through read-across based on 4 days acute fish test, flow-through grouping of system, natural water substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Jordanella floridae LC50 (4 d): 2500 µg/L 2 (reliable with Spehar RL (1976) dissolved (meas. (not restrictions) freshwater specified)) key study flow-through read-across based on American Public Health Association grouping of 1971 - Standard methods for the substances (category examination of water and waste waters.

approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Salmo salar LC50 (24 d): 2300 µg/L 2 (reliable with Bishop & McIntosh dissolved (meas. (not restrictions) (1982) freshwater specified)) key study semi-static read-across based on fish 24d mortality test in semi-static grouping of system, natural water substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Salmo salar LC50 (24 d): 34 µg/L 2 (reliable with Rombough & dissolved (meas. (not restrictions) garside (1982) freshwater specified)) key study semi-static read-across based on 24d mortality test on juveniles grouping of substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across)

Discussion

All good quality short-term data that were available for all Cd-substances were considered together, since the toxicity of the Cd++ ion is key to the hazard assessment of Cd in water.

Data were available on 7 fish species. The lowest short-term EC50 is observed on Salmo Salar: 34 µg Cd/l (single measured value). The EC50 values ranged between 34 and 6470 µg Cd/l. Toxicity was generally low with EC50 in 6 out of 7 species > 700µg Cd/l. The results were obtained in a pH range of 6.5 -7.8. The toxicity was in general highest at lower hardness.

The following information is taken into account for acute fish toxicity for the derivation of PNEC:

The good quality short-term data that were available for all Cd-substances were considered together, since the toxicity of the Cd++ ion is key to this analysis.

Data were available on 7 fish species. The lowest short-term EC50 is observed on Salmo Salar: 34 µg Cd/l (single measured value). The EC50 values ranged between 34 and 6470 µg Cd/l.

7.1.1.1.2. Long-term toxicity to fish

Table 44. Overview of long-term effects on fish

Method Results Remarks Reference Salvelinus fontinalis NOEC (10 d): 8 µg/L 2 (reliable with Jop KM, Askew dissolved (meas. (not restrictions) AM and Foster RB freshwater specified)) based on: (1995) survival key study survival, growth NOEC (10 d): 18 µg/L read-across based on static with renewal dissolved (meas. (not grouping of specified)) based on: growth substances (category other rate approach)

NOEC (10 d): 62 µg/L Test material dissolved (meas. (not (IUPAC name): specified)) based on: cadmium (See survival endpoint summary for justification of NOEC (10 d): 132 µg/L read-across) dissolved (meas. (not specified)) based on: growth rate

LOEC (10 d): 18 µg/L dissolved (meas. (not specified)) based on: survival

LOEC (10 d): 132 µg/L dissolved (meas. (not specified)) based on: survival Oncorhynchus kisutch NOEC (27 d): 1.3 µg/L 2 (reliable with Eaton et al. (1978) dissolved (meas. (TWA)) restrictions) freshwater based on: Standing crop (biomass) key study embryos, sac-fry stage and juveniles, standing crop read-across based on grouping of flow-through substances (category approach) Embryos: test containers screen- bottom glass jars 6 cm diameter - after Test material hatching, young fish released into glass (IUPAC name): larval test chambers (15cm wide, 30 cadmium dichloride cm deep, 30 cm long) containing ± 10 l (See endpoint of water. summary for sac-fry stage incubated before testing justification of read- across) Estimated replacement time of 90% water in each chamber is 6 to 7 h

Method Results Remarks Reference Salvelinus fontinalis NOEC (65 d): 1.1 µg/L 2 (reliable with Eaton et al. (1978) dissolved (meas. (TWA)) restrictions) freshwater based on: standing crop (biomass) key study embryo & larvae-juveniles NOEC (126 d): 1.1 µg/L read-across based on flow-through dissolved (meas. (TWA)) grouping of based on: standing crop substances (category Embryos: test containers screen- (biomass) approach) bottom glass jars 6 cm diameter - after hatching, young fish released into glass Test material larval test chambers (15cm wide, 30 (IUPAC name): cm deep, 30 cm long) containing ± 10 l cadmium dichloride of water. (See endpoint Estimated replacement time of 90% summary for water in each chamber is 6 to 7 h justification of read- across) Salmo gairdneri (new name: NOEC (84 d): 12 µg/L 2 (reliable with Lowe-Jinde & Oncorhynchus mykiss) dissolved (meas. (TWA)) restrictions) Niimi (1984) based on: adult mortality freshwater key study LOEC (84 d): 36 µg/L adult fish: (sub)lethal effects dissolved (meas. (TWA)) read-across based on based on: adult mortality grouping of flow-through substances (category approach) Fish kept in 300l tanks supplied by aerated well water at 10°C ± 1°C Test material Feeding ad libitum every other day (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Jordanella floridae NOEC (100 d): 4.1 µg/L 2 (reliable with Spehar (1976) dissolved (meas. (not restrictions) freshwater specified)) based on: reproduction key study early-life stage: reproduction, (sub)lethal effects NOEC (100 d): 8.1 µg/L read-across based on dissolved (meas. (not grouping of flow-through specified)) based on: growth substances (category rate approach) other method LOEC (100 d): 16 µg/L Test material dissolved (meas. (not (IUPAC name): specified)) based on: growth cadmium dichloride rate (See endpoint summary for justification of read- across) Salvelinus fontinalis NOEC (36 mo): 1.7 µg/L 2 (reliable with Benoit DA, dissolved (meas. (not restrictions) Leonard EN, freshwater specified)) based on: Christensen GM mortality key study and Fiandt JT mortality, growth, reproduction (1976b) NOEC (36 mo): 1.7 µg/L read-across based on flow-through dissolved (meas. (not grouping of

American Public Health Association et specified)) based on: growth substances (category al. 1971 for chemical measurements rate (of 16 weeks old approach) juveniles) Test material NOEC (36 mo): 0.9 µg/L (IUPAC name): dissolved (meas. (not cadmium dichloride specified)) based on: weight (See endpoint (of youngs from second summary for generation) justification of read- across) NOEC (36 mo): 6.4 µg/L dissolved (meas. (not specified)) based on: reproduction Salmo salar NOEC (46 d): 0.47 µg/L 2 (reliable with Rombough and dissolved (meas. (not restrictions) Garside (1982) freshwater specified)) based on: total biomass key study growth and total biomass LOEC (46 d): 0.78 µg/L read-across based on semi-static dissolved (meas. (not grouping of specified)) based on: total substances (category long term growth inhibition test of biomass approach) eggs and alevins Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Salvelinus fontinalis NOEC (10 d): 8 µg/L 2 (reliable with Jop KM, Askew dissolved (meas. (not restrictions) AM and Foster RB freshwater specified)) based on: (1995) survival key study survival, growth NOEC (10 d): 18 µg/L read-across based on static with renewal dissolved (meas. (not grouping of specified)) based on: growth substances (category other rate approach)

NOEC (10 d): 62 µg/L Test material dissolved (meas. (not (IUPAC name): specified)) based on: cadmium (See survival endpoint summary for justification of NOEC (10 d): 132 µg/L read-across) dissolved (meas. (not specified)) based on: growth rate

LOEC (10 d): 132 µg/L dissolved (meas. (not

specified)) based on: survival Pimephales promelas NOEC (60 d): 13 µg/L 3 (not reliable) Pickering QH and dissolved (meas. (not Gast MH (1972) freshwater specified)) based on: supporting study reproduction (pond fish) life cycle: reproduction, (sub)lethal experimental result effects NOEC (60 d): 14 µg/L dissolved (meas. (not Test material (EC static for fish and static and continuous specified)) based on: name): cadmium for fry reproduction (laboratory fry) sulphate statis and continuous flow tests on fish and fry (60d) Salmo gairdneri (new name: NOEC (48 d): 4 µg/L 3 (not reliable) Dave G, Andersson Oncorhynchus mykiss) dissolved (nominal) based K, Berglind R and on: median survival time supporting study Hasselrot B (1981) freshwater experimental result median survival time Test material (EC semi-static name): cadmium sulphate semi-static 28d survival test Danio rerio (reported as Brachydanio NOEC (36 d): 1 µg/L 3 (not reliable) Bresch H. (1982) rerio) dissolved (nominal) based on: reproduction supporting study freshwater LOEC (24 d): 10 µg/L read-across based on mortality, growth and reproduction dissolved (nominal) based grouping of on: reproduction substances (category semi-static approach) other, no details Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Oryzias latipes NOEC (18 d): 6 µg/L 3 (not reliable) Canton JH and dissolved (meas. (not Slooff (1982) freshwater specified)) based on: supporting study mortality and abnormal mortality and abnormal behavior behaviour in hard water read-across based on grouping of semi-static NOEC (18 d): 3 µg/L substances (category dissolved (meas. (not approach) equivalent or similar to Dutch specified)) based on: Standardisation Organisation (NEN mortality and abnormal Test material 6409, 6502, 6504, 6506, 1980) behavior in soft water (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Mugil cephalus NOEC (8 wk): 20 µg/L 2 (reliable with Hilmy, AM, MB

Method Results Remarks Reference dissolved (nominal) based restrictions) Shabana, AY saltwater on: mortality Daabees (1985) key study embryo and sac-fry stage: (sub)lethal effects read-across based on grouping of semi-static substances (category approach) 8 weeks mortality test on fry of the fish Mugil cephalus, designed for dose- Test material response (IUPAC name): cadmium metal (See endpoint summary for justification of read-across) Epinephelus coioides NOEC (7 d): 33.33 µg/L 2 (reliable with Chien-Min Chen, dissolved (estimated) based restrictions) Ming-Chao Liu. saltwater on: immobility (2006a) key study early-life stage: reproduction, (sub)lethal effects read-across based on grouping of static substances (category approach) 7-d immobility test on the spotted grouper (Epinephelus coioides), Test material designed for dose-response (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Mugil cephalus NOEC (8 wk): 20 µg/L 2 (reliable with Hilmy, AM, MB dissolved (nominal) based restrictions) Shabana, AY saltwater on: mortality Daabees (1985) key study embryo and sac-fry stage: (sub)lethal effects read-across based on grouping of semi-static substances (category approach) 8 weeks mortality test on fry of the fish Mugil cephalus, designed for dose- Test material response (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Atherinopsis affinis NOEC (14 d): 10 µg/L 2 (reliable with Rose WL, Hobbs dissolved (nominal) based restrictions) JA, Nisbet RM, saltwater on: growth Green PG, Cherr key study GN, Anderson SL early-life stage: reproduction, (2005) (sub)lethal effects read-across based on grouping of semi-static substances (category approach) U.S. EPA. 1995. Short-term methods

Method Results Remarks Reference for estimating the chronic toxicity of Test material effluents and receiving waters to West (IUPAC name): Coast marine and estuarine organisms, cadmium dichloride 1st ed. EPA/600/R-95-136. Technical (See endpoint Report. Cincinnati, OH With summary for deviations justification of read- across) Lates calcarifer EC10 (7 d): 794 µg/L 2 (reliable with Thongra-ar W & dissolved (nominal) based restrictions) Musika C (1997) saltwater on: growth key study early-life stage: reproduction, (sub)lethal effects read-across based on grouping of semi-static substances (category approach) 7-d growth test on seabass larvae, designed for dose-response Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Menidia menidia EC10 (11 d): 259.8 µg/L 2 (reliable with Voyer RA, Heltsche dissolved (estimated) based restrictions) JF & Kraus RA saltwater on: mortality (1979) key study embryo and sac-fry stage: (sub)lethal effects read-across based on grouping of flow-through substances (category approach) short term chronic mortality test, designed for dose-response Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Pseudopleuronectes americanus EC10 (7 d): 283.7 µg/L 2 (reliable with Voyer RA, dissolved (estimated) based restrictions) Wentworth Jr. CE, saltwater on: development, mortality Barry EP & key study Hennekey RJ embryo and sac-fry stage: (sub)lethal (1977) effects read-across based on grouping of static substances (category approach) development and mortality tests on winter flounder, designed for dose- Test material response (IUPAC name): cadmium dichloride (See endpoint summary for justification of read-

across) Mugil cephalus NOEC (8 wk): 20 µg/L 2 (reliable with Hilmy, AM, MB dissolved (nominal) based restrictions) Shabana, AY saltwater on: mortality Daabees (1985) key study embryo and sac-fry stage: (sub)lethal effects read-across based on grouping of semi-static substances (category approach) 8 weeks mortality test on fry of the fish Mugil cephalus, designed for dose- Test material (EC response name): cadmium chloride (See endpoint summary for justification of read-across)

Discussion

Freshwaters:

16 reliable studies on 12 different species were considered for chronic toxicity for species sensitivity distribution.

Fish species NOECs were combined with other marine chronic data in the SSD to give the HC5 from which the PNEC is derived.

Marine waters:

Relevant and reliable chronic toxicity data on marine fish were found in 6 families: Atherinidae, Serranidae, Centropomidae, Atherinidae, Mugilidae and Pleuronectidae. The species are equally distributed over the species sensitivity distribution (SSD). Fish species NOECs were combined with other marine chronic data in the SSD to give the HC5 from which the PNEC is derived.

The following information is taken into account for long-term fish toxicity for the derivation of PNEC:

Freshwater: Data on 12 fish species: NOECs range between 0.47 and 13.5 µg/l Cd (dissolved concentrations) Marine waters: Data on 6 fish species belonging to 6 different families are available. Species NOECs range between 10 and 794 µg Cd/L (dissolved concentrations).

7.1.1.2. Aquatic invertebrates

7.1.1.2.1. Short-term toxicity to aquatic invertebrates

Table 45. Overview of short-term effects on aquatic invertebrates

Method Results Remarks Reference Daphnia magna LC50 (48 d): 110 µg/L 2 (reliable with Janssen dissolved (meas. (initial)) restrictions) Pharmaceutica freshwater based on: mobility (1993a) key study static read-across based on

OECD Guideline 202 (Daphnia sp. grouping of Acute Immobilisation Test) substances (category approach)

Test material (IUPAC name): cadmium (See endpoint summary for justification of read-across) Daphnia magna LC50 (36 h): 203.8 µg/L 2 (reliable with Attar EN and Maly dissolved (meas. (arithm. restrictions) EJ (1982) freshwater mean)) based on: mortality key study flow-through LC50 (48 h): 58.16 µg/L dissolved (meas. (arithm. read-across based on other - flow through system, 96h mean)) based on: mortality grouping of mortality test substances (category LC50 (60 h): 15.8 µg/L approach) dissolved (meas. (arithm. mean)) based on: mortality Test material (IUPAC name): LC50 (72 h): 8.88 µg/L cadmium dichloride dissolved (meas. (arithm. (See endpoint mean)) based on: mortality summary for justification of read- LC50 (96 h): 5 µg/L across) dissolved (meas. (arithm. mean)) based on: mortality Daphnia magna LC50 (48 h): 38 µg/L 2 (reliable with Lewis PA and dissolved (meas. (not restrictions) Horning II WB freshwater specified)) based on: (1991) mortality key study static read-across based on EPA 600/4-78 012 grouping of substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Daphnia pulex LC50 (48 h): 42 µg/L 2 (reliable with Lewis PA and dissolved (meas. (not restrictions) Horning II WB freshwater specified)) based on: (1991) mortality key study static read-across based on EPA 600/4-78 012 grouping of substances (category approach)

Test material (IUPAC name):

cadmium dichloride (See endpoint summary for justification of read- across) Daphnia magna LC50 (48 h): 36 µg/L 2 (reliable with Schuytema GS, dissolved (meas. (not restrictions) Nelson PO, Malueg freshwater specified)) based on: KW, Nebeker AV, mortality key study Krawczyk DF, static and continuous Ratcliff (1984) LC50 (48 h): 49 µg/L read-across based on E729-80 from American Society for dissolved (meas. (not grouping of Testing and Materials specified)) based on: substances (category mortality approach) Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Daphnia magna EC50 (24 h): 1900 µg/L 2 (reliable with Kühn R, Pattard M, dissolved (meas. (not restrictions) Pernak KD and freshwater specified)) based on: Winter A (1989) mortality key study semi-static read-across based on DIN-Standard 38412, part II - Daphnia grouping of short time test substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) other aquatic crustacea: Barytelphusa LC50 (96 h): 1820 µg/L 2 (reliable with Venugopal NBRK, guerini dissolved (nominal) based restrictions) Ramesh TVDD, on: mortality Reddy DS and freshwater key study Reddy SLN (1997) semi-static read-across based on grouping of Short term mortality test substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Daphnia magna LC50 (48 d): 110 µg/L 2 (reliable with Janssen

Method Results Remarks Reference dissolved (meas. (initial)) restrictions) Pharmaceutica freshwater based on: mobility (1993a) key study static read-across based on OECD Guideline 202 (Daphnia sp. grouping of Acute Immobilisation Test) substances (category approach)

Test material (IUPAC name): cadmium (See endpoint summary for justification of read-across) Daphnia magna LC50 (48 d): 750 µg/L 2 (reliable with Janssen dissolved (meas. (initial)) restrictions) Pharmaceutica freshwater based on: mobility (1993b) key study static read-across based on OECD Guideline 202 (Daphnia sp. grouping of Acute Immobilisation Test) substances (category approach)

Test material (IUPAC name): oxocadmium (See endpoint summary for justification of read-across)

Discussion

The good quality short-term data that were available for all Cd-substances were considered together, since the toxicity of the Cd++ ion is key to this analysis. Data were available on 2 Daphnia species. The lowest short-term EC50 is observed on Daphnia pulex: 42 µg Cd/l (single measured value). The EC50 values ranged between 38 and 1900 µg Cd/l. Species geomean for Daphnia is 130 µg Cd/l.

The following information is taken into account for short-term toxicity to aquatic invertebrates for the derivation of PNEC:

The good quality short-term data that were available for all Cd-substances were considered together, since the toxicity of the Cd++ ion is key to this analysis. Data were available on 2 Daphnia species and the crab Barythelphusa guerini. The lowest short-term EC50 is observed on Daphnia pulex: 42 µg Cd/l (single measured value). The EC50 values ranged between 38 and 1900 µg Cd/l. Species geomean for Daphnia is 130 µg Cd/l.

7.1.1.2.2. Long-term toxicity to aquatic invertebrates

Table 46. Overview of long-term effects on aquatic invertebrates

Method Results Remarks Reference Ceriodaphnia dubia NOEC (7 d): 19 µg/L 2 (reliable with Jop KM, Askew

Method Results Remarks Reference dissolved (meas. (not restrictions) AM and Foster RB freshwater specified)) based on: (1995) survival key study static with renewal NOEC (7 d): 11 µg/L read-across based on other, survival, reproduction dissolved (meas. (not grouping of specified)) based on: substances (category reproduction approach)

NOEC (7 d): 19 µg/L Test material dissolved (meas. (not (IUPAC name): specified)) based on: cadmium (See survival endpoint summary for justification of NOEC (7 d): 10 µg/L read-across) dissolved (meas. (not specified)) based on: reproduction

LOEC (7 d): 19 µg/L dissolved (meas. (not specified)) based on: reproduction

LOEC (7 d): 19 µg/L dissolved (meas. (not specified)) based on: reproduction other aquatic mollusc: Physa integra NOEC (21 d): 8.3 µg/L 2 (reliable with Spehar RL, dissolved (meas. (not restrictions) Anderson RL and freshwater specified)) based on: Fiandt JT (1978b) mortality key study semi-static read-across based on Intermittent-flow exposure system 28d grouping of survival test substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Daphnia magna NOEC (21 d): 0.6 µg/L 2 (reliable with Kühn R, Pattard M, dissolved (nominal) based restrictions) Pernak KD and freshwater on: reproduction Winter A (1989) key study

Method Results Remarks Reference semi-static read-across based on grouping of equivalent or similar to substances (category Umweltbundeamt - 1984 - Extended approach) toxicity test using Daphnia magna - determination of NOEC for Test material reproduction rate, mortality and time of (IUPAC name): the appearance of the first offspring. cadmium dichloride (See endpoint summary for justification of read- across) Daphnia magna NOEC (21 d): 0.8 µg/L 2 (reliable with Knowles CO and dissolved (meas. (not restrictions) McKee M.J (1987) freshwater specified)) based on: reproduction key study flow-through read-across based on ATSM 1985 grouping of substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) other aquatic mollusc: Aplexa NOEC (26 d): 4.41 µg/L 2 (reliable with Holcombe GW, hypnorum dissolved (meas. (not restrictions) Phipps GL and specified)) based on: growth Marier JW (1984) freshwater key study flow-through read-across based on grouping of other - growth test - shell length substances (category measured after 26d exposure (starting approach) from hatching) Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Ceriodaphnia dubia NOEC (7 d): 19 µg/L 2 (reliable with Jop KM, Askew dissolved (meas. (not restrictions) AM and Foster RB freshwater specified)) based on: (1995) survival key study static with renewal NOEC (7 d): 11 µg/L read-across based on other, survival, reproduction dissolved (meas. (not grouping of specified)) based on: substances (category reproduction approach)

NOEC (7 d): 19 µg/L Test material

dissolved (meas. (not (IUPAC name): specified)) based on: cadmium (See survival endpoint summary for justification of NOEC (7 d): 10 µg/L read-across) dissolved (meas. (not specified)) based on: reproduction

LOEC (7 d): 19 µg/L dissolved (meas. (not specified)) based on: reproduction

LOEC (7 d): 19 µg/L dissolved (meas. (not specified)) based on: reproduction Ceriodaphnia dubia NOEC (7 d): 1.5 µg/L 3 (not reliable) Winner RW (1988) dissolved (nominal) based freshwater on: mortality supporting study static experimental result other - synthetic water, static system Test material (EC name): cadmium sulphate Daphnia magna NOEC (7 d): 2 µg/L 3 (not reliable) Winner RW (1988) dissolved (nominal) based freshwater on: reproduction supporting study static experimental result other - synthetic water, static system Test material (EC name): cadmium sulphate Daphnia magna NOEC (21 d): 3.2 µg/L 3 (not reliable) Van Leeuwen CJ, dissolved (nominal) based Luttmer WJ and freshwater on: intrinsic rate of natural supporting study Griffioen PS (1985) increase semi-static experimental result NOEC (21 d): 1 µg/L other - no details dissolved (nominal) based Test material on: mortality (IUPAC name): cadmium dichloride Daphnia magna NOEC (21 d): 0.16 µg/L 3 (not reliable) Chapman G., Ota, S dissolved (meas. (not and Recht, F. freshwater specified)) based on: supporting study (1980)

Method Results Remarks Reference reproduction (hardness 100) statis-renewal read-across based on NOEC (21 d): 0.21 µg/L grouping of equivalent or similar to EPA OPPTS dissolved (meas. (not substances (category 850.1300 (Daphnid Chronic Toxicity specified)) based on: approach) Test) reproduction (hardness 200) Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Daphnia magna NOEC (14 d): 2.5 µg/L 3 (not reliable) Elnabarawy MT, dissolved (nominal) based Welter AN and freshwater on: reproduction impairment supporting study Robideau RR (1986) semi-static read-across based on grouping of Reproductive impairment defined as substances (category decrease in the average cumulative approach) number of young per adult. Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Ceriodaphnia dubia NOEC (14 d): 0.25 µg/L 3 (not reliable) Elnabarawy MT, dissolved (nominal) based Welter AN and freshwater on: reproduction impairment supporting study Robideau RR (1986) semi-static read-across based on grouping of Reproductive impairment defined as substances (category decrease in the average cumulative approach) number of young per adult. Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Daphnia pulex NOEC (14 d): 7.5 µg/L 3 (not reliable) Elnabarawy MT, dissolved (nominal) based Welter AN and freshwater on: reproduction impairment supporting study Robideau RR (1986) semi-static read-across based on grouping of Reproductive impairment defined as substances (category decrease in the average cumulative approach) number of young per adult. Test material (IUPAC name): cadmium dichloride (See endpoint

summary for justification of read- across) Daphnia magna NOEC (25 d): 2.5 µg/L 3 (not reliable) Bodar CWM, Van dissolved (nominal) based Leeuwen CJ, Voogt freshwater on: biomass supporting study PA and Zandee DI production/female (1988) Semi-continuous flow read-across based on grouping of endpoint = biomass production per substances (category female approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Daphnia magna NOEC (21 d): 1 µg/L 3 (not reliable) Biesinger KE and dissolved (nominal) based Christensen GM freshwater on: weight/animal supporting study (1972) semi-continuous flow read-across based on grouping of Weight measurement after exposure: 3 substances (category week old animals were collected on approach) paper toweling, transferred to small plastic cups and dried to a constant Test material weight, then weighed. (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Daphnia pulex NOEC (104 d): 1 µg/L 3 (not reliable) Bertram PE and dissolved (nominal) based Hart BA (1979) freshwater on: longevity supporting study semi-continuous flow read-across based on grouping of Determination of average longevity substances (category with exposure to cadmiated water or approach) food Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Daphnia sp. NOEC (154 d): 2 µg/L 4 (not assignable) Marshall JS (1978) dissolved (nominal) based freshwater on: number of individuals supporting study semi-static read-across based on grouping of

Determination of average longevity substances (category with exposure to cadmiated water approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Ceriodaphnia sp. NOEC (9 d): 3.4 µg/L 3 (not reliable) Spehar RL and dissolved (meas. (not Carlson AR (1984) freshwater specified)) based on: supporting study reproduction Mount DI and static read-across based on Norberg TJ (1984) grouping of Method described by Mount&Norberg substances (category 1984 (see reference) approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) other aquatic crustacea: Hyalella NOEC (42 d): 0.51 µg/L 3 (not reliable) Ingersoll C and azteca dissolved (meas. (not Kemble N (2000) specified)) based on: supporting study freshwater survival read-across based on flow-through grouping of substances (category other - no details approach)

Test material (IUPAC name): Cadmium (See endpoint summary for justification of read-across) other aquatic arthropod: Chironomus NOEC (20 d): 5.8 µg/L 3 (not reliable) Ingersoll C and tentans dissolved (meas. (not Kemble N (2000) specified)) based on: weight supporting study freshwater read-across based on flow-through grouping of substances (category other - no details approach)

Test material (IUPAC name): Cadmium (See endpoint summary for justification of read-across) Eirene viridula, Cnidaria, Medusa, NOEC (3 mo): 100 µg/L 2 (reliable with Karbe L (1972)

Method Results Remarks Reference Eirenidae dissolved (nominal) based restrictions) on: development saltwater key study semi-static experimental result

3-mo hydroid development test Test material (EC name): cadmium sulphate other aquatic mollusc: Tresus nuttalli, NOEC (48 h): 42 µg/L 2 (reliable with Cardwell, R.D., Horse clam, Molluscs dissolved (nominal) based restrictions) C.E. Woelke, M.I. on: larval development Carr, and E.W. saltwater key study Sanborn (1979) static experimental result

48h larval development test on the Test material (EC horse clam Tresus nuttalli name): cadmium sulphate other aquatic crustacea: Artemia LC10 (24 h): 33 µg/L 2 (reliable with Raquel Sarabia, fransiscana, brine shrimp dissolved (meas. (not restrictions) Jose Del Ramo, specified)) based on: Inma Varo, Javier saltwater mortality key study Di´Az-Mayans, Amparo (2002) static LC10 (24 h): 46.7 µg/L read-across based on dissolved (meas. (not grouping of 24h mortality test on instar II nauplii, specified)) based on: substances (category designed for dose-response mortality approach) Test material (EC name): cadmium metal (See endpoint summary for justification of read- across) other aquatic crustacea: Artemia LC10 (24 h): 111 µg/L 2 (reliable with Raquel Sarabia, parthenogenetica, brine shrimp dissolved (meas. (not restrictions) Jose Del Ramo, specified)) based on: Inma Varo, Javier saltwater mortality key study Di´Az-Mayans, Amparo (2002) static LC10 (24 h): 66.1 µg/L read-across based on dissolved (meas. (not grouping of 24h mortality test on instar II nauplii, specified)) based on: substances (category designed for dose-response mortality approach)

LC10 (24 h): 162.6 Test material (EC dissolved (meas. (not name): cadmium specified)) based on: metal (See endpoint mortality summary for justification of read- across) other aquatic crustacea: Artemia LC10 (24 h): 99.5 µg/L 2 (reliable with Raquel Sarabia, persimilis, brine shrimp dissolved (meas. (not restrictions) Jose Del Ramo, specified)) based on: Inma Varo, Javier saltwater mortality key study Di´Az-Mayans, Amparo (2002) static read-across based on grouping of 24h mortality test on instar II nauplii,

Method Results Remarks Reference designed for dose-response substances (category approach)

Test material (EC name): cadmium metal (See endpoint summary for justification of read- across) other aquatic crustacea: Artemia LC10 (24 h): 58.6 µg/L 2 (reliable with Raquel Sarabia, salina, brine shrimp dissolved (meas. (not restrictions) Jose Del Ramo, specified)) based on: Inma Varo, Javier saltwater mortality key study Di´Az-Mayans, Amparo (2002) static LC10 (24 h): 54.9 µg/L read-across based on dissolved (meas. (not grouping of 24h mortality test on instar II nauplii, specified)) based on: substances (category designed for dose-response mortality approach) Test material (EC name): cadmium metal (See endpoint summary for justification of read- across) other aquatic worm: Ctenodrilus NOEC (21 d): 1000 µg/L 2 (reliable with Reish DJ & Carr RS serratus, Annelid, Polychaete, dissolved (zinc) (nominal) restrictions) (1978) Ctenodrilidae based on: reproduction key study saltwater read-across based on static grouping of substances (category 21-d annelid reproduction test approach)

Test material (EC name): cadmium chloride (See endpoint summary for justification of read-across) other aquatic worm: Neanthes NOEC (9 mo): 50 µg/L 2 (reliable with Reish DJ & arenaceaodentata, Annelid, dissolved (estimated) based restrictions) Gerlinger TV Polychaete, Nereididae on: reproduction (1984) key study saltwater NOEC (9 mo): 100 µg/L dissolved (nominal) based read-across based on semi-static on: reproduction grouping of substances (category 9-months annelid reproduction test NOEC (6 mo): 320 µg/L approach) dissolved (nominal) based on: reproduction Test material (EC name): cadmium LOEC (9 mo): 320 µg/L chloride (See dissolved (nominal) based endpoint summary on: reproduction for justification of read-across) LOEC (6 mo): 1000 µg/L

dissolved (nominal) based on: reproduction other aquatic worm: Capitella NOEC (2 mo): 126.5 µg/L 2 (reliable with Reish DJ, Gerlinger capitata, Annelida, Polychaete worm, dissolved (estimated) based restrictions) TV, Phillips CA & Capitellidae on: reproduction Schmidtbauer PD key study (1977) saltwater NOEC (2 mo): 160 µg/L dissolved (nominal) based read-across based on semi-static on: reproduction grouping of substances (category 2 months annelid reproduction test NOEC (2 mo): 100 µg/L approach) dissolved (nominal) based on: reproduction Test material (EC name): cadmium chloride (See endpoint summary for justification of read-across) other aquatic worm: Ctenodrilus NOEC (35 d): 103 µg/L 2 (reliable with Reish DJ, Gerlinger serratus, Annelida, Polychaeta, dissolved (estimated) based restrictions) TV, Phillips CA & Nereididae on: reproduction Schmidtbauer PD key study (1977) saltwater NOEC (35 d): 100 µg/L dissolved (nominal) based read-across based on semi-static on: reproduction grouping of substances (category 35-42d annelid reproduction test NOEC (35 d): 106 µg/L approach) dissolved (nominal) based on: reproduction Test material (EC name): cadmium chloride (See endpoint summary for justification of read-across) other aquatic worm: Ophiotrocha NOEC (30 d): 100 µg/L 2 (reliable with Roed K.H. (1980) labronica dissolved (estimated) based restrictions) on: growth rate, size at saltwater maturity time to maturity key study semi-static read-across based on grouping of >30-d exposure test on annelid, substances (category designed for dose-response approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Campanularia flexuosa, Hydroid, NOEC (11 d): 87.7 µg/L 2 (reliable with Moore, M.N., and Cnidaria dissolved (estimated) based restrictions) A.R.D. Stebbing on: growth (1976) saltwater key study semi-static read-across based on

11-d growth test on the hydroid grouping of Campanularia flexuosa, designed for substances (category dose-response approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) other aquatic crustacea: Paragrapsus NOEC (4 d): 105 µg/L 2 (reliable with Ahsanullah M & quadridentatus, Toothed Shore Crab, dissolved (zinc) (estimated) restrictions) Arnott GH (1978) Grapsidae based on: mortality key study saltwater read-across based on semi-static grouping of substances (category 4-d survival test on crab larvae approach)

Test material (EC name): cadmium chloride (See endpoint summary for justification of read-across) Mysidopsis bahia (new name: NOEC (33 d): 2 µg/L 1 (reliable without Carr, R.S., J.W. Americamysis bahia) dissolved (estimated) based restriction) Williams, F.I. on: growth Saksa, R.L. Buhl, saltwater key study and J.M. Neff (1985) flow-through read-across based on grouping of 33-d growth test on mysids, designed substances (category for dose-response approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) other aquatic crustacea: Peneus NOEC (7 d): 33.33 µg/L 2 (reliable with Chien-Min Chen, monodon, Tiger shrimp dissolved (estimated) based restrictions) Ming-Chao Liu. on: immobilisation (2006b) saltwater key study static read-across based on grouping of ELS tests methods standardized by substances (category EPA Taiwan with modifications approach)

Test material (IUPAC name): cadmium dichloride

(See endpoint summary for justification of read- across) other aquatic crustacea: Tigriopus EC10 (10 d): 34.94 µg/L 2 (reliable with Le Dean L & brevicornis, Copepod, Harpacticidae dissolved (nominal) based restrictions) Devineau J (1987) on: reproduction (larval saltwater development) key study static EC10 (10 d): 41.48 µg/L read-across based on dissolved (nominal) based grouping of 10-d reproductive toxicity and larval on: reproduction substances (category development of copepods test (prod/female) approach)

EC10 (10 d): 34.04 µg/L Test material (EC dissolved (nominal) based name): cadmium on: reproduction chloride (See (copepodites/total larv. Prod)endpoint summary for justification of EC10 (10 d): 36.7 µg/L read-across) dissolved (estimated) based on: reproduction other aquatic crustacea: Elminius NOEC (28 d): 316 µg/L 2 (reliable with Rainbow PS & modestus dissolved (meas. (not restrictions) White SL (1989) specified)) based on: saltwater mortality key study semi-static read-across based on grouping of 28 days mortality test on the barnacle substances (category Elminius modestus approach)

Test material (EC name): cadmium chloride (See endpoint summary for justification of read-across) Mysidopsis bahia (new name: EC10 (28 d): 6.3 µg/L 2 (reliable with Voyer, R.A., and Americamysis bahia) dissolved (meas. (not restrictions) D.G. McGovern specified)) based on: (1991) saltwater mortality key study flow-through EC10 (28 d): 1.6 µg/L read-across based on dissolved (meas. (not grouping of 28d mortality test on mysids, designed specified)) based on: substances (category for dose-response mortality approach)

EC10 (28 d): 1.1 µg/L Test material dissolved (meas. (not (IUPAC name): specified)) based on: cadmium dichloride mortality (See endpoint summary for justification of read- across) other aquatic crustacea: Balanus NOEC (6 d): 5 µg/L 2 (reliable with Wu, R.S.S., P.K.S. amphitrite dissolved (estimated) based restrictions) Lam, and B. Zhou

Method Results Remarks Reference on: behaviour, settlement (1997) saltwater key study static read-across based on grouping of 6d settlement behaviour test on the substances (category barnacle Balanus amphitrite, designed approach) for dose-response Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Arbacia lixula, Sea Urchin, Arbaciidae NOEC (38 h): 357 µg/L 2 (reliable with Cesar A, Marín- dissolved (estimated) based restrictions) Guirao L, Vita R & saltwater on: development Marín A (2002) key study static read-across based on equivalent or similar to EPA/600/ R- grouping of 95-136, substances (category approach) equivalent or similar to Environment Canada EPS 1/RM/27 Test material (EC name): cadmium equivalent or similar to CETESB chloride (See L5.250 endpoint summary for justification of read-across) Spherechinus granularis, Sea Urchin, NOEC (38 h): 623 µg/L 2 (reliable with Cesar A, Marín- Arbaciidae dissolved (estimated) based restrictions) Guirao L, Vita R & on: development Marín A (2002) saltwater key study static read-across based on grouping of equivalent or similar to EPA/600/ R- substances (category 95-136, approach) equivalent or similar to Environment Test material (EC Canada EPS 1/RM/27 name): cadmium chloride (See equivalent or similar to CETESB endpoint summary L5.250 for justification of read-across) Lytechinus pictus, sea urchin, NOEC (80 min): 12.5 µg/L 2 (reliable with Jonczyk, E., K.G. Echinodermata dissolved (nominal) based restrictions) Doe, P.C. Wells, on: fertilization and S.G. Yee saltwater key study (1991) NOEC (80 min): 4.2 µg/L static dissolved (estimated) based read-across based on on: fertilization grouping of ASTM (1987) Sea Urchin Fertilization substances (category Test method 1008. US EPA (1988) approach) Short-Term method for estimating chronic toxicity of effluents and Test material receiving waters to marine and (IUPAC name):

Method Results Remarks Reference estuarine organisms. 600/4-87/028. cadmium dichloride (See endpoint summary for justification of read- across) Strongylocentrotus droebachiensis, sea NOEC (80 min): 12.5 µg/L 2 (reliable with Jonczyk, E., K.G. urchin, Echinodermata dissolved (nominal) based restrictions) Doe, P.C. Wells, on: fertilization and S.G. Yee saltwater key study (1991) static read-across based on grouping of ASTM (1987) Sea Urchin Fertilization substances (category Test method 1008. US EPA (1988) approach) Short-Term method for estimating chronic toxicity of effluents and Test material receiving waters to marine and (IUPAC name): estuarine organisms. 600/4-87/028. cadmium dichloride (See endpoint summary for justification of read- across) Asterias amurensis, Northern Pacific NOEC (80 min): 10000 µg/L2 (reliable with Lee CH, Ryu TK, Seastar, Asteriidae dissolved (estimated) based restrictions) Chang M & Choi on: fertilization JW (2004) saltwater key study LOEC (80 min): 80000 µg/L static dissolved (nominal) based read-across based on on: fertilization: presence of grouping of equivalent or similar to EPA/600/ R- fertilization membrane substances (category 95-136 approach)

Test material (EC name): cadmium chloride (See endpoint summary for justification of read-across) Paracentrotus lividus, sea urchin, NOEC (60 min): 11.2 µg/L 2 (reliable with Pagano G, Esposito Echinodermata dissolved (nominal) based restrictions) A, Giordano GG on: fertilization (1982) saltwater key study static read-across based on grouping of 60 min fertilization test on substances (category Paracentrotus lividus, designed for approach) dose-response Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) other aquatic mollusc: Isognomon NOEC (4 d): 0.3 µg/L 2 (reliable with Ringwood, A.H. californicum, bivalve, molluscs dissolved (estimated) based restrictions) (1992)

Method Results Remarks Reference on: larval growth saltwater key study semi-static read-across based on grouping of 4d growth test on bivalves Isognomon substances (category californicum, designed for dose- approach) response Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Paracentrotus lividus, echinoid, NOEC (75 min): 112.4 µg/L 2 (reliable with Warnau M, Echinodermata dissolved (nominal) based restrictions) Iaccarino M, De on: fertilization Biase A, Temara A, saltwater key study Jangoux M, Dubois NOEC (72 h): 112.4 µg/L P & Pagano G static dissolved (nominal) based read-across based on (1996) on: embryonic development grouping of 85 min fertilization test on sperm cells substances (category of the echinoid Paracentrotus lividus, approach) designed for dose-response Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) other aquatic mollusc: Mytilus NOEC (2 d): 250 µg/L 2 (reliable with Beiras R & galloprovincialis, Blue mussel, dissolved (nominal) based restrictions) Albentosa M (2004) Mytilidae on: embryogenesis key study saltwater read-across based on static grouping of substances (category 2-d larval development of marine approach) mollusks, dose-response designed test Test material (EC name): cadmium chloride (See endpoint summary for justification of read-across) other aquatic mollusc: Ruditapes EC10 (2 d): 265 µg/L 2 (reliable with Beiras R & decussatus, Grooved Carpet shell dissolved (nominal) based restrictions) Albentosa M (2004) clam, Veneridae on: development key study saltwater read-across based on static grouping of substances (category 2-d larval development of marine approach) mollusks, dose-response designed test Test material (EC

name): cadmium chloride (See endpoint summary for justification of read-across) other aquatic mollusc: Meretrix NOEC (7 d): 33.33 µg/L 2 (reliable with Chien-Min Chen, lusoria, Hard clam dissolved (estimated) based restrictions) Ming-Chao Liu. on: immobilisation (2006b) saltwater key study static read-across based on grouping of ELS tests methods standardized by substances (category EPA Taiwan with modifications approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) other aquatic mollusc: Ilyanassa NOEC (142 min): 112.4 2 (reliable with Conrad, GW (1988) obsoleta µg/L dissolved (nominal) restrictions) based on: development saltwater key study static read-across based on grouping of 142 min development test on the substances (category mudsnail, Ilyanassa obsoleta, Molluscs approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Mya arenaria NOEC (7 d): 50 µg/L 2 (reliable with Eisler R (1977) dissolved (nominal) based restrictions) saltwater on: mortality key study static read-across based on lab designed test for dose-response grouping of substances (category approach)

Test material (EC name): cadmium chloride (See endpoint summary for justification of read-across) other aquatic mollusc: Haliotis rubra, EC10 (2 d): 520 µg/L 2 (reliable with Gorski J & Blacklip Abalone, Haliotidae dissolved (nominal) based restrictions) Nugegoda D (2006)

Method Results Remarks Reference on: development saltwater key study static read-across based on grouping of Similar to: Hunt JW, Anderson BS. substances (category 1990. Abalone larval development: approach) Short-term toxicity test protocol. In: Anderson BW, Hunt JW, Turpen SL, Test material (EC Coulon AR, Martin M, McKeown DL, name): cadmium Palmer FH, eds, Procedures Manual chloride (See for Conducting Toxicity Tests endpoint summary Developed by the Marine Bioassay for justification of Project. 90-10WQ. California State read-across) Water Resources Control Board, Sacramento, CA, USA, pp 17–48. other aquatic mollusc: Mytilus edulis LC5 (96 h): 480 µg/L 2 (reliable with Nelson DA, Miller dissolved (nominal) based restrictions) JE & Calabrese A saltwater on: mortality (1988) key study static renewal read-across based on lab designed test for dose-response grouping of substances (category approach)

Test material (EC name): cadmium chloride (See endpoint summary for justification of read-across) other aquatic mollusc: Perna viridis, NOEC (24 h): 140 µg/L 1 (reliable without Panggabean LMG Green mussel, Molluscs dissolved (meas. (not restriction) (1997) specified)) based on: larval saltwater development key study static read-across based on grouping of ASTM 1993. Standard guide for substances (category conducting static acute toxicity test approach) starting with embryos of four species of saltwater bivalve molluscs. Method Test material E724-89. (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) other aquatic mollusc: Mytilus NOEC (2 d): 1100 µg/L 2 (reliable with Pavicic J, Skreblin galloprovincialis, Blue mussel, dissolved (nominal) based restrictions) M, Kregar I, Mytilidae on: development (shell Tusekznidaric M & length) key study Stegnar P (1994) saltwater read-across based on static grouping of substances (category 2-d larval development of marine approach) mollusks, lad designed test for dose-

Method Results Remarks Reference response Test material (EC name): cadmium chloride (See endpoint summary for justification of read-across) Echinometra mathaei, sea urchin, NOEC (3 h): 10 µg/L 2 (reliable with Ringwood, A.H. Echinodermata dissolved (nominal) based restrictions) (1992) on: fertilization saltwater key study static read-across based on grouping of 3h fertilization test on sea urchin substances (category echinometra mathaei, designed for approach) dose-response Test material (EC name): cadmium chloride (See endpoint summary for justification of read-across) other aquatic mollusc: Crassostrea EC10 (4 d): 13 µg/L 2 (reliable with Watling HR (1982) gigas, Oyster, Ostreidae dissolved (estimated) based restrictions) on: growth (valve width) saltwater key study semi-static read-across based on grouping of 4-d growth inhibition test of oyster substances (category larvae, test designed for dose-response approach)

Test material (EC name): cadmium chloride (See endpoint summary for justification of read-across) other aquatic mollusc: Crassostrea NOEC (4 d): 5 µg/L 2 (reliable with Watling HR (1982) cucullata, Oyster, Ostreidae dissolved (estimated) based restrictions) on: growth (valve width) saltwater key study semi-static read-across based on grouping of 4-d growth inhibition test of oyster substances (category larvae, tests designed for dose- approach) response Test material (EC name): cadmium chloride (See endpoint summary for justification of read-across) other aquatic mollusc: Crassostrea EC10 (4 d): 12.6 µg/L 2 (reliable with Watling HR (1982) margaritacea , Oyster, Ostreidae dissolved (estimated) based restrictions) on: growth (valve width)

Method Results Remarks Reference saltwater key study semi-static read-across based on grouping of 4-d growth inhibition test of oyster substances (category larvae, test designed for dose-response approach)

Test material (EC name): cadmium chloride (See endpoint summary for justification of read-across) Monhystera disjuncta NOEC (11 d): 3333 µg/L 2 (reliable with Vranken, G., R. dissolved (estimated) based restrictions) Vanderhaeghen, saltwater on: mortality and C. Heip (1985) key study static read-across based on chronic toxicity test for mortality on grouping of nematods, designed for dose-response substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Monhystera microphtalma EC6 (13 d): 1000 µg/L 2 (reliable with Vranken, G., R. dissolved (nominal) based restrictions) Vanderhaeghen, saltwater on: mortality and C. Heip (1985) key study static read-across based on chronic toxicity test for mortality on grouping of nematods, designed for dose-response substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Pellioditis marina NOEC (8 d): 25000 µg/L 2 (reliable with Vranken, G., R. dissolved (estimated) based restrictions) Vanderhaeghen, saltwater on: mortality and C. Heip (1985) key study static read-across based on chronic toxicity test for mortality on grouping of nematods, designed for dose-response substances (category approach)

Test material

(IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) other aquatic crustacea: Moina EC10 (21 d): 1.78 µg/L 1 (reliable without Wang Z., C. Yan monogolica dissolved (meas. (not restriction) and X. Zhang specified)) based on: (2009) saltwater reproduction (net key study reproductive rate) semi-static read-across based on grouping of ASTM (2004) substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) other aquatic mollusc: Mytilus NOEC (48 h): 6.25 µg/L 1 (reliable without Prato E & galloprovincialis dissolved (nominal) based restriction) Biandolino F (2007) on: larval development saltwater key study static read-across based on grouping of ASTM, E1563-98 Standard guide for substances (category conducting static acute toxicity tests approach) with echinoid embryos (2004) EPA / 600/R95/136 Short-term methods for Test material estimating the chronic toxicity of (IUPAC name): effluents and receiving waters to west cadmium dinitrate coast marine and estuarine Organisms (See endpoint summary for justification of read- across)

Discussion

Freshwater: 22 studies on 8 invertebrate species (Crustaceans, Insect and Gastropods) were selected in the EU RA to derive the PNEC freshwater. NOECs range between 0.16 and 11 µg/l Cd in dissolved concentrations.

Marine: Relevant and reliable marine chronic toxicity data on invertebrates were found in 6 taxonomic groups including Annelids (4 families), Cnidarians (2 families), Crustaceans (8 families), Echinoderms (7 families), Molluscs (9 families) and Nematods (2 families). The invertebrate dataset covers a large range of NOEC values going from 0.3 µg/L up to 25000 µg/L. Data on the 6 invertebrate taxonomic groups are combined together with the other marine chronic data in the species sensitivity distribution to give the HC5 from which the PNEC is derived.

The following information is taken into account for long-term toxicity to aquatic invertebrates for the derivation of PNEC: freshwater: 22 studies on 8 invertebrate species were selected in the EU RA to derive the PNEC freshwater. NOECs range between 0.16 and 11 µg/l Cd in dissolved concentrations.

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 160 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 marine waters: Data on 40 invertebrate species are available. Species NOECs range between 0.3 µg Cd/L (Isognomon californicum, Isognomonidae, Molluscs) up to 25000 µg Cd/L (Pellioditis marina, Rhabditidae, Nematods). Concentrations are expressed as dissolved ones.

7.1.1.3. Algae and aquatic plants

Table 47. Overview of effects on algae and aquatic plants

Method Results Remarks Reference Coelastrum proboscideum (algae) NOEC (1 d): 6.3 µg/L 2 (reliable with Müller KW and dissolved (meas. (not restrictions) Payer HD (1979) freshwater specified)) based on: biomass key study static NOEC (1 d): 27 µg/L experimental result 24h growth test dissolved (meas. (not specified)) based on: Test material (EC biomass name): cadmium sulphate Selenastrum capricornutum (new EC50 (72 h): 23 µg/L 1 (reliable without K. Van der Kerken name: Pseudokirchnerella dissolved (meas. (not restriction) (1998) subcapitata) (algae) specified)) based on: biomass key study freshwater NOEC (3 d): 2.4 µg/L read-across based on static dissolved (meas. (not grouping of specified)) based on: cell substances (category OECD Guideline 201 (Alga, Growth number approach) Inhibition Test) Test material (IUPAC name): cadmium (See endpoint summary for justification of read-across) Selenastrum capricornutum (new EC50 (72 h): 70 µg/L 1 (reliable without Janssen name: Pseudokirchnerella dissolved (meas. (TWA)) restriction) Pharmaceutica subcapitata) (algae) based on: growth rate (1993c) key study freshwater read-across based on static grouping of substances (category OECD Guideline 201 (Alga, Growth approach) Inhibition Test) Test material (IUPAC name): cadmium (See endpoint summary for justification of read-across) Asterionella formosa (algae) NOEC (1 d): 0.85 µg/L 2 (reliable with Conway HL and dissolved (meas. (not restrictions) Williams SC (1979) freshwater specified)) based on: biomass key study static

1-d growth rate test LOEC (1 d): 1.9 µg/L read-across based on dissolved (meas. (not grouping of specified)) based on: substances (category biomass approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Selenastrum capricornutum (new EC50 (72 h): 23 µg/L 1 (reliable without K. Van der Kerken name: Pseudokirchnerella dissolved (meas. (not restriction) (1998) subcapitata) (algae) specified)) based on: biomass key study freshwater NOEC (3 d): 2.4 µg/L read-across based on static dissolved (meas. (not grouping of specified)) based on: cell substances (category OECD Guideline 201 (Alga, Growth number approach) Inhibition Test) Test material (IUPAC name): cadmium (See endpoint summary for justification of read-across) Selenastrum capricornutum (new EC50 (72 h): 70 µg/L 1 (reliable without Janssen name: Pseudokirchnerella dissolved (meas. (TWA)) restriction) Pharmaceutica subcapitata) (algae) based on: growth rate (1993c) key study freshwater read-across based on static grouping of substances (category OECD Guideline 201 (Alga, Growth approach) Inhibition Test) Test material (IUPAC name): cadmium (See endpoint summary for justification of read-across) Selenastrum capricornutum (new EC50 (72 h): 120 µg/L 1 (reliable without Janssen name: Pseudokirchnerella dissolved (meas. (TWA)) restriction) Pharmaceutica subcapitata) (algae) based on: growth rate (1993d) key study freshwater read-across based on static grouping of substances (category OECD Guideline 201 (Alga, Growth approach) Inhibition Test) Test material (IUPAC name): oxocadmium (See

endpoint summary for justification of read-across) Selenastrum capricornutum (new EC50 (72 h): 18 µg/L 1 (reliable without LISEC (1998a) name: Pseudokirchnerella dissolved (meas. (not restriction) subcapitata) (algae) specified)) based on: growth rate key study freshwater read-across based on static grouping of substances (category OECD Guideline 201 (Alga, Growth approach) Inhibition Test) Test material (IUPAC name): oxocadmium (See endpoint summary for justification of read-across) Coelastrum proboscideum (algae) NOEC (1 d): 6.3 µg/L 2 (reliable with Müller KW and dissolved (meas. (not restrictions) Payer HD (1979) freshwater specified)) based on: biomass key study static NOEC (1 d): 27 µg/L experimental result 24h growth test dissolved (meas. (not specified)) based on: Test material biomass (IUPAC name): cadmium sulfate Chlamydomonas reinhardtii (algae) NOEC (7 d): 7.5 µg/L 3 (not reliable) Lawrence SG, dissolved (nominal) based Holoka MH and freshwater on: cell number supporting study Hamilton RD (1989) flow-through LOEC (7 d): 10 µg/L read-across based on dissolved (nominal) based grouping of Lawrence SG and two-stage, nitrogen-limited chemostat - on: cell number substances (category Holoka MH (1979) 7d experiment with endpoint = steady approach) state cell number Two-stage chemostat apparatus Test material described by Lawrence & Holoka (IUPAC name): (1979), see reference above cadmium dichloride (See endpoint summary for justification of read- across) Lemna paucicostata (algae) NOEC (7 d): 5 µg/L 3 (not reliable) Nasu Y and dissolved (nominal) based Kugimoto M (1989) freshwater on: number of fronds supporting study static NOEC (7 d): 10 µg/L read-across based on dissolved (nominal) based grouping of 7d growth experiment (number of on: number of fronds substances (category fronds) approach)

Test material (IUPAC name): cadmium dichloride

(See endpoint summary for justification of read- across) Scenedesmus quadricauda (algae) NOEC (7 d): 31 µg/L 3 (not reliable) Bringmann G and dissolved (nominal) based Kühn R (1980) freshwater on: biomass supporting study static read-across based on grouping of 7d static test with endpoint = biomass substances (category approach)

Test material (IUPAC name): cadmium dinitrate (See endpoint summary for justification of read- across) Chaetoceros compressum (algae) EC10 (3 d): 18.3 µg/L 2 (reliable with Fisher NS & Frood dissolved (estimated) based restrictions) D (1980) saltwater on: growth rate key study static read-across based on 3-d growth inhibition test with marine grouping of diatom, designed for dose-response substances (category approach)

Test material (EC name): cadmium chloride (See endpoint summary for justification of read-across) Ulva pertusa (algae) NOEC (5 d): 63 µg/L 2 (reliable with Taejun Han, Gye- dissolved (nominal) based restrictions) Woon Choi (2005) saltwater on: reproduction, sporulation key study static read-across based on 5-d sporulation test with marine grouping of macroalga, designed for dose-response substances (category approach)

Discussion

Effects on algae / cyanobacteria

The good quality data that were available for all Cd-substances were considered together, since the toxicity of the Cd++ ion is key to this analysis. freshwater short-term:

Data were available on 1 species. The lowest short-term EC50 is observed on Selenastrum caprocornutum: 18 µg Cd/l (single measured value). This value is used as the reference value for short-term toxicity to aquatic organisms, used for classification. The EC50 values on this species ranged between 18 and 120 µg Cd/l. Results were obtained at neutral/high pH where toxicity is expected to be highest.

Long-term toxicity: 8 reliable studies were considered for algae on 6 differents species. The NOECs, ranging from 0.85 to 31 µg/l Cd dissolved) were conbined to the other chronic data in the SSD to determine HC5 and further the PNEC.

Marine toxicity:

Relevant and reliable chronic toxicity data were found for one species of micro-algae (family Chaetocerotacae) and one species of macro-algae (family Ulvacae). Those two species are not among the most sensitive endpoints in the species sensitivity distribution (SSD) but they are situated in the first half of the fraction affected (NOEC range: 18.3 -63 µg Cd/L).

Algae species NOECs were combined together with other marine chronic data in the SSD to give the HC5 from which the PNEC is derived.

The following information is taken into account for effects on algae / cyanobacteria for the derivation of PNEC: freshwater short-term: The good quality short-term data that were available for all Cd-substances were considered together, since the toxicity of the Cd++ ion is key to this analysis. Data were available on 1 species. The lowest short-term EC50 is observed on Selenastrum capricornutum: 18 µg Cd/l (single measured value). The EC50 values on this species ranged between 18 and 120 µg Cd/l. marine waters: Data on 2 algae species available. Species NOECs values are of 18.3 µg Cd/L for the micro- algae Chaetoceros compressum and of 63 µg Cd/L for the macro-algae Ulva pertusa.

Value used for CSA:

EC50/LC50 for freshwater algae: 0.018 mg/L

7.1.1.4. Sediment organisms

Table 48. Overview of long-term effects on sediment organisms

Method Results Remarks Reference Leptocheirus plumulosus NOEC (28 d): 1370 mg/kg 1 (reliable without DEWITT T, sediment dw (meas. (not restriction) SWARTZ RC, saltwater specified)) based on: HANSEN DJ, survival, growth (length) andweight of evidence MCGOVERN D, long-term toxicity (laboratory study) reproduction BERRY WJ. (1996) (offspring/female) read-across based on semi-static grouping of substances (category 28 d chronic sediment toxicity test on approach) the amphipod Leptocheirus plumulosus Test material (IUPAC name): cadmium (See endpoint summary

for justification of read-across) Caenorhabditis elegans NOEC (72 h): 1226.4 mg/kg 1 (reliable without HOSS S., T sediment dw (meas. (geom. restriction) HENSCHEL, M freshwater mean)) based on: growth HAITZER, W (body length) weight of evidence TRAUNSPURGER short-term toxicity (laboratory study) , CEW read-across based on STEINBERG static grouping of (2001) substances (category analysis of contaminants performed approach) according to DIN, ISO and EN. Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Chironomus sp. NOEC (56 wk): 115 mg/kg 2 (reliable with Hare L., R. sediment dw (nominal) restrictions) Carignan and M. A. freshwater based on: abundance Huerta-Diaz (1994) weight of evidence long-term toxicity (field study) read-across based on field grouping of substances (category field test approach)

Test material (IUPAC name): cadmium dinitrate (See endpoint summary for justification of read- across) Annelids, molluscs, arthropods, NOEC (117 d): 1.3 µmol/g 2 (reliable with Hansen DJ, nematods, sipuncula, cniderians, measured SEM (meas. (not restrictions) Mahony JD, Berry rhinocaelians, chordates specified)) based on: taxa WJ, Benyi SJ, Pratt richeness, abundance supporting study SD, Di Toro DM saltwater and Abel MB read-across based on (1996) long-term toxicity (field study) grouping of substances (category flow-through approach)

118d in situ colonization study (field Test material (EC study) looking at taxa richeness and name): Cadmium abundance of benthic invertebrates chloride (See endpoint summary for justification of read-across)

Discussion

Freshwater PNECsediment: Conclusion

The assessment of the freshwater PNECsedimentfor cadmium identified only two long-term ecotoxicity studies

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 166 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 from the scientific literature. However, both the “Added” EqP (using partitioning coefficients and a robust aquatic toxicity database from the Cd RAR) and AF (using the lowest NOEC from a field colonization study) approaches produced consistent derivations for the freshwater benthic compartment. The resulting value is considered protective for EU freshwater ecosystems: freshwaterPNECadd, sedimentof 1.80 mg/kg d. w. (equivalent to 0.40 mg/kg w. w.). It is emphasized that this is an added PNEC, i. e. natural background needs to be taken into account when characterising the risk from monitored data.

Marine PNECsediment: Conclusion

The assessment of the marinePNECsedimentfor cadmium identified only two long-term ecotoxicity studies from the scientific literature. However, an “Added” EqP (using partitioning coefficients and a robust aquatic toxicity database) approach provided a reliable derivation for the marine benthic compartment. The resulting value is considered protective for EU marine ecosystems: marinePNECsediment, addedof 0.64 mg/kg d. w. (equivalent to 0.14 mg/kg w. w.). It is emphasised that this is an added PNEC, i. e. natural Bg needs to be taken into account when characterising the risk from monitored data.

The following information is taken into account for sediment toxicity for the derivation of PNEC:

Freshwater: chronic sediment data are available for one species of benthic nematode (Caenorhabditis elegans) with a reported NOEC growth of 1225 mg/kg d. w. (geometric mean of three NOECs from same study). The test was performed in unpolluted sediment with a background cadmium concentration of <1 mg/kg d. w. In addition, an in-situ recolonization study is also available for freshwater systems with a NOEC abundance reported of 115 mg/kg d. w. The test was performed in unpolluted sediment with a background cadmium concentration of 2.8 mg/kg d. w. Marine water: chronic sediment data are available for one species of benthic marine crustacean (Leptocheirus plumulosus) with a reported NOEC growth, survival and reproduction of 1370 mg/kg d. w. The test was performed in unpolluted sediment with a background cadmium concentration of <0.001 mg/kg d. w. In addition, a field colonization study is also available for marine systems with a reported NOEC abundance and taxa richeness of 169 mg added Cd/kg d. w.

7.1.1.5. Other aquatic organisms

Table 49. Overview of short-term effects on other aquatic organisms

Method Results Remarks Reference Xenopus laevis NOEC (100 d): 9 µg/L 3 (not reliable) Canton JH and dissolved (meas. (not Slooff (1982) freshwater specified)) based on: supporting study inhibition of larval semi-static development read-across based on grouping of other - no details substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Ciona intestinalis, vase tunicate, NOEC (20 h): 512 µg/L 2 (reliable with Juan Bellas, Elsa

Method Results Remarks Reference Ascidiacea, Chordata dissolved (estimated) based restrictions) Vazquez, Ricardo on: development Beiras (2001) saltwater key study static read-across based on grouping of Bellas J, Beiras R, Vazquez E (2003) substances (category A standardisation of Ciona intestinalis approach) (Chordata, Ascidiacea) embryo-larval bioassay for ecotoxicological studies. Test material Water Research 37 4613–4622 (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Ciona intestinalis, vase tunicate, NOEC (20 h): 362 µg/L 2 (reliable with Bellas J, Beiras R, Ascidiacea, Chordata dissolved (estimated) based restrictions) Vazquez E (2004) on: development saltwater key study static read-across based on grouping of Bellas J, Beiras R, Vazquez E (2003) substances (category A standardisation of Ciona intestinalis approach) (Chordata, Ascidiacea) embryo-larval bioassay for ecotoxicological studies. Test material Water Research 37 4613–4622 (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) natural phytoplancton communities NOEC (4 h): > 1.5 µg/L 2 (reliable with Wolter K, U. from field dissolved (estimated) based restrictions) Rabsch, P. on: C fixation rate Krischker and A. G. saltwater supporting study Davies (1984) NOEC (24 h): 2.5 µg/L static dissolved (meas. (not read-across based on specified)) based on: C grouping of Field experiment on natural fixation rate substances (category phytoplancton communities looking at approach) C fixation rates as the endpoint, designed for dose-response Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across)

Discussion

In this section, we report chronic toxicity data on organims that do not belong to the invertebrate, algae or fish groups. Indeed, reliable and relevant chronic cadmium toxicity data were found for one species of marine ascidians (Ciona intestinalis, Ascidiacae, Urochordata). The datapoint was added to the aquatic marine SSD.

Field data are also reported in this section. They are important as PNECs for dissolved metals are primarily based on single species data determined in the laboratory. It is important to check their capacity for protecting

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 168 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 the environment through field data, making the relationship between measured metal levels and observed ecosystem effects in the field.

Freshwater:

Marine waters:

A study on phytoplankton communities dominated by diatoms was conducted at three different locations (Kiel Fjord in Baltic Sea, North Sea and Atlantic ocean off Portugal). The lower NOEC carbon fixation rate was recorded in Kiel Fjord with a value of 1.5 µg/L (Wolter et al. 1984).

The following information is taken into account for any hazard / risk assessment:

Toxicity to other aquatic organims: Marine waters: One ascidian species NOEC available (species mean NOEC value for Ciona intestinalis of 430.5 µg Cd/L). Field data on freshwater: Field data on marine water: A field study on phytoplancton assemblages dominated by diatoms conducted in Kiel Fjord, Baltic Sea presents a NOEC carbon fixation rate of 1.5 µg Cd/L (Wolter et al. 1984).

7.1.2. Calculation of Predicted No Effect Concentration (PNEC)

7.1.2.1. PNEC freshwater

In the EU RA, it was concluded that the conditions for using a statistical extrapolation method to derive the PNEC for Cd in freshwater were met. Accordingly, this approach is also used for the present analysis. All chronic data mentioned in table above are used in a species sensitivity distribution (SSD), and the PNEC is derived based on the HC5 concentration. The EU RA discussed the differences between using RI 1 and 2 data only, or using these data combined with RI 3 data Further, several ways of using the data were also discussed, i.e. using all NOECs as such (no species geomean), using the species geomean, using the lowest NOEC by species, or using a “case-by-case” geomean value.

Selection on data quality does affect the value of the HC5: when all the data as such were used, there was a difference in HC5 between using RI 1 and RI 2 data only, or combining them with RI 3 data: 0.39 µg Cd/l versus 0.35 µg Cd/l, resp. (RA Cd, table 3.2.10.). Including less reliable data thus decreases the HC5. However, by using all the distinct data (and not using the species geomean) for the species sensitivity distribution, the more documented species were over-represented. Using one geomean value per species or using the lowest NOEC per species was considered not appropriate for the generic PNEC, because information from the database was lost with these approaches.

Finally, species geomean values were calculated on the RI 1, RI 2, RI 3 data combined, on a “case-by-case” basis: NOECs were only averaged when obtained in similar medium. If this was not the case, or different endpoints were mentioned, no geomean was calculated, and the distinct data were included as such in the SSD. These NOECs were used in the species sensitivity distribution (ECB 2008), presented in figure below. There was no difference between the log-normal and the log-logistic distribution. The HC5 calculated out of this SSD is 0,38 µg Cd/l.

100 ) % ( 80 n o i t u b i r t s i 60 d

y -1 c HC5 = 0.38 µg L n e u q e

r 40 f

e v i t a

l fish/amphibians u

m 20 aquatic invertebrates u

C primary producers distribution curve 0 0.1 1 10 100 Cd in solution (µg L-1)

Figure 6. The cumulative frequency distribution of the NOEC values of Cd toxicity tests of data quality group and RI 1-3 used to calculate the HC5 (case-by-case geometric mean calculation; n = 44). Selected data and logistic distribution curve fitted on the data (figure taken from the RA Cd/CdO, ECB 2008).

Discussion on the species sensitivity distribution. The diversity of the data used for the SSD (44 NOEC values on 28 species) is large enough to use the statistical extrapolation method for PNEC derivation. The uncertainty on the SSD and derived HC5 can further be checked according to set criteria to assign the additional assessment factor to the HC5 in order to calculate the PNEC:  The taxonomic diversity meets the requirements: it covers 28 species from 16 different families, including warm and cold water fish, amphibians, crustaceans, insects, algae and higher plants. So, according to this criterion, there is no need for an additional safety factor on the HC5.  All NOEC data are from real chronic studies; test durations are between 7 days and 3 years except for the unicellular algae, where different life stages are covered. So, according to this criterion, there is no need for an additional safety factor on the HC5.  The SSD is statistically significant: the species sensitivity distribution (lognormal) is statistically accepted (calculation with the ETX programme) at all levels (0.1-0.01 significance level) following both the Anderson-Darling test ((A-D statistic 0.42) and the Kolmogorov-Smirnov test (K-S statistic 0.69). So, according to this criterion, there is no need for an additional safety factor on the HC5.  Many tests included in the SSD database are performed in synthetic water resulting in a lower degree of Cd-complexation than under natural water conditions. This means that the test results were in general conservative, with regard to the aquatic toxicity of Cd in the real environment. So, according to this criterion, there is no need for an additional safety factor on the HC5.  The RA discussed some data from microcosm model ecosystems. The data were checked for reliability like the single species tests. Nine multi-species (MS) studies were discussed (for detail see RA Cd/CdO, table 3.2.11.), and the NOECs and LOECs from these studies were compared with HC5 values corrected for the specific hardness of the microcosm test according to the US-EPA hardness correction (see below). This revealed that in 8 out of 9 cases, the hardness corrected HC5 values were within the range of the reported MS-NOECs and below the MS-LOEC values. The one MS-LOEC below the HC5 may be an argument to apply an additional assessment factor of 2 on the HC5 to derive the PNEC.

 The whole of the single-species database, containing 168 reliable single species test results, contained 3 reliable LOECs below the HC5. This was also used in the RA as an argument to apply the additional assessment factor 2 on the HC5 to derive the PNEC. Following the argumentation summarised above, the RA applied an additional safety factor 2 to set the generic PNEC freshwater at HC5/2 = 0.19µg/l (ECB 2008). This value is also applied in the current analysis. It is emphasised that this value is very conservative, given the richness of the available dataset.

Bioavailability considerations Expression of the PNEC freshwater as a function of hardness Hardness is the main determining factor for Cd toxicity to aquatic organisms (RAR 2008). Cd-toxicity is more important under conditions of low hardness. The effect of water hardness on Cd toxicity has been quantified by the US-EPA (US-EPA 2001). Based on data for e.g. Daphnia magna, Pimephales promelas and Salmo trutta, a quantitative relationship between hardness and chronic toxicity could be derived. US-EPA derived a hardness correction formula that was used in the RA to express PNECs as a function of hardness (H) in the following way: a) all NOEC values of the SSD were converted to NOEC values at the reference hardness of 50 mg 0.7409 CaCO3/l (=NOECH=50) by applying the formula NOECH=50 =NOECHx (50/Hx) (US-EPA 2001). b) The normalised NOECs were again put into the SSD and the reference HC5 (at hardness 50) was calculated c) the assessment factor 2 was then applied to give the PNEC for waters of hardness 50 (0.09µg/l). d) Finally, the equation from EPA was again used to calculate PNECs for different hardnesses:

0.7409 PNECHx= 0.09 (50/Hx) By this procedure, the following hardness-dependent PNECs were calculated in the EU risk assessment report (ECB 2008): Hardness 40 mg CaCO3/l: 0.08, H50: 0.09, H100: 0.15, H200: 0.25. These calculations in the RA were interpreted later in the setting of the Cd-water quality standard in the EU water framework directive as follows: o H ≤ 40 mg CaCO3/l: 0.08 µg/l;

o H = 40 - <50 mg CaCO3/l: 0.08 µg/l;

o H = 50 - <100 mg CaCO3/l: 0.09 µg/l;

o H = 100 - <200 mg CaCO3/l: 0.15 µg/l.

o H = ≥ 200 mg CaCO3/l: 0.25 µg/l

For water assessment, bioavailability correction can be thus applied by using a hardness-specific PNEC when hardness or Ca-concentration are documented for the receiving water. When the local values of water hardness are unknown, the generic PNEC value (0.19 µg dissolved Cd/l) should generally be used. Regional data on hardness can be used as an alternative, but always with caution. The possible mitigating effect of dissolved organic carbon (DOC), and other water parameters on the bioavailability of Cd in water needs further study.

7.1.2.2. PNEC water Marine

Discussion on the assessment factor to apply on the HC5 for PNEC derivation

Based on uncertainty considerations, an assessment factor (AF) between 1 and 5 should be applied to the 5th percentile value of the species sensitivity distribution curve at 50% confidence value (thus PNEC = 5th percentile value / AF). The AF is to be judged on a case by case basis.

According to the ECHA Guidance (2008), the following points have to be considered when determining the size of the assessment factor:

1. the overall quality of the database and the endpoints covered, e.g., if all the data are generated from “true” chronic studies (e.g., covering all sensitive life stages); 2. the diversity and representativity of the taxonomic groups covered by the database, and the extent to which differences in the life forms, feeding strategies and trophic levels of the organisms are represented; 3. knowledge on presumed mode of action of the chemical (covering also long-term exposure). Details on justification could be referenced from structurally similar substances with established mode of action; 4. statistical uncertainties around the 5th percentile estimate, e.g., reflected in the goodness of fit or the size of confidence interval around the 5th percentile, and consideration of different levels of confidence (e.g. by a comparison between the 5% of the SSD (50%) with the 5% of the SSD (lower confidence interval); 5. comparisons between field and mesocosm studies, where available, and the 5th percentile to evaluate the laboratory to field extrapolation.

Based on the available chronic NOEC data for the marine environment, the following points were considered when determining the size of the assessment factor:

1. The overall quality of the database and the end-points covered, e.g., if all the data are generated from “true” chronic studies (e.g. covering all sensitive life stages); The marine Cd-database covered lethal and sub-lethal endpoints that are all relevant for potential effects at population level: mortality/immobilization, reproduction, development of early life stages including e.g. fertility of sperm cells, behaviour (i.e. settlement of pelagic larvae) and growth including time to maturity. ‘Chronic’ exposure times or relevant exposure periods for sensitive life-stages are also achieved for the nine taxonomic groups covered in the Cd database reporting accepted data. The exposure times for algae were of 3 days on diatoms and of 5 days on the macro-algae Ulva pertusa. Regarding the invertebrates, exposure times went from a few hours on very sensitive life-stages (e.g. sperm cell toxicity tests on echinoderms) up to 9 months (reproduction tests on annelids), and for fish, exposure times varied from 7 days up to 8 weeks on fertilized eggs or larvae. An additional group belonging to the Chordata that is the Ascidian group could also be included in the database with early life stage data (embryos). Sensitive life stages were covered at all trophic levels. Fertilized eggs or newly fertilized embryos were used in the following groups: echinoderms, molluscs, ascidians and fish. Echinoderms (seastars and sea urchins) sperm cell experiments were also retained in the Cd marine database. Larvae were extensively used and represented in the group of annelids, crustaceans (including nauplii and cyprid stages), and molluscs. Juveniles and young adults were finally found in the group of annelids, molluscs and nematods. Experiments made with adults deal with long-term chronic experiments, i.e. from 10 d with the crustacean Tigriopus brevicornis up to 9 months with the annelid Neanthes arenaceodentata..

2. The diversity and representativeness of the taxonomic groups covered by the database; The Figure below illustrates the marine biodiversity in terms of percentage of species across the various phyla (ECETOC, 2001). The Molluscs group is the largest taxonomic group in marine waters, followed by the Crustaceans group (ECETOC, 2001). These groups are the ones for which a large number of toxicity data are available for cadmium and so both groups were found to be broadly represented in the database. Among the various trophic levels, the invertebrates cover the largest part of taxonomic biodiversity. The marine database also includes typical marine groups such as echinoderms and cnidarians. In addition to the inter-taxonomic diversity, the cadmium marine database covers in each group a number of families which reflects a high level of intra-taxonomic diversity and a large range of toxicity-related responses (see e.g. the group of echinoderms and molluscs which display a large range of no effects levels, from 4.2 µg Cd/L to 10 mg Cd/L and 0.3 to 520 µg Cd/L, respectively). The most sensitive endpoints come from molluscs and crustaceans. However it is interesting to note that those two taxonomic groups are homogeneously distributed along the SSD.

Figure 7. Species diversity in the marine environment (from ECETOC 2001). The stars highlight taxonomic groups represented in the cadmium marine database.

The algae database contains macro and micro-algae data. Only two species passed the relevancy criteria, but additional toxicity information is available at large in the Q3 dataset. Those data are situated in the 20-50% fraction affected in the species sensitivity distribution and so do not reflect any particular sensitivity of those organisms towards cadmium in the single species SSD. As for fish, the 6 species represented in the database are also scattered along the SSD with the lowest value situated at 25 % of the affected fraction. Therefore, there is no particular sensitivity to be noted in this trophic level.

From the extracted data, the Cd-database does largely fulfil the requirement of 10-15 different NOEC values (62 individual NOEC values resulting in 48 species mean NOEC values).

3. Statistical uncertainties around the 5th percentile estimate, e.g., reflected in the goodness-of-fit or the size of confidence interval around the 5th percentile; A log-normal distribution was calculated and accepted at all significance levels. A factor of 2.45 was observed between the one-sided 95% left and the 50% confidence limit. The log-logistic distribution presented a slightly lower A-D test value (0.21 instead of 0.35), meaning that there is a slightly better fit to the input toxicity data.

4. Comparisons between field and mesocosm studies and the 5th percentile and mesocosm/field studies to evaluate the laboratory to field extrapolation. The available mesocosm data (Wolter et al. 1984) demonstrate that the no effect concentration level observed for phytoplankton in Kiel Fjord water may be lower than the HC5 coming from the single species SSD calculated from the lognormal distribution. However, experiments made in seawater from the North Sea and Atlantic Ocean did not reveal any significant effect of Cd neither on carbon fixation rates nor on bacterial glucose incorporation even at the highest concentration added to subsamples which is 2.5 µg/L. Those results should be interpreted with care as little information about test organisms and test conditions is provided.

5. NOEC values lower than the HC5-50 There are three NOEC/EC10 values reported in the Cd marine dataset that are slightly lower than the HC5-50. The 28-d EC10 of the crustacean Mysidopsis bahia (2.2 µg/L) and the 21-d EC10 of the crustacean Moina monogolica (1.8 µg/L). The lowest value is found for the mollusk Isognomon californicum (4-d NOEC of 0.3 µg/L). However, the other NOEC values within those groups are well scattered in the SSD which means that mollusks and crustaceans do not specifically show a particular sensitivity towards cadmium in marine waters. Moreover, if there is a high number of data in the SSD the chance of having values which are similar or below the HC5 is significant. This surely applies to the marine SSD counting 48 entries.

Conclusion on Assessment Factor (AF)

The following considerations are made on the uncertainty around the HC5: - The chronic NOEC database is very extensive and contains 48 species entries that cover much more than the requirements for taxonomic groups (8) and species (at least 10, preferably more than 15) set out in the guidance;  no justification to put an AF - Sensitive life stages or long chronic exposure periods (a few months) are represented in each taxonomic group as set out in the guidance;  no justification to put an AF - The large number of species in the SSD results in a low uncertainty on the HC5 value, as is shown by the small difference between the 50% confidence level and the 95% confidence limits found for the lognormal distribution: less than a factor of 2.5;  no justification to put an AF - The lognormal distribution that was used for PNEC derivation resulted in an HC5 of 2.28 µg/l, which is slightly lower than the HC5 value calculated from the log-logistic distribution (2.54 µg/l), which provided the best fit. So the HC5 that is used for the PNEC derivation highlights the conservative character of the log-normal distribution;  no justification to put an AF - comparing to field data, the HC5 value from the log-normal SSD may not be protective  justification to put an AF higher than 1 (2) - There is no indication for a particular sensitive group in the SSD. In addition, whenever an SSD includes > 20 data points, the chance of having a value below the HC5 is significant. So, having one or more values below the HC5 is inherent to bigger datasets and is not an issue as such;  no justification to put an AF

Based on these observations, it is proposed to divide the HC5 by an assessment factor of 2 which results in a PNEC saltwater for cadmium of 1.14 µg/L (HC5/2).

Difference between freshwater and saltwater PNEC The PNEC for Cd toxicity on saltwater organisms is higher than the PNEC for freshwater organisms. The mitigating effect of salinity on cadmium uptake and toxicity has been demonstrated for a variety of species (see e.g. Blust et al. 1992, Bjerregaard and Depledge 1994, Blackmore and Wang 2003). Indeed, for the same total metal concentration, the free ion activity is generally lower in a saltwater environment (high ionic strength) compared to a freshwater environment (low ionic strength). This is essentially due to complexation effects with chlorides and to effects of ionic strength on activity coefficients of the different metal species present. A high ionic strength also results in an increased protective effect towards cadmium uptake via calcium or other major cation transporters. This all explains why the Cd PNEC saltwater is higher than the Cd PNEC freshwater. This is also confirmed in other environmental jurisdictions e.g.: in the Australian and New Zealand guidelines for fresh and marine water quality where trigger values for Cd in fresh and marine waters are of 0.2 and 5.5 µg/L, respectively (ANZECC and ARMCANZ 2000).

Table 50. PNEC water

PNEC Assessment Remarks/Justification factor PNEC aqua 2 Extrapolation method: statistical extrapolation (freshwater): 0.19 µg/L The following considerations are made on the uncertainty around the HC5: The chronic freshwater database covers 28 species from 16 different families, including warm and cold water fish, amphibians, crustaceans, insects, algae and higher plants --> Based on this there is no need for an AF • All NOEC data are from real chronic studies; test durations are between 7 days and 3 years except for the unicellular algae, where different life stages are covered --> Based on this there is no need for an AF • The SSD is statistically significant: the species sensitivity distribution (lognormal) is statistically accepted (calculation with the ETX programme) at all levels (0.1-0.01 significance level) following both the Anderson-Darling test ((A-D statistic 0.42) and the Kolmogorov-Smirnov test (K-S statistic 0.69) --> Based on this there is no need for an AF •

PNEC Assessment Remarks/Justification factor

Many tests included in the SSD database are performed in synthetic water resulting in a lower degree of Cd-complexation than under natural water conditions. This means that the test results were in general conservative, with regard to the aquatic toxicity of Cd in the real environment --> Based on this there is no need for an AF • The RA discussed some data from microcosm model ecosystems: one out of 9 multi-species was found below the HC5 --> this was used as an argument to apply an AF2 on the HC5 to derive the PNEC • In the database containing 168 reliable single species test results, 3 reliable LOECs were below the HC5 --> this was also used as an argument to apply an AF2 on the HC5 to derived the PNEC PNEC aqua (marine 2 Extrapolation method: statistical extrapolation water): 1.14 µg/L The following considerations are made on the uncertainty around the HC5: - The chronic NOEC database is very extensive and contains 48 species entries that cover much more than the requirements for taxonomic groups (8) and species (at least 10, preferably more than 15) set out in the guidance; --> no justification to put an AF -Sensitive life stages or long chronic exposure periods (a few months) are represented in each taxonomic group as set out in the guidance; --> no justification to put an AF - The large number of species in the SSD results in a low uncertainty on the HC5 value, as is shown by the small difference between the 50% confidence level and the 95% confidence limits found for the lognormal distribution: less than a factor of 2.5; --> no justification to put an AF - The lognormal distribution that was used for PNEC derivation resulted in an HC5 of 2.28 µg/l, which is slightly lower than the HC5 value calculated from the log-logistic distribution (2.54 µg/l), which provided the best fit. So the HC5 that is used for the PNEC derivation highlights the conservative character of the log-normal distribution; --> no justification to put an AF - comparing to field data, the HC5 value from the log-normal SSD may not be protective --> justification to put an AF higher than 1 (2) - There is no indication for a particular sensitive group in the SSD. In addition, whenever an SSD includes > 20 data points, the chance of having a value below the HC5 is significant. So, having one or more values below the HC5 is inherent to bigger datasets and is not an issue as such; --> no justification to put an AF Based on these observations, there is a need to divide the HC5 by an assessment factor 2 which results in a PNEC saltwater for cadmium of 1.14 µg/L (HC5/2). Intermittent releases is not applicable for cadmium.

7.1.2.3. PNEC sediment

Freshwater chronic PNEC - establishing the dataset In this CSR, the results of the chronic freshwater sediment toxicity studies are expressed as the actual (measured) concentration of cadmium. Consistent with approved methodology, the reported benthic toxicity data presented here represent total (bulk)-cadmium concentrations, i.e. the dissolved plus particulate fraction.

The chronic freshwater benthic toxicity literature for cadmium was checked according to the general criteria for data quality:  Study design preferably conform to OECD guidelines or equivalent  Toxicological endpoints, which may affect the species at the population level, are taken into account. In general, these endpoints are survival, growth and reproduction.  For PNEC derivation a full life-cycle test, in which all relevant toxicological endpoints are studied, is normally preferred to a test covering not a full life cycle and/or not all relevant endpoints.  If for one species several chronic NOEC values (from different tests) based on the same toxicological endpoint are available, these values are averaged by calculating the geometric mean, resulting in the “species mean” NOEC.  If for one species several chronic NOEC values based on different toxicological endpoints are available, the lowest value is selected. The lowest value is determined on the basis of the geometric mean if more than one value for the same endpoint is available.  In some cases, NOEC values for different life stages of a specific organism are available. If from these data it appeared that a distinct life stage was more sensitive, the result for the most sensitive life stage is selected.  Only the results of tests in which the organisms were exposed to cadmium alone are used, thus excluding tests with metal mixtures.  Like in the RAR, unbounded NOEC values (i.e. no effect was found at the highest concentration tested) are not used.

Ecotoxicity data for freshwater sediment The EU RA contained 2 studies on chronic cadmium toxicity:  One single-species test in a freshwater-sediment system with cadmium was found (Hoss et al., 2001). The only available study was for a benthic nematode (Caenorhabditis elegans). Although short in duration, the available study represents a life-cycle test (72 hours exposure), which sufficiently provides information on survival, growth and reproduction effects. The test was performed in unpolluted sediment with a background cadmium concentration (Cb) of <1 mg/kg d.w. The NOEC value (growth) obtained from this study was 1,226.4 mg/kg d.w., which is the geometric mean of three NOECs from the same study.  One in-situ recolonisation study evaluated the toxicity and accumulation of cadmium from sediment by benthic invertebrates along a cadmium gradient created in nature (Hare et al., 1994). The cadmium concentration of sediments from a shield lake in Quebec was adjusted to obtain Cd : AVS ratios of from 0.05 to 10 and then subjected to in situ colonization by invertebrates over a 14-month period. The test was performed in unpolluted sediment with a background cadmium concentration (Cb) of 2.8 mg/kg d.w. The abundance of only one of the insect taxa present, Chironomus, was significantly related to the Cd : AVS molar ratio. The NOEC value (abundance) obtained from this study was 115 mg/kg d.w., which was equivalent to a Cd : AVS of two. However, a general lack of expected toxicity for other taxa at high Cd : AVS molar ratios (up to 10) in the field study suggests that the sensitivities to cadmium vary considerably among animal species used in the laboratory and in the field.  No further information on cadmium toxicity in freshwater sediments was found.

Deriving the PNEC The available ecotoxicity database for freshwater sediment is limited to one single-species test and one field colonization study so a statistical extrapolation approach was not justified for estimating an HC5 (concentration estimated for the 5th percentile of the distribution). Instead, the Equilibrium Partitioning (EqP) approach, as described in the Cd RAR (2008) is used to translate the PNEC estimated for the robust aquatic freshwater dataset (44 species) into a PNECsediment. The estimated PNECsediment value was considered with published studies regarding world-wide compilation of background concentrations of cadmium in freshwater sediments. In addition, the Assessment Factor [AF] approach for estimating PNECsediment values was also evaluated for

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 176 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 comparison.

Deriving the PNEC with the EqP Approach

Aquatic Ecotoxicity Data

The freshwater PNECaquatic is taken from the RAR (2008) freshwater aquatic database for cadmium (28 high quality species mean NOECs based on 44 species, from 16 taxonomic families covering three trophic levels). A lognormal distribution of the aquatic dataset resulted in a PNEC, with an AF of 2 included, of 0.19 µg Cd/L (see section on PNEC water derivation).

EqP Calculation

In conformity with the calculation of the PEC for sediment (RAR 2008), the properties of suspended matter are used to calculate the PNEC for sediment, i.e., PNECsediment = PNECsusp matter. Studies characterizing the equilibrium partitioning of cadmium to suspended matter in freshwater systems were complied to determine a median partitioning constant (Kpsusp) for cadmium (RAR 2008). Briefly, according to the TGD, the Ksusp-water and PNECsediment are calculated using the following equations:

1. Ksusp-water : Fwatersusp + (Fsolidsusp x Kpsusp x RHOsolid)

2. PNECsediment = PNECsusp matter : (Ksusp-water / RHOsusp) x PNECaquatic Where:

3 3 Ksusp-water = volumetric suspended matter / water partition coefficient (m /m )

3 3 Fwatersusp = volume fraction water in suspended matter (m /m )

3 3 Fsolidsusp = volume fraction solids in suspended matter (m /m )

3 Kpsusp = suspended matter / water partition coefficient (m /kg)

3 RHOsolid = density of the solid fraction (kg/m )

PNECsediment = Predicted No Effect Concentration in sediment (mg/kg wet sediment)

PNECsusp matter = Predicted No Effect Concentration in suspended matter (mg/kg wet suspended matter)

3 RHOsusp = bulk density of wet suspended matter (kg/m )

3 PNECaquatic = Predicted No Effect Concentration in water (mg/m )

Studies characterizing the equilibrium partitioning of cadmium to suspended matter in freshwater systems were complied to determine a median partitioning coefficient (Kpsusp) for cadmium (RAR 2008). The range in Kpsusp values from various natural freshwater sediment studies was 17,000-224,000 L/kg (RAR 2007). According to the RA, a median Kpsusp value was calculated to be 130,000 L/kg. Using this median value, the PNEC would be calculated with the EqP approach as follows (according to the TGD):

1. Ksusp-water : Fwatersusp + (Fsolidsusp x Kpsusp x RHOsolid) =

3 3 3 3 3 3 0.9 m /m + (0.1 m /m x 130 m /kg x 2,500 kg/m ) = 0.9 m3/m3 + 32,500 m3/m3 = 32,501 m3/m3

2. PNECsediment = PNECsusp matter : (Ksusp-water / RHOsusp) x PNECaquatic = (32,501 m3/m3 / 1,150 kg/m3) x 0.19 mg/m3 = 5.37 mg/kg wet sediment

The above PNECsediment of 5.37 mg/kg w.w. (22% solids by weight) is equivalent to a PNECsediment of 24.4 mg/kg d.w. As described in the Cd RAR (2008), the TGD stipulates an upper limit of Kp beyond which an additional safety

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 177 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 factor of 10 should be included (either in PNEC or in PEC) to take the risk of direct ingestion into account. This upper limit is at Kp of about 2,000 L/kg. This situation is certainly the case for cadmium, therefore the PNEC should be lowered by a factor of 10 in all cases. Using the additional safety factor, the EqP approach results in a PNECsediment of 0.54 mg/kg w.w. (equivalent to 2.44 mg/kg d.w.).

Comparison of the “Total” PNECsediment with the Natural Background Cadmium is a natural element that is present in natural background concentration in all sediments. A summary of measured background cadmium concentrations for freshwater sediments reported in the Cd RAR is provided below.  For Belgium, in 2001 monitoring data from the Flemish Environment Agency (VMM) reported a range of 0.02 to 7.4 mg/kg d.w. (n=512).  For France, cadmium data for sediments from the Réseau National de Donnéés sur l’Eau (RNDE) ranged from 1 to 20 mg/kg d.w. (n=192).  In the Netherlands, data available from the Rijkswaterstaat (RWS; n=12) and the COMMPS database (n=6) ranged from 0.05 to 4.89 mg/kg d.w. and 0.63 to 4.68 mg/kg d.w., respectively.  For Spain, eight values from the COMMPS database ranged from 0.1 to 0.52 mg/kg d.w.  A Swedish dataset gathered by the Swedish University of Agricultural Sciences (SLU) between 1998-2000 reported a range of cadmium concentrations from 0.12 to 7.64 mg/kg d.w.  The 10P, 50P and 90P values for all EU data (1296 samples) are 2.66, 0.85 and 0.31 mg/kg d.w., respectively.  In addition, a publication by Chapman et al. (1999) summarized natural background concentrations for 22 metals and metalloids from different jurisdictions in the U.S.A., Canada, The Netherlands, Norway, Australia, New Zealand, and China. For cadmium, site-specific background cadmium concentrations in freshwater sediments ranged from 0.5 to 2.5 mg/kg d.w. with a median value of 1.0 mg/kg d.w.

When considering the PNECsediment proposed above with information on background cadmium concentrations measured in freshwater sediments in the EU (90P = 2.7 mg/kg d.w.; see above), it can be argued that a PNEC of 2.4 mg Cd/kg d.w. could not be differentiated from the range of measured background concentrations (0.02-20 mg/kg d.w.). That is, because of the natural variability background cadmium concentrations in sediment observed throughout Europe, the “total risk” approach does not provide adequate resolution for determining risk among pristine or potentially contaminated sites. As a result, the PNEC”total” is not useful, and an alternative approach has to be developed.

EqP Calculation Using “Added” Approach

To reliably differentiate the PNECsediment value from background concentrations, it is proposed to use the EqP methodology in an “added risk” approach, to account for background. Since the EqP approach translates aquatic ecotoxicity information to loads for suspended matter, the background correction must be applied to the PNECaquatic. However, instead of correcting for each species NOEC in the aquatic freshwater database, the PNECaquatic (0.19 μg/L dissolved Cd) is corrected using the natural background cadmium concentration (0.05 μg/L dissolved Cd; Cd RAR, 2008). This value was also used as the natural background concentration in the calculation of PECcontinentalwater (Cd RAR, 2008).

From equation #2 above, the PNECaquatic can be substituted with PNECadd, aquatic using the background corrected value (i.e., 0.19 – 0.05 = 0.14 μg/L):

2. PNECadd, sed = PNECadd, susp : (Ksusp-water / RHOsusp) x PNECadd, aquatic = (32,501 m3/m3 / 1,150 kg/m3) x 0.14 mg/m3 = 3.96 mg/kg wet sediment

The above PNECadd, sediment of 3.96 mg/kg w.w. (22% solids by weight) is equivalent to a PNECadd, sediment of 18.0 mg/kg d.w.

Again, because the applied Kp value exceeds 2,000 L/kg, an additional safety factor of 10 is applied to account for the potential risk of direct ingestion. Using the additional safety factor, the EqP approach results in a PNECadd, sediment of 0.40 mg/kg w.w. (equivalent to 1.80 mg/kg d.w.). Although this PNECadd, sediment is in the same order of magnitude as the background, it can be distinguished from the background.

Discussion on the uncertainty on the PNEC derivation

The following considerations are made on the uncertainty around the PNECadd, sediment and for determining the size of the assessment factor:  Although only one long-term chronic toxicity test with cadmium was available, the NOEC for C. elegans (growth; 1,226.4 mg/kg d.w.) is nearly 700-fold higher than the PNECadd, sediment estimated above (1.8 mg/kg d.w.). This difference suggests that the calculated PNECadd, sediment is sufficiently conservative to provide adequate protection for benthic organisms in freshwater systems and there is no need for an additional assessment factor.  In the colonization study (Hare et al., 1994), the NOEC (115 mg/kg d.w.) is nearly 60-fold greater than the

estimated PNECadd, sediment presented here (1.8 mg/kg d.w.). This study provides the best experimental representation of ecosystem effects from cadmium exposure in nature since mixed metal pollution is the rule rather than the exception in the field. As such, this study provides additional confidence that the estimated PNECsediment is sufficiently conservative to provide adequate protection for benthic organisms in freshwater systems and there is no need for an additional assessment factor.

 The freshwater aquatic dataset (PNECaquatic) used for the calculation of the PNECadd, sediment in the EqP approach is extensive and of high quality and relevancy for the freshwater environment. Similarly, the Kp dataset used for deriving a median Kp value for use in the EqP approach is extensive and robust, and taken

straight from EU RA. Therefore the freshwater Kp is considered reliable for the derivation of the PNECadd, sediment in the present exercise.  All currently available natural background data for freshwater sediment are in the same order of magnitude (average = 1.32 mg/kg d.w.; range 0.02 to 20 mg/kg d.w.). From the available dataset for freshwater sediments, approximately 10% of the sediments have measured cadmium concentrations exceeding 2.66 mg/kg d.w. (90P). Given the variability and relatively wide range (two orders of

magnitude) of background cadmium concentrations for sediments, the PNECsediment must be represented using the “added risk” approach (PNECadd, sediment) to reliably differentiate environmental exposures from natural background. The resulting PNECadd, sediment value (1.80 mg/kg d.w.) thus provides a more conservative estimate than using the “total” approach and there is no need for an additional assessment factor.

An alternative approach for estimating a PNECsediment value was investigated. Here, the Assessment Factor (AF) approach, as described in the Cd RAR (2008), was evaluated for comparison to the EqP approach described above. The following considerations are made on the uncertainty around the PNECadd, sediment:

 In the Cd RAR (2008), it was concluded that the PNECsediment be based on the AF approach applied to the lowest observed NOEC from the field colonization study (115 mg/kg d.w.). As prescribed, this NOEC is divided by an AF of 50. The choice of an AF of 50 instead of 100 was justified by the number of acute toxicity data, showing no differences between species. This results in PNECsediment = 115 mg/kg d.w. / 50 = 2.3 mg/kg d.w. (equivalent to 0.49 mg/kg w.w.). The AF method presented here yields a PNECsed- iment value that is nearly 30% greater than the PNECadd, sediment value derived with the EqP method (1.8 mg/kg d.w.). This difference suggests that the calculated PNECadd, sediment is sufficiently conservative to provide adequate protection for benthic organisms in freshwater systems and there is no need for an additional assessment factor.  The AF approach described above could also be applied to the only long-term single species test indentified from the literature. Given that there is only one long-term test for freshwater benthic organisms, the TGD (2003; Table 19) prescribes that an AF = 100 be applied for datasets comprising at least “One long-term test (NOEC or EC10)”. As such, the lowest NOEC of the chronic dataset (C. elegans; 1,226.4 mg/kg d.w.) is divided by an AF of 100. This results in a PNECsediment = 1,226.4 mg/kg d.w. / 100 = 12.26 mg/kg d.w. (equivalent to 2.70 mg/kg w.w.). Although sufficiently conservative compared to the lowest NOEC value from the field colonization study, this value is 10-fold higher than the global average background cadmium concentration (discussed above). As such, the PNECadd, sediment

estimated using the EqP approach provides adequate protection for benthic organisms in freshwater systems.

Freshwater PNECsediment: Conclusion

The assessment of the freshwater PNECsediment for cadmium identified only two long-term ecotoxicity studies from the scientific literature. However, both the “Added” EqP (using partitioning coefficients and a robust aquatic toxicity database from the Cd RAR) and AF (using the lowest NOEC from a field colonization study) approaches produced consistent derivations for the freshwater benthic compartment. The resulting value is considered protective for EU freshwater ecosystems: freshwater PNECadd, sediment of 1.80 mg/kg d.w. (equivalent to 0.40 mg/kg w.w.). It is emphasized that this is an added PNEC, i.e. natural background needs to be taken into account when characterising the risk from monitored data.

Accounting for bioavailability in freshwater sediment It should be noted that different approaches for characterizing the bioavailable fraction of metals e.g. cadmium in sediment have been studied for nearly 20 years. Examples of these approaches include consideration of organic matter content as well as acid volatile sulfide (AVS) and simultaneous extractable metals (SEM). The sulfide fraction in sediment, as quantified by the AVS, is a reactive pool that binds metals, e.g. Cd and makes them unavailable for biota. The affinity for metal binding on the sulfide fraction in the sediment has been well established for the metals Cu, Cd, Pb, Zn and Ni. In that order, these metals will be bound on the sulfide present in the sediment and, as a consequence, will not be available anymore for uptake and possible toxicity. If the molar difference between SEM and AVS (i.e., SEM-AVS) is less than zero, no toxicity is expected, while a molar difference greater than zero suggests that toxic effects may occur. Although the background and application of this method was described in detail in the Cd RAR (2008), the approach was not applied in the EU risk assessment on cadmium. However, it was fully worked out in the subsequent discussions on the Zn RA (ECB 2008), and applied for the risk characterization. Because of the fact that Cd will bind to sulfide preferentially over zinc, it can be anticipated that the AVS/SEM concept applies also to cadmium. It is therefore considered possible to apply the concept on a local site-specific scale (Cd RAR, 2008).

Marine chronic PNEC - establishing the dataset In this CSR, the results of the chronic marine sediment toxicity studies are expressed as the actual (measured) concentration of cadmium. Consistent with approved methodology, the reported benthic toxicity data presented here represent total (bulk)-cadmium concentrations, i.e. the dissolved plus particulate fraction. The chronic marine benthic toxicity literature for cadmium was checked according to the general criteria for data quality:  Study design preferably conform to OECD guidelines or equivalent  Toxicological endpoints, which may affect the species at the population level, are taken into account. In general, these endpoints are survival, growth and reproduction.  For PNEC derivation a full life-cycle test, in which all relevant toxicological endpoints are studied, is normally preferred to a test covering not a full life cycle and/or not all relevant endpoints.  If for one species several chronic NOEC values (from different tests) based on the same toxicological endpoint are available, these values are averaged by calculating the geometric mean, resulting in the “species mean” NOEC.  If for one species several chronic NOEC values based on different toxicological endpoints are available, the lowest value is selected. The lowest value is determined on the basis of the geometric mean if more than one value for the same endpoint is available.  In some cases, NOEC values for different life stages of a specific organism are available. If from these data it appeared that a distinct life stage was more sensitive, the result for the most sensitive life stage is selected.  Only the results of tests in which the organisms were exposed to cadmium alone are used, thus excluding tests with metal mixtures.

 Like in the RAR, unbounded NOEC values (i.e. no effect was found at the highest concentration tested) are not used.  Like in the RAR, only the results of tests with soluble cadmium salts are used, thus excluding tests with “insoluble” cadmium salts.

Ecotoxicity data for marine sediment Most of the studies on marine sediment involve exposure to a mix of substances. Therefore only two studies were identified in a marine-sediment system with cadmium:  One single-species study was for a benthic crustacean (Leptocheirus plumulosus) represents a long- term chronic test (4 weeks exposure), which sufficiently provides information on survival, growth and reproduction effects. The test was performed in unpolluted sediment with a background cadmium concentration (Cb) of <0.001 mg/kg d.w. The lowest NOEC value (survival, growth and reproduction) obtained from this study was 1,370 mg/kg d.w.  The influence of interstitial cadmium and AVS in controlling the bioavailability of sediment-associated metal was examined using a chronic saltwater benthic colonization test (Hansen et al., 1996). The colonization study, reported no observed effects on taxa richness or abundance at added (measured-Cb) cadmium concentrations of 169 mg/kg d.w. (throughout the 4 months exposure). Authors also concluded that the EqP-based theories used to predict the acute biological consequences of divalent metals in sediments may be applicable to chronically exposed benthic organisms.  No further information on cadmium toxicity in marine sediments was found.

Deriving the PNEC

The toxicity of cadmium to marine benthic organisms was evaluated to develop PNECsediment. The available ecotoxicity database for marine sediment was limited to one field colonization study and one single-species test so a statistical extrapolation approach was not justified for estimating an PNEC (concentration estimated for the 5th percentile of the distribution). Instead, the Equilibrium Partitioning (EqP) approach, as described in the Cd RAR (2008) was used to translate the PNEC estimated for the robust aquatic marine dataset (48 species) into a PNECsediment. The estimated PNECsediment value is considered with published studies regarding world-wide compilation of background concentrations of cadmium in marine sediments. In addition, the Assessment Factor [AF] approach for estimating PNECsediment values was also evaluated for comparison.

Deriving the PNEC with the EqP Approach

Aquatic Ecotoxicity Data

The marine PNECaquatic is derived from the marine aquatic database for cadmium, which largely fulfils the species and taxonomic requirements for input chronic toxicity data as explained in the RIP R. 10 guidance (at least 10 species NOECs and 8 taxonomic groups). Indeed, 48 species mean NOECs, from 9 taxonomic groups covering three trophic levels were found to fulfill the relevancy and reliability requirements as explained by Klimisch et al. 1997. A lognormal distribution of the aquatic dataset resulted in a PNEC, with an AF of 2, of 1.14 µg Cd/L (Cd RAR, 2008).

EqP Calculation

In conformity with the calculation of the PEC for sediment (RAR 2008), the properties of suspended matter are used to calculate the PNEC for sediment, i.e., PNECsediment = PNECsusp matter. Studies characterizing the equilibrium partitioning of cadmium to suspended matter in estuarine and marine systems were complied to determine a median partitioning constant (Kpsusp) for cadmium (RAR 2008). Briefly, according to the TGD, the Ksusp-water and PNECsediment are calculated using the following equations:

1. Ksusp-water : Fwatersusp + (Fsolidsusp x Kpsusp x RHOsolid)

2. PNECsediment = PNECsusp matter : (Ksusp-water / RHOsusp) x PNECaquatic

Where:

3 3 Ksusp-water = volumetric suspended matter / water partition coefficient (m /m )

3 3 Fwatersusp = volume fraction water in suspended matter (m /m )

3 3 Fsolidsusp = volume fraction solids in suspended matter (m /m )

3 Kpsusp = suspended matter / water partition coefficient (m /kg)

3 RHOsolid = density of the solid fraction (kg/m )

PNECsediment = Predicted No Effect Concentration in sediment (mg/kg wet sediment)

PNECsusp matter = Predicted No Effect Concentration in suspended matter (mg/kg wet suspended matter)

3 RHOsusp = bulk density of wet suspended matter (kg/m )

3 PNECaquatic = Predicted No Effect Concentration in water (mg/m )

The range in Kpsusp values from 18 separate natural marine sediment studies was 65-5,600 L/kg (Turner 1993, 1996 and 2002). A median Kpsusp value was calculated to be 587 L/kg. Using this median value, the EqP approach would be calculated as follows (according to the TGD):

1. Ksusp-water : Fwatersusp + (Fsolidsusp x Kpsusp x RHOsolid) =

3 3 3 3 3 3 0.9 m /m + (0.1 m /m x 0.587 m /kg x 2,500 kg/m ) = 0.9 m3/m3 + 146.8 m3/m3 = 148 m3/m3

2. PNECsediment = PNECsusp matter : (Ksusp-water / RHOsusp) x PNECaquatic = (148 m3/m3 / 1,150 kg/m3) x 1.14 mg/m3 = 0.15 mg/kg wet sediment

The above PNECsediment of 0.15 mg/kg w.w. (22% solids by weight) is equivalent to a PNECsediment of 0.67 mg/kg d.w.

Comparison of the “Total” PNECsediment with the Natural Background Cadmium is a natural element that is present in natural background concentration in all sediments. A summary of measured background cadmium concentrations for marine sediments is provided below.  An extensive monitoring program in Belgium (Belgian Marine Data Center) reported measured data for coastal, estuarine and open sea sediment measurements covering years 2000-2008. Results show that the median cadmium concentrations (10 and 90 P) for coastal, estuarine and open sea sediments are 0.44 (0.18-0.94), 2.76 (0.50-10.4) and 0.17 (0.02-0.60) mg/kg d.w., respectively.  A publication by Chapman et al. (1999) summarized natural background concentrations for 22 metals and metalloids from different jurisdictions in the U.S.A., Canada, The Netherlands, Norway, Australia, New Zealand, and China. For cadmium, site-specific background cadmium concentrations in marine sediments ranged from 0.05 to 1.2 mg/kg d.w., with a median value of 0.83 mg/kg d.w.

When considering the PNECsediment proposed above with the available background cadmium concentrations measured in marine sediments (90P = 1.2 mg/kg d.w.; see above), it can be argued that addition of 0.67 mg Cd/kg d.w. could not be differentiated from the range of measured background concentrations (0.02-10.4 mg/kg d.w.). That is, because of the natural variability background cadmium concentrations in sediment observed throughout Europe, the “total risk” approach does not provide adequate resolution for determining risk among pristine or potentially contaminated sites. As a result, the PNEC”total” is not useful, and an alternative approach has to be developed.

EqP Calculation Using “Added” Approach

To reliably differentiate the PNECsediment value from background concentrations, it is proposed to use the EqP methodology in an “added risk” approach, to account for background. Since the EqP approach translates aquatic ecotoxicity information to loads for suspended matter, the background correction must be applied to the PNECaquatic. However, instead of correcting for each species NOEC in the aquatic marine database, the PNECaquatic (1.14 μg/L dissolved Cd) is corrected using the natural background cadmium concentration (0.025 μg/L dissolved Cd; Cd RAR, 2008). This value is the highest reported Background Reference Concentration (BRC) reported by the UK National Marine Monitoring Programme between 1999 and 2001.

From equation #2 above, the PNECaquatic can be substituted with PNECadd, aquatic using the background corrected value (i.e., 1.14 – 0.025 = 1.12 μg/L):

2. PNECadd, sed = PNECadd, susp : (Ksusp-water / RHOsusp) x PNECadd, aquatic = (148 m3/m3 / 1,150 kg/m3) x 1.12 mg/m3 = 0.14 mg/kg wet sediment

The above PNECadd, sediment of 0.14 mg/kg w.w. (22% solids by weight) is equivalent to a PNECadd, sediment of 0.64 mg/kg d.w. Although this PNECadd, sediment is in the same order of magnitude as the background, it can be distinguished from the background.

Discussion on the uncertainty on the PNEC derivation

The following considerations are made on the uncertainty around the PNECadd, sediment and for determining the size of the assessment factor:  Although only one long-term chronic toxicity test with cadmium is available, the sensitivity of L. plumulosus (survival, growth and reproduction; 1,370 mg/kg d.w.) is nearly 1000-fold higher than the PNECadd, sediment calculated using the EqP approach (0.64 mg/kg d.w.). This difference suggests that the calculated PNECadd, sediment is sufficiently conservative to provide adequate protection for benthic organisms in marine systems and there is no need for an assessment factor higher than 1.

 In the colonization study (Hansen et al., 1996), the NOECecosystem (169 mg/kg d.w.) is over 250-fold greater than the estimated PNECadd, sediment presented here (0.64 mg/kg d.w.). This study provides the best experimental representation of ecosystem effects from cadmium exposure in nature since mixed metal pollution is the rule rather than the exception in the field. As such, this study provides additional confidence that the estimated PNECsediment is sufficiently conservative to provide adequate protection for benthic organisms in marine systems and there is no need for an additional assessment factor.

 The marine aquatic dataset (PNECaquatic) used for the calculation of the PNECadd, sediment in the EqP approach is extensive and of high quality and relevancy for the marine environment. Similarly, the Kp dataset used for deriving a median Kp value for use in the EqP approach is extensive and robust, including data from both EU and N. American waters. As such it is comparable in size and representativity with the dataset on marine Kp, used in the EU RA. Therefore the marine Kp is considered reliable for the derivation of the PNECadd, sediment in the present exercise.  All currently available natural background data for marine sediment are in the same order of magnitude (average = 0.8 mg/kg d.w.; range 0.02 to 10.4 mg/kg d.w.). From the available dataset for marine sediments, approximately 10% of the sediments have measured cadmium concentrations exceeding 1.2 mg/kg d.w. (90P). Given the variability and relatively wide range (two orders of magnitude) of background cadmium concentrations for sediments, the PNECsediment must be represented using the “added risk” approach (PNECadd, sediment) to reliably differentiate environmental exposures from natural background. The resulting PNECadd, sediment value (0.64 mg/kg d.w.) thus provides a more conservative estimate than using the “total” approach and there is no need for an additional assessment factor.

An alternative approach for estimating a PNECsediment value was investigated for comparison to the EqP approach. Here, the Assessment Factor (AF) approach, as described in the Cd RAR (2008), was evaluated for comparison to the EqP approach described above. The following considerations are made on the uncertainty around the PNECadd, sediment:  The RIP guidance prescribes that an AF = 100 be applied for datasets comprising at least “One long- term freshwater and one saltwater sediment test representing different living and feeding conditions”. As such, a NOECgrowth for a freshwater benthic nematode (Caenorhabditis elegans) was reported as 1,226.4 mg/kg d.w. (Hoss et al., 2001). Given that the freshwater NOEC is slightly lower that the

NOEC obtained for the marine crustacean (1,370 mg/kg d.w.; discussed above), the freshwater NOEC is divided by an AF of 100. This results in a PNECsediment = 1,226.4 mg/kg d.w. / 100 = 12.3 mg/kg d.w. (equivalent to 2.71 mg/kg w.w.). This value is nearly 20-times higher than the recommended PNEC add, sediment (0.64 mg/kg d.w.) and 10-times higher than the 90P background concentration for marine sediments (1.2 mg/kg d.w.).

Marine PNECsediment: Conclusion

The assessment of the marine PNECsediment for cadmium identified only two long-term ecotoxicity studies from the scientific literature. However, an “Added” EqP (using partitioning coefficients and a robust aquatic toxicity database) approach provided a reliable derivation for the marine benthic compartment. The resulting value is considered protective for EU marine ecosystems: marine PNECsediment, added of 0.64 mg/kg d.w. (equivalent to 0.14 mg/kg w.w.). It is emphasised that this is an added PNEC, i.e. natural Bg needs to be taken into account when characterising the risk from monitored data.

Accounting for bioavailability in marine waters As for the freshwater, it is noted that different approaches for characterizing the bioavailable fraction of metals e.g. cadmium in sediment have been studied for nearly 20 years. Examples of these approaches include consideration of organic matter content as well as acid volatile sulfide (AVS) and simultaneous extractable metals (SEM). The sulfide fraction in sediment, as quantified by the AVS, is a reactive pool that binds metals, e.g. Cd and makes them unavailable for biota. The affinity for metal binding on the sulfide fraction in the sediment has been well established for the metals Cu, Cd, Pb, Zn and Ni. In that order, these metals will be bound on the sulfide present in the sediment and, as a consequence, will not be available anymore for uptake and possible toxicity. If the molar difference between SEM and AVS (i.e., SEM-AVS) is less than zero, no toxicity is expected, while a molar difference greater than zero suggests that toxic effects may occur. Although the background and application of this method was described in detail in the Cd RAR (2008), the approach was not applied in the EU risk assessment on cadmium. However, it was fully worked out in the subsequent discussions on the Zn RA (ECB 2008), and applied for the risk characterisation. Because of the fact that Cd will bind to sulfide preferentially over zinc, it can be anticipated that the AVS/SEM concept applies also to cadmium. It is therefore considered possible to apply the concept on a local site-specific scale (Cd RAR, 2008), also in the marine environment.

Table 51. PNEC sediment

PNEC Assessment Remarks/Justification factor PNEC sediment 1 Extrapolation method: partition coefficient (freshwater): 1.8 mg/kg sediment dw It is emphasized that the reported PNEC for freshwater sediments is an added PNEC, i.e. natural background needs to be taken into account when characterizing the risks from monitored data. The following considerations are made for determining the size of the assessment factor: •The proposed EqP-derived PNECadd, sediments is nearly 700 fold lower than the only long-term chronic NOEC (NOEC growth for C. elegans: 1226.4 mg/kg d.w.) •The AF method presented in this assessment and based on the lowest NOEC from the field colonization study/AF50 yields a PNECsediment value that is nearly 30% greater than the PNEcadd, sediment value derived with the EqP method (115 mg/kg d.w./AF50 = 2.3 mg/kg d.w.) • The AF approach could also be applied to the only long- term single species test identified in the literature. An AF 100 would then be applied which would result in a PNEC of 1226.4 mg/kg d.w. /100 = 12.26 mg/kg d.w. As such, the PNEcadd, sediment based on the EqP approach provides adequate protection for benthic organisms in freshwater systems. PNEC sediment 1 Extrapolation method: partition coefficient (marine water): 0.64

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 184 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 mg/kg sediment dw It is emphasized that the reported PNEC for saltwater sediments is an added PNEC, i.e. natural background needs to be taken into account when characterizing the risks from monitored data. The following considerations are made for determining the size of the assessment factor: • The only single species long-term chronic NOEC found is a thousand times higher than the proposed EqP-derived PNEC (NOEC survival, growth and reproduction for L. plumulosus: 1370 mg/kg d.w.) • The proposed EqP PNEC is considered protective for ecosystems, according to field study (NOEC ecosystem: 169 mg/kg d.w.; Hansen et al. 1996) •AF approach-derived PNEC based on the lowest NOEC from both saltwater and freshwater dataset (1226.4 mg/kg d.w. /AF100 = 12.3 mg/kg d.w.) is 10 to 20 times higher than the recommended EqP-derived PNEC of 0.64 mg/kg d.w.

7.2. Terrestrial compartment 7.2.1. Toxicity test results

1) Chronic data – establishing the dataset

A significant amount of data is available on Cd toxicity to soil or litter microflora, soil fauna and higher plants in the EU risk assessment (RA; ECB 2008). The quality and relevancy of those data have been reviewed in detail during the EU risk assessment process. Reliability indices 1, 2 and 3 (RI 1, RI 2 and RI 3) data were used in the PNEC derivation, while reliability 4 data were excluded. Because the RI 1 and 2 data group has limited number of species, the RA has proposed to include the reliability 3 data too as basis for deriving the PNEC. This is mainly due to plant data that are excluded from the group RI 1-2, whereas plants seem to be the most sensitive group. For the present analysis, the same approach was followed, to be conform with the EU RA. Moreover, studies assigned RI 3 are still quite well documented and therefore be considered reliable.

In this assessment, an update of the literature was made and new toxicity data for Cd in soil were found useful to be added to the dataset. Reliability was reviewed based on the same reliability indices as those in the RA and using the same criteria. For each test, a RI was given according to the following criteria (RA, ECB 2008):

RI 1: standard test, including the OECD 207 acute toxicity test withEisenia fetidain OECD-soil and the ISO 1994: soil quality effects of soil pollutants on Collembolla (Folsomia candida): method for the determination of effects on reproduction.

RI 2: no standard test but complete background information is given, i. e. the following information is present: a) soil pH b) soil organic matter or carbon content c) texture (class or texture fractions) d) total Cd content of the soil at zero Cd application if the NOEC or LOEC value is below 2m g/g e) equilibration time after soil contamination and prior to the test f) statistical analysis of the dose-response relationship g) no varying metal contamination along with increasing Cd application h) the control soil must be tested along with at least two Cd concentrations above the background concentration i) the soil must be homogeneously mixed with the metal prior to the test

RI 3: no standard test and one or more of the following information from the above-mentioned list is missing as background information: b), c), e) or f). All other information from that list is present.

RI 4: no standard test and one or more of the following information from the above-mentioned list is missing as background information: a), d), g), h) or i). The requirement d) is critical since some tests reporting LOEC values < 2m g/g are considered unreliable. Background Cd concentrations in soil typically range between 0.1 and 0.5m g/g and the lack of reporting the background concentration may underestimate the total Cd concentration in soil at which the first toxic effects are found. Unbounded NOECs were not used. Tests performed in substrates that were judged as not representative for soils (e. g. pure quartz sand or farmyard manure) were not included in this effects assessment.

Additional toxicity literature for cadmium was also checked according to the general criteria for data quality:

· Toxicological endpoints, which may affect the species at the population level, are taken into account. In general, these endpoints are survival, growth and reproduction.

· If for one species, several NOEC values on the same endpoint are available, the geometric mean of the NOEC values was first calculated and the most sensitive endpoint was taken forward in the SSD for PNEC derivation.

· Only the results of tests in which the organisms were exposed to cadmium alone were used, thus excluding tests with metal mixtures.

· Like in the RA, unbounded NOEC values were not used in the assessment.

· Like in the RA, only the results of tests with soluble Cd2+ salts were used.

· The NOECs used are reported as nominal values and were taken as such for the PNEC derivation. No correction for natural background was thus applied.

From the present revision of the terrestrial dataset, four new species of macro-organisms were found to respond to the criteria. Among them, three additional arthropod species and one plant species were included, allowing for a revision of the invertebrates + plants SSD. New data on species already figuring in the RA – database were also considered and species geometric mean NOEC values were recalculated based on new information. A new HC5 “plants and invertebrates” could subsequently be calculated (see Section 3).

2) Single-species data for Cd toxicity in soil

The available database of chronic terrestrial toxicity tests for single-species with cadmium provides information on several species of soil micro-organisms, invertebrates and plants. These species are routinely utilized for assessing the toxicity of substances in spiked soils and standard test protocols exist.

Microflora dataset

The microflora dataset of the RA contains 21 entries (12 tests on respiration, 4 tests on N-cycle, 4 tests on soil enzymes and one test on N2fixation). The individual NOEC values varied from 3.6 mg/kg for the N2fixation endpoint up to 3000 mg/kg for respiration. No new data on microflora was found in this update and the microflora dataset from the RA remains thus unchanged. The microflora entries are summarized in the table 55.

Invertebrates dataset

The invertebrates dataset now contains 9 species among which: four species of annelids, one species of nematod and four species of arthropods. The available data on macroinvertebrate organisms include only long-term tests, from 21 to 294 days, which cover growth and reproduction effects. Three new species of arthropods (Onychiurus yodai, Sinella umesaoi and Paronychiurus kimi) were added to the RA-dataset with NOEC values for reproduction of 50, 25 and 25 mg Cd/kg, respectively. A new NOEC value for growth of 12.5 mg Cd/kg was

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 186 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 also found for the annelid L. rubellus and two new NOEC values of 25 and 80 mg Cd/kg were found for the reproduction endpoint the collembol Folsomia candida. Considering those new values, the endpoint reproduction becomes the most sensitive endpoint for F. candida. Overall, the individual NOEC values varied from 5 mg/kg for the annelid Eisenia foetida up to 320 mg/kg for F. candida. The invertebrates entries are summarized in the table 53.

Plants dataset

The updated plants dataset provides information on 15 species, including exposure times from 14 to 100 days and covering growth (length, weight, biomass) and germination effects. As compared to the RA, one new species was added to the dataset, i. e. Brassica campestris L. cv. Chinensis with a NOEC for growth (biomass) and NOEC for germination of 25 and 100 mg Cd/kg, respectively. New NOECs were found for the wheat seedling (Triticum aestivum; NOEC root elongation of 20 mg Cd/kg), for the oat (Avena sativa; NOEC biomass of 6.3 mg Cd/kg and NOEC germination of 25 mg Cd/kg) and the lettuce (Lactuca sativa; NOEC biomass of 3.1 mg Cd/kg and NOEC germination of 12.5 mg Cd/kg). The individual NOEC values varied from 1.8 mg/kg for the species Picea sitchensis up to 100 mg/kg for B. campestris var. Chinensis. The plants entries are summarized in the table 54.

The geometric mean NOEC values calculated for invertebrates and plants on the most sensitive endpoint are reported in table below. NOECs of soil microbial assays have not been averaged across soils because of the intrinsic variability of the microbial population between soils.

Table 52. Summary table of species geometric mean NOECs for the most sensitive endpoints of plants and invertebrates used in the SSD. New species to the ones mentioned in the RA or species for which new information was found are highlighted in bold. The newly added individual NOECs are underlined in the last column.

organism phylum/class Order family endpoint Species geometric mean NOEC

(µg g-1)

Dendrobaena Annelida Haplotaxida Lumbricidae Reproduction 10 Geometric mean rubida of 10, 10

Eisenia fetida Annelida Haplotaxida Lumbricidae Reproduction 5

Lumbricus Annelida Haplotaxida Lumbricidae Growth 43.3 geometric mean rubellus of 150, 12.5

Eisenia Annelida Haplotaxida Lumbricidae Growth 13.4 Geometric mean andrei of 10, 18

Onychiurus Arthropoda Isotonida Onychiuridae Reproduction 50 yodai

Sinella Arthropoda Isotonida Onychiuridae Reproduction 25 umesaoi

Paronychiuru Arthropoda Isotonida Onychiuridae Reproduction 25 s kimi

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 187 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 organism phylum/class Order family endpoint Species geometric mean NOEC

(µg g-1)

Folsomia Arthropoda Collembola Isotomidae Reproduction 50.5 geometric mean candida of 25, 80

Plectus Nematoda Araeolaimida Plectidae Growth 32 acuminatus

Avena sativa Avena sativa Cyperale Poaceae Growth 8.6 geometric mean of 6.3, 10, 10

Picea Pinopsida Pinales Pinaceae Growth 1.8 sitchensis

Triticum Liliopsida Cyperales Poaceae Growth 16.9 geometric mean aestivum of 7.1, 20, 20, 29

Glycine max Magnoliopsida Fabales Fabaceae Growth 6.6 geometric mean of 2.5, 5, 10, 10, 10

Raphanus Magnoliopsida Capparales Brassicaceae Growth 20 geometric mean sativus of 10 and 40

Lactuca Magnoliopsid Asterales Asteraceae Growth 9 geometric mean sativa a of 2, 2.5, 3.1, 3.2, 5, 5, 10, 10, 20, 20, 32, 40, 40

Lycosperisico Magnoliopsida Solanales Solanaceae Growth 50.6 geometric mean n esculentum of 32 and 80

Phaseolus Magnoliopsida Fabales Fabaceae Growth 20 vulgaris Liliopsida Cyperales Poaceae 10 Zea mays Magnoliopsida Violales Cucurbitaceae 80 Cucurbita pepo Magnoliopsida Capparales Brassicaceae 5

Lepidium Magnoliopsida Capparales Brassicaceae 10 sativum Magnoliopsida Apiales Apiaceae 10 Brassica rapa

Daucus carota

Brassica Magnoliopsida Capparales Brassicaceae Growth 25 campestris var. chinensis

2010-09-07 CSR-PI-5.2.1 CHEMICAL SAFETY REPORT 188 EC number: cadmium sulphate CAS number: 233-331-6 10124-36-4 organism phylum/class Order family endpoint Species geometric mean NOEC

(µg g-1)

Beta vulgaris Magnoliopsida Caryophyllales Chenopodiacea Growth 34 geometric mean e of 20, 20, 20, 40, ‘40, 40, 40, 80

7.2.1.1. Toxicity to soil macro-organisms

Table 53. Overview of effects on soil macro-organisms

Method Results Remarks Reference Lumbricus rubellus (annelids) NOEC (84 d): 150 mg/kg 2 (reliable with Ma W.C. (1982) soil dw (nominal) based on: restrictions) long-term toxicity (laboratory study) mortality, weight key study Substrate: natural soil read-across based on 84 days exposure mortality and weight grouping of test on the annelid Lumbricus rubellus substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Eisenia andrei (annelids) NOEC (21 d): 10 mg/kg soil 2 (reliable with van Gestel CAM, dw (nominal) based on: restrictions) Dirven-van long-term toxicity (laboratory study) juvenile/adult Breemen EM and key study Baerselman R Substrate: OECD soil (1993) read-across based on 21 days growth and number of cocoons grouping of test on annelid Eisenia andrei substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Dendrobaena rubida (annelids) NOEC (110 d): 10 mg/kg 2 (reliable with Bengtsson G, soil dw (nominal) based on: restrictions) Gunnarsson T and long-term toxicity (laboratory study) cocoon production Rundgren S (1986) key study Substrate: natural soil

110 and 270 days exposure test on NOEC (110 d): 10 mg/kg read-across based on Dendrobaena rubida soil dw (nominal) based on: grouping of hatching success substances (category approach)

Test material (IUPAC name): cadmium dinitrate (See endpoint summary for justification of read- across) Eisenia fetida (annelids) NOEC (84 d): 18 mg/kg soil 3 (not reliable) van Gestel CAM, dw based on: growth van Dis WA, long-term toxicity (laboratory study) supporting study Dirven-van Breemen EM, Substrate: OECD soil read-across based on Sparenburg PM and grouping of (1991) 84 days exposure growth, mortality substances (category and development test on the annelid approach) Eisenia foetida andrei Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Plectus acuminatus (nematods) NOEC (21 d): 32 mg/kg soil 3 (not reliable) Kammenga JE, Van dw (nominal) based on: Koert PHG, Riksen long-term toxicity (laboratory study) juvenile/adult ratio supporting study JAG, Korthals GW and Bakker J (1996) Substrate: OECD-soil read-across based on grouping of 21d juvenile/adult ratio test on substances (category nematod Plectus acuminatus in an approach) OECD-soil Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Lumbricus rubellus (annelids) NOEC (294 d): 12.5 mg/kg 3 (not reliable) D. J. Spurgeon, C. soil dw (nominal) based on: Svendsen, P. Kille, long-term toxicity (laboratory study) mean weight supporting study A. J. Morgan, J. M. Weeks (2004) Substrate: artificial soil read-across based on grouping of 294d growth ecotoxicity soil tests on substances (category earthworms Lumbricus rubellus approach)

Test material (IUPAC name): cadmium dichloride (See endpoint

summary for justification of read- across) Eisenia fetida (annelids) NOEC (56 d): 5 mg/kg soil 3 (not reliable) Spurgeon DJ and dw (nominal) based on: Hopkin SP (1995) long-term toxicity (laboratory study) cocoon production supporting study Substrate: OECD soil read-across based on grouping of OECD Guideline 207 (Earthworm, substances (category Acute Toxicity Tests) approach)

Test material (IUPAC name): cadmium dinitrate (See endpoint summary for justification of read- across) Folsomia candida (Collembola (soil- NOEC (42 d): NOEC 1 (reliable without van Gestel CAM dwelling springtail)) (nominal) based on: restriction) and Hensbergen PJ reproduction (1997) long-term toxicity (laboratory study) key study

ISO 1994: soil quality effects of soil read-across based on pollutants on Collembolla (Folsomia grouping of candida): method for the determination substances (category of effects on reproduction approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Folsomia candida (Collembola (soil- NOEC (35 d): NOEC based 2 (reliable with Crommentuijn T, dwelling springtail)) on: number of offspring restrictions) Brils J and van Straalen NM (1993) long-term toxicity (laboratory study) key study

ISO 1994: soil quality effects of soil read-across based on pollutants on Collembolla (Folsomia grouping of candida): method for the determination substances (category of effects on reproduction approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Folsomia candida (Collembola (soil- NOEC (4 wk): NOEC 1 (reliable without T. Nakamori, S. dwelling springtail)) (nominal) based on: restriction) Yoshida, Y. reproduction Kubota, T. Ban- long-term toxicity (laboratory study) key study Nai, N. Kaneko, M.

Method Results Remarks Reference Hasegawa (2008) ISO 11267 (Inhibition of Reproduction read-across based on of Collembola by Soil Pollutants) grouping of substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Onychiurus yodai (Collembola (soil- NOEC (4 wk): NOEC 1 (reliable without T. Nakamori, S. dwelling springtail)) (nominal) based on: restriction) Yoshida, Y. reproduction Kubota, T. Ban- long-term toxicity (laboratory study) key study Nai, N. Kaneko, M. Hasegawa (2008) ISO 11267 (Inhibition of Reproduction read-across based on of Collembola by Soil Pollutants) grouping of substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Sinella umesaoi (Collembola (soil- NOEC (4 wk): NOEC 1 (reliable without T. Nakamori, S. dwelling springtail)) (nominal) based on: restriction) Yoshida, Y. reproduction Kubota, T. Ban- long-term toxicity (laboratory study) key study Nai, N. Kaneko, M. Hasegawa (2008) ISO 11267 (Inhibition of Reproduction read-across based on of Collembola by Soil Pollutants) grouping of substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Folsomia candida (Collembola (soil- NOEC (28 d): NOEC 1 (reliable without I. N. Herbert, C. dwelling springtail)) (nominal) based on: restriction) Svendsen, P. K. reproduction Hankard, D. J. long-term toxicity (laboratory study) key study Spurgeon (2004) ISO 11267 (Inhibition of Reproduction read-across based on of Collembola by Soil Pollutants) grouping of substances (category approach)

Test material

(IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Paronychiurus kimi (Collembola (soil- NOEC (28 d): NOEC 3 (not reliable) J. Son, M. I. Ryoo, dwelling springtail)) (nominal) based on: J. Jung, K. Cho reproduction supporting study (2007) long-term toxicity (laboratory study) read-across based on 28 days exposure Cd soil test on the grouping of collembol P. kimi; artificial soil substances (category prepared according to ISO (1999) approach)

Discussion of effects on soil macro-organisms except arthropods

Chronic soil data are available for 4 species of annelids and one species of nematod with reported geometric mean NOECs varying from 5 mg/kg d. w. for Eisenia fetida up to 43.3 mg/kg d. w. for Lumbricus rubellus.

The following information is taken into account for effects on soil macro-organisms except arthropods for the derivation of PNEC: chronic soil data are available for 4 species of annelids and one species of nematod with reported geometric mean NOECs varying from 5 mg/kg d. w. for Eisenia fetida up to 43.3 mg/kg d. w. for Lumbricus rubellus.

Discussion of effects on soil arthropods

Chronic soil data are available for 4 species of arthropods with reported geometric NOECs varying from 25 mg/kg d. w. for Sinella umesaoi and Paronychiurus kimi up to 50.5 mg/kg d. w. for Folsomia candida.

The following information is taken into account for effects on soil arthropods for the derivation of PNEC: chronic soil data are available for 4 species of arthropods with reported geometric NOECs varying from 25 mg/kg d. w. for Sinella umesaoi and Paronychiurus kimi up to 50.5 mg/kg d. w. for Folsomia candida.

7.2.1.2. Toxicity to terrestrial plants

Table 54. Overview of effects on terrestrial plants

Method Results Remarks Reference Lactuca sativa Avena sativa: NOEC (10 d): 1 (reliable without A. X. da Rosa

Method Results Remarks Reference 25 mg/kg soil dw based on: restriction) Corrêa, L. Rubi Brassica campestris var. chinensis germination Rörig, M. A. key study Verdinelli, S. Avena sativa Avena sativa: NOEC (10 d): Cotelle (2006) 6.25 mg/kg soil dw based read-across based on long-term toxicity (laboratory study) on: biomass grouping of substances (category germination (%) and biomass Brassica campestris var. approach) chinensis: NOEC (10 d): 100 Substrate: natural soil mg/kg soil dw based on: Test material germination (IUPAC name): ISO (1995) guideline cadmium (See Brassica campestris var. endpoint summary chinensis: NOEC (10 d): 25 for justification of mg/kg soil dw based on: read-across) biomass

Lactuca sativa: NOEC (10 d): 12.5 mg/kg soil dw based on: germination

Lactuca sativa: NOEC (10 d): 3.12 mg/kg soil dw based on: biomass Picea sitchensis (Gymnospermae Picea sitchensis: NOEC 2 (reliable with Burton KW, (conifers)) (100 d): 1.8 mg/kg soil dw restrictions) Morgan E and Roig (nominal) based on: growth A (1984) long-term toxicity (laboratory study) (root length) key study seed germination/root elongation read-across based on toxicity test grouping of substances (category Substrate: natural soil approach) long term growth (root length) test Test material performed on the stika spruce (Picea (IUPAC name): sitchensis) cadmium dichloride (See endpoint summary for justification of read- across) Triticum aestivum (Dicotyledonae Triticum aestivum: NOEC (3 2 (reliable with Q. Cao, Q-H. Hu, S. (dicots)) d): 20 mg/kg soil dw restrictions) Khan, Z.-J. Wang, (nominal) based on: root A.-J. Lin, X. Du, Y- short-term toxicity (laboratory study) elongation key study G. Zhu (2007) seed germination/root elongation read-across based on toxicity test grouping of substances (category Substrate: natural soil approach)

3d root elongation test on wheat Test material seedlings of the species Triticum (IUPAC name): aestivum in a natural silt loam soil cadmium dichloride (See endpoint summary for justification of read- across)

Method Results Remarks Reference Triticum aestivum (Dicotyledonae Triticum aestivum: NOEC 2 (reliable with Reber HH (1989) (dicots)) (28 d): 7.1 mg/kg soil dw restrictions) (nominal) based on: growth long-term toxicity (laboratory study) (shoot dry weight) key study shoot dry weight test Triticum aestivum: NOEC read-across based on (28 d): 29 mg/kg soil dw grouping of Substrate: natural soil (nominal) based on: growth substances (category (shoot dry weight) approach) 28d growth test on Triticum aestivum Test material (IUPAC name): oxocadmium (See endpoint summary for justification of read-across) Beta vulgaris (Dicotyledonae (dicots)) Lactuca sativa: NOEC (63 3 (not reliable) Mahler RJ, d): 40 mg/kg soil dw Bingham FT and Lactuca sativa (Dicotyledonae (nominal) based on: growth supporting study Page AL (1978) (dicots)) (shoot dry weight) experimental result long-term toxicity (laboratory study) Lactuca sativa: NOEC (63 d): 40 mg/kg soil dw Test material (EC early seedling growth toxicity test (nominal) based on: growth name): cadmium (shoot dry weight) sulphate Substrate: natural soil Lactuca sativa: NOEC (63 63 days exposure growth test on lettuce d): 10 mg/kg soil dw and chard (nominal) based on: growth (shoot dry weight)

Lactuca sativa: NOEC (63 d): 20 mg/kg soil dw (nominal) based on: growth (shoot dry weight)

Lactuca sativa: NOEC (63 d): 2.5 mg/kg soil dw (nominal) based on: growth (shoot dry weight)

Beta vulgaris: NOEC (63 d): 20 mg/kg soil dw (nominal) based on: growth (shoot dry

weight)

Beta vulgaris: NOEC (63 d): 20 mg/kg soil dw (nominal) based on: growth (shoot dry weight)

Beta vulgaris: NOEC (63 d): 80 mg/kg soil dw (nominal) based on: growth (shoot dry weight) Phaseolus vulgaris (Dicotyledonae Phaseolus vulgaris: NOEC : 3 (not reliable) Bingham FT, Page (dicots)) 20 mg/kg soil dw (nominal) AL, Mahler RJ and based on: growth (bean dry supporting study Ganje TJ (1975) Glycine max (G. soja) (Dicotyledonae weight) (dicots)) experimental result Glycine max (G. soja): Triticum aestivum (Dicotyledonae NOEC : 2.5 mg/kg soil dw Test material (EC (dicots)) (nominal) based on: growth name): cadmium (bean dry weight) sulphate Zea mays (Dicotyledonae (dicots)) Triticum aestivum: NOEC : Lycopersicon esculentum 20 mg/kg soil dw (nominal) (Dicotyledonae (dicots)) based on: growth (grain weight) Cucurbita pepo (Dicotyledonae (dicots)) Zea mays: NOEC : 10 mg/kg soil dw (nominal) based on: Brassica oleracea var. capitata growth (kernal weight) (Dicotyledonae (dicots)) Lycopersicon esculentum: Oryza sativa (Dicotyledonae (dicots)) NOEC : 80 mg/kg soil dw (nominal) based on: growth Lactuca sativa (Dicotyledonae

(dicots)) (ripe fruit weight)

Lepidum sativum (Dicotyledonae Cucurbita pepo: NOEC : 80 (dicots)) mg/kg soil dw (nominal) based on: growth (fruit Spinacia oleracea (Dicotyledonae weight) (dicots)) Brassica rapa: NOEC : 10 Brassica rapa (Dicotyledonae (dicots)) mg/kg soil dw (nominal) based on: growth (tuber Raphanus sativus (Dicotyledonae weight) (dicots)) Lactuca sativa: NOEC : 5 Daucus carota (Dicotyledonae mg/kg soil dw (nominal) (dicots)) based on: growth (head weight) long-term toxicity (laboratory study) Lepidum sativum: NOEC : 5 weight of dry bean, grain, kernal, ripe mg/kg soil dw (nominal) fruit, fruit head, shoot and tuber based on: growth (shoot weight) Substrate: natural soil Spinacia oleracea: NOEC : long term (up to maturity) growth test 1.25 mg/kg soil dw on various plants (nominal) based on: growth (shoot weight)

Raphanus sativus: NOEC : 40 mg/kg soil dw (nominal) based on: growth (tuber weight)

Daucus carota: NOEC : 10 mg/kg soil dw (nominal) based on: growth (tuber weight) Spinacia oleracea (Dicotyledonae Beta vulgaris: NOEC (48 3 (not reliable) Kádár I (1995) (dicots)) mo): 90 kg/ha based on: biomass supporting study Kádár I, Szabo L Beta vulgaris (Dicotyledonae (dicots)) and Sarkadi J Spinacia oleracea: NOEC experimental result (1998) long-term toxicity (field study) (72 mo): 90 kg/ha based on: biomass Test material (EC biomass name): cadmium sulphate Substrate: natural soil

Field experiment on various plants in a calcareous chernozem soil Raphanus sativus (Dicotyledonae Raphanus sativus: NOEC 3 (not reliable) Khan DH and (dicots)) (42 d): 10 mg/kg soil dw Frankland B (1983) (nominal) based on: growth supporting study long-term toxicity (laboratory study) (shoot dry weight) read-across based on growth (shoot dry weight) test grouping of substances (category Substrate: natural soil approach) 42 days growth test on the radish plant

Raphanus sativus Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Glycine max (G. soja) (Dicotyledonae Glycine max (G. soja): 3 (not reliable) Miller JE, Hassett (dicots)) NOEC (28 d): 10 mg/kg soil JJ and Koeppe DE dw (nominal) based on: supporting study (1976) long-term toxicity (laboratory study) growth (shoot dry weight) read-across based on growth (shoot dry weight) test Glycine max (G. soja): grouping of NOEC (28 d): 10 mg/kg soil substances (category Substrate: natural soil dw (nominal) based on: approach) growth (shoot dry weight) 28d growth test on the soya (Glycine Test material max) Glycine max (G. soja): (IUPAC name): NOEC (28 d): 5 mg/kg soil cadmium dichloride dw (nominal) based on: (See endpoint growth (shoot dry weight) summary for justification of read- Glycine max (G. soja): across) NOEC (28 d): 10 mg/kg soil dw (nominal) based on: growth (shoot dry weight) Lactuca sativa (Dicotyledonae Lactuca sativa: NOEC (2 3 (not reliable) Adema D. M. M. (dicots)) wk): 32 mg/kg soil dw and L. Henzen (nominal) based on: growth supporting study (1989) Lycopersicon esculentum (shoot fresh weight) (Dicotyledonae (dicots)) read-across based on Lactuca sativa: NOEC (2 grouping of Avena sativa (Dicotyledonae (dicots)) wk): 3.2 mg/kg soil dw substances (category (nominal) based on: growth approach) long-term toxicity (laboratory study) (shoot fresh weight) Test material shoot fresh weight Lycopersicon esculentum: (IUPAC name): NOEC (2 wk): 32 mg/kg soilcadmium dichloride Substrate: artificial soil dw (nominal) based on: (See endpoint growth (shoot fresh weight) summary for OECD Guideline 208 (Terrestrial justification of read- Plants Test: Seedling Emergence and Avena sativa: NOEC (2 wk): across) Seedling Growth Test) 10 mg/kg soil dw (nominal) based on: growth (shoot fresh weight)

Avena sativa: NOEC (2 wk): 10 mg/kg soil dw (nominal) based on: growth (shoot fresh weight) Phaseolus vulgaris (Dicotyledonae Phaseolus vulgaris: NOEC 3 (not reliable) Sajwan KS, Ornes (dicots)) (30 d): 6.7 mg/kg soil dw WH, Youngblood (meas. (not specified)) based supporting study TV and Alva AK long-term toxicity (field study) on: growth (biomass) (1996) read-across based on early seedling growth toxicity test grouping of substances (category

Substrate: natural soil approach)

30 days field study on the bush beans Test material (EC Phaseolus vulgaris name): cadmium chloride (See endpoint summary for justification of read-across) Lactuca sativa (Dicotyledonae Lactuca sativa: NOEC (42 3 (not reliable) Jasiewicz C (1994) (dicots)) d): 2 mg/kg soil dw (nominal) based on: growth supporting study long-term toxicity (laboratory study) (shoot dry weight) read-across based on growth (shoot dry weight) test grouping of substances (category Substrate: natural soil approach) long term growth test on Lactuca sativa Test material (IUPAC name): cadmium dinitrate (See endpoint summary for justification of read- across) Nicotina tabacum (Dicotyledonae Nicotina tabacum: NOEC (2 4 (not assignable) Mench M, (dicots)) mo): 5.44 mg/kg soil dw Tancogne J, Gomez (meas. (not specified)) based supporting study A and Juste C Nicotina rustica (Dicotyledonae on: biomass (1989) (dicots)) read-across based on Nicotina rustica: NOEC (2 grouping of Zea mays (Dicotyledonae (dicots)) mo): 5.44 mg/kg soil dw substances (category (meas. (not specified)) based approach) long-term toxicity (field study) on: biomass Test material (EC biomass test Zea mays: NOEC (144 mo): name): Cadmium 7.2 mg/kg soil dw (meas. nitrate (See endpoint Substrate: natural soil (not specified)) based on: summary for biomass justification of read- 2 months field Cd-enriched natural soil across) experiment on Nicotina spp. and Zea Zea mays: NOEC (144 mo): mays 8.3 mg/kg soil dw (meas. (not specified)) based on: biomass

Discussion

Chronic soil data are available for 15 plant species with reported NOECs varying from 1.8 mg/kg d. w. for Picea sitchensis up to 100 mg/kg d. w. for Brassica campestris var. chinensis. In addition, field colonization studies are also available for terrestrial systems and the NOEC vary from >6.7 up to 50 mg/kg d. w.

The following information is taken into account for toxicity on terrestrial plants for the derivation of PNEC: chronic soil data are available for 15 plant species with reported NOECs varying from 1.8 mg/kg d. w. for Picea sitchensis up to 100 mg/kg d. w. for Brassica campestris var. chinensis. In addition, field colonization studies are also available for terrestrial systems and the NOEC vary from >6.7 up to 50 mg/kg d. w.

7.2.1.3. Toxicity to soil micro-organisms

Table 55. Overview of effects on soil micro-organisms

Method Results Remarks Reference Species/Inoculum: native soil NOEC (490 d): 150 mg/kg 2 (reliable with Doelman P and microflora soil dw (nominal) based on: restrictions) Haanstra L (1984) respiration rate >300 days respiration test on native key study soil microflora NOEC (301 d): 150 mg/kg soil dw (nominal) based on: read-across based on respiration rate grouping of substances (category NOEC (630 d): 150 mg/kg approach) soil dw (nominal) based on: respiration rate Test material (IUPAC name): NOEC (560 d): 3000 mg/kg cadmium dichloride soil dw (nominal) based on: (See endpoint respiration rate summary for justification of read- NOEC (574 d): 400 mg/kg across) soil dw (nominal) based on: respiration rate Species/Inoculum: native soil NOEC (33 d): 10 mg/kg soil 2 (reliable with Dusek (1995) microflora dw (nominal) based on: restrictions) nitrate formation rate 33 days exposure test on nitrification key study of native soil microflora NOEC (33 d): 50 mg/kg soil dw (nominal) based on: read-across based on nitrate formation rate grouping of substances (category NOEC (33 d): 100 mg/kg approach) soil dw (nominal) based on: nitrate formation rate Test material (IUPAC name): NOEC (33 d): 50 mg/kg soil cadmium dichloride dw (nominal) based on: (See endpoint nitrate formation rate summary for justification of read- across) Species/Inoculum: native soil NOEC (560 d): 55 mg/kg 2 (reliable with Haanstra L and microflora soil dw (nominal) based on: restrictions) Doelman P (1984) glutamic acid decomposition Long term (560 days) glutamic acid time key study decomposition time test on various soils NOEC (560 d): 150 mg/kg read-across based on soil dw (nominal) based on: grouping of glutamic acid decomposition substances (category time approach) Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across)

Method Results Remarks Reference Species/Inoculum: native soil NOEC (98 d): 14.3 mg/kg 2 (reliable with Walter C and microflora soil dw (nominal) based on: restrictions) Stadelmann F respiration rate (1979) Long term respiration and key study ammonification tests on loamy sand soil read-across based on grouping of substances (category approach)

Test material (IUPAC name): cadmium dinitrate (See endpoint summary for justification of read- across) Species/Inoculum: native soil NOEC (84 min): 3.6 mg/kg 2 (reliable with Reber H.H. (1989) microflora soil dw (nominal) based on: restrictions) respiration rate 84 min. respiration test on soil key study microflora from various soil types NOEC (84 min): 3.6 mg/kg soil dw (nominal) based on: read-across based on respiration rate grouping of substances (category NOEC (84 min): 14.3 mg/kg approach) soil dw (nominal) based on: respiration rate Test material (IUPAC name): oxocadmium (See endpoint summary for justification of read-across) Species/Inoculum: native soil NOEC (56 d): 5 mg/kg soil 3 (not reliable) Cornfield AH microflora dw (nominal) based on: (1977) respiration rate supporting study 56 days respiration test on sandy soil experimental result

Test material (EC name): cadmium sulphate Species/Inoculum: Rhizobium NOEC (90 wk): 4 mg/kg soil3 (not reliable) Chaudri AM, leguminosarum bv. trifolii dw (meas. (not specified)) McGrath SP and based on: cell number supporting study Giller KE (1992) 18 months exposure test on Rhizobium (survival) leguminosarum bv. trifolii in sandy experimental result loam Test material (EC name): cadmium sulphate Species/Inoculum: native soil NOEC (30 wk): 112 mg/kg 3 (not reliable) Frostegard A, microflora soil dw (nominal) based on: Tunlid A and Baath ATP content supporting study E (1993) 6 months exposure test on respiration rate and ATP content of forest soil and NOEC (30 wk): 60 mg/kg experimental result arable soil microflora soil dw (nominal) based on: respiration rate Test material (EC name): cadmium

sulphate Species/Inoculum: native soil NOEC (28 d): 50 mg/kg soil 3 (not reliable) Saviozzi A, Levi- microflora dw (nominal) based on: Minzi R, Cardelli R respiration (substrate supporting study and Riffaldi R 28 days respiration (substrate induced induced CO2 evolution) (1997) CO2 evolution) test on native soil read-across based on microflora grouping of substances (category approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Species/Inoculum: native soil NOEC (45 d): 10 mg/kg soil 3 (not reliable) Khan DH and microflora dw (nominal) based on: Frankland B (1984) cellulolytic activity supporting study 45 days exposurecellulolytic activity test on native soil microflora read-across based on grouping of substances (category approach)

Discussion

The microflora dataset of the RA contains 21 entries (12 tests on respiration, 4 tests on N-cycle, 4 tests on soil enzymes and one test on N2fixation). The individual NOEC values varied from 3.6 mg/kg for the N2fixation endpoint up to 3000 mg/kg for respiration.

The following information is taken into account for toxicity on soil micro-organisms for the derivation of PNEC:

The microflora dataset of the RA contains 21 entries (12 tests on respiration, 4 tests on N-cycle, 4 tests on soil enzymes and one test on N2 fixation). The individual NOEC values varied from 3.6 mg/kg for the N2 fixation endpoint up to 3000 mg/kg for respiration.

7.2.1.4. Toxicity to other terrestrial organisms

7.2.2. Calculation of Predicted No Effect Concentration (PNEC soil)

PNEC derivation a. Statistics on the species sensitivity distribution (SSD)

As in the RA, the statistical extrapolation approach is proposed in the PNEC derivation. We tested the lognormal distribution in the statistical approach as default option using the RIVM program ETX version 2.0. As in the RA (ECB, 2008), the HC5 is calculated for three different scenarios of data selection. The first scenario is by using microflora NOEC values only. The values were taken as such from the Cd RA, as no new data were added to the dataset. The second scenario is based on the use of the revised database for invertebrates and plants, (going from 20 to 24 species). The third scenario is making use of the whole terrestrial toxicity database, i. e. using data on microflora, plants and invertebrate organisms, as applied to other RA on metals (Cu, Ni) and recommended by the Scientific Committee for Health and Environmental Risks (SCHER) for the zinc RA. The statistics of the curve-fitting on the chronic NOEC data are summarized in Table below.

Table 56. Summary statistics for the SSD on chronic NOEC values for cadmium in soil

Scenario N HC5 at 50% A-D test and K-S test and Statistical (Lower estimate significance levelsignificance level acceptance on HC5) mg Cd/kg

Microflora 21 2.3 (0.7) 0.50 0.74 Accepted

(P>0.1) (P>0.1)

Plants+Invertebr 24 3.6 (2.0) 0.29 0.63 Accepted ates (P>0.1) (P>0.1)

Microflora+plan 45 2.4 (1.0) 0.46 0.69 Accepted ts+invertebrates (P>0.1) (P>0.1)

Using both the Anderson-Darling (A-D) and the Kolmogorov-Smirnov (K-S) tests for normality, the lognormal distribution fits significantly at a level of 1% for all tested scenarios.

The terrestrial data set is split in two groups: microbial processes and soil invertebrates + higher plants. The endpoints for microbial processes are relevant at the ecosystem functioning level, while the endpoints for soil fauna and plants are relevant at the species level. The principle of splitting the terrestrial data in two groups is open to criticism: there is no scientific argument (e. g. field validation) for either option. However, this approach was taken forward in the Cd RA (ECB, 2008) and is therefore also applied in the present assessment. It is however noted that recently, this split has not been applied in more recent metal RAs, e.g. on Ni, Cu.

As in the RA, the lowest NOEC selection approach was not performed because such a selection would not yield a representative data set for the terrestrial ecosystem (e. g. all clay soils would be excluded). The HC5 for the microflora is lower than the HC5 for soil fauna and plants. In conclusion, we propose to use the HC5 based on the microflora data set for the PNEC derivation i. e. HC5microflora= 2.3 μ g Cd/g d. w. This approach is in accordance with the Cd RA (ECB, 2008) and results in the lowest of the three HC5 values following from the three tested scenarios.

For the sake of comparison, if the assessment factor approach would be applied, using the lowest NOEC divided by an assessment factor (AF) 10, this would yield a PNEC soil of 1.8 µg g-1/AF10 or 0.18 µg/g. This value is within the range of cadmium background concentrations in soils which typically range between 0.1 and 0.5 µg/g (Cd RA, 2008).

b. Discussion on the uncertainty on the HC5 for PNEC soil derivation

Based on the uncertainty considerations, an assessment factor between 1 and 5 should be applied to the HC5 at

50% confidence levels (thus PNEC=HC5/AF). The AF is to be judged on a case by case basis.

The following considerations are made on the uncertainty around the HC5 and for determining the size of the AF:

Species diversity The HC5 value of the terrestrial ecosystem is derived from 21 individual NOECs covering 5 different microbial processes. The plants belong to 9 different families and 9 different taxonomic orders and the invertebrates belong to 4 different families and 3 different taxonomic orders. This diversity meets the recommendation for deriving a PNEC for soil using statistical extrapolation method, i.e. the data set contains more than 8 different taxa. Based on this criterion, there is no need for an AF.

Types of soils The data should be based on a diversity of soil properties. The tests on which the HC5 value is based are performed in soils with pH 3.1-7.9 % carbon 0.6-47 and % clay 2-70. This range in soil properties covers most of the European topsoils. Based on this criterion, there is no need for an AF.

Field studies There are field data that allow deriving threshold concentrations of Cd in soil at the field scale. Cadmium is usually associated with other metals in the field and these other metals can be more readily toxic than Cd itself. In most cases, Cd pollution is associated with Zn pollution. Effects of smelter contamination on plants or on earthworms are often attributed to Zn and not to Cd (Tiller, 1989; Spurgeon and Hopkin, 1995).

 Field observations (Sajwan et al. 1996) In this field test, effect of Cd was measured in bush beans grown on a loamy sand located on the Savannah River Site, near Aiken in South Carolina, US. No growth effects were noted at the highest tested concentration i.e. up to 6.7 µg Cd/g soil d.w (measured concentration). The Cd level in the control treatment was of 0.6 µg/g Cd (Sajwan et al., 1996).

 Field trials (Kádár, 1995; Kádár et al., 1998) A long term field trial was performed in Nagyhörcsök, Hungary on a calcareous chernozem, characterised by a high cation exchange capacity, high pH and

high base saturation. Cationic metals are strongly sorbed into this soil. Cadmium (as CdSO 4) was applied to the soil at 4 concentrations above control with three fold replication. No toxic effect of Cd on plant growth was detected up to the highest test concentration (810 kg/ha.y) during the first 4 years. Toxic effects (significantly different from control) were observed at 270 kg/ha loading in 1995 and 1996, in spinach and red beet, i.e. 162 mg Cd/kg soil (Table 54). The resulting NOECs values for those species in the field were both 50 mg Cd/kg soil, i.e. well above the HC5 values calculated in the present analysis. No effects were observed for wheat grain (Table 54).

 Field trials (Mench et al. 1989) Another long-term field trial took place in 1988-1990 in Bordeaux (F). Three nominal Cd concentrations were tested: 10, 20 and 40 g Cd/g. The field has plots with pH 5.3- 5.6 and plots with pH 6.7-7.0. The corn shoot yield data of 2000 are given in Table 54. Cadmium was more toxic in the most acid plots and had no significant effect on corn shoot yield up to 7-8 g Cd/g. The LOECs at 15 g Cd/g were associated with a 50 % (high pH) and 61 % (low pH) lower shoot yield than the control.

 Bingham et al. 1975 This paper refers to pot trial experiments on various plant species grown to commercial harvest stage on a soil pre-treated with municipal sewage sludge (1%). Effects levels (EC25s) are reported for 14 species. The lowest reported EC25 is for the spinach Spinacia oleracea with a value of 4 µg Cd/g. This value is 4-fold lower than in the field where 25% yield reduction is observed at 18 µg Cd/g (see Table 54, Kadar 1995). The phytotoxic effects of Cd were then observed at higher concentrations in the field trials compared to pot trials. This is also the case for wheat grain.

Table 57. Phytotoxicity of Cd salts in field trials (from Cd RA, 2008) test soil properties Results* substance CdSO4 Nagyhörcsök (Hungary): 1991: 1single Cd application Kádár et al., 1998 calcareous Chernozem; (kg Cd/ha) 0 30 90 270 810 pH (CaCl2) = 7.3; 3% 1994: soil Cd (g) 0.3 18 50 162 not meas. org. matter; 5%CaCO3; CEC 22 cmolc/kg yield (ton FW/ha) 1991: corn n.s. n.s. n.s. n.s. 1992: carrot n.s. n.s. n.s. n.s. 1993: potato n.s. n.s. n.s. n.s. 1994: pea n.s. n.s. n.s. n.s. 1995: red beet 14.6a 7.4a 9.5a 3.7b 0.7b 1996: spinach 16.3a 12.1a 11.4a 9.8b 3.7b 1997: wheat grain 6.8a n.d. 7.3a 6.4a 5.4a

Cd(NO3)2 Borde aux (France) 1988-1990 Cd applications Mench, pers. com. pH (CaCl2) = 5.3-5.6; 2000:soil Cd (mg Cd/kg) 1.3 7.2 15 35 (2000) CEC 10 cmolc/k g 2000: corn (g FW/plant) 59.9a 39.9a 23.3b 18.6b

Cd(NO3)2 Bordeaux (France) 1988-1990 Cd applications Mench, pers. com. pH (CaCl2) = 6.7-7.0; 2000:soil Cd (mg Cd/kg) 1.2 8.3 15 32 (2000) a a b b CEC 15 cmolc/kg 2000: corn (g FW/plant) 35.6 44.0 17.9 16.4

*values in the same row with the same superscript do not differ significantly n. s. Not specified n. d. Not determined

The table below summarizes the chronic long term field NOEC values together with the exposure period and soil type that are taken from the various studies discussed in this chapter. Table 58. Chronic long term field NOEC values taken from table 54.

Species Soil type Exposure NOEC growth References period (mg/kg) Phaseolus vulgaris Natural loamy sand 30 days >6.7 (unbounded) Sajwan et al. 1996 (bush bean) Spinacia oleracea Natural calcareous 4 years 50 Kadar 1995, Kadar et al. (Spinach) chernozem 1998 Beta vulgaris (Red beet) Natural calcareous 5 years 50 Kadar 1995, Kadar et al. chernozem 1998 Triticum aestivum Natural calcareous 6 years >162 Kadar 1995, Kadar et al. (Wheat grain) chernozem 1998 Zea mays (Corn) Sandy-clay soil (low 12 years 7.2 Mench et al. Pers. pH) Comm.. 2000 Zea mays (Corn) Sandy-clay soil (high 12 years 8.3 Mench et al. Pers. pH) Comm.. 2000 Various plant species Silt loam, xerollic Up to EC25 range: 4- Bingham et al. 1975 including Spinach calciorthid soil enriched maturity >640 which was the most with 1% sewage sludge sensitive tested species

To conclude, field data yield NOECs that are well above the HC5 of 2.3 g Cd/g (see summary table). There is currently no indication of higher toxicity of Cd salts in the field than in the laboratory. Given this, there is no need for an assessment factor higher than one.

Goodness-of-fit of the SSD The goodness-of-fit of the SSD's is tested with the Anderson-Darling and Kolmogorov-Smirnov tests. The log-normal distribution is accepted at the 1-10% significance levels when applied on the microbial data set on which the HC5 is based. A factor of 3.4 is observed between the 95% lower confidence level and the HC5 microflora. This factor goes down to 1.9 with the combined dataset, which is showing that the statistical uncertainty is strongly reduced. Based on this, there is no need for an AF higher than

Toxicity values below the HC5 In the soil dataset, two NOEC values are reported to be below the lowest HC5. One is from the species Picea sitchensis, a conifer species, and the other one comes from the lettuce Lactuca sativa, for which a range of NOECs are available. It must be recalled that there is no single test in the entire database (including tests with RI 4) at which a toxic effect of Cd was found at or below the PNECsoil from the RA = 2.3 g Cd/g.

Setting the PNEC soil

The PNEC soil is set based on the lowest observed HC5 derived by statistical extrapolation from the microflora data, i. e. 2.3 µg Cd/kg d. w. In the Cd RA, an AF 1 or 2 was considered. The current analysis rather suggests using an AF1 on the HC5 to derive the PNEC. It is noted that thePNECsoil based on secondary poisoning is 0.9 µg Cd/g dw which is below the proposed value. The latter value is therefore proposed and used for PNECsoil in this assessment. This is in accordance with the approach followed in the Cd RA (ECB 2008).

Table 59. PNEC soil

PNEC Assessment Remarks/Justification factor PNEC soil: 0.9 1 Extrapolation method: statistical extrapolation mg/kg soil dw A PNECsoil was derived by statistical extrapolation of the extensive soil microflora data, as in the EU risk assessment. This resulted in a HC5 of 2.3 mg Cd/kg d.w. (AF1). However, a PNEC for soil based on secondary poisoning was also derived, effectively suggesting that biotransfer of Cd from soil to higher trophic levels is the most critical pathway for Cd. This PNECsoil secondary poisoning is based on the HC5-50% value of a distribution of soil concentrations leading to critical kidney concentration of 400µg/g d.w. measured in 8 mammal species. This HC5-50% is 0.9 µg Cd/g d.w. soil and, since it is lower than the value derived for microflora sensitivity, is used as the PNECsoil. This approach is in accordance with the one applied in the EU risk assessment on Cd/CdO (ECB 2008).

7.3. Atmospheric compartment

The EU RA indicated for this scenario: “A quantitative risk characterisation for exposure of organisms to airborne cadmium is not done because there are no useful data on the effects of airborne cadmium in environmental organisms and thus no PNEC air could be derived. The PECs in air are used for the risk assessment of man indirectly exposed via the environment (chapter 4). Inorganic cadmium air emissions are primarily associated with particulates in the air. Emission to air will settle out to soil. The impact of industrial air emissions at local scale is therefore included in the conclusions on the terrestrial compartment.”

The same approach is followed in the present analysis.

7.4. Microbiological activity in sewage treatment systems

The EU risk assessment discussed available data for Cd toxicity to micro-organisms. There were 2 high quality studies available, both performed according to OECD protocol (OECD 209) for testing effect on sludge respiration, showing similar NOEC values when Cd was expressed as the dissolved fraction.

The LOEC values observed on the dissolved Cd fraction were high as compared to LOEC values for aquatic species. This suggested low sensitivity of bacteria to Cd was confirmed by results on bacterial cultures of

Pseudomonas putida, Zoogloea ramigera and Escherichia coli, which also showed LOECs in the 1mg/l range (RA Cd/Cd0 table 3.2.32.).

The PNEC for STP was derived in the EU risk assessment by applying an assessment factor of 10 on the lowest observed NOEC (200 µg Cd/l) which yielded a PNECSTP of 20 µg Cd/l. The same PNEC is used for the present exercise. This concentration refers to the Cd in the ionic form (dissolved fraction). 7.4.1. Toxicity to aquatic micro-organisms

Table 60. Overview of effects on micro-organisms

Method Results Remarks Reference activated sludge of a predominantly NOEC (3 h): 200 µg/L 1 (reliable without LISEC (1998b) domestic sewage dissolved (meas. (arithm. restriction) mean)) based on: respiration freshwater rate key study static NOEC (3 h): 32600 µg/L read-across based on test mat. (meas. (arithm. grouping of OECD Guideline 209 (Activated mean)) based on: respiration substances (category Sludge, Respiration Inhibition Test) rate approach)

LOEC (3 h): 800 µg/L Test material dissolved (meas. (arithm. (IUPAC name): mean)) based on: respiration cadmium (See rate endpoint summary for justification of LOEC (3 h): 100000 µg/L read-across) test mat. (meas. (arithm. mean)) based on: respiration rate

Discussion

Lowest NOEC is of high quality study.

The following information is taken into account for effects on aquatic micro-organisms for the derivation of PNEC:

Lowest NOEC of high quality study: 0.2mg Cd/l

Value used for CSA:

EC10/LC10 or NOEC for aquatic micro-organisms: 0.2 mg/L

7.4.2. PNEC for sewage treatment plant

Table 61. PNEC sewage treatment plant

Value Assessment Remarks/Justification factor PNEC STP: 20 µg/L 10 Extrapolation method: assessment factor

The PNEC for STP was derived in the EU Cd risk assessment by applying an assessment factor of 10 on the lowest observed NOEC (200 µg Cd/l) from the two available studies on Cd toxicity to micro-organisms, testing effects on sludge respiration, which yielded a PNECSTP of 20 µg Cd/l. The same PNEC is used for the present exercise.

7.5. Non compartment specific effects relevant for the food chain (secondary poisoning) 7.5.1. Toxicity to birds

The EU risk assessment on cadmium identified 4 good quality feeding studies on birds, using Cd-spiked diets. According to the RA, the PNEC oral secondary poisoning is derived from the lowest NOEC on Mallard ducks (1.6 mg Cd/kg diet; White et al 1978). The PNEC oral can be calculated applying an assessment factor of 10 on this long-term feeding study, i.e. 0.16mg Cd/kg diet. The dataset allows to derive a PNEC from statistical extrapolation. This PNEC would be higher than the one obtained with the assessment factor method (RA, ECB 2008). However, following the approach of the RA, it is decided to use the more conservative value from the assessment factor approach as the PNEC.

Table 62. Overview of effects on birds

Method Results Remarks Reference Gallus domesticus NOEC (28 d): 12 mg/kg diet 2 (reliable with Leach RM, Wang based on: reproductive restrictions) KWL and Baker repeated dose toxicity test (feed) parameters (egg production) DE (1978) weight of evidence Doses: 0-3-12-48 µg/g of basal diet. LOEC (28 d): 48 mg/kg diet based on: reproductive experimental result Repeated dose toxicity test with parameters (egg production) laboratory feeding of Cd-containing Test material (EC food name): cadmium sulphate Anas platyrhynchos NOEC (90 d): 1.6 mg/kg diet2 (reliable with White DH, Finley based on: reproductive restrictions) MT and Ferrell JF Repeated dose toxicity test (feed) parameters (1978) (spermatogenesis) weight of evidence Doses: O-2-20-200 mg Cd/kg Wet weight LOEC (90 d): 15.2 mg/kg read-across based on diet based on: reproductive grouping of Repeated dose toxicity test with parameters substances (category laboratory feeding of Cd-containing (spermatogenesis) approach) food Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Anas platyrhynchos NOEC (84 d): 10 mg/kg diet 2 (reliable with Cain BW, Sileo L, based on: kidney lesions restrictions) Fransson JC and repeated dose toxicity test (feed) Moore J (1983) NOEC (84 d): 10 mg/kg diet weight of evidence

Doses: 0-5-10-20 mg/kg of basal diet based on: haemoglobin read-across based on concentrations grouping of Repeated dose toxicity test with substances (category laboratory feeding of Cd-containing LOEC (84 d): 20 mg/kg diet approach) food based on: kidney lesions Test material LOEC (84 d): 20 mg/kg diet (IUPAC name): based on: haemoglobin cadmium dichloride concentration (See endpoint summary for justification of read- across) Coturnix coturnix japonica NOEC (42 d): 38 mg/kg diet 2 (reliable with Richardson ME, based on: growth restrictions) Spivey Fox MR and chronic repeated dose toxicity test Fry BE (1974) (feed) LOEC (42 d): 75 mg/kg diet weight of evidence based on: growth Doses: 0-75 mg/kg of basal diet read-across based on grouping of repeated dose test with adminstration substances (category of Cd through the diet. approach)

Test material (IUPAC name): cadmium dichloride (See endpoint summary for justification of read- across) Gallus domesticus NOEC (28 d): 12 mg/kg diet 2 (reliable with Leach RM, Wang based on: reproductive restrictions) KWL and Baker repeated dose toxicity test (feed) parameters (egg production) DE (1978) weight of evidence Doses: 0-3-12-48 µg/g of basal diet. LOEC (28 d): 48 mg/kg diet based on: reproductive read-across based on Repeated dose toxicity test with parameters (egg production) grouping of laboratory feeding of Cd-containing substances (category food approach)

Test material: (IUPAC name): cadmium sulphate

Discussion

Results from 4 studies were available. The results obtained on mallard ducks give the lowest NOEC of 5 values. It is used for calculating the PNEC oral for birds.

The following information is taken into account for effects on birds for the derivation of PNEC:

Repeated dose toxicity of Cd administered through the diet was studied on several species. The NOEC ranged from 1.6mg Cd/kg FW food to 38 mg Cd/kg FW food. The LOEC ranged between 15.2mg Cd/kg FW food and 75 mg Cd/kg FW food.

7.5.2. Toxicity to mammals

The EU risk assessment on cadmium identified 5 good quality feeding studies on mammals, using Cd-spiked diets. According to the RA, the PNEC oral secondary poisoning is derived from the lowest NOEC on monkey (3 mg Cd/kg diet; Masoaka et al 1994). According to the RA, the PNEC oral is calculated applying an assessment factor of 10 on this long-term feeding study, i.e. 0.3mg Cd/kg diet.

The dataset allows to derive a PNEC from statistical extrapolation. This PNEC would be higher than the one obtained with the assessment factor method (RA, ECB 2008). However, following the approach of the RA, it is decided to use the more conservative value from the assessment factor approach as the PNEC.

7.5.3. Calculation of PNECoral (secondary poisoning)

The 4 studies on bird toxicity and 5 studies on mammals allow for the calculation of a PNEC oral for birds and mammals exposed through the diet. The lowest value of the two is used as PNEC oral.

Table 63. PNEC oral

PNEC Assessment Remarks/Justification factor PNEC oral: 0.16 10 The EU risk assessment on cadmium identified 4 and 5 good quality mg/kg food feeding studies on birds and mammals, respectively, using Cd-spiked diets. According to the RA, the PNEC oral secondary poisoning is derived from the lowest NOEC of the 9 chronic studies (NOEC for Mallard ducks of 1.6 mg Cd/kg diet; White et al 1978) divided by an AF10.

7.6. Conclusion on the environmental hazard assessment and on classification and labelling

Environmental classification justification

Cadmium and soluble Cd-compounds are classified based on the Cd++ ion. The substance releases sufficient Cd-ions at 1 mg/l loading to exceed the reference acute aquatic toxicity value of 18 µg Cd /l. Consequently, it is classified as

-N, R50/53 (very toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment; cfr Annex 1 dangerous substances directive 67/548/EEC)

-H410 (very toxic to aquatic life with long lasting effects; cfr GHS)

General discussion

A basic assumption made in this hazard assessment and throughout this CSR, (in accordance to the same assumption made in the EU RA process) is that the ecotoxicity of cadmium and cadmium compounds is due to the Cd++ion. As a consequence, all aquatic, sediment and terrestrial toxicity data in this report are expressed as “cadmium”, not as the test compound as such, because ionic cadmium is considered to be the causative factor for toxicity. A further consequence of this is that all ecotoxicity data obtained on different cadmium compounds, are mutually relevant for each other. For that reason, the available ecotoxicity databases related to cadmium and the different cadmium compounds are combined before calculating the PNECs. The only way cadmium compounds can differ in this respect is in their capacity to release cadmium ions into (environmental) solution. That effect is checked eventually in the transformation/dissolution tests and may result in different classifications.

8. PBT AND VPVB ASSESSMENT

8.1. Assessment of PBT/vPvB Properties

Persistence

Cadmium is an element and as such, the criterion “persistence” is not applicable to Cd and Cd-compounds.

As an alternative for persistency (for organic substances), the concept of “removal from the water column” has been developed for inorganic elements.

This characteristic has not yet been studied for cadmium.

Bio-accumulation

Data on bioaccumulation of cadmium are presented and discuused under section 4.3. From this analysis, the following was concluded:

The available evidence makes it difficult to decide whether or not Cd is to be considered as a bioaccumulative substance in the environment. The high BCF /BAF factors observed in the lower levels of the food chain (algae notably) would suggest Cd is to be considered as bioaccumulative. However, there are some uncertainties with the data: the high BCF/BAF factors observed in the algae are (at least partly) due to external absorption, not to uptake; the higher levels in invertebrates maybe related to lack of gut clearance of the organisms studied. BCF in fish are generally below the criterion for considering a substance bioaccumulative.

In terms of hazard identification/classification, several considerations speak against a conclusion of considering Cd as bioaccumulative substance:

-the BCF/BAF values observed with Cd consistently decrease with increasing exposure, which clearly shows some level of physiological regulation of uptake. One of the key theoretical conditions of the BCF model in terms of its relevance for chronic toxicity and applicability to the hazard identification/classification of chemicals is that the BCF/BAF should be independent of exposure. BCF/BAF values should in other words remain fairly constant over a range of exposures, which is clearly not the case for Cd.

-Evidence related to biomagnification in the aquatic food chain consistently shows that Cd is not biomagnifying.

Based on an extensive review of evidence on a wide variability of taxonomic groups, McGeer et al (2003) concluded that the BCF/BAF criteria, as conceived for organic substances, are inappropriate for the hazard identification and classification of metals, including Cd. They highlighted the inconsistency between BCF/BAF values and toxicological data, as BCF values are highest (suggesting hazard) at low exposure concentrations and are lowest (indicating no hazard) at the highest exposure concentrations, were toxicity is likely.

So the case on Cd bioaccumulation for hazard identification/classification is inconclusive. In any case, the main question to pose in this respect is on secondary poisoning. This aspect is discussed below.

Related to secondary poisoning , the following was concluded from the analysis in section 4.4.:

In the freshwater compartment, the risk of secondary poisoning of fish eating birds by Cd is predicted to be smaller than the direct effects of Cd in the aquatic environment. The RA demonstrated, using BCF’s of fish (mentioned in section 4.3) that the Cd concentration in whole fish at the PNECwater of 0.19 µg Cd/l (section 7.) could be predicted to range between 0.0001 and 0.13 mg Cd/kg fresh weight using the whole range of BCF’s (0.5-684 l/kg fresh weight). It was concluded that these Cd concentrations were below the PNECoral for birds or birds+mammals (ECB 2008).

In the terrestrial compartment, a PNEC for secondary poisoning was calculated from the lowest observed PNECoral for mammals and birds, which was derived from feeding studies with Cd salt spiked diets. Nine feeding studies were selected (sub-chronic and chronic studies), four studies with birds and 5 studies with mammals. The PNECoral of 0.9 µg Cd/g DW soil was calculated from the lowest NOEC using an assessment factor (see section 7). It follows from the risk characterisation under section 10.2.2. (Environment (combined for all emission sources)), that the PNEC secondary poisoning is in general not reached in soil.

Toxicity

The reference values for aquatic toxicity following from section 7 are 18µg/l for acute toxicity, and 0.21 µg Cd/l for chronic aquatic toxicity. 8.1.1. Summary and overall conclusions on PBT or vPvB properties

Considering the elements mentioned above, the case on PBT and vPvB properities of cadmium and its compounds is inconclusive.

9. EXPOSURE ASSESSMENT

9.1. GES CdSO4 solution-0: Industrial isolation of the Intermediate Cadmium Sulphate solution (273-721-3) from Cadmium and/or Cadmium compounds leaching, refining or extraction steps, by settling, filtering and other hydrometallurgical processes

9.1.1. Exposure scenario

Table 64. GES CdSO4 solution-0

Exposure Scenario Format (1) addressing uses carried out by workers Title of Exposure Scenario number GES CdSO4 solution -0: Industrial isolation of the Intermediate Cadmium Sulphate solution (273-721-3) from Cadmium and/or Cadmium compounds leaching, refining or extraction steps, by settling, filtering and other hydrometallurgical processes. List of all use descriptors related to the life cycle stage and all the uses under it; include market sector (by PC), if relevant; SU: 3, 8, 14 PROC: 2, 3, 4, 5, 8b, 9, 13, 26 PC: 19 AC: not applicable ERC: 1 Further explanations (if needed) Cadmium metal cake or cadmium compound bearing scrap is grinded and leached in order to produce cadmium sulphate solution. Process is carried out in semi-closed leaching tanks, settlers and filter units, with occasional controlled exposure and transfer of the solution for further extraction of cadmium metal or production of cadmium compounds. Exposure Scenario 9.1.1.1 Contributing scenario (1) controlling environmental exposure for the Industrial isolation of the Intermediate Cadmium Sulphate solution (273-721-3) from Cadmium bearing material leaching, refining or extraction steps, by settling, filtering and other hydrometallurgical processes.

Further specification:

 Stockpiling of the primary Cd-material (Cd-metal cake and Cd-bearing recycled scrap) in closed and well ventilated buildings.  Feeding of the primary materials into the mixing tank. The leaching reaction with sulphuric acid solutions is kept at the proper temperature and proper pH (~4.2).

 Filtration of the leach-residue occurs on pressfilters, under ventilated hood  Oxidation of some of the present elements may be necessary (i.e. Te > TeO2 or others), followed by another filtration step, if necessary  Further transfer of the Cadmium sulphate solution occurs by pipes or in specially designed transfer units that prevent any exposure  Maintenance activities Product characteristics Product related conditions:

The Intermediate Cadmium Sulphate solution has a Cadmium-concentration that can vary between 70 g/L ( acidic solution) and 200 g/L (neutral solution – pH 4.5)

Amounts used Daily and annual amount per site:

Up to 50 t/month of Cadmium contained

Frequency and duration of use

Continuous production

Environment factors not influenced by risk management Flow rate of receiving surface water:

Default is used unless specified otherwise

Other given operational conditions affecting environmental exposure Other given operational conditions: e.g. technology or process techniques determining the initial release of substance from process (via air and waste water); dry or water based processes; conditions related to temperature and pressure; indoor or outdoor use of products; work in confined area or open air;  Most of the operations are in wet phase.

 All steps involving any potential exposure to CdSO4 are conducted in a controlled environment protected by efficient and performance-monitored filters with verified removal efficiency for sub- micron particles in excess of 99.9%. The efficiency, flow rate and pressure drop in the filters is continually monitored.

 The manufacturing environment is fully fire protected by automated fire detection and extinguishing systems.

 Chemical storage is within a controlled, isolated area having monitored secondary containment.

 Air emissions are processed through efficient filters prior to discharge into the atmosphere.

 Waste water is being treated by state-of-the-art technology through precipitation, filtration, ion- exchange, neutralization and fully monitored batch discharge system.

 All residues containing Cd are recycled.

Technical conditions and measures at process level (source) to prevent release Process design aiming to prevent releases and hence exposure to the environment; this includes in particular conditions ensuring rigorous containment; performance of the containment to be specified (e.g. by quantification of a release factor in section 9.x.2 of the CSR);

 Process enclosures and closed circuits whenever technically possible.

 Containment of liquid volumes in sumps to collect/prevent accidental spillage, acid solutions are treated appropriately.

Technical onsite conditions and measures to reduce or limit discharges, air emissions and releases to soil Technical measures, e.g. on-site waste water and waste treatment techniques, scrubbers, filters and other technical measures aiming at reducing releases to air, sewage system, surface water or soil; this includes strictly controlled conditions (procedural and control technology) to minimise emissions; specify effectiveness of measures; specify the size of industrial sewage treatment plant (m3/d), degradation effectiveness and sludge treatment (if applicable);

 On-site waste water treatment techniques can be applied to prevent releases to water (if applicable) e.g.: chemical precipitation, sedimentation and filtration (efficiency 90-99.98%).

 Containment of liquid volumes in sumps to collect/prevent accidental spillage

 Air emissions are controlled by use of scrubbers, filters, demisters.

Organizational measures to prevent/limit release from site Specific organisational measures or measures needed to support the functioning of particular technical measures. Those measures need to be reported in particular for demonstrating strictly controlled conditions.

 In general, emissions are controlled and prevented by implementing an integrated management system e.g. ISO 9000, ISO 1400X series, or alike, and, when applicable, by being IPPC-compliant (cf. NFM- BREF).

Such management system, aiming at ensuring ‘strictly controlled conditions’, should include general industrial practice like e.g.: ⁰ The substance is rigorously contained by technical means during the whole lifecycle including manufacture, purification, cleaning/maintenance of equipment, sampling, analysis, loading and unloading of equipment or vessels, waste disposal or purification and storage

⁰ Procedural and control technologies shall be used that minimise emission and any resulting exposure

⁰ Only properly trained and authorised personnel handles the substance

⁰ For cleaning/maintenance, special procedures such as system purging and washing before opening devices

⁰ Procedures, control technologies for accidents and waste

⁰ Substance-handling procedures well documented and strictly supervised

• Treatment and monitoring of releases to outside air, and exhaust gas streams (process & hygiene), according to national regulation.

 SEVESO 2 compliance, if applicable

Conditions and measures related to municipal sewage treatment plant Size of municipal sewage system/treatment plant (m3/d); specify degradation effectiveness; sludge treatment technique (disposal or recovery); measures to limit air emissions from sewage treatment (if applicable); please note: the default size of the municipal STP (2000 m3/d) will be rarely changeable for downstream uses.

In cases where applicable: default size, unless specified otherwise.

Conditions and measures related to external treatment of waste for disposal

Fraction of used amount transferred to external waste treatment for disposal; type of suitable treatment for waste generated by work-ers uses, e.g. hazardous waste incineration, chemical-physical treatment for emulsions, chemical oxidation of aqueous waste; specify effectiveness of treatment;

 If any, all hazardous wastes are collected, transported, treated and finally disposed by authorized/certified contractors according to EU and national legislation.

Conditions and measures related to external recovery of waste Fraction of used amount transferred to external waste treatment for recovery: specify type of suitable recovery operations for waste generated by workers uses, e.g. re-distillation of solvents, refinery process for lubricant waste, recovery of slags, heat recovery out-side waste incinerators; specify effectiveness of measure;

 All residues formed during the leaching process, are recovered and either further treated in the system or handled according to the waste legislation.

 Users of Cd and Cd-compounds have to favour the recycling channels of the end-of-life products

 Users of Cd and Cd-compounds have to minimize Cd-containing waste, promote recycling routes and, for the remaining, dispose the waste streams according the Waste regulation.

9.1.1.2 Contributing scenario (2) controlling worker exposure for Industrial isolation of the Intermediate Cadmium Sulphate solution (273-721-3) from Cadmium and/or Cadmium- compounds leaching, refining or extraction steps, by settling, filtering and other hydrometallurgical processes. Name of contributing scenario 2: Cadmium metal cake or cadmium compound bearing scrap is grinded and leached in order to produce cadmium sulphate solution. Process is carried out in semi-closed leaching tanks, settlers and filter units, with occasional controlled exposure and transfer of the solution for further extraction of cadmium metal or production of cadmium compounds. Further specification

Product characteristic Product related conditions, e.g. the concentration of the substance in a mixture, the physical state of that mixture (solid, liquid; if solid: level of dustiness), package design affecting exposure)

• The isolated substance is a Cadmium sulphate rich solution (concentration TBC)

Amounts used Amounts used at a workplace (per task or per shift); note: sometimes this information is not needed for assessment of worker’s expo-sure

Maximum 50 t/month, 1t/shift of cadmium contained

Frequency and duration of use/exposure Duration per task/activity (e.g. hours per shift) and frequency (e.g. single events or repeated) of exposure

8hrs shift

Human factors not influenced by risk management Particular conditions of use, e.g. body parts potentially exposed as a result of the nature of the activity

Uncovered body parts: (potentially) face

Other given operational conditions affecting workers exposure Other given operational conditions: e.g. technology or process techniques determining the initial release of substance from process into workers environment; room volume, whether the work is carried out outdoors/indoors, process conditions related to temperature and pressure.

 All processes are carried out in confined areas with a minimum of operators

 The process is managed and controlled from a separate control-room.

Technical conditions and measures at process level (source) to prevent release Process design aiming to prevent releases and hence exposure of workers; this in particular includes conditions ensuring rigorous containment; performance of containment to be specified (e.g. by quantification of residual losses or exposure)

 Process enclosures or semi-enclosures are applied whenever technically feasible.  Local exhaust ventilation on furnaces and other work areas with potential dust generation, dust capturing and high-efficiency capturing/removal techniques (filters with > 99.9% efficiency)  If applicable, liquid volumes are handled/stored in secondary containments to collect/prevent accidental spillage

Technical conditions and measures to control dispersion from source towards the worker Engineering controls, e.g. exhaust ventilation, general ventilation; specify effectiveness of measure

 Local exhaust ventilation systems (high efficiency 90-99.9%),

 Scrubbers/ demisters (for minimizing air emissions): efficiency: 85-95% (Scrubbers, Absorbers, demisters...)

 Cd in dust/aerosols needs to be measured in the workplace air (static or individual) according to national regulations.  Special care for the general establishment and maintenance of a clean working environment by e.g.:

1. Cleaning of process equipment and workshop

o Storage of solutions in covered vessels and thickeners

Organisational measures to prevent /limit releases, dispersion and exposure Specific organisational measures or measures needed to support the functioning of particular technical measures (e.g. training and supervision). Those measures need to be reported in particular for demonstrating strictly controlled conditions (to justify exposure based waiving).

 The protection of workers in the Cd-related industry is achieved by the systematic implementation of a carefully designed stepwise risk management system, outlining measures to control worker exposure and combining measurements of both exposure and effect. The system is aimed at prevention of exposure and protection against early manifestation of (subclinical) effect at the level of the critical organ, the kidney. The system is described in detail in the industry guidance document “Management of the risk related to the chronic occupational exposure to cadmium and its compounds” (ICdA 2006). It involves essentially 2 phases of action: 1) Controlling the Cd-concentration in the workplace air Firstly, technical measures are taken to comply with the indicative EU (i-)OEL of 4 µg respirable Cd/m3 proposed by SCOEL in compliance with art. 3 of directive 98/24/EC (2009). This i-OEL is taken forward as a DNEL; compliance with the i-OEL is mandatory if no other measurements of Cd-exposure and effect (as described below) are performed. The OEL of 4µg Cd/m3 is applicable to Cd and Cd-compounds in general, unless the limited solubility of a given Cd-compound is documented. The total/inhalable fraction corresponding to the respirable fraction is function of the particle size of the inhaled particles. 2) Individual medical follow up of parameters of exposure and effect  In general when working with cadmium, and, notably, if compliance with the i-OEL cannot be ensured in a consistent way, protection of the worker is ensured by complementary risk reduction measures and compliance with biological indicator limit values at the individual level. These measures include:

 Personal respiratory protection and hygiene measures if appropriate (see below, section “Conditions and measures related to personal protection, hygiene and health evaluation” for detail), in combination with  Medical follow-up of the worker involving regular measurement of biological indicators of both exposure and effect: o exposure: measurement of Cd in urine (µg Cd/g Creatinine) and /or Cd in blood (µg Cd/l) to assess integrated systemic exposure of the individual o effect: measurement of early (subclinical) indicators of tubular (kidney) dysfunction. Well- established biological indicators (BI) for Cd-effect are e.g. β-microglobuline (β2-MG) and retinol binding protein (RPB). The specific medical supervision (for details see ICdA 2006 – part II, section 4) is complementary to the technical and hygiene measures taken. It integrates exposure through all possible routes by assessing the Cd- body burden and assesses early biological indicators (BI’s) of (subclinical) renal effect. It ensures as such that the risk to Cd-exposed workers is fully controlled.

The results of the medical supervision are applied as follows (see also Figure below):

Figure: Illustration of Eurometaux/ICdA medical supervision guidance (2006) (BI: biological indicators; C: creatinine)

General medical follow-up level

 Cd-U ≤ 2 µg Cd/g creatinine (C). This is a conservative threshold based on general population studies, as described in Section 5.6.2. In this situation, the worker is followed by general medical follow-up (complementary indicator: Cd-B ≤ 5 µg Cd/L). No further special action is required beyond proper implementation of the general hygiene procedures and medical surveillance.

Action level

 2 < Cd-U ≤ 5 µg Cd /g creatinine: Action level zone. This zone is defined by the threshold based on studies at the workplace, as described in Section 5.6.2. Observation of Cd-U (or Cd-B) values in this “ action” zone triggers (complementary trigger: 5 µg Cd/l < Cd-B ≤ 8 µg Cd/l) an individual follow up of the worker characterized by:

o Systematic and frequent follow up of exposure by measuring Cd-U (complementary analysis: Cd-B), combined with individual analysis and follow-up of hygiene behaviour

o Measurement of biological indicators (BI’s) of early renal dysfunction (e.g. beta-2

microglobuline (B2-M) or retinol-binding protein (RBP) on a regular basis;

When the worker moves into this action level zone, the occupational doctor and plant hygiene team will check for the reason for the increased exposure (analysis of the workplace, with a view to identify possible substance releases, analysis of compliance with hygienic procedures, and interview with the worker to assess possible other causes, e.g. due to current or previous exposure, due to personal hygiene behaviour?).

Based on the results of the individual medical surveillance programme, the following management decisions are taken:

 The worker remains in the action zone: If the Cd-U (Cd-B) values do not progress further towards the threshold and the BI’s remain stable and below the reference value (e.g. 300 µg/g creatinine for β2-MG and RBP), the worker is kept at the workplace. Additional hygiene measures are taken as appropriate, and medical follow-up is strictly continued.

 The worker is removed from exposure:

o If Cd-U > 5 µg Cd/g creatinine (or Cd-B > 8 µg/l) and/or

o If the BI’s are exceeding the reference values or showing a consistent pattern of increase which may lead to approaching the reference values

 The management scheme as outlined above is applicable to workers that entered the Cd industry rather recently. Workers that have been working in the Cd-industry for long may have been historically exposed to elevated Cd -levels, and may show e.g. Cd-U levels exceeding 5 µg/gC due to historical exposure. The supervising medical doctor will evaluate these individuals carefully, focusing on the BI’s. In any case, when BI values exceed the BI-reference values or approach them, the worker will be removed from Cd-exposure.

 In addition to the above, general industrial hygiene programmes are to be implemented , as required by EU Directive 98/24/EC on protection of workers from chemical agents and other referenced systems on best practice : IPPC-BREF notes, BIMSCH or equivalent, ICH-Q7, FAMI-QS, ISO9000, ISO 13.100 or alike: 1. General industrial hygiene practice 2. Collective protection measures and use of warning & safety signs 3. Minimizing the number of workers exposed or likely to be exposed 4. Workplace cleanliness: ensure procedures are designed, written and implemented so as to make sure cleanliness is obtained at workstations, work sections, traffic and storage areas, upper areas, building structures and various horizontal surfaces, air suction ducts. 5. Procedures for process control

Conditions and measures related to personal protection, hygiene and health evaluation Personal protection, e.g. wearing of gloves, face protection, full body dermal protection, goggles, respirator; specify effectiveness of measure; specify the suitable material for the PPE (where relevant) and advise how long the protective equipment can be used before replacement (if relevant) Wearing of gloves and protective clothing is compulsory (efficiency >=90%).

With normal handling, no respiratory personal protection (breathing apparatus) is necessary. If risk for exceedance of OEL/DNEL, use e.g.: -dust filter-half mask P1 (efficiency 75%) -dust filter-half mask P2 (efficiency 90%) -dust filter-half mask P3 (efficiency 95%) -dust filter-full mask P1 (efficiency 75%) -dust filter-full mask P2 (efficiency 90 %) -dust filter-full mask P3 (efficiency 97.5%) Eyes: safety glasses are optional but recommended

9.1.2. Exposure estimation

9.2. GES CdSO4 solution-2: Industrial use of the Intermediate Cadmium Sulphate solution (273-721-3) in the ultimate manufacturing of Cadmium or Cadmium compounds by several metallurgical processes. 9.2.1. Exposure scenario

Table 65. GES CdSO4 solution-2

Exposure Scenario Format (1) addressing uses carried out by workers Title of Exposure Scenario number GES CdSO4 solution-2: Industrial use of the Intermediate Cadmium Sulphate solution (273-721-3) in the ultimate manufacturing of Cadmium or Cadmium compounds by several metallurgical processes. List of all use descriptors related to the life cycle stage and all the uses under it; include market sector (by PC), if relevant; SU: 3, 8, 14 PROC: 2, 3, 4, 5, 8b, 9, 13, 26 PC: 19 AC: not applicable ERC: 6a Further explanations (if needed) The Intermediate Cadmium Sulphate solution is unloaded, potentially blended with other material streams and loaded in vessels for further use, reaction and production of Cadmium metal or Cadmium compounds. Exposure Scenario 9.2.1.1 Contributing scenario (1) controlling environmental exposure for the Industrial use of the Intermediate Cadmium Sulphate solution (273-721-3) in the ultimate manufacturing of Cadmium or Cadmium compounds by several metallurgical processes.

Further specification:

 The Cadmium sulphate solution is unloaded, potentially mixed with other solutions or reagents and transferred to the reaction vessels through especially designed transfer launders,  This Intermediate is typically used in production units of Cadmium metal or Cadmium compounds.  Maintenance activities Product characteristics

Product related conditions:

The Intermediate Cadmium Sulphate solution has a Cadmium-concentration that can vary between 70 g/L ( acidic solution) and 200 g/L (neutral solution – pH 4.5)

Amounts used Daily and annual amount per site:

Up to 50 t/month of Cadmium contained

Frequency and duration of use

Continuous production

Environment factors not influenced by risk management Flow rate of receiving surface water:

Default is used unless specified otherwise

Other given operational conditions affecting environmental exposure Other given operational conditions: e.g. technology or process techniques determining the initial release of substance from process (via air and waste water); dry or water based processes; conditions related to temperature and pressure; indoor or outdoor use of products; work in confined area or open air;  Most of the operations are in wet phase.

 All steps involving any potential exposure to CdSO4 are conducted in a controlled environment protected by efficient and performance-monitored filters with verified removal efficiency for sub- micron particles in excess of 99.9%. The efficiency, flow rate and pressure drop in the filters is continually monitored.

 The manufacturing environment is fully fire protected by automated fire detection and extinguishing systems.

 Chemical storage is within a controlled, isolated area having monitored secondary containment.

 Air emissions are processed through efficient filters prior to discharge into the atmosphere.

 Waste water is being treated by state-of-the-art technology through precipitation, filtration, ion- exchange, neutralization and fully monitored batch discharge system.

 All residues containing Cd are recycled.

Technical conditions and measures at process level (source) to prevent release Process design aiming to prevent releases and hence exposure to the environment; this includes in particular conditions ensuring rigorous containment; performance of the containment to be specified (e.g. by quantification of a release factor in section 9.x.2 of the CSR);  Process enclosures and closed circuits where relevant and possible.

 Containment of liquid volumes in sumps to collect/prevent accidental spillage, acid solutions are treated appropriately. Technical onsite conditions and measures to reduce or limit discharges, air emissions and releases to soil Technical measures, e.g. on-site waste water and waste treatment techniques, scrubbers, filters and other technical measures aiming at reducing releases to air, sewage system, surface water or soil; this includes strictly controlled conditions (procedural and control technology) to minimise emissions; specify effectiveness of measures; specify the size of industrial sewage treatment plant (m3/d), degradation effectiveness and sludge treatment (if applicable);

 On-site waste water treatment techniques can be applied to prevent releases to water (if applicable) e.g.: chemical precipitation, sedimentation and filtration (efficiency 90-99.98%).

 Containment of liquid volumes in sumps to collect/prevent accidental spillage  Air emissions are controlled by use of scrubbers, filters, demisters.

Organizational measures to prevent/limit release from site Specific organisational measures or measures needed to support the functioning of particular technical measures. Those measures need to be reported in particular for demonstrating strictly controlled conditions.

 In general, emissions are controlled and prevented by implementing an integrated management system e.g. ISO 9000, ISO 1400X series, or alike, and, when applicable, by being IPPC-compliant (cf. NFM- BREF).

Such management system, aiming at ensuring ‘strictly controlled conditions’, should include general industrial practice like e.g.: ⁰ The substance/ UVCB is rigorously contained by technical means during the whole lifecycle including manufacture, purification, cleaning/maintenance of equipment, sampling, analysis, loading and unloading of equipment or vessels, waste disposal or purification and storage

⁰ Procedural and control technologies shall be used that minimise emission and any resulting exposure

⁰ Only properly trained and authorised personnel handles the substance

⁰ For cleaning/maintenance, special procedures such as system purging and washing before opening devices

⁰ Procedures, control technologies for accidents and waste

⁰ Substance-handling procedures well documented and strictly supervised

• Treatment and monitoring of releases to outside air, and exhaust gas streams (process & hygiene), according to national regulation.

 SEVESO 2 compliance, if applicable

Conditions and measures related to municipal sewage treatment plant Size of municipal sewage system/treatment plant (m3/d); specify degradation effectiveness; sludge treatment technique (disposal or recovery); measures to limit air emissions from sewage treatment (if applicable); please note: the default size of the municipal STP (2000 m3/d) will be rarely changeable for downstream uses.

In cases where applicable: default size, unless specified otherwise.

Conditions and measures related to external treatment of waste for disposal Fraction of used amount transferred to external waste treatment for disposal; type of suitable treatment for waste generated by work-ers uses, e.g. hazardous waste incineration, chemical-physical treatment for emulsions, chemical oxidation of aqueous waste; specify effectiveness of treatment;

 If any, all hazardous wastes are collected, transported, treated and finally disposed by authorized/certified contractors according to EU and national legislation.

Conditions and measures related to external recovery of waste Fraction of used amount transferred to external waste treatment for recovery: specify type of suitable recovery operations for waste generated by workers uses, e.g. re-distillation of solvents, refinery process for lubricant waste, recovery of slags, heat recovery out-side waste incinerators; specify effectiveness of measure;

 All residues formed during the leaching process, are recovered and either further treated in the system

or handled according the waste legislation.

 Users of Cd and Cd-compounds have to favour the recycling channels of the end-of-life products

 Users of Cd and Cd-compounds have to minimize Cd-containing waste, promote recycling routes and, for the remaining, dispose the waste streams according the Waste regulation.

9.2.1.2 Contributing scenario (2) controlling worker exposure for Industrial use of the Intermediate Cadmium Sulphate solution (273-721-3) in the ultimate manufacturing of Cadmium or Cadmium compounds by several metallurgical processes. Name of contributing scenario 2: The Intermediate Cadmium Sulphate solution is unloaded, potentially blended with other material streams and loaded in vessels for further use, reaction and production of Cadmium metal or Cadmium compounds. Further specification

Product characteristic Product related conditions, e.g. the concentration of the substance in a mixture, the physical state of that mixture (solid, liquid; if solid: level of dustiness), package design affecting exposure)

• The isolated substance/ UVCB is a Cadmium sulphate rich solution

• With occasional (sampling, cleaning, maintenance) and minimized exposure for workers

• The average Cadmium content of the solution lies between 70 - 200 g/L

Amounts used Amounts used at a workplace (per task or per shift); note: sometimes this information is not needed for assessment of worker’s expo-sure

Maximum 50 t/month, 1t/shift of Cadmium contained

Frequency and duration of use/exposure Duration per task/activity (e.g. hours per shift) and frequency (e.g. single events or repeated) of exposure

8hrs shift

Human factors not influenced by risk management Particular conditions of use, e.g. body parts potentially exposed as a result of the nature of the activity

Uncovered body parts: (potentially) face

Other given operational conditions affecting workers exposure Other given operational conditions: e.g. technology or process techniques determining the initial release of substance from process into workers environment; room volume, whether the work is carried out outdoors/indoors, process conditions related to temperature and pressure.

 All processes are carried out in confined areas with a minimum of operators

 The process is managed and controlled from a separate control-room.

Technical conditions and measures at process level (source) to prevent release Process design aiming to prevent releases and hence exposure of workers; this in particular includes conditions ensuring rigorous containment; performance of containment to be specified (e.g. by quantification of residual losses or exposure)

 Local exhaust ventilation on work areas with potential dust generation, dust capturing and removal techniques  Process enclosures closed circuits or semi-enclosures where appropriate.

 Containment of liquid volumes in sumps to collect/prevent accidental spillage Technical conditions and measures to control dispersion from source towards the worker Engineering controls, e.g. exhaust ventilation, general ventilation; specify effectiveness of measure

 Local exhaust ventilation systems (generic LEV (84%)),  Scrubbers/ demisters (for minimizing air emissions): efficiency: 85-95% (Scrubbers, Absorbers, demisters...)  Cd in dust/aerosols needs to be measured in the workplace air (static or individual) according to national regulations.  Special care for the general establishment and maintenance of a clean working environment by e.g.:

1. Cleaning of process equipment and workshop

o Storage of solutions in covered vessels and thickeners

Organisational measures to prevent /limit releases, dispersion and exposure Specific organisational measures or measures needed to support the functioning of particular technical measures (e.g. training and supervision). Those measures need to be reported in particular for demonstrating strictly controlled conditions (to justify exposure based waiving).

 The protection of workers in the Cd-related industry is achieved by the systematic implementation of a carefully designed stepwise risk management system, outlining measures to control worker exposure and combining measurements of both exposure and effect. The system is aimed at prevention of exposure and protection against early manifestation of (subclinical) effect at the level of the critical organ, the kidney. The system is described in detail in the industry guidance document “Management of the risk related to the chronic occupational exposure to cadmium and its compounds” (ICdA 2006). It involves essentially 2 phases of action: 3) Controlling the Cd-concentration in the workplace air Firstly, technical measures are taken to comply with the indicative EU (i-)OEL of 4 µg respirable Cd/m3 proposed by SCOEL in compliance with art. 3 of directive 98/24/EC (2009). This i-OEL is taken forward as a DNEL; compliance with the i-OEL is mandatory if no other measurements of Cd-exposure and effect (as described below) are performed. The OEL of 4µg Cd/m3 is applicable to Cd and Cd-compounds in general, unless the limited solubility of a given Cd-compound is documented. The total/inhalable fraction corresponding to the respirable fraction is function of the particle size of the inhaled particles. 4) Individual medical follow up of parameters of exposure and effect  In general when working with cadmium, and, notably, if compliance with the i-OEL cannot be ensured in a consistent way, protection of the worker is ensured by complementary risk reduction measures and compliance with biological indicator limit values at the individual level. These measures include:  Personal respiratory protection and hygiene measures if appropriate (see below, section “Conditions and measures related to personal protection, hygiene and health evaluation” for detail), in combination with  Medical follow-up of the worker involving regular measurement of biological indicators of both exposure and effect: o exposure: measurement of Cd in urine (µg Cd/g Creatinine) and /or Cd in blood (µg Cd/l) to assess integrated systemic exposure of the individual o effect: measurement of early (subclinical) indicators of tubular (kidney) dysfunction. Well- established biological indicators (BI) for Cd-effect are e.g. β-microglobuline (β2-MG) and retinol binding protein (RPB).

The specific medical supervision (for details see ICdA 2006 – part II, section 4) is complementary to the technical and hygiene measures taken. It integrates exposure through all possible routes by assessing the Cd- body burden and assesses early biological indicators (BI’s) of (subclinical) renal effect. It ensures as such that the risk to Cd-exposed workers is fully controlled.

The results of the medical supervision are applied as follows (see also Figure below):

Figure: Illustration of Eurométaux/ICdA medical supervision guidance (2006) (BI: biological indicators; C: creatinine)

General medical follow-up level

 Cd-U ≤ 2 µg Cd/g creatinine (C). This is a conservative threshold based on general population studies, as described in Section 5.6.2. In this situation, the worker is followed by general medical follow-up (complementary indicator: Cd-B ≤ 5 µg Cd/L). No further special action is required beyond proper implementation of the general hygiene procedures and medical surveillance.

Action level

 2 < Cd-U ≤ 5 µg Cd /g creatinine: Action level zone. This zone is defined by the threshold based on studies at the workplace, as described in Section 5.6.2. Observation of Cd-U (or Cd-B) values in this “ action” zone triggers (complementary trigger: 5 µg Cd/l < Cd-B ≤ 8 µg Cd/l) an individual follow up of the worker characterized by:

o Systematic and frequent follow up of exposure by measuring Cd-U (complementary analysis: Cd-B), combined with individual analysis and follow-up of hygiene behaviour

o Measurement of biological indicators (BI’s) of early renal dysfunction (e.g. beta-2 microglobuline (B2-M) or retinol-binding protein (RBP) on a regular basis;

When the worker moves into this action level zone, the occupational doctor and plant hygiene team will check for the reason for the increased exposure (analysis of the workplace, with a view to identify possible substance releases, analysis of compliance with hygienic procedures, and interview with the worker to assess possible other causes, e.g. due to current or previous exposure, due to personal hygiene behaviour?).

Based on the results of the individual medical surveillance programme, the following management decisions are taken:

 The worker remains in the action zone: If the Cd-U (Cd-B) values do not progress further towards the threshold and the BI’s remain stable and below the reference value (e.g. 300 µg/g creatinine for β2-MG

and RBP), the worker is kept at the workplace. Additional hygiene measures are taken as appropriate, and medical follow-up is strictly continued.

 The worker is removed from exposure:

o If Cd-U > 5 µg Cd/g creatinine (or Cd-B > 8 µg/l) and/or

o If the BI’s are exceeding the reference values or showing a consistent pattern of increase which may lead to approaching the reference values

 The management scheme as outlined above is applicable to workers that entered the Cd industry rather recently. Workers that have been working in the Cd-industry for long may have been historically exposed to elevated Cd -levels, and may show e.g. Cd-U levels exceeding 5 µg/gC due to historical exposure. The supervising medical doctor will evaluate these individuals carefully, focusing on the BI’s. In any case, when BI values exceed the BI-reference values or approach them, the worker will be removed from Cd-exposure.  In addition to the above, general industrial hygiene programmes are to be implemented , as required by EU Directive 98/24/EC on protection of workers from chemical agents and other referenced systems on best practice : IPPC-BREF notes, BIMSCH or equivalent, ICH-Q7, FAMI-QS, ISO9000, ISO 13.100 or alike: 1. General industrial hygiene practice 2. Collective protection measures and use of warning & safety signs 3. Minimizing the number of workers exposed or likely to be exposed 4. Workplace cleanliness: ensure procedures are designed, written and implemented so as to make sure cleanliness is obtained at workstations, work sections, traffic and storage areas, upper areas, building structures and various horizontal surfaces, air suction ducts. 5. Procedures for process control

Conditions and measures related to personal protection, hygiene and health evaluation Personal protection, e.g. wearing of gloves, face protection, full body dermal protection, goggles, respirator; specify effectiveness of measure; specify the suitable material for the PPE (where relevant) and advise how long the protective equipment can be used before replacement (if relevant) Wearing of gloves and protective clothing is compulsory (efficiency >=90%). With normal handling, no respiratory personal protection (breathing apparatus) is necessary. If risk for exceedance of OEL/DNEL, use e.g.: -dust filter-half mask P1 (efficiency 75%) -dust filter-half mask P2 (efficiency 90%) -dust filter-half mask P3 (efficiency 95%) -dust filter-full mask P1 (efficiency 75%) -dust filter-full mask P2 (efficiency 90 %) -dust filter-full mask P3 (efficiency 97.5%)

Eyes: safety glasses are optional but recommended

9.2.2. Exposure estimation

10. RISK CHARACTERISATION

10.1. (Title of exposure scenario 1)

10.1.1. Human health

10.1.1.1. Workers

10.1.1.2. Consumers

10.1.1.3. Indirect exposure of humans via the environment

10.1.2. Environment

10.1.2.1. Aquatic compartment (incl. sediment)

10.1.2.2. Terrestrial compartment

10.1.2.3. Atmospheric compartment

10.1.2.4. Microbiological activity in sewage treatment systems

10.2. (Title of exposure scenario 2)

10.3. Overall exposure (combined for all relevant emission/release sources)

10.3.1. Human health (combined for all exposure routes)

10.3.2. Environment (combined for all emission sources)

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