Dicopper Oxide

Regulation (EU) No 528/2012 concerning the making available on the market and use of biocidal products

Evaluation of active substance

Assessment Report

Dicopper oxide

Product-type 21

January 2016

France Dicopper oxide PT 21 Product-type 21 January 2016

TABLE OF CONTENT

1 STATEMENT OF SUBJECT MATTER AND PURPOSE ...... 3 1.1 Principle of evaluation and procedure followed ...... 3 1.2 Purpose of the assessment ...... 4 1.3 Applicant ...... 4 2 OVERALL SUMMARY AND CONCLUSIONS ...... 5 2.1 Presentation of the active substance and biocidal product ...... 5 Identity, physico-chemical properties and methods of analysis of active substance . 5 2.1.1.1 Identity...... 5 2.1.1.2 Purity/Impurities, additives ...... 5 2.1.1.3 Physico-chemical properties ...... 5 2.1.1.4 Analytical methods for determination and identification ...... 6 2.1.1.5 Identity...... 6 2.1.1.6 Physico-chemical properties ...... 7 2.1.1.7 Analytical methods for determination and identification ...... 8 2.2 Intended uses and efficacy ...... 9 Field of use/function ...... 9 Object to be protected, target organisms ...... 9 Efficacy ...... 9 Mode of action ...... 9 Resistance ...... 10 2.3 Classification and labelling ...... 10 Current classification of active substance ...... 10 2.3.1.1 Current classification proposed by the applicant ...... 10 2.3.1.2 Proposed classification by the RMS ...... 10 Classification of biocidal product ...... 11 2.3.1.3 Proposed classification of the representative biocidal product INTERSMOOTH 360 SPC by the RMS ...... 11 2.3.1.4 Proposed classification of the representative biocidal product HEMPEL’S ANTIFOULING OLYMPIC 86951 by the RMS ...... 11 2.4 Summary of the risk assessment ...... 12 Summary of human health risk assessment ...... 12 2.4.1.1 Hazard identification of active substance ...... 12 2.4.1.2 Hazard identification of product ...... 18 2.4.1.3 Summary of exposure assessment and risk characterization ...... 18 Summary of environmental risk assessment ...... 29 2.4.1.4 Fate and distribution in the environment ...... 29 2.4.1.5 Effects assessment on environmental organisms (active substance) .. 30 2.4.1.6 Environmental effect assessment (product) ...... 35 2.4.1.7 Environmental exposure assessment and risk characterisation ...... 35 2.5 Overall conclusions ...... 59 2.6 Requirement for further information related to the product ...... 62 APPENDIX 1: LIST OF ENDPOINTS...... 63 APPENDIX 2: LIST(S) OF ABBREVATIONS ...... 80 APPENDIX 3: LIST OF STUDIES ...... 87

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1 STATEMENT OF SUBJECT MATTER AND PURPOSE

1.1 Principle of evaluation and procedure followed

This assessment report has been established as a result of the evaluation of the active substance of cuprous oxide or dicopper oxide CAS n° 1317-39-1, as product-type 21 (Antifouling), carried out in the context of the work programme for the review of existing active substances provided for in Article 16(2) of Directive 98/8/EC concerning the placing of biocidal products on the market1, with the original view to the possible inclusion of this substance into Annex I or IA to that Directive, then carried out in the context of Regulation (EU) No 528/20122, with a view to the possible approval of this active substance.

The evaluation has therefore been conducted to determine whether it may be expected, in light of the common principles laid down in Annex VI to Directive 98/8/EC, that there are products in product-type 21 containing cuprous oxide that will fulfil the requirements laid down in Article 5(1) b), c) and d) of that Directive.

Cuprous oxide (CAS-no: 1317-39-1) was notified as an existing active substance, by the EU Antifouling Copper Task Force (EUACTF) for product-type 21. Data on representative biocidal products were submitted by the two biocidal product manufacturers International paint Ltd and Hempel.

Data submitted were collected to compile a complete dossier on the hazard assessment of the active substance. Therefore, there will be references to the data submitted by both manufacturers and EUACTF in this report.

Commission Regulation (EC) No 1451/2007 of the 4th of December 20073 lays down the detailed rules for the evaluation of dossiers and for the decision-making process in order to include or not an existing active substance into the Annex I or IA of the Directive.

In accordance with the provisions of Article 3 paragraph 2 of that Regulation, France was designated as Rapporteur Member State to carry out the assessment of cuprous oxide on the basis of the dossier submitted by the applicant. The deadline for submission of a complete dossier for cuprous oxide as an active substance in product-type 21 was the 30 th Avril 2006, in accordance with Article 9 paragraph 2 of Regulation (EC) No 1451/2007.

The hazard assessment of cuprous oxide was conducted in line with the assessment of copper compounds dossiers for PT8 for which the active substances have already been included into the annex I of Directive 98/8/EC. It has to be noted that the EUACTF has a letter of access for the PT8 copper compounds dossiers, which permit to use several agreed endpoints for PT8 copper compounds in the assessment of cuprous oxide as PT21.

On the 28th April 2006, the French competent authority received a dossier from EU Antifouling Copper Task Force (EUACTF) and from the biocidal product manufacturers International paint Ltd and Hempel. The Rapporteur Member State accepted the dossier as complete for the purpose of the evaluation, taking into account the supported uses, and confirmed the acceptance of this dossier on the 9th March 2007.

1 Directive 98/8/EC of the European Parliament and of the Council of 16 February 1998 concerning the placing biocidal products on the market, OJ L 123, 24.4.98, p.1 2 Regulation (EU n° 528/2012 of the European Parliament and of the council o 22 May 2012 concerning the making available on the market and use of biocidal products. 3 Regulation EC n° 1451/2007 of december 2007 on the second phase of 10-year work programme referred to in article 16(2) of Directive 98/8/EC of the European Parliament and of the Council concerning the placing biocidal products on the market OJ L 325, 11.12.2007, p. 3.

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In order to review the competent authority report and the comments received on it, consultations of technical experts from all Member States (peer review) were organised by the Agency. Revisions agreed upon were presented at the Biocidal Products Committee and its Working Groups meetings and the competent authority report was amended accordingly.

1.2 Purpose of the assessment

The aim of the assessment report is to support a decision on the approval of coated cuprous oxide for product-type 21, and should it be approved, to facilitate the authorisation of individual biocidal products in product-type 21 that contain cuprous oxide. In the evaluation of applications for product-authorisation, the provisions of Regulation (EU) No 528/2012 shall be applied, in particular the provisions of Chapter IV, as well as the common principles laid down in Annex VI.

The conclusions of this report were reached within the framework of the uses that were proposed and supported by the applicant (see Appendix II). For the implementation of the common principles of Annex VI, the content and conclusions of this assessment report shall be taken into account.

However, where conclusions of this assessment report are based on data protected under the provisions of Regulation (EU) No 528/2012, such conclusions may not be used to the benefit of another applicant, unless access to these data has been granted.

1.3 Applicant

Name: EU Antifouling Copper Task Force

Address: Regulatory Compliance Limited Bilston Glen Business Centre Loanhead Edinburgh, UK EH20 9LZ

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2 OVERALL SUMMARY AND CONCLUSIONS

2.1 Presentation of the active substance and biocidal product

Identity, physico-chemical properties and methods of analysis of active substance

2.1.1.1 Identity

Ta ble 0-1: Ide ntification of Cuprous oxide

CAS-No. 1317- 39-1 EINECS- No. 215-270-7 Other No. {CIPAC, ELINCS CI PAC 8084 IUPAC Name Copper (I) oxide Common name, synonyms Cuprous oxide, dicopper oxide Molecular formula Cu20 Structural formula Cu I Cu-0

Molecular weight (g/mol) 143.09

The active substance is cu rrently named cuprous oxide in the CAR however the EC name is dicopper oxide (or the I UPAC name is copper (I) oxide).

2.1.1.2 Purity/I mpurities. addit ives

The active substance as manufactured is cuprous oxide and reacts on fouling organisms as cupric ion Cu2+.

The specifications of cuprous oxide of each applicant are presented in the confidential doc III A2 of the Competant Authority Report. Cuprous oxide as manufactured contains four relevant impurities: arsenic, cadmium, nickel and lead.

The specifications of the active substance cuprous oxide have been assessed according to what has been ag reed as reference specifications of copper compounds PT8 already included into annex I of Directive 98/8/EC. The assessment of data submitted conducted to conclude that the three sources are acceptable for the approval of the active substance cuprous oxide as their specifications are covered by the batches used in the toxicological and ecotoxycological studies.

2.1.1.3 Physico-chemical properties

Cuprous oxide is an orange, fine and odorless powder. It has a density of 5.87. The measure of vapour pressure is not necessary as the melting point is above 300 °C. Cuprous oxide is not soluble in water (0.639 mg/Lat pH 6.5 and 20°C). The solubilisation

5 Dicopper oxide PT 21 Product-type 21 January 2016 results of the oxido-reduction reaction of the copper (I) oxide into ionic copper. Cu+ rapidly gives Cu2+ predominantly. At low pH, the reaction is promoted.

Cuprous oxide is slightly soluble in toluene (14mg/L), DCM (10mg/L), n-hexane and ethyl acetate (12mg/L), in acetone (13mg/L) and in methanol (9.3 mg/L). The partition coefficient n-octano/water is not relevant for the ecotoxicological risk assessment due to the specific absorption mechanism of copper.

Cuprous oxide is not oxidizing and not explosive. Further data should be provided for the flammability and auto-flammability.

As the active substance is a solid, particle size distribution should be provided. Active substance in form of nanomaterial is not considered in this assessment.

2.1.1.4 Analytical methods for determination and identification

The content of the active ingredient copper (I) in cuprous oxide technical was determined by conversion of the test substance batches with iron (III) chloride solution and potentiometric back-titration with cerium (IV) sulfate solution. The determined reducing power allows to obtained cuprous oxide content by calculation after the determination of copper metal content.

Analytical method is validated for Spiess Urania. Further validation data would be required for American Chemet and Nordox for the approval of the active substance.

Relevant trace metals can be determined by HPLC –AES (Atomic Emission Spectroscopy), ICP-AES (Inductively Coupled Plasma – Atomic Emission Spectroscopy) or by AAS, the samples are previously digested in dilute nitric acid. Complete validation data are missing for Nordox and American Chemet and would be required for the approval of the active substance. Validated analytical methods have been provided by Spiess Urania for the determination of other impurities. Analytical methods and validation data are missing for Nordox and American Chemet and would be required for the approval of the active substance.

The analyses of copper in environmental matrices and body fluids and tissues are routinely performed in many laboratories. As these methods were collaborately validated and are very widely used, limited validation data were accepted. Moreover, the EUACTF has a letter of access for the PT8 copper dossiers where the methods are described.

Allthough no method is required for dicopper oxide in food and feedings stuff, a method has been provided for the determination of copper in fresh fish by ICP-AES.

Identity, physic-chemical properties and methods of analysis of biocidal products

2.1.1.5 Identity

There are two representative biocidal products in the cuprous oxide dossier; Intersmooth 360 SPC (International paint) and Olympic 86951 (Hempel).

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Table 0-1: identity of Intersmooth 360 SPC

Trade name Intersmooth 360 SPC Manufacturer’s development BEA 368 code No(s) Ingredient of preparation Function Content Cuprous oxide Active substance 42.56% Zinc pyrithione Active substance 4.00% Other formulants Details of the product composition and information on the co-formulants are confidential and are presented in the confidential part of the dossier IIIB.2 Physical state of preparation Liquid wet paint

42.56% of cuprous oxide is equivalent to 37.8 % of copper in the product.

Table 0-2: Identity of Hempel’s Antifouling Olympic 86951

Trade name Hempel’s Antifouling Olympic 86951 Manufacturer's 86951-60700 development code number(s) Ingredient of Function Content preparation Cuprous oxide Active substance 37.46% Other formulants Details of the product composition and information on the co-formulants are confidential and are presented in the confidential part of the dossier IIIB.2 Physical state of Viscous liquid solvent borne paint preparation

37.46% of cuprous oxide is equivalent to 33.3% of copper in the product.

2.1.1.6 Physico-chemical properties

2.1.1.6.1 Intersmooth 360 SPC

Intersmooth 360 SPC is a dark brown liquid paint with a typical aromatic solvent odour. Its pH is neutral (pH = 6.0 at 1% dispersion). It has a density of 1.551. Intersmooth360 SPC is classified as flammable; R10. However it is not possible to conclude on the flammability of the product under the CLP. As the flash-point is below 23 °C, the boiling point is necessary to classified H226 cat 1 or 2. It has neither oxidizing nor explosive properties.

It is not possible to conclude on the stability of the product during 56 days at 40°C, the zinc pyrithione content increases of 6.7%, moreover the long term storage stability study (2 years) has not been provided. The study is required at the product authorization stage to set the shelf life of the product. Moreover no data has been provided on the effect of light. The stability of the product at 0°C and the surface tension of the pure product should be provided at the product authorization stage.

Due to the presence of lumps during storage, a recommendation should be set on the label: shake well before use.

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Residues exceeds 5% limit, however the product is not diluted, therefore a study to determine true residue level in container after use or a management of the packaging in a specialized processing dedicated circuit is required.

2.1.1.6.2 Hempel’s Antifouling Olympic 86951

Hempel’s Antifouling Olympic 86951is a red liquid paint. Ist odour is assumed to ressemble of the sweet odour of xylene. It has a density of 1.8112 and is classified as flammable R10 and H226 cat.3. However as the flash-point is an estimated value closed to 21 °C and 23 °C which are the limit values for classification R11 and H225 or H224, a full flash point test according to relevant standard will be necessary at the product authorisation stage. Moreover if the flash-point is below 23°C the boiling point of the product will be required for the classification H224 or H225. It has neither oxidizing nor explosive properties.

It is not possible to conclude on the stability of the product. A full accelerated storage stability study conducted under GLP (14 days at 54°C) and a long term storage stability study (2 years) are required at the product authorisation stage. Moreover no data has been provided on the effect of light and the compatibility of the packaging.

The stability of the product at 0°C, the surface tension of the pure product and a full pourability test according to CIPAC MT 148 should be provided at the product authorization stage.

2.1.1.7 Analytical methods for determination and identification

2.1.1.7.1 Intersmooth 360 SPC

The analytical method for the determination of copper in the product Intersmooth 360 SPC is not acceptable and a validated analytical method for the identification and determination of cuprous oxide in the product Intersmooth 360 SPC should be provided at the product authorization stage.

The method for the determination of Zinc pyrithione in the product Intersmooth 360 SPC is not fully validated. Further data on specificity should be provided at the product authorization stage in order to show that there are no interference with the co- formulants of Intersmooth 360 SPC.

2.1.1.7.2 Hempel’s Antifouling Olympic 86951

The analytical method for the determination of copper in the product Hempel’s Antifouling Olympic 86951is not acceptable and a validated analytical method for the identification and determination of cuprous oxide in the product Olympic should be provided at the product authorization stage.

2.1.1.7.3 Residues analytical methods

For residue analysis of cuprous oxide please refer to data given in active substance part (see 2.1.1.4 in the document). For the the product Intersmooth 360 SPC, no analytical methods for zinc pyrithione and/or residues of zinc pyrithione have been provided in the dossier.

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2.2 Intended uses and efficacy

The assessment of the biocidal activity of the active substance demonstrates that it has a sufficient level of efficacy against the target organism(s) and the evaluation of the summary data provided in support of the efficacy of the accompanying product, establishes that the product may be expected to be efficacious.

In addition, in order to facilitate the work of Member States in granting or reviewing authorisations, the intended uses of the substance, as identified during the evaluation process, are listed in Appendix II.

Field of use/function

Main group: 4 – Other biocidal products Product type 21–Antifouling products

Cuprous oxide as Cu2+ is used in the control of fouling organisms in marine and freshwater environments.

Object to be protected, target organisms

Cuprous oxide is intended to be used for the protection against fouling of both mobile (including but not limited to marine and freshwater vessels) and stationary (including but not limited to buoys, aquaculture nets, immersed structures) objects.

Efficacy

Cuprous oxyde is used on vessels which potentially cover large geographical ranges; they are potentially exposed to multiple marine biotypes. The number of fouling organisms to which a vessel may be exposed is therefore large; there are over 4000 fouling species with representatives from a variety of phyla, for example: - slime, diatoms species e.g. Achnanthes and Amphora species,aquatic plants such as Green and red algae spores e.g. Enteromorpha spp, Polysiphonia, animal, barnacles, mussels, tubeworms e.g Serpulids, sponges.

Efficacy of the product Intersmooth 360 SPC (42.56 % w/w Cu2O and 4.00 % Zinc pyrithione) has been proved in European sea waters during 19 months and in tropical sea waters during 12 months, with a dry film thickness of 200 µm. No efficacy data has been provided neither for fresh water nor for static objects.

Efficacy of Cuprous oxide has been proved in European sea waters during 103 weeks and in tropical sea waters during 32 weeks, with a dry film thickness of 100 µm, in field tests performed with the product Hempel’s Antifouling Olympic 86951 (37.5 % w/w Cu2O). Efficacy Cuprous oxide in combination with Zinc oxide has been proved in European sea waters during 19 months and in tropical sea waters during 12 months, with a dry film thickness of 200 µm, in field test performed with the product Intersmooth 360 SPC (42.56 % w/w Cu2O and 4.00 % Zinc pyrithione).

Mode of action

When copper from metallic copper, copper thiocyanate or cuprous oxide leaches into marine water in presence of oxygen, the predominant form of the copper is the active substance, the cupric ion, Cu2+. The cupric ion acts to retard settlement of the

9 Dicopper oxide PT 21 Product-type 21 January 2016 microscopic larvae of fouling organisms within a m icrolayer of water at t he paint surface via two mechanisms: ( 1) the ion ret ards organism's vital processes by inactivating enzymes; (2) the ion acts more directly by precipitating cytoplasmic proteins as met allic proteinates.

Resistance

There have never been any recorded cases of resistance in populations of fouling organisms through the use of Copper based anti-fouling paints in the literature up to now. However, some studies, in the literature, showed some impacts of copper pollution on marine life and indicate that some hull-fouling species have copper tolerance.

2.3 Classification and labelling

Current classification of active substance

2.3.1.1 Current classification proposed by the applicant

None

2.3.1.2 Proposed classification by the RMS

No harmonised classification according to Regu lation (EC) No 1272/ 2008 (CLP Regulation) of active substance is available. However the RAC opinion4 adopted in December 2014 contains the following classification :

Table 0-1 : Proposed classification according to regulation 1272/2008

Classification accordina to the CLP Reaulation Hazard Class and Acute tox. 4, H302 Category Codes Acute tox. 4, H332 Eye dam 1, H318 Aq uatic Acute 1, H400 Aq uatic chronic l , H4 10 Labellina Pictoarams GHSOS , GHS07 GHS09 Signal Word Danger Hazard Statement Codes H302: Harmful if swallowed H332 Harmful if inhaled H318: Causes serious eye damage. H410: very toxic to aquatic life with long lasting effects

Specific Concentration Aquatic Acute 1: M-factor = 100 limits, M-Factors Aq uatic chronic 1: M-factor = 100

4 Opinion proposing harmonised cl assification and labelling at EU level of Copper(II) oxide EC number: 215- 269-1, CAS number: 1317-38-0, CLH- 0 -0000001412-86-45/ F- Adopted 04 December 2014

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The American Chemet, Spiess Urania and Nordox sources of cuprous oxide should be classified for Skin Sens. 1 H317 since they contain nickel as an impurity above the classification limit for skin sensitisation (SCL in Skin Sens. for nickel is :2:0 .0 1% w/w).

Classification of biocidal product

2.3.1.3 Proposed classification of the representative biocidal product INTERSMOOTH 360 SPC by the RMS

According to the available studies and to CLP regulation, the classification is:

Classification accordina to the CLP Reaulation Hazard Class and Acute tox.,H332 Category Codes Acute tox. 4, H302 Eye irritant of category 2, H319 Skin irritant of category 2, H315 Aquatic Acute 1, H400 Aauatic chronic 1 H4 10 Labellina Pictoarams GHS07, GHS09 Signal Word Warning Hazard Statement Codes H332: Harmful if inhaled H302: Harmful if swallowed H319 : Causes serious eye irritation H315: Causes skin irritation . H410: very toxic to aquatic life with long lasting effects

Based on the available data, it is not possible to conclude on the CLP classification for the flammability properties.

2.3.1 .4 Proposed classification of the representative biocidal product HE MPEL'S ANTI FOU LING OLYM PIC 86951 by the RMS

According to the available studies and to CLP regulation, the classification is:

Classification accordina to the CLP Reaulation Hazard Class and Flam. Liq. 3, H226 Category Codes Acute tox. 4, H332 Skin sensit isation 1, H317 Aquatic Acute 1, H400 Aquatic chronic 1, H410 Labellina Pictograms GHS02,GHS07,GHS09 Siana! Word Warnina Hazard Statement Codes H226 Flammable liquid and vapour H332: Harmful if inhaled. H317 : May cause an allergic skin reaction H410: very toxic to aquatic life with long lasting effects

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2.4 Summary of the risk assessment

Summary of human health risk assessment

2.4.1.1 Hazard identification of active substance

Foreword

Copper is a micronutrient. It is essential for life and necessary for all living cells. It is used in many enzyme systems, particularly in energy transfer where the property of electron transfer is exploited in photosynthesis and catabolism. It is involved in the reactions and functions of many enzymes (e.g. amine oxidase, ceruloplasmin, cytochrome-c oxidase...) and in addition, copper is involved in angiogenesis, neurohormoneangiogenesis, neuro-hormone release, oxygen transport and regulation of genetic expression. Copper is present in almost all foods, and some products. Most human diets naturally include between 1 and 2 mg/person/day of copper, with some containing up to 4 mg/person/day.

The copper transport mechanisms in the organism form part of the system of homeostasis: the body is able to maintain a balance of dietary copper intake and excretion that allows normal physiological processes to take place. The relationship between copper concentration and observed effects show a flattened ‘U’-shaped dose- response curve. The left side of the ‘U’ curve represents deficiency, where intake of copper is less than required. This can lead to lethality, especially in children, where copper is essential for growth. Copper deficiency is associated with growth retardation, anemia, skin lesions, impaired immunity, intestinal atrophy, impaired cardiac function, reproductive disturbance, neurological defects and skeletal lesions. Copper is essential for normal physiological function such as cellular respiration, free radical defence, synthesis of melanin, connective tissue, iron metabolism, regulation of gene expression, and normal function of the heart, brain and immune system.

Figure 1: Dose-response curve for copper (adapted from Ralph and McArdle, 2001).

The central near-horizontal part of the ‘U’ curve represents homeostasis, where intake and excretion are balanced and copper level is in a normal range. The right-hand part of the ‘U’ represents toxicity or excess copper disease. Chronic copper toxicity is extremely rare, and the upper limit of homeostasis has never been strictly defined.

The active substance released from cuprous oxide is the cupric ion.

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Although a full guideline ADME study has not been performed for copper, the knowledge of copper in the human body at the level of the organism, organ, cell and gene is sufficient to meet the requirements of the Regulation. Extensive information is available relating to the toxicokinetics and toxicodynamics of the copper ion within the human body. The cupric ion is an inorganic charged species that cannot exist in an un-solvated, un-associated state and so cannot be prepared in a pure form. Submission of toxicology data for Cu2+ is therefore not possible or relevant. Under these circumstances, information relating to copper sulfate pentahydrate is provided instead and where data for the copper sulfate pentahydrate is not available, information has been supplied with other forms of copper which have been demonstrated to all produce cupric ion in a bioequivalence study.

2.4.1.1.1 Metabolism

Absorption

Oral administration:

The proportion absorbed in a clinical study over 90 days varied between 56 % for subjects receiving 0.8 mg Cu/day, 36 % for individuals receiving 1.7 mg Cu/day and 12 % for individuals receiving 7.5 mg Cu/day (A6.2/01).

To determine the systemic NOAEL, as stated in Technical Meeting (TM)III08, consistencely with the EU RAR5, the percentage of the administered copper sulfate pentahydrate retained to be available for absorption following administration in the diet for rats is 25 % whereas 36 % will be used as the oral absorption value in humans.

Dermal administration:

For the active substance, in order to harmonize BPR dossier and EU RAR, the dermal delivery of copper compound (in solution) retained in TMIII08 was 5 %.

This value will be used in the risk assessment for general situation of exposure to Cu2O.

However, it is recognized that a strong matrix effect of paint on the dermal absorption of substances exists. For the product intersmooth 360 SPC,a study with formulation close to Intersmooth 360 SPC was provided in the PT 21 dossier leading to a value of 0.14% for copper contained in Intersmooth 360.

For the product Hempel’s Antifouling Olympic 86951, a dermal penetration study on a formulation close to Hempel’s Antifouling Olympic 86951was provided in the PT 21 dossier leading to a value of 0.34 % for copper contained in Hempel’s Antifouling Olympic 86951.

It should be noted that these studies present some methodological deviations. However, at this stage it would not be reasonable to require new dermal absorption studies.

Nevertheless, for the purpose of this dossier of substance approval, RMS proposes to use these values of 0.14% and 0.34% for copper dermal absorption as they are much more realistic than the default value of 5%. It was agreed at WG IV-2015 that these values would only apply for active substance approval. Hence, studies of better reliability should absolutely be provided at the product authorization level. In the absence of news studies, the value of 5% will be used.

5 Voluntary risk assessment reports (VRAR) submitted to ECHA based on industry initiative to follow the risk assessment procedures of Existing Substance Regulation (EEC) No 793/93 June 2008

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It is also important to note that the rinse of the skin with water and soap is inefficient. Consequently, paint stays in the skin and in the stratum corneum. As the stratum corneum was removed from skin at the end of the study (24 hours) by stripping and exluded to determination of dermal absorption, an efficient removal of residual paint on the skin by professional and non professional should be performed after the use of paints.

Inhalation administration:

No animal or human studies were available to supply an inhalation absorption level. Thus, the default absorption value of 100 % is used in risk characterisation as worst-case value of copper salts penetration.

Distribution

Once absorbed by oral route, copper is bound to albumin and transcuprein and then rapidly transported to the liver where it is incorporated to ceruloplasmin, a transport protein that circulates in the organism and deliver the copper to other organs. It should be however noted that a minor fraction of the absorbed dose can directly be distributed to peripheral organs. In both humans and animals, copper is tightly regulated at a cellular level, involving metallothionein and metallochaperones. These regulating molecules prevent from the accumulation of potentially toxic, free copper ions within the cell. In addition to the liver, the brain is another organ which contains relatively high concentrations of copper.

Elimination

Biliary excretion, with subsequent elimination in the faeces, represents the main route of excretion for copper in animals (rats) and humans, with an excretion rate approximately of 1.7 mg Cu/day in humans. Available data show that copper is excreted in the bile in a relatively inabsorbable form. Consequently, little enterohepatic absorption takes place. Biliary excretion of copper and elimination in the faeces is recognised to be essential to the homeostatic regulation of copper in animals and humans. A small amount of copper is also excreted in urine and sweat.

2.4.1.1.2 Acute toxicity

Based on the results of the acute oral toxicity studies, Cu2O is classified as “Harmful “ according to the classification criteria as given in Annex VI of Commission directive 2001/59/EC, with the risk phrase R22 “Harmful if swallowed” (LD50 = 1340 mg/kg bw).

Based on the CLP criteria, a classification Acute Tox.4-H302 is proposed.

Cu2O is not hazardous or classified by the dermal route.

Based on the results of the acute inhalation toxicity studies, cuprous oxide requires the classification Xn, R20 “harmful by inhalation” (3/5 males and 3/5 females died on day 1 after exposure of 5.78 mg/L during 4 hours), indeed LC50 was lower than 5.78 mg/L and approximately 5 mg/l, which is the limit value used in classification. Moreover, the clinical signs observed in different studies are moderately severe (haemorrhagic appearance of lungs, hunched appearance, apathy, difficult respiration). Moreover, classifications R20 for copper (I) oxide is proposed on the peer review of copper compounds of EFSA based on one study not available in this dossier.

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Besides, a classification Acute Tox.4-H332 is proposed based on the CLP criteria.

2.4.1.1.3 Skin and eye irritation

Cuprous oxide is not hazardous or classified as a skin irritant. A classification Eye Dam. 1-H318 was proposed in RAC opinion of December 2014.

2.4.1.1.4 Skin sensitization

Cuprous oxide is not hazardous or classified as a skin sensitising.

For systemic effect after repeated exposure, the most toxic form of any copper salt is the Cu2+ ion. The copper compound which releases more Cu2+ is the most soluble salt: copper sulphate. In this context, to avoid repeating assay in animals, it was decided at TM III 08 to extrapolate data from copper sulphate to the other copper compounds when no other data is available. This read across between copper compounds and copper sulphate for repeated toxicity and CMR endpoints was adopted by TM for previous PT8 and PT2 copper dossiers. This approach was also presented in the CLH report for the classification and labelling of copper compounds.

2.4.1.1.5 Oral repeated toxicity

With regard to oral repeated dose toxicity, the 90-day dietary study was considered to be the pivotal study for Cu2+ presented as copper sulphate pentahydrate. Based on kidney damages, consisting in an increase of cytoplasmic protein droplets, a NOAEL of 1000 ppm in rats (16.3 and 17.3 mgCu/kg bw/day in male and female rats respectively) was determined. Other findings such as liver inflammation and lesions of the forestomach were also reported at 2000 ppm and above (corresponding to doses from 34 mgCu/kg bw/day).The NOAEL of 16.3 mg/kg bw/d was used for the risk characterisation.

Mice equally displayed forestomach lesions when exposed through diet to copper sulphate for 92 days but this occurred at a much higher dose (4000 ppm, corresponding to 187 and 267 mgCu/kg bw/day in males and females, respectively). No other damage was observed in mice

Subchronic and chronic studies in the dog can be waived, as the dog is an unsuitable animal model for studying copper toxicity in relation to man. Indeed, dogs have a different form of albumin compared to rats and humans, and cannot excrete copper in the bile as readily as most other species. The dog is not a good animal model for human risk assessment of copper.

2.4.1.1.6 Dermal repeated toxicity

There were no dermal repeated dose toxicity studies. However, these studies are not required considering the ability to read-across from the above oral study. Moreover, due to the lack of toxicity observed in the acute dermal toxicity and the weak rate of dermal penetration, a toxic effect is not expected.

2.4.1.1.7 Inhalation repeated toxicity

15 Dicopper oxide PT 21 Product-type 21 January 2016

A study performed on cuprous oxide was provided for the antifouling copper compound dossier. Cuprous oxide was administered via whole body as 6 hours to male and female Sprague Dawley rats for 1, 2, 3 or 4 weeks (5 days/week) at 0.2, 0.4, 0.8 and 2 mg/m3. Effects observed are essentially local effect (LDH and protein increase in the bronchoalveaolar lavage fluid, minimal inflammation and the decrease in wet/dry lung weight ratio), reversible in 13-week recovery period except the decrease the effects on the lung weight.

2.4.1.1.8 Genotoxicity

 In vitro tests There was no evidence of mutagenic activity in Salmonella typhimurium strains in the presence or absence of the metabolic activation system when tested with copper sulphate pentahydrate. Although limited, these in vitro data were deemed sufficient and no further in vitro assays were required, considering the results of the in vivo tests.

 In vivo tests In vivo studies, conducted with copper sulphate pentahydrate, induced neither micronuclei in the polychromatic erythrocytes from the bone marrow of mice, nor DNA damage in a rat hepatocyte UDS assay. Equivocal results of additional in vivo genotoxicity studies from the public domain (Bhunya and Pati, 1987; Agarwal et al., 1990; Tinwell and Ashby, 1990) are observed but these studies do not meet the higher reliability criteria (1 or 2) under the regulation. Copper is therefore considered as non genotoxic

2.4.1.1.9 Chronic toxicity and carcinogenicity

No carcinogenic potential of copper sulphate was detected in rats and mice. However, all available data are of limited value to evaluate the carcinogenic potential of copper compounds. Study durations are in particular too short (<2 years) and group sizes are small for drawing formal conclusions. However, based on the available data, human data and due to the lack of genotoxicity there is no need to conduct new carcinogenicity studies.

2.4.1.1.10 Reproductive toxicity

Developmental toxicity

A developmental study in mice was submitted but suffers from major methodological deficiencies including no information on maternal toxicity and is neither adequate for classification and labelling nor for risk assessment.

Subsequent to the original submission, the EU Antifouling Copper Task Force submitted another study, that conforms to Annex V and OECD methods for a teratogenicity test (Annex V method B.31; OECD method 414). This study provides the most reliable animal data concerning the developmental toxicity of copper.

Technical copper hydroxide was given by gavage to groups of mated female rabbit during days 7 to 28 of pregnancy at three different doses (6, 9 and 18 mg Cu/kg bw/d). Administration of copper to pregnant rabbits at 18 and 9 mg Cu /kg bw/d was associated with marked initial bodyweight loss, inappetance, abortion and death.

16 Dicopper oxide PT 21 Product-type 21 January 2016

Pups in litters from surviving dams showed slightly lower mean foetal weight and slightly increased incidence of retarded ossification of skull and pelvic bones at 18 mg Cu/kg bw/d. Therefore, the maternal no observed effect level was 6 mg/kg bw/d and the foetal no observed effect level was 9 mg/kg bw/d.

Fertility

According to the two-generation oral reproduction study in rats administered with copper sulphate pentahydrate, the NOAEL for reproductive toxicity for parental males was 1500 ppm (the highest concentration tested corresponding to 23.6 mg/kg bw/d), The NOAEL for parental females was only 1000 ppm (15.2-35.2 mg/kg bw/d), based on the reduced spleen weight at 1500 ppm. This reduction also occurred in F1 and F2 generations at the same dose level in both males and females. However the reduced spleen weights were not considered a reproductive endpoint as it did not affect growth and fertility. Therefore as the results of this study do not indicate specific reproductive toxicity at the highest dose level tested, it is proposed that copper sulphate and cuprous oxide (by read across) should not be classified as reprotoxic compounds.

2.4.1.1.11 Neurotoxicity

From a neurotoxicological point of view, copper has been recently suspected to be involved in the pathogenesis of the Alzheimer's disease and other prion-mediated encephalopathies. Although no valid neurotoxicity study was submitted, no evidence of a neurotoxic potential of copper is suspected from the available studies in animals up to now. No further study was therefore deemed necessary.

2.4.1.1.12 AEL derivation

The key health effect to consider in the risk characterization is kidney and forestomach damages observed in the 90-day dietary study, which determined a NOAEL of 1000 ppm (16.3 and 17.3 mgCu/kg bw/day in male and female respectively) in rats. This NOAEL is considered to be the most appropriate in the risk characterization for short-term and chronic exposures (carcinogenicity studies considered unnecessary).

To determine the systemic NOAEL, as stated in TMIII08, in order to harmonize BPD dossier and EU RAR, the percentage of the administered copper sulphate pentahydrate retained to be available for absorption following administration in the diet for rats is 25%.

Therefore, the systemic NOAEL, based on the NOAEL of 16.3 mgCu/Kg bw/d and the oral absorption of 25% for animals is:

1 NOAELsystemic NOAEL .0* 25  1.4 mgCukg bw/ d

To derive the AEL from the NOAEL, the NOAEL is first converted to a systemic NOAEL then then it is divided by the assessment factors taking into account uncertainties and extrapolations. The assessment factors were discussed during the TM IV08 and TMI09 for TP 8 copper substances and we will use the same way in these assessments.

 Acute-term AEL The acute-term AEL is the NOAEL (16.3 mg Cu/kg bw/day) times 25%, the absorption factor, divided by the 50-fold safety factor, corresponding to the MOEref (5 for inter- species variation and 10 for intra-species variation). An acute-term AEL of 0.082 mg Cu/kg/d is proposed.

17 Dicopper oxide PT 21 Product-type 21 January 2016

 Medium-term AEL The medium-term AEL is the NOAEL (16.3 mg Cu/kg bw/day) times 25%, the absorption factor, divided by the 50-fold safety factor, corresponding to the MOEref (5 for inter- species variation and 10 for intra-species variation). A medium-term AEL of 0.082 mg Cu/kg/d is proposed.

 Long-term AEL The long-term AEL is the NOAEL (16.3 mg Cu/kg bw/day) times 25%, the absorption factor, divided by the 100-fold safety factor, corresponding to the MOEref (5 for inter- species variation, 10 for intra-species variation and 2 for the duration of exposure from sub-chronic to chronic). A long-term AEL of 0.041 mg Cu/kg/d is proposed.

Generally AEL long-term is used to characterize the risk for professional. However, it has been agreed among MS (TM III 2011), the medium-term AEL should be used for risk characterization of professional applying or removing antifouling product, given the expected periodic uses of antifouling agents.

The acute-term AEL value is also used to characterize the risk for non professional.

2.4.1.2 Hazard identification of product

INTERSMOOTH 360 SPC

The acute toxity studies for oral and inhalation routes, eye irritation and sensitisation were considered not acceptable. In this context, the toxicity for these endpoints was determined by calculation according to Directive 99/45/CE and CLP regulation. No death was observed in the acute dermal toxicity study. However, irritation of skin was observed in the appropriate study.

Hempel’s Antifouling Olympic 86951

The product has low toxicity by oral and dermal routes. It is not irritant for skin and eyes but it is a skin sensitiser. No study was provided for inhalation route. In this context, the toxicity for this endpoint was determined by calculation according to Directive 99/45/CE and CLP Regulation.

2.4.1.3 Summary of exposure assessment and risk characterization

Two representative products are proposed for this active substance. Hence the risk assessment will be assessed for each product.

These two products are ready to use paints, intended to be used by professionals as well as non professionals.

Four steps during the antifouling use could lead to exposure to humans:  Mixing and loading  Paint application  Post-application cleaning  Paint removal

For professional use, different actors are potentially exposed:

18 Dicopper oxide PT 21 Product-type 21 January 2016

 Potman (on the floor) who mixes and loads the antifoulant paint from supply container to high pressure pump reservoir ensuring continuous supply to the spray gun. After application, potman cleans the spray equipment.  Professional who applies paint to the surface: o By spraying (mainly). Sprayer works from a manoeuvrable platform which is operated either by himself or by an ancillary worker He can also clean the spray equipment. o By brush and roller (to recover any mistakes)  Ancillary worker, keeping paint lines free, manoeuvring mobile spray platforms as well as other tasks intended to aid the sprayer’s job  Blast worker who performs a total or partial removal of the expired coating from the ship hull using abrasive grit or high-pressure water  Grit filler who assists the blast worker in regularly filling the mixing kettle with grit and monitoring the grit and water supply to the kettle and air to the tower wagon.

The non professional can apply the product by brushing/roller. He can also remove old paint, washing the boat with a power washer and the scrubbing loose or blistered parts of the paint in order to remove the leached layer of paint giving a good surface to apply a new coat paint.

Secondary exposure can occur in connection to non-professional application of paint:  toddler touching wet and dry paint with subsequent hand-to-mouth transfer.

Several models (TNsG or Links study) were available to determine the exposure during the different tasks. However, in order to harmonise the approach, an opinion of HEEG was endorsed during the TM IV 2012: HEEG opinion on the paper by links at al. 2007 on occupational exposure during application and removal of antifouling paints. This dossier will follow these recommandations.

2.4.1.3.1 Primary exposure

2.4.1.3.1.1 Professional exposure

For professional exposure assessment, the following parameters and models were used:

Model Duration Exposure min Spraying Potman – mixing TNsG 2002 Model 6: Loading liquid 180 Dermal and and loading antifoulant into reservoir for airless inhalation spray application (user guidance) Potman/sprayer- BEAT model: Delago study 10 Dermal cleaning of equipment Sprayer- spraying TNsG 2002 Model 3: Airless spraying 180 Dermal and viscous solvent-based liquids at > 100 inhalation bar pressure, overhead and forwards Ancillary worker Covered by assessment of sprayer, considering that ancillary worker wears the same PPEs. Brushing/roller Mixing and loading Links study 90 Dermal and Application inhalation Cleaning of brush Model proposed by HEEG: “primary Not Dermal exposure scenario - washing out of a relevant brush which has been used to apply

19 Dicopper oxide PT 21 Product-type 21 January 2016

paint” Other Blast worker Links study 180 Dermal and inhalation Grit filler Links study 180 Dermal and inhalation

Two steps assessments were performed:  Tier I: no PPE are worn. Gloves can be included at this step when no exposure without gloves is available in the models  Tier II: PPE/RPE are worn

INTERSMOOTH 360 SPC

Table 0-1: The exposures compared to AEL medium term:

Total systemic AEL Exposure Task PPE exposure mg Risk % AEL mg Cu/kg/d Cu/kg/d Potman Mixing and No PPE 2.39 E-01 8.2E-02 291% Unacceptable loading of paint Gloves and in pump impermeable 6.52 E-02 8.2E-02 80% Acceptable reservoir coverall Cleaning spray 1.51E-02 8.2E-02 18% No PPE Acceptable equipment

2.54E-01 No PPE 8.2E-02 309% Unacceptable

Combined exposure: M&L M&L of paint in 8.03E-02 8.2E-02 98% and cleaning pump reservoir: gloves and Acceptable impermeable coverall Cleaning: no PPE Application by spraying Gloves 8.09 E-01 8.2E-02 986% Unacceptable Coated coverall, Spraying gloves and mask 5.31 E-02 8.2E-02 65% Acceptable APF 40 Cleaning spray No PPE 1.51E-02 8.2E-02 18% Acceptable equipment Combined Spraying: gloves 8.24E-01 8.2E-02 1005% Unacceptable exposure: Cleaning: no PPE Spraying phase Spraying: coated 6.82E-02 8.2E-02 83% Acceptable and cleaning coverall, gloves and mask APF 40 Cleaning: no PPE Application by brush/roller Brushing No PPE 1.35E-01 8.2E-02 165% Unacceptable

20 Dicopper oxide PT 21 Product-type 21 January 2016

Total systemic AEL Exposure Task PPE exposure mg Risk % AEL mg Cu/kg/d Cu/kg/d Gloves and tyvek 3.66E-03 8.2E-02 4% Acceptable Cleaning of No PPE 1.8E-03 8.2E-02 2% Acceptable brush Combined No PPE 1.37E-01 8.2E-02 167% Unacceptable exposure: Tyvek coverall mixing and and gloves during loading, M&L and brushing 5.46E-03 8.2E-02 7% Acceptable application by and no PPE brush/roller and during and cleaning cleaning Sand blasting No PPE 5.52E-01 8.2E-02 673% Unacceptable Protective water- proof overalls, an airstream helmet with rubber flaps Paint removal that covered a 5.72E-02 8.2E-02 70% Acceptable large part of their upper body and strong protective gloves and mask APF 10 Grit filling No PPE 1.40 8.2E-02 1704% Unacceptable Coated coverall, Grit filling gloves, mask APF 5.79 E-02 8.2E-02 71% Acceptable 40

A risk for potman during mixing and loading exists when no PPE are worn. However, when gloves and impermeable coverall are worn, the risk becomes acceptable. No PPE is required for cleaning.

A risk for sprayer during application under the conditions specified above (with gloves but without coverall and mask) exists. However, when gloves, coated coverall and mask APF 40 are worn the risk becomes acceptable. The combined risk with cleaning of spray equipment if gloves, coated coverall and mask APF 40 are worn during spraying is also acceptable. No PPE are required for cleaning task.

The combined risk is acceptable for brusher when an equivalent Tyvek coverall and gloves are worn during mixing and loading of paint into trail and application of the paint.

A risk for sand blaster without PPE exists. However, when protective water-proof overalls, an airstream helmet with rubber flaps that covered a large part of their upper body, strong protective gloves and and mask APF 10 are worn the risk becomes acceptable.

A risk for grit filler exists without PPE. However, when coated coverall, gloves and mask APF 40 are worn the risk becomes acceptable.

Hempel’s Antifouling Olympic 86951

21 Dicopper oxide PT 21 Product-type 21 January 2016

Table 0-2: The exposures compared to AEL medium term

Total AEL systemic Exposure Task PPE mg Risk exposure % AEL Cu/kg/d mg Cu/kg/d Potman No PPE 4.54E-01 8.2E-02 554% Unacceptable Mixing and Gloves, loading of paint impermeable 4.74 E-02 8.2E-02 58% Acceptable in pump reservoir coverall and mask APF 10 Cleaning spray Tier I: No PPE 3.77E-02 8.2E-02 46% Acceptable equipment Tier II: gloves 1.56E-02 8.2E-02 19% Acceptable 4.92E-01 8.2E-02 600% Unacceptable

No PPE

Combined exposure: M&L M&L of paint in 6.31E-02 8.2E-02 77% Acceptable and cleaning pump reservoir: gloves, impermeable coverall and mask APF 10 Cleaning: gloves Application by spraying Gloves 1.22 8.2E-02 1483% Unacceptable Impermable Spraying coverall, gloves 5.84 E-02 8.2E-02 71% Acceptable and mask APF 40 Cleaning spray Tier I: No PPE 3.77E-02 8.2E-02 46% Acceptable equipment Tier II: gloves 1.56E-02 8.2E-02 19% Acceptable Combined Spraying: 1.25 8.2E-02 1529% Unacceptable exposure: gloves Spraying phase Cleaning: no and cleaning PPE Spraying: 7.40 E-02 8.2E-02 90% Acceptable impermeable coverall, gloves and mask APF 40 Cleaning: gloves Application by brush/roller No PPE 2.86E-01 8.2E-02 348% Unacceptable Brushing Gloves and 3.66E-03 8.2E-02 4% Acceptable tyvek Cleaning of brush No PPE 4.50E-03 8.2E-02 5% Acceptable No PPE 2.90E-01 8.2E-02 354% Unacceptable Combined Tyvek coverall exposure: mixing and gloves and loading, during M&L and application by 8.16E-03 8.2E-02 10% Acceptable brushing and no brush/roller and PPE during and cleaning cleaning

22 Dicopper oxide PT 21 Product-type 21 January 2016

Total AEL systemic Exposure Task PPE mg Risk exposure % AEL Cu/kg/d mg Cu/kg/d Sand blasting No PPE 4.92E-01 8.2E-02 600% Unacceptable Protective water-proof overalls, an airstream helmet with Paint removal rubber flaps that covered a large 5.27E-02 8.2E-02 64% Acceptable part of their upper body and strong protective gloves and mask APF 10 Grit filling No PPE 1.34 8.2E-02 1633% Unacceptable Coated coverall, Grit filling gloves, mask 7.42 E-02 8.2E-02 91% Acceptable APF 40

A risk for potman during mixing and loading exists when no PPE are worn. However, when gloves, impermeable coverall and mask APF 10 are worn, the risk becomes acceptable. To take into consideration the combined risk with cleaning task, although the risk is acceptable without PPE for the cleaning task alone, gloves are required for this task.

A risk for sprayer during application under the conditions specified above (with gloves but without coverall and mask) exists. However, when gloves, impermeable coverall and mask APF 40 are worn the risk becomes acceptable. To take into consideration the combined risk with cleaning task, although the risk is acceptable without PPE for the cleaning task alone, gloves are required for this task. The combined risk is acceptable for brusher when an equivalent Tyvek coverall and gloves are worn during mixing and loading of paint into trail and application of the paint.

A risk for sand blaster without PPE exists. However, when PPEs equivalent to protective water-proof overalls, an airstream helmet with rubber flaps that covered a large part of their upper body, strong protective gloves and and mask APF 10 are worn the risk becomes acceptable.

A risk for grit filler exists without PPE. However, when coated coverall, gloves and mask APF 40 are worn the risk becomes acceptable.

23 Dicopper oxide PT 21 Product-type 21 January 2016

2.4.1.3.1.2 Non-Professional exposure

For non-professional exposure assessment, the following parameters and models were used:

Model Duration Exposure min Brushing/roller Mixing and loading TNsG 2002: model 4 – non professionals 90 Dermal and application brush and roller painting of antifoulant inhalation on the underside of small boats (user guidance) Cleaning Model proposed by HEEG: « primary Not Dermal exposure scenario - washing out of a relevant brush which has been used to apply paint »

No relevant model is available to assess the exposure of non professional during the removal of paint. . However, it was considered that this scenario will be covered by the scenario“application of the paint“.

The use of gloves by non professional is usually not accepted, several discussions occured on the use of PPE by non-professionals at the previous TMs (TM I 2011 and TM III 2011) and some documents provided (i.e. TMI 2011: Agenda point 3a. "Feasibility for non-professional users of antifouling to wear gloves"). TMIII 2011 agreed that all PT 21 CARs having non-professional applications should include two exposure/risk assessments; one assessment where no gloves are worn and a second assessment where gloves are worn. In this context, assessments for these products were performed also with gloves for non- professional.

INTERSMOOTH 360 SPC

Table 0-3: the exposures compared to AEL acute term

Total systemic exposure AEL Exposure Task PPE Risk b(dermal) mg Cu/kg/d % AEL mg Cu/kg/d Mixing and loading application Unacceptab No PPE 8.58E-02 8.2E-02 105% le Brushing* Gloves 3.96E-02 8.2E-02 48% Acceptable

Cleaning

Cleaning of brush No PPE 1.8E-03 8.2E-02 2% Acceptable

Combined exposure Combined 8.76E-02 8.2E-02 107% Unacceptab exposure: mixing No PPE le and loading of

24 Dicopper oxide PT 21 Product-type 21 January 2016

Total systemic exposure AEL Exposure Task PPE Risk b(dermal) mg Cu/kg/d % AEL mg Cu/kg/d paint, application Househ 4.14E-02 8.2E-02 51% and cleaning brush old gloves during mixing and loading Acceptable and applica tion No PPE during cleanin g Note*: In the study used to determine exposure of non professional during brushing, the brushing was performed outdoor.

The risk for combined exposure is unacceptable for non professional without household gloves. The risk would be acceptable only if appropriate PPE were worn.

In consequence, according to the guidance document CA-March14-Doc.4.2-Final- “Antifouling (PT21): Way forward for the management of active substances and the authorisation of biocidal products”, persons making products containing copper flakes (coated with aliphatic acid) available on the market for non-professional users shall make sure that the products are supplied with appropriate gloves. This measure is however without prejudice to the provisions of paragraph 63 of Annex VI to BPR, whereby Member States shall normally not authorise antifoulings to the general public if the wearing of personnel protective equipment (PPE), such as gloves, is the only risk mitigation measure to reduce exposure to acceptable levels.

Hempel’s Antifouling Olympic 86951

Table 0-4: the exposures compared to AEL acute term

Total systemic exposure AEL Exposure Task PPE Risk b(dermal) mg Cu/kg/d % AEL mg Cu/kg/d Mixing and loading application 1.83E-01 8.2E-02 223% Unacceptable No PPE

Brushing* 8.41E-02 8.2E-02 103% Unacceptable Gloves

Cleaning 4.50E-03 8.2E-02 5% Acceptable Cleaning of No PPE brush

Combined exposure

25 Dicopper oxide PT 21 Product-type 21 January 2016

Total systemic exposure AEL Exposure Task PPE Risk b(dermal) mg Cu/kg/d % AEL mg Cu/kg/d No PPE 1.87E-01 8.2E-02 228% Unacceptable

Combined exposure: mixing and Household 8.45E-02 8.2E-02 103% Unacceptable loading of gloves paint, during application mixing and and cleaning loading and brush application No PPE during cleaning Note*: In the study used to determine exposure of non professional during brushing, the brushing was performed outdoor.

The risk for combined exposure is unacceptable for non professional brusher (even if household gloves are worn during application). In this context, the use for non professional cannot be authorized.

2.4.1.3.2 Secondary exposure

For professional uses, secondary exposure could occur to bystanders if individuals working in the dock yard were to pass by or stop to watch a spraying or blasting operation. However, it was decided at TM III2011 that no quantitative risk assessment should be performed for this group but that the product should be labelled with the phrases “unprotected persons be kept out of treatment areas”. If a person is in an area where he/she could be exposed then that person would need to suitably attire him/herself with the relevant PPE/RPE.

For non professional uses, secondary exposure could occur in connection to non- professional application of paint, when toddlers (as a worst case) touch wet or dry paint with subsequent hand-to-mouth transfer. The exposure level was compared to AEL acute term. Exposure to the by-stander is covered by the exposure of the non-professional who applies the paint.

Intersmooth 360 SPC

As the non professional use cannot be authorized (see above), these assessments are presented for information. AEL Exposure Exposure Scenario mg Risk mg Cu/kg/d % AEL Cu/kg/d Systemic 1.14 8.2E-02 1392% Unacceptable exposure – toddler touching wet treated surface Systemic 1.51 E-01 8.2E-02 184% Unacceptable exposure – toddler touching

26 Dicopper oxide PT 21 Product-type 21 January 2016

dry treated surface Systemic 2.11E-02 8.2E-02 26% Acceptable exposure – toddler touching dry treated surface (refined)

An unacceptable risk is identified (from dermal and hand-to-mouth exposure, % of AEL is >100) for a toddler touching wet paint on the boat. However, the risk is acceptable for a toddler touching dry paint. Therefore, it is considered that this potential risk to children can be mitigated by suitable labelling of products containing copper flakes intended for non-professional use indicating that unprotected persons should be kept away from treated surfaces until they are dry. This measure to manage potential risks to children is proposed in the document of European Commission: “Antifouling (PT21),: way forward for the management of active substances and the authorisation of biocidal products”, adopted during the Competant Authorities meeting of March 2014.

Hempel’s Antifouling Olympic 86951

As the non professional use cannot be authorized (see above), this assessment is presented only for information.

Scenario Exposure AEL Exposure Risk mg Cu/kg/d mg % AEL Cu/kg/d Systemic 3.90 8.2E-02 4757 % Unacceptable exposure – toddler touching wet treated surface Systemic 4.91 E-01 8.2E-02 599% Unacceptable exposure – toddler touching dried treated surface Systemic 2.03 E-02 8.2E-02 25% Acceptable exposure – toddler touching dried treated surface (refinement)

27 Dicopper oxide PT 21 Product-type 21 January 2016

2.4.1.3.2.1 Secondary exposure via food contamination

It is stated in the last MOTA6 that “in specific cases for PT 21, where it can be demonstrated that there residues of the a.s. in fish and shellfish are not to be expected, even in cases of misuse, the monitoring method is not required. A specific justification has to be presented, together with the sound proof that there would be no residue also in cases of misuse“. As stated in the toxicological foreword, the case of copper is rather particular since this element is naturally present in the environment and also at stake and essential for many metabolic functions and reactions for both plants and animals. Copper is also used as fungicide in plants for phytopharmaceutical purposes and for veterinary purposes7. Copper is authorized as a feed additive under EU Reg. 479/20068 in nutrition of livestock including fish and shellfish (involved in PT21) with a maximum content in the complete feedingstuffs of 25 mg/kg for fish and 50 mg/kg for crustaceans. It is also present in many food supplements, according to Directive 2002/46/EC9. There is currently no harmonized methodology to assess the level in foodstuff of a substance involved in PT21. The most relevant methodology currently available to estimate level in fish and shellfish is based on a rough calculation with highest Predicted Environmental Concentration (PEC) calculated from the marine environment and the Bio Concentration Factor (BCF). Based on the particular case of copper (ionic form) and its properties (high solubility/dilution in sea water, complexation, low bio-accumulation, natural occurrence and physiological needs), at the state of the art, this approach is not deemed relevant. Indeed, because of the homeostasis of metals, BCF values are not indicative of the potential bioaccumulation. There is therefore limited evidence of accumulation and secondary poisoning of inorganic forms of metals. In addition, an in-depth literature search showed the absence of copper biomagnification across the trophic chain in the aquatic and terrestrial food chains. Differences in sensitivity among species were not related to the level in the trophic chain but to the capability of internal homeostasis and detoxification. Field evidence had further provided no indications of secondary poisoning.Hence no PECoral, predator was assessed for this product. Consequently an assessment of the risk to food consumers due to contamination of fish/shellfish is not deemed relevant in this case.

Additionally, copper is already significantly involved for phytopharmaceutical purposes under EU Reg. 396/2005 with rather significant rates (in the order of kg/ha/year) covered by MRLs under the EU regulation Reg. (EC) N°149/200810 (in the order of 2-

6 Manual of Technical Agreements of the Biocides Technical Meeting (MOTA) V.6 last version n°6 of 2013, p. 1-60 : http://echa.europa.eu/documents/10162/19680902/mota v6 en.pdf 7 The European Agency for the Evaluation of Medicinal Products (EMEA), Veterinary Medicines Evaluation Unit, EMEA/MRL/431/98-Final, May 1998, Committee for Veterinary Medicinal Products – Copper Chloride, Copper Gluconate, Copper Heptanoate, Copper Oxide, Copper Methionate, Copper Sulphate and Dicopper Oxyde – summary report, p.1-4 : http://www.ema.europa.eu/docs/en GB/document library/Maximum Residue Limits - Report/2009/11/WC500013010.pdf 8 COMMISSION REGULATION (EC) No 479/2006 of 23 March 2006 as regards the authorization of certain additives belonging to the group compounds of trace elements, OJ L 86 24/03/2006, p. 4-7 : http://eur-lex.europa.eu/legal- content/EN/TXT/PDF/?uri=CELEX:32006R0479&qid=1399886943661&from=EN 9 DIRECTIVE 2002/46/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 10 June 2002 on the approximation of the laws of the Member States relating to food supplements, OJ L 183, 12.7.2002, p. 1-16 http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02002L0046- 20111205&qid=1399993783567&from=EN

10 Commission Regulation (EC) No 149/2008 of 29 January 2008 amending Regulation (EC) No 396/2005 of the European Parliament and of the Council by establishing Annexes II, III and IV setting maximum residue levels for products covered by Annex I thereto (Text with EEA relevance), OJ L 58, 01/03/2008, p. 1–398 : http://eur-lex.europa.eu/legal- content/EN/TXT/PDF/?uri=CELEX:32008R0149&qid=1399895764828&from=EN

28 Dicopper oxide PT 21 Product-type 21 January 2016

1000 mg/kg). There is currently no EU MRL for fish and shellfish under this regulation or associated with veterinary purposes and consequently no risk of additive exposures which would induce MRLs to be revised accordingly.

An acceptable risk is identified for potential exposure via food contamination. This is based on available knowledge about the natural occurrence of copper, physiological needs, physico-chemical properties and regulations already in force. Exposure via food contamination may need to be reassessed when a uniform methodology to assess dietary exposure induced by an antifouling application is available.

2.4.1.3.2.2 Overall conclusion for human health

With regard to human health exposures and effects, safe use of dicopper oxide antifouling based product is identified if both professional and non-professional operators wear appropriate personal protective equipment.

Summary of environmental risk assessment

2.4.1.4 Fate and distribution in the environment

As a result of the unique fate of copper in water, soil, sediment and sludge, many of the data requirements listed in Section A7 of the Technical notes for Guidance are not applicable for inorganic compounds and metals; in particular e.g. hydrolysis, photodegradation and biodegradation. It is not applicable to discuss copper in terms of degradation half-lives or possible routes of degradation. Subsequently, dicopper oxyde, which is an inorganic salt, cannot be transformed into related degradation products other than copper ions (Cu2+) and water in solution. As with all metals, copper becomes complexed to organic and inorganic matter in waters, soil and sediments and this affects copper speciation, bioavailability and thus toxicity, which mainly depends of the abundance of the copper ion .

An important parameter determining the distribution of copper in the aquatic and soil environment is the adsorption onto solid materials and therefore partitioning coefficients. For an organic compound, solid-liquid/solution partitioning is related to its hydrophobic properties, as determined using octanol-water partitioning coefficient Kow and organic carbon partitioning coefficient Koc. Since metals do not have the hydrophobic or lipophilic characteristics of organic compounds, the concept of Kow and Koc is not applicable. The distribution of metals is not only controlled by pure adsorption/desorption mechanisms.

The distribution of metals between aqueous phase and soil/sediment/suspended matter should preferentially be described on the basis of measured soil/water, sediment/water and suspended matter/water equilibrium distribution coefficient (TECHNICAL GUIDANCE DOCUMENT on Risk Assessment Part II Appendix VIII, 2003; TECHNICAL GUIDANCE DOCUMENT Annex 4-VIII Environmental risk assessment for metals and metal compounds (RIP 3.2-2). From the literature overview, the following partitioning coefficients have thus been derived for Cu metal and Cu compounds:

Partition coefficient in freshwater suspended matter th - Kpsusp = 30,246 l/kg (log Kp (pm/w) = 4.48) (50 percentile) - (Heijerick et al, 2005) Partition coefficient in freshwater sediment - Kpsed = 24,409 l/kg (log Kp(sed/w) = 4.39) (50th percentile) - -(Heijerick et al., 2005) Partition coefficient in soil

29 Dicopper oxide PT 21 Product-type 21 January 2016

th - Kd = 2120 l/kg (log Kp = 3.33) (50 percentile) - (Sauvé et al. 2000)

Partition coefficient in marine suspended matter th - Kpsusp = 131826 l/kg (log Kp (pm/w) = 5.12) (50 percentile) - (Heijerick and van Sprang 2008) Partition coefficient in estuarine suspended matter th - Kpsusp = 56234 l/kg (log Kp (pm/w) = 4.45) (50 percentile) - (Heijerick and van Sprang 2008)

The 50th percentile value of the distribution function represents a typical suspended matter/sediment partition coefficient for EU waters and will be used for the derivation of local and typical regional PECs.

As all metals, copper becomes complexed to organic and inorganic matter in waters, soil and sediments and this affects copper speciation, bioavailability and toxicity.

Because of the homeostasis of metals, BCF values are not indicative of the potential bioaccumulation. There is therefore limited evidence of accumulation and secondary poisoning of inorganic forms of metals, and biomagnification in food webs.

2.4.1.5 Effects assessment on environmental organisms (active substance)

2.4.1.5.1 Aquatic compartment (including water, sediment and STP)

2.4.1.5.1.1 PNEC for aquatic organisms

Information on the mode of action of copper exposure indicated that the target tissue for copper toxicity were the water/organism interface with cell wall and gill-like surfaces acting as target biotic ligands in all species investigated.

 Freshwater pelagic compartment

For the freshwater pelagic compartment, 139 individual NOEC/EC10 values resulting in 27 different species-specific NOEC values, covering different trophic levels (fish, invertebrates and algae) were used for the PNEC derivation. The large intra-species variabilities in the reported single species NOECs were related to the influence of test media characteristics (e.g., pH, dissolved organic carbon, hardness) on the bioavailability and thus toxicity of copper. Species-specific NOECs were therefore calculated after normalizing the NOECs towards a series of realistic environmental conditions in Europe (typical EU scenario’s, with welldefinedpH, hardness and DOC). Such normalization was done by using chronic copper bioavailability models (Biotic Ligand Models), developed and validated for three taxonomic groups (fish, invertebrates and algae) and additional demonstration of the applicability of the models to a range of other species. The species- specific BLM-normalized NOECs were used for the derivation of log-normal Species Sensitivity Distributions (SSD) and HC5-50 values (the median fifth percentile of the SSD), using statistical extrapolation methods. The HC5-50 values of the typical EU scenarios ranged between 7.8 to 22.1 μg Cu/L. Additional BLM scenario calculations for a wide range of surface waters across Europe further demonstrated that the HC5-50 of 7.8 μg Cu/L, is protective for 90% of the EU surface waters and can thus be considered as a reasonable worst case for Europe in a generic context.

Copper threshold values were also derived for three high quality mesocosm studies, representing lentic and lotic systems. The mesocosm studies included the assessment of

30 Dicopper oxide PT 21 Product-type 21 January 2016 direct and indirect effects to large variety of taxonomic group and integrate potential effects from uptake from water as well as from food. BLM-calculated HC5-50 values (Assessment Factor (AF) = 1) were used as PNEC for the risk characterisation.

The AF = 1 has been chosen due to the uncertainty concerning 1) the mechanism of action; 2) the overall evaluation of the database; 3) the robustness of the HC5-50 values; 4) corrections for bioavailability (reducing uncertainty); 5) the sensitivity analysis with regards to DOC and read-across assumptions; 6) the factor of conservatism “built in into” the data and assessment (such as no acclimation of the test organisms and no pre equilibration of test media); 7) results from multi-species mesocosm studies ; 8) comparison with natural backgrounds and optimal concentration ranges for copper, an essential metal.

The choice of the AF of 1 has been challenged during the WG-IV 2015 and it was stated, with a slight majority of MSs, that the AF of 1 should be kept to derive the PNECwater. However, it was also concluded that the conditions for using an AF of 1 in general should be re-discussed in the frame of the revision of Vol. IV Part B of the guidance document. And therefore, this AF should be re-discussed at the renewal stage of the first copper substances (in PT8) in case the revision of the guidance or new data available show the need of a revised AF.

The HC5-50, with an AF=1, was used to derive a PNECfreshwater of 7.8 µg Cu/l for Europe in a generic context in absence of site-specific information on bioavailability parameters (pH, DOC, hardness).

 Marine compartment

For the marine PNEC derivation, 56 high-quality chronic NOEC/EC10 values, resulting in 24 different species-specific NOEC values covering different trophic levels (fish, invertebrates, algae), were retained for the PNEC derivation. NOEC values were related to the DOC concentrations of the marine test media. Species-specific NOECs were therefore calculated after DOC normalizing of the NOECs. These species-specific NOECs were used for the derivation of species sensitivity distributions (SSD) and HC5-50 values, using statistical extrapolation methods. Considering that the log-normal distribution had a poor data fit according to goodness of fit tests, HC5-50 values, obtained by using the best-fitting parametric distribution, were considered for the PNEC derivation. The organic carbon normalisation was carried out at a DOC level typical for harbours and marinas (2 mg/l), for surrounding waters (0.5 mg/l) and sea (0.2 mg/l) and resulted in an HC5-50 value of 5.2 µg Cu/L for harbours and marinas, 2.3 µg Cu/L for surrounding waters and 1.3 µg Cu/L for sea. Additionally a semi-parametric statistical analysis of the NOECs distribution was performed and a HC5-50 derived. Because the differences between the HC5-50 by either approach were similar, the HC5-50 derived by the parametric curve fitting (using the fit function that fitted best) was used. The evaluations of lower-quality NOECs and EC50s from single species and multi-species marine studies added weight to the HC5-50 value derived from the best-fitting distribution.

No reliable mesocosm or semi-field study was available for the marine compartment at the time of the final version of the effects assessments of copper and its compounds on the marine organisms of the EU-RAR (2008). This was underlined by the SCHER in its opinion in 2009. TC NES agreed that, considering the large amount of information available, the assessment factor used in the derivation of the PNEC (AF=2) could be reduced in future if the HC5-50 could be validated with reliable, representative and

31 Dicopper oxide PT 21 Product-type 21 January 2016 comprehensive mesocosm data (TC NES opinion 2008). The SCHER also “agreed with the logic of this approach” (Scher opinion 2009).

Therefore, the applicant has submitted a marine mesocosm which is of high quality. This study revealed a marine NOEC of 5.7 µg Cu/L which validates the HC5-50 of 5.2 µg Cu/L derived from the Q1 database.

However, this mesocosm study was not considered sufficient to lower the assessment factor, in the light of the higher variability of the marine ecosystem during the discussion at the WG IV-2015. Therefore, an assessment factor of 2 was still applied to the HC5-50 derived from the different marine environments.

The HC5-50 (AF=2) of 2.6 µg Cu/L for harbours and marinas, 1.15 µg Cu/L for surrounding waters and 0.65 µg Cu/L for sea was used as PNEC to the risk characterisation.

2.4.1.5.1.2 PNEC for STP micro-organisms

For the STP compartment, high-quality NOECs from respiration or nitrification inhibition studies, relevant to the functioning of a Sewage Treatment Plant (STP), resulted from biodegradation/removal studies and NOECs for ciliated protozoa were used to derive the PNEC for STP micro-organisms.

The lowest reliable observed NOEC value was noted for the inhibition of respiration (AF=1) of 0.23 mg/l expressed as dissolved copper and carried forward as PNEC to the risk characterisation.

2.4.1.5.1.3 PNEC for sediment

 Freshwater sediment

The sediment PNEC included using a weight of evidence approach considering different sources and tiered approaches of information: (1) sediment ecotoxicity data, (2) pelagic ecotoxicity data in combination with Kd values derived through different approaches, (3) soil ecotoxicity data and soil bioavailability models and (4) mesocosm/field ecotoxicity. High-quality chronic benthic NOECs for six benthic species, representing 62 NOEC values were retained for the PNEC derivation. NOEC values were related to sediment characteristics (e.g., Organic Carbon (OC) and Acid Volatile Sulphides (AVS)), influencing the bioavailability and thus toxicity of copper to benthic organisms. The derivation of the freshwater HC5-50sediment for copper was therefore based on the OC-normalized dataset, containing only low-AVS sediments. Using the log-normal species sensitivity distribution a freshwater HC5-50sediment of 1741 mg Cu/kg OC was derived through the statistical extrapolation method.

Using the equilibrium partitioning (EqP) approach, the derived HC5-50sediment (EP) values were comparable or higher than the HC5-50 derived from whole sediment tests. The comparison between the sensitivity of soil and benthic organisms added weight to the HC5-50 from whole sediment tests. The same did sediment threshold values and benthic NOECs that were obtained from four mesocosm studies and one field cohort study.

The AF of 1 has been chosen due to the uncertainty concerning 1) weight of evidence provided; 2) the overall quality of the database; 3) the robustness of the HC5-50 values;

32 Dicopper oxide PT 21 Product-type 21 January 2016

4) corrections for bioavailability (reducing uncertainty); 5) the conservative factor built into the system (no acclimation of the test organisms and only low AVS sediments retained); 6) validations from multi-species mesocosm studies and field studies and 7) comparison with natural backgrounds and optimal concentration ranges.

As for the PNECwater derivation, the choice of the AF of 1 has been challenged during the WG-IV 2015 and it was stated, that the AF of 1 should be kept to derive the PNECsediment. However, this AF should be re-discussed at the renewal stage of the first copper substances (in PT8) in case the revision of the guidance document or new data available show the need of a revised AF.

In case of natural sediments both the amount of AVS and organic carbon present in the sediment has dictated the observed effect levels for copper and were used for the risk characterisation. In absence of AVS data, a default AVS value of 0.77 μmol/kg dry weight was used. This value corresponded to the 10th percentile of the AVS obtained from a wide Flemish monitoring database and additional AVS data from other European countries.

The HC5-50, with an AF=1, was used to estimate a PNECsediment of 1741 mg Cu/kg OC, for Europe in a generic context. This corresponding to 87 mg Cu/kg dry weight for a sediment with 5 % O.C. (TGD default value).

 Marine compartment

As no reliable toxicity data are available for the marine sediment compartment, the PNECmarine sediment was calculated according to the equilibrium partitioning concept based th on a PNECwater using the 10 percentile of the Kd value for marine sediment according to the Guidance for environmental risk assessment for metals and metal compounds (Appendix R.7.13-2).

The PNECmarine sediment of 98.8 mg Cu/kg dw sediment (corresponding to 21.48 mg Cu/kg ww sediment) is carried forward to the risk characterization.

2.4.1.5.1.4 Terrestrial compartment

A high-quality dataset of 252 individual chronic NOEC/EC10 values from 28 different species and processes representing different trophic levels (i.e., decomposers, primary producers, primary consumers) has been retained for the PNEC derivation. The observed intra-species differences in toxicity data were related to differences in bioavailability, the latter related to differences in soil properties and to differences in ageing and application mode and rate. The soil property best explaining the variability in toxicity for most of the endpoints was the eCEC (effective Cation Exchange Capacity).

For the normalisation of the ecotoxicity data, the respective Cu background concentrations were added on all NOEC/EC10 values which were subsequently normalised to representative EU soils using the relevant regression (bio)availability models, generating so soil-type specific HC5-50 values. Species Sensitivity Distributions were constructed using the normalised NOEC/EC10 data. HC5-50 values from log-normal distributions ranging between 13.2 and 94.4 mg Cu/kg dry weight were obtained. A total of eight single species studies were available in which the toxicity of Cu to microorganisms, invertebrates and plants in field-contaminated aged soils was investigated for a wide range of European soil types (peaty, sandy, clay). A total of five multi-species studies were available, three of which studied the effects of copper in freshly spiked soils and 2 in field contaminated aged soils. Invertebrates, plants

33 Dicopper oxide PT 21 Product-type 21 January 2016 and micro-organisms were studied. Single species and multi-species field studies indicate that effects did not occur at an exposure level at the HC5-50-value. Normalized HC5-50 values (AF=1) were used as PNEC for the risk characterisation.

The uncertainty analysis that provides arguments for the AF=1 was based on: 1) the overall quality of the database and the end-points covered; 2) the diversity and representativeness of the taxonomic groups covered by the database; 3) corrections for differences in bioavailability (soil properties); 4) the statistical uncertainties around the 5th percentile estimate; 5) NOEC values below the HC5-50 and 6) field and mesocosm studies and comparisons of their results with the HC5-50. To account for the observed difference between lab-spiked soils and field-contaminated soils, a conservative leaching-ageing factor of 2 was agreed based on test data from the mechanistic research on ageing and ionic strength (leaching) effects.

For the PT21 biocidal product dossier, unlikely to the VRA, a leaching ageing “L/A” factor of 2 was not used to derive the PNECsoil but it was taken into account in the assessment of the PEC soil (PEC divided by 2).

As for the PNECwater derivation, the choice of the AF of 1 has been challenged during the WG-IV 2015 and it was stated, that the AF of 1 should be kept to derive the PNECsoil. However, this AF should be re-discussed at the renewal stage of the first copper substances (in PT8) in case the revision of the guidance document or new data available show the need of a revised AF.

The HC5-50, with an AF=1, was used to derive a PNECsoil of 45.6 mg Cu/kg dry weight for Europe in absence of site-specific information on soil properties.

2.4.1.5.1.5 Non compartment specific effects relevant to the food chain (secondary poisoning)

An in-depth literature search showed the absence of copper biomagnification across the trophic chain in the aquatic and terrestrial food chains. Differences in sensitivity among species were not related to the level in the trophic chain but to the capability of internal homeostasis and detoxification. Field evidence had further provided no indications of secondary poisoning.

2.4.1.5.1.6 Summary of PNEC values

Table 0-1: Summary of the selected PNEC values used for the risk characterisation

ENVIRONMENTAL COMPARTMENT PNEC Unit

PNECSTP 0.23 mg Cu/L

PNECsurface water 7.8 µg Cu/L

PNECmarine water - Harbour – Marinas 2.6 µg Cu/L - Surrounding waters 1.15 - Sea 0.65

PNECsediment freshwater 87 mg Cu/ kgdwt

34 Dicopper oxide PT 21 Product-type 21 January 2016

equivalent to 18.9 mg Cu/ kgwwt

98.8 mg Cu/ kgdwt PNECsediment marinewater equivalent to 21.48 mg Cu/ kgwwt 45.6 µg Cu/kgdwt PNECsoil Equivalent to 40.20 µg Cu/ kgwwt

2.4.1.6 Environmental effect assessment (product)

No data were provided for the representative product.

2.4.1.7 Environmental exposure assessment and risk characterisation

2.4.1.7.1 Environmental exposure

Biocides from antifouling paints enter the marine environment as a result of direct leaching from the paint while a treated vessel is in service. A second route of environmental exposure is associated with vessel maintenance and construction. The OECD ESD presents default scenarios for application, removal and in service phases of antifouling products (for commercial harbours, marina and shipping lanes when relevant). Therefore the two main situations identified in the ESD leading to potential emissions of biocides from antifouling paint applied on ship hulls to the environment are:

 New Building, Maintenance and Repair (M&R) of ships

During these phases, the antifouling paint is applied or removed. There are potential emissions of antifouling paint droplets, and thus biocide, to surface water, soil and STP (Sewage Treatment Plant). For these scenarios, the OECD ESD for PT21 distinguishes commercial vessels and pleasure crafts but also professional and non-professional users.

 Service-life of ships

During service-life, the antifouling paint leaches into water, preventing organisms to attach to the ship hulls. For this emission phase, the OECD ESD for PT21 distinguishes different environments of release: marinas, commercial harbours (and their adjacent areas) and shipping lanes (open sea).

The OECD ESD scenarios propose releases to the marine compartment only. In fact, direct emissions to the freshwater environment have not been assessed due to the lack of a harmonized scenario and should be considered during product assessment, if appropriate.

The antifouling products Intersmooth 360 SPC and Olympic 86951 used to support the approval of cuprous oxide is a paint applied by professional and non-professional users for the following field of uses: - professional applications on commercial, Navy and Government vessels, super-yachts and pleasure crafts; - non-professional applications on pleasure crafts only.

The exposure assessment for the different compartments of interest were conducted according to the equations of the Emission Scenario Document (ESD) for Antifouling Products (Product Type 21) in OECD’s countries (OECD, 2004), considering the amendments from European consultations and papers. Direct releases to the marine

35 Dicopper oxide PT 21 Product-type 21 January 2016 compartments were also covered by MAMPEC 2.5 modelling for their assessment (service-life phase) and refinement (new-building, maintenance and repair and cumulative assessment).

For every scenario, a ‘typical case’ (TC) and a ‘realistic worst case’ were defined. For the ‘typical case’, more realistic control measures preventing the releases to the environment are applied. The considered mitigation measures are different for each scenarios and detailed in the exposure assessment.

The following scenarios were developed to cover all the situations of exposure:

Table 0-2: Proposed scenarios for the exposure assessment

Boat type User Exposure Environment New Building –Application of paint Commercial Professional Direct exposure Aquatic compartment vessels (harbour) Pleasure crafts Professional Direct exposure Soil and STP (Sewage Treatment Plant) Indirect exposure Aquatic (freshwater and via the STP marina) and soil compartments Maintenance and repair – Removal of paint Commercial Professional Direct exposure Aquatic compartment vessels (harbour) Pleasure crafts Professional Direct exposure Aquatic (marina) and soil compartments, STP (Sewage Treatment Plant) Indirect exposure Aquatic (freshwater and via the STP marina) and soil compartments Pleasure crafts Non - Direct exposure Aquatic (marina) and soil professional compartments, STP (Sewage Treatment Plant) Indirect exposure Aquatic (freshwater and via the STP marina) and soil compartments Maintenance and repair – Application of paint Commercial Professional Direct exposure Aquatic compartment vessels (harbour) Pleasure crafts Professional Direct exposure Soil and STP (Sewage Treatment Plant) Indirect exposure Aquatic (freshwater and via the STP marina) and soil compartments Pleasure crafts Non - Direct exposure Soil and STP (Sewage professional Treatment Plant) Indirect exposure Aquatic (freshwater and via the STP marina) and soil compartments Service-life of ships All types - Direct exposure Marine aquatic compartment (harbour, marina, shipping lane)

36 Dicopper oxide PT 21 Product-type 21 January 2016

For each direct release scenario, the exposure assessment considering the ESD equations was based in Tier 1 on daily releases and on cumulated releases over the year at once. For the aquatic compartment, a Tier 2 using MAMPEC modelling was proposed for the cumulative assessment.

A cumulative assessment using MAMPEC was also conducted considering the potential simultaneous releases from the different phases of emissions to harbour and marina. The following situations have been considered: commercial shipping in harbour area : direct releases during New Building and M & R (daily emission from New Building as a worst case) + service-life, professional pleasure craft in marina: direct releases during M&R (Removal) + indirect releases during New Building (Application) + service-life, non professional pleasure craft in marina: during M&R (Removal) + indirect releases during M&R (Removal) + service- life.

Exposure assessment based on total Cu concentrations

The risk assessment was carried out on the basis of total concentrations of copper in the environment. The PEC values issued from the ESD equations, initially calculated as "added values" were corrected in order to integrate the background concentrations in copper. Concerning MAMPEC modelling, the concentrations were derived in integrating or not the background directly in the model. The worst case value was considered for the risk assessment (without the integration of the background for surface water and with the integration of the background for sediment). Total copper concentrations were calculated in taking into account of the regional copper background concentrations only (as agreed under the Council Regulation (EEC) 793/93 on Existing Substances - EU-RAR). These background concentrations are presented in the table below. For the risk assessment, total concentrations considering the regional backgrounds are always considered.

Table 0-3: Regional Background background concentratio Natural/ pristine concentration ns used for background Unit the exposure concentration assessmentC ompartment 1.1 (coastal waters, harbours, marinas) Marine surface [µg.L-1 ] water - 0.50 (open sea)

1 Marine - 16.1 [mg.kgdwt- ] sediment 3.5 [mg.kgwwt-1] Freshwater 0.88 2.9 [µg .L-1] 1 Freshwater 21 67.5 [mg .kgdwt- ] Sediment 4.56 14 .7 [mg.kgwwt-1] 12 24 .4 [ mg .kgdwt-1] Soil 10.6 21.6 [mg.kgwwt-1] Ground water 0.88 2.9 [µg.L-1]

37 Dicopper oxide PT 21 Product-type 21 January 2016

Leaching rate for in-service exposure

A specific leaching rate calculated with the CEPE method and based on the intended application rate was set to 44.00 µg/cm2/day for the product Intersmooth 360 SPC and 42.42 µg/cm2/day for the product Olympic 86951. Additional information on the leaching rate of copper in antifouling paints is available in the ESD for antifouling products (ESD PT21, 2004). A default value of 50 µg/cm2/day was determined by the CEPE Antifouling Working Group and can be used in the MAMPEC model. This value is based on literature data and an expertise available within the CEPE Antifouling Working Group (MAMPEC v1.4 main report, van Hattum et al. 2002, Report number E-02-04 / Z 3117). As the specific leaching rates for Intersmooth 360 SPC and Olympic 86951 were comparable to the default value from the literature, the generic leaching rate of 50 µg/cm2/d for copper was only used to evaluate the exposure from ship hull service-life as a worst case.

The leaching rate correction factor of 2.9 for vessels at berth was not applied for copper based paints.

2.4.1.7.2 Risk characterisation

2.4.1.7.2.1 Sewage treatment plant

The PEC values for copper and the corresponding PEC/PNEC ratios for the sewage treatment plant (STP) resulting from the use of Intersmooth 360 SPC product and Olympic 86951 product as antifouling are presented below for new building and maintenance & repair phases of pleasure crafts by professionals and non-professionals.

Table 0-4: INTERSMOOTH 360 SPC - PEC/PNEC ratios for the STP for Copper in Intersmooth 360 SPC on pleasure crafts by professionals and non-professionals

PEC (mg/L) PEC/PNEC

Exposure Scenario PNECmicro-organisms = 0.23 mg/L WC TC WC TC New building, pleasure craft, 3.67E-03 1.60E-02 professional M&R removal, pleasure craft, 2.81E- 2.81E- 1.22E- 1.22E-03 professional 03 04 02 M&R application, pleasure craft, 1.69E- 7.03E- 7.33E- 3.06E-03 professional 03 04 03 M&R removal, pleasure craft, non- 3.93E- 5.05E- 1.71E- 2.19E-03 professional 03 04 02 M&R application, pleasure craft, 1.40E-04 6.10E-04 non-professional WC: worst case / TC: typical case / M&R = Maintenance and repair

Table 0-5: OLYMPIC 86951 - PEC/PNEC ratios for the STP for Copper in Olympic 86951 on pleasure crafts by professionals and non-professionals

PEC (mg/L) PEC/PNEC

Exposure Scenario PNECmicro-organisms = 0.23 mg/L WC TC WC TC New building, pleasure craft, 3.78E-03 1.64E-02 professional M&R removal, pleasure craft, 2.89E-03 2.89E-04 1.26E-02 1.26E-03 professional M&R application, pleasure 1.74E-03 7.23E-04 7.55E-03 3.14E-03

38 Dicopper oxide PT 21 Product-type 21 January 2016

craft, professional M&R removal, pleasure craft, 4.04E-03 5.19E-04 1.76E-02 2.26E-03 non-professional M&R application, pleasure 1.44E-04 6.27E-04 craft, non-professional WC: worst case / TC: typical case / M&R = Maintenance and repair

These results indicate acceptable risks to the STP, with PEC/PNEC ratios < 1, during the application and removal of paint for pleasure crafts by professional and non-professional users, whatever the scenario applied (realistic worst case or typical case) for both products Intersmooth 360 SPC and Olympic 86951.

2.4.1.7.2.2 Aquatic compartment (including sediment)

Marine Compartment - Direct releases to the aquatic compartment

The PEC values for copper and the corresponding PEC/PNEC ratios for the marine aquatic environment (surface water and sediment) resulting from the use of Intersmooth 360 SPC product and Olympic 86951 product as antifouling are presented below for new building, maintenance & repair phases and service-life of commercial vessels and pleasure crafts, leading to direct releases to harbour and marinas. Tables below present the values for marine surface water in Tier 1 and Tier 2 (refined with MAMPEC when relevant) respectively.

39 Dicopper oxide PT 21 Product-type 21 January 2016

Table 0-6: INTERSMOOTH 360 SPC - PEC/PNEC ratios for marine surface water after direct releases to the environment - TIER 1 - Average dissolved concentrations considering the background (not integrated in the model for service-life)

Exposure Scenario PEC (µg/ L) PEC/ PNEC PNECmarinas, harbours = 2.6 µg/L PNECsurround ing waters = 1.15 µg/L PNECsea = 0.65 µg/L = Sh ipping lane scenario WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR {M8tR) SCENARIOS Commercial vessels - Harbour New building 1.82 1.25 0.70 0.48 Daily emission New building 2.54 1.41 0.98 0.54 Cu mulat ive emission M&R, Removal 1. 59 1.17 0.61 0.45 Da ily emission M&R, Removal 3.37 1.30 Cu mulative emission M&R, Application Daily 1.82 1.25 0.70 0.48 emission M&R, Application - 29.88 7.27 11.49 2.79 Cu mulative emission Pleasure crafts - Marina - Professionals M&R, Removal - Daily 1. 27 1.12 0.49 0.43 emission M&R, Removal - 32.14 4 .20 12.36 1.62 Cu mulative emission Pleasure crafts - Marina - Non-professionals M&R, Removal - Daily 1. 34 1.13 0.51 0.43 emission M&R, Removal - 22.66 3.87 8.71 1.49 Cu mulat ive emission

SERVICE LIFE SCENARIOS {Generic leaching rate of 50 µg/cm2 /day)

OECD Shipping Lane 0.50 0.77 OECD Commercial 1. 35 0.52 Harbou r Surroundings of OECD 1.11 0.96 Commercial Harbour OECD Marina 2.02 0.78 Surroundings of OECD 1.11 0.96 Marina WC : worst case I TC: typical case I M&R = Maintenance and repair

40 Dicopper oxide PT 21 Product-type 21 January 2016

Table 0-7: INTERSMOOTH 360 SPC - PEC/PNEC ratios for marine surface water after direct releases to the environment - TIER 2 - MAMPEC modelling for New building and Maintenance 8t Repair - Average dissolved concentration considering the background (not integrated in the model for service life)

Exposure Scenario PEC (µg/L) PEC/PNEC PNECmarinas, harbours = 2.6 µg/L PNECsurrou ndinq waters = 1.15 µg/L WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (M8tR) SCENARIOS MAMPEC Modelling Commercial vessels - Harbour 1.86 1.26 0.72 0.49 ( New building as a worst case) Commercial vessels - Surrounding area of Harbour 1.12 1.11 0.98 0.96 (New buildino as worst case) Professionals - Marina 1.11 1.10 0.43 0.42 (M&R Removal as worst case) Professionals - Surrounding area of Marina (M&R, Removal as 1.10 1.10 0.96 0.96 worst case) Non-professionals - Marina 1.11 1.10 0.43 0.42 (M&R, Removal as worst case) Non-professionals - Surrounding area of Marina (M&R, Removal as 1.10 1.10 0.96 0.96 worst case) WC : worst case I TC: typical case I M&R = Maintenance and repair

Table 0-8: OLYMPIC 86951 - PEC/PNEC ratios for marine surface water after direct releases to the environment - TIER 1 - Average dissolved concentrations considering the background (not integrated in the model for service-life)

41 Dicopper oxide PT 21 Product-type 21 January 2016

Exposure Scenario PEC (µg/L} PEC/PNEC M&R, Applicat ion - 22.15 5.61 8.52 2.16 Cumulat ive emission Pleasure crafts - Marina - Professionals M&R, Removal - Daily 1.27 1.12 0.49 0.43 em ission M&R, Removal - 33.04 4.29 12.71 1.65 Cumulative emission Pleasure crafts - Marina - Non-professionals M&R, Removal - Daily 1.34 1.13 0.52 0.44 emission M&R, Removal - 23.28 3.95 8.95 1.52 Cumulat ive emission

SERVICE LIFE SCENARIOS (Generic leaching rate of SO pg/cm2 /day}

OECD Shipping Lane 0.50 0.77 OECD Commercial 1. 35 0.52 Harbour Surroundings of OECD 1.11 0.96 Commercial Harbour OECD Marina 2.02 0.78 Surroundings of OECD 1.11 0.96 Marina WC: worst case I TC: typical case I M&R = Maintenance and repair

Table 0-9: OLYMPIC 86951 - PEC/PNEC ratios for marine surface water after direct releases to the environment - TIER 2 - MAMPEC modelling for New building and Maintenance St Repair - Average dissolved concentration considering the background (not integrated in the model for service life}

Exposure Scenario PEC (µg/L} PEC/PNEC PNECmarina, harbours = 5.2 µg/L PNECcoastal waters surroundinas of harbours and marinas= 2.3 µg/L WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (M&R} SCENARIOS MAMPEC Modelling Commercial vessels -Harbour 1.66 1.22 0.64 0.47 ( New buildino as a worst case) Commercial vessels - Surrounding area of Harbour 1.12 1.10 0.97 0.96 ( New buildina as worst case) Professionals - Ma rina 1.11 1.10 0.43 0.42 ( M&R, Removal as worst case) Professionals - Surrounding area of Marina (M&R, Removal as 1.10 1.10 0.96 0.96 worst case) Non-professionals - Marina 1.11 1.10 0.43 0.42 ( M&R, Removal as worst case) Non-professionals - Surrounding area of Marina (M&R, Removal as 1.10 1.10 0.96 0.96 worst case)

42 Dicopper oxide PT 21 Product-type 21 January 2016

WC: worst case I TC : typical case I M&R = Maintenance and repair

As presented in tables above, for both products Intersmooth 360 SPC and Olympic 86951, considering a one-day emission, the results indicate acceptable risks to the marine surface water, with PEC/PNEC ratios < 1, during the application and removal of paint for commercial vessels and pleasure crafts by professional a non- professional users, whatever the scenario applied (realistic worst case or typical case). The risks are also deemed acceptable for the service-life of ship hulls in considering a generic leaching rate for copper of 50 µg/cm2/day.

The Tier 1 cumulative assessments considering the releases over the year lead to unacceptable risks for the application and removal phases of M&R for commercial vessels and for the removal phase of M&R for pleasure crafts. Nevertheless, the Tier 1 approach seems to be unrealistic as it does not consider complex transport and exchange processes in marine environments. Therefore a Tier 2 approach based on MAMPEC modelling is proposed to refine the risk assessment for direct releases (Table 0-7) and shows acceptable risk for all the scenarios and for both products Int ersmooth 360 SPC and Olympic 86951.

Tables below contain values for marine sediment in Tier 1 and Tier 2 respectively.

Table 0-10: INTERSMOOTH 360 SPC - PEC/PNEC ratios for marine sediment after direct releases to the environment (TIER 1) - Concentration on suspended matter considering the background (integrated in the model for service-life)

43 Dicopper oxide PT 21 Product-type 21 January 2016

Exposure PEC (mg/kg wwt) PEC/PNEC Scenario M&R, Removal - 23.71 6.10 1.10 0.28 Daily emission M&R, Removal - Cumulative 1842.97 16.49 85.80 0.77 emission SERVICE LIFE SCENARIOS (Generic leaching rate of 50 µg/cm2 /day) OECD Shipping 8.67 0.40 Lane OECD Commercial 12.09 0.56 Harbour Surroundings of OECD Commercial 5.80 0.27 Harbour OECD Marina 31.96 1.49 Surroundings of 5.83 0.27 OECD Marina WC : worst case I TC: typical case I M&R = Maintenance and repair

Table 0-11: INTERSMOOTH 360 SPC - PEC/PNEC ratios for marine sediment after direct releases to the environment - TIER 2 - MAMPEC modelling for New building and Maintenance 8t Repair - Average concentration on suspended solids considering the background (integrated in the model)

Exposure Scenario PEC (mg/kg wwt) PEC/PNEC PNECmarine sediment = 21.48 mg/kg wwt WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (MStR} SCENARIOS MAMPEC Modelling Commercial vessels -Harbour 26.74 9.70 1.24 0.45 (New buildino as a worst case) Commercial vessels - Surrounding area of Harbour 6.28 5.74 0.29 0.27 (New building as worst case) Professionals - Ma rina 5.83 5.61 0.27 0.26 (M&R Removal as worst case) Professionals - Surrounding area of Marina (M&R, Removal as 5.61 5.61 0.26 0.26 worst case) Non-professionals - Marina 5.93 5.61 0.28 0.26 (M&R, Removal as worst case) Non-professionals - Surrounding area of Marina (M&R, Removal as 5.61 5.61 0.26 0.26 worst case) WC : worst case I TC: typical case I M&R = Maintenance and repair

Table 0-12: OLYMPIC 86951 - PEC/PNEC ratios for marine sediment after direct releases to the environment (TIER 1) - Concentration on suspended matter considering the background (integrated in the model for service-life)

44 Dicopper oxide PT 21 Product-type 21 January 2016

Exposure PEC (mg/kg wwt) PEC/PNEC Scenario PNECmarinesediment = 21.48 mg/ kg wwt WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (MltR} SCENARIOS Commercial vessels - Harbour New building 48.41 13.12 2.25 0.61 Daily emission New building Cumulat ive 93.33 22.75 4.34 1.06 emission M&R, Removal 34.30 7.97 1.60 0.37 Dailv emission M&R, Removal Cumulative 145.48 6.77 em ission M&R, Application 48.41 13.12 2.25 0.61 Daily emission M&R, Application - Cumulative 1800.08 388.48 83.80 18.09 emission Pleasure crafts - Marina - Professionals M&R, Removal - 18 .39 4.99 0.86 0.23 Daily emission M&R, Removal - Cumulat ive 2729.02 276.05 127.05 12.85 emission Pleasure crafts - Marina - Non-professionals M&R, Removal - 24.30 6.17 1.13 0.29 Daily emission M&R, Removal - Cumulative 1896.22 16.87 88.28 0.79 emission SERVICE LIFE SCENARIOS (Generic leaching rate of 50 µg/cm2 /day) OECD Sh ipping 8.67 0.40 La ne OECD Commercial 12.09 0.56 Harbour Surroundings of OECD Commercial 5.80 0.27 Harbour OECD Marina 31.96 1.49 Surroundings of 5.83 0.27 OECD Marina WC : worst case I TC: typical case I M&R = Maintenance and repair

Table 0-13: OLYMPIC 86951 - PEC/PNEC ratios for marine sediment after direct releases to the environment - TIER 2 - MAMPEC modelling for New building and Maintenance 8t Repair - Average concentration on suspended solids considering the background (integrated in the model)

45 Dicopper oxide PT 21 Product-type 21 January 2016

Exposure Scenario PEC (mg/ kg wwt) PEC/ PNEC PNECm arinesedi ment = 9.50 mg/ kg wwt WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (MltR) SCENARIOS MAMPEC Modelling Commercial vessels - Harbour 20.98 8.43 0.98 0.39 ( New building as a worst case) Commercial vessels - Surrounding area of Harbour 6.11 5.70 0.28 0.27 ( New buildino as worst case) Professionals - Marina 5.85 5.61 0.27 0.26 ( M&R, Removal as worst case) Professionals - Su rrounding area of Marina (M&R, Removal as 5.61 5.61 0.26 0.26 worst case) Non-professionals - Marina 5.96 5.63 0.28 0.26 ( M&R, Removal as worst case) Non-professionals - Surrounding area of Marina (M&R, Removal as 5.61 5.61 0.26 0.26 worst case) WC: worst case I TC : typical case I M&R = Maintenance and repair

As presented in the tables above, for New building and M&R of commercial vessels and pleasure crafts, risks to sediment are unacceptable considering cu mulative emissions in Tier 1, except for t he removal phase in typical case by non-professionals. Concerning t he service-life of ship hulls, t he risks are deemed except inside the marinas considering a generic leaching rate for copper of 50 µg/ cm 2/ day for both products.

The Tier 1 approach conducted for New building and M&R seems to be unrealistic as it does not consider com plex t ransport and exchange processes in marine environments. Therefore a Tier 2 approach based on MAMPEC modelling is proposed to refine the risk assessment for direct releases and shows acceptable risk for all the scenarios except inside commercial harbour for Intersmooth 360 SPC (realistic worst case).

Marine Comoartment - Indirect releases to the aquatic comoartment

The PEC values for copper and the corresponding PEC/ PNEC ratios for the marine aquatic environment (surface water and sediment) resulting from the use of Intersmooth 360 SPC product and Olympic 86951 product as antifouling are presented below for new building, maintenance & repair phases of pleasure crafts, leading to indirect releases to marinas via t he STP. Tables below present the values for marine surface water and for marine sediment for both products. As a worst case for the marine compartment, the PNEC for coastal waters and surroundings of marina has been considered instead of the PNEC for marina.

Table 0-14: INTERSMOOTH 360 SPC - PEC/ PNEC ratios for marine surface water after indirect re leases via the STP to the environment - Dissolved concentration considering the background

Exposure Scenario I PEC (µg/ L) IPEC/ PNEC PNECsurrou nding waters = 1.15 µg/ L lwc ITC lwc ITC NEW BUILDING - MAINTENANCE AND REPAIR (MltR) SCENARIOS Pleasure crafts - Professionals

46 Dicopper oxide PT 21 Product-type 21 January 2016

New building - Daily emission 1.11 0.97

M&R, Removal - Daily emission 1.11 1.10 0.96 0.96

M&R, Application - Daily emission 1.11 1.10 0.96 0.96 Pleasure crafts - Non-professionals

M&R, Removal - Daily emission 1.11 1.10 0.97 0.96

M&R, Application - Daily emission 1.10 0.96

WC : worst case I TC: typical case I M&R = Maintenance and repair

Table 0-15: OLYMPIC 86951 - PEC/PNEC ratios for marine surface water after indirect releases via the STP to the environment - Dissolved concentration considering the background

Exposure Scenario PEC (µg/L) PEC/PNEC PNE Csurrounding waters = 1.15 µg/L WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (MltR} SCENARIOS Pleasure crafts - Professionals

New building - Daily emission 1.11 0.97

M&R, Removal - Daily em ission 1.11 1.10 0.96 0.96

M&R, Application - Daily emission 1.11 1.10 0.96 0.96 Pleasure crafts - Non-professionals

M&R, Removal - Daily em ission 1.11 1.10 0.97 0.96

M&R, Application - Daily emission 1.10 0.96

WC : worst case I TC: typical case I M&R = Maintenance and repair

Table 0-16: INTERSMOOTH 360 SPC - PEC/PNEC ratios for marine sediment after indirect releases via the STP to the environment - Concentration on suspended matter considering the background

Exposure Scenario PEC (mg/kg wwt) PEC/PNEC PNECmarinesediment = 21.48 mg/kg wwt WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (MltR} SCENARIOS Pleasure crafts - Professionals

New building - Daily emission 3.85 0.18

M&R, Removal - Daily emission 3.77 3.53 0.18 0.16

M&R, Application - Daily emission 3.66 3.57 0.17 0.17 Pleasure crafts - Non-professionals

47 Dicopper oxide PT 21 Product-type 21 January 2016

M&R, Removal - Dai ly emission 3.88 13.55 0.18 10.17

M&R, Application - Daily emission 3 .51 0.16 WC : worst case I TC: typical case I M&R = Maintenance and repair

Table 0-17: OLYMPIC 86951 - PEC/PNEC ratios for marine sediment after indirect releases via the STP to the environment - Concentration on suspended matter considering the background

Exposure Scenario PEC (mg/kg wwt) PEC/PNEC PNECmarine sediment = 21.48 mg/kg wwt WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (MltR) SCENARIOS Pleasure crafts - Professionals New building - Daily emission 3 .86 0.18

M&R, Removal - Daily emission 3.78 3.53 0.18 0.16

M&R, Application - Daily emission 3.67 3.57 0.17 0 .17 Pleasure crafts - Non-professionals

M&R, Removal - Daily emission 3.89 3.55 0.18 0.17

M&R, Application - Daily emission 3.51 0.16 WC : worst case I TC: typical case I M&R = Maintenance and repair

These results indicate acceptable risks to the marine surface water and sediment for both products, with PEC/PNEC ratios < 1, during t he application and removal of paint for pleasure crafts by professional and non-professional users, whatever the scenario applied (realistic worst case or typical case), for indirect contamination of the environment via the STP.

Cumulatjye assessment for djrect apd jpdjrect releases to the commercial harbour and marina

The following situat ions have been considered for a cumulative assessment using MAM PEC modelling and considering each environment (harbour and marina) and each activity sector (professional and non- professional users) : commercial shipping in harbour area : direct releases during New Building and M & R (daily emission from New Building as a worst case) +service-life, professional pleasure craft in marina: direct releases during M&R (Removal) + indirect releases during New Bu ilding (Application) + service-life, non professional pleasure craft in marina: during M&R (Removal) + indirect releases during M&R (Removal) +service- life.

A generic leaching rate for copper of 50 µg/cm2/day for t he service-life of ship hulls was considered as a worst case for this cumulative assessment.

48 Dicopper oxide PT 21 Product-type 21 January 2016

Table 0-18: INTERSMOOTH 360 SPC - CUMULATIVE ASSESSMENT - PEC/ PNEC ratios for marine surface water after direct and indirect releases via the STP to the environment - Average dissolved concentrations considering the background (not integrated in the model)

Exposure Scenario PEC (µg/L) PEC/PNEC PNECmarinas, harbours = 2.6 µg/L PNECsurroundinn waters = 1.15 uq/L WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (M8tR} SCENARIOS MAMPEC Modelling

Commercial vessels -Harbour 2.11 1. 51 0.81 0.58

Commercial vessels Surrounding - 1.13 1.11 0.98 0.97 area of Harbour

Professionals - Marina 2.03 2.02 0.78 0.78

Professionals Surrounding area of - 1.11 1.11 0.96 0.96 Marina

Non-professionals - Marina 2.03 2.02 0.78 0.78

Non-professionals -Surrounding of 1.11 1.11 0.96 0.96 marina WC : worst case I TC: typical case I M&R = Maintenance and repair

Table 0-19: OLYMPIC 86951 - CUMULATIVE ASSESSMENT - PEC/PNEC ratios for marine surface water after direct and indirect releases via the STP to the environment - Average dissolved concentrations considering the background (not integrated in the model)

Exposure Scenario PEC (µg/L) PEC/PNEC PNECmarinas, harbours = 2.6 µg/L PNECsurroundina waters = 1.15 µg/L WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (M8tR} SCENARIOS MAMPEC Modelling

Commercial vessels -Harbour 1.91 1.47 0.73 0.56

Commercial vessels Surrounding - 1.13 1.11 0.98 0.97 area of Harbour

Professionals - Marina 2.03 2.02 0.78 0.78

Professionals Surrounding area of - 1.11 1.11 0.96 0.96 Marina

Non-professionals - Marina 2.03 2.02 0.78 0.78

Non- professionals -Surrounding of 1.11 1.11 0.96 0.96 marina WC : worst case I TC: typical case I M&R = Maintenance and repair

49 Dicopper oxide PT 21 Product-type 21 January 2016

Table 0-20: INTERSMOOTH 360 SPC - CUMULATIVE ASSESSMENT - PEC/ PNEC ratios for marine sediment after direct and indirect releases via the STP to the environment - Average concentrations on suspended solids considering the background (integrated in the model)

Exposure Scenario PEC (mg/kg wwt) PEC/PNEC PNE Cm arine sediment = 21.48 mg/ kq wwt WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (M•R) SCENARIOS MAMPEC Modelling

Commercial vessels -Harbour 33.91 16.85 1.58 0.78

Commercial vessels Surrounding - 6.52 5.96 0.30 0.28 area of Harbour

Professionals - Marina 32.17 31.96 1.50 1.49

Professionals - Surrounding area of 5.85 5.83 0.27 0.27 Marina

Non-professionals - Marina 32.39 31.96 1.51 1.49

Non-professionals -Surrounding of 5.85 5.83 0.27 0.27 marina WC : worst case I TC: typical case I M&R = Maintenance and repair

Table 0-21: OLYMPIC 86951 - CUMULATIVE ASSESSMENT - PEC/PNEC ratios for marine sediment after direct and indirect releases via the STP to the environment - Average concentrations on suspended solids considering the background (integrated in the model)

Exposure Scenario PEC (mg/kg wwt) PEC/PNEC PNECmarinesediment = 21.48 mg/ kg wwt WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (M•R) SCENARIOS MAMPEC Modelling

Commercial vessels -Harbour 28.04 15.59 1.31 0.73

Commercial vessels Surrounding - 6.33 5.93 0.29 0.28 area of Harbour

Professionals - Marina 32.17 31.96 1.50 1.49

Professionals - Surrounding area of 5.85 5.83 0.27 0.27 Marina

Non-professionals - Marina 32.39 31.96 1.51 1.49

Non- professionals -Surrounding of 5.85 5.83 0.27 0.27 marina WC : worst case I TC: typical case I M&R = Maintenance and repair

For both products, these results indicate acceptable risks t o the marine surface water, with PEC/ PNEC ratios < 1, for a cumulative assessment in harbours and marinas. For

so Dicopper oxide PT 21 Product-type 21 January 2016 marine sediment the risks are only acceptable for the surrounding areas of harbours and marinas, except for the commercial harbour in typical case. It worth noting that for marinas, the risk is led by t he service-life of ship hulls. I n this case, direct or indirect releases for new building or maintenance & repair consist in negligible emissions compared to service- life.

I t has to be hignlighted t hat this cumulative risk assessment is based upon the approach outlined in the "Transitional Guidance on mixture toxicity assessment for biocidal products for the environment" (May 2014).

Freshwater Compartment - Indirect releases to the aquatic compartment

The PEC values for copper and the corresponding PEC/PN EC ratios for the fresh aquatic environment (surface water and sediment) resulting from the use of Intersmooth 360 SPC product and Olympic 86951 product as antifouling are present ed below for new bu ilding, maintenance & repair phases of pleasure crafts, leading to indirect releases to marinas via the STP. Tables below present the values for freshwater water and for fresh sediment for both products.

Table 0-22: INTERSMOOTH 360 SPC - PEC/PNEC ratios for freshwater after indirect releases via the STP to the environment - Dissolved concentration considering the background

Exposure Scenario PEC (1Jg/L) PEC/PNEC PNECtreshwater= 7.8 µg/L WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (M•R) SCENARIOS Pleasure crafts - Professionals

New building - Daily emission 3.15 0.40

M&R, Removal - Daily emission 3.09 2.92 0.40 0.37

M&R, Application - Daily emission 3.02 2.95 0.39 0.38 Pleasure crafts - Non-professionals

M&R, Removal - Daily emission 3.17 2.93 0.41 0.38

M&R, Application - Daily emission 2.91 0.37

WC : worst case I TC: typical case I M&R = Maintenance and repair

Table 0-23: OLYMPIC 86951 - PEC/PNEC ratios for freshwater after indirect releases via the STP to the environment - Dissolved concentration considering the background

Exposure Scenario PEC (1Jg/L) PEC/PNEC PNECtreshwater= 7 .8 µg/L WC ITC WC ITC NEW BUILDING - MAINTENANCE AND REPAIR (M•R) SCENARIOS Pleasure crafts - Professionals

New building - Daily emission 3.16 0.41

51 Dicopper oxide PT 21 Product-type 21 January 2016

Exposure Scenario PEC (µg/L} PEC/PNEC

M&R, Removal - Daily emission 3.10 2.92 0.40 0.37

M&R, Application - Daily emission 3.02 2. 95 0.39 0.38 Pleasure crafts - Non-professionals

M&R, Removal - Daily emission 3.18 2.94 0.41 0.38

M&R, Application - Daily emission 2.91 0.37

WC : worst case/ TC: typical case I M&R = Maintenance and repair

Table 0-24: INTERSMOOTH 360 SPC - PEC/PNEC ratios for fresh sediment after indirect releases via the STP to the environment - Concentrations on suspended matter considering the background

Exposure Scenario PEC (mg/kg wwt} PEC/PNEC PNECfresh sediment = 18. 90 mg/kg wwt WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (M•R} SCENARIOS Pleasure crafts - Professionals

New building - Daily emission 16.36 0.87

M&R, Removal - Daily emission 15.97 14.83 0.85 0.78

M&R, Application - Daily emission 15.46 15.02 0.82 0.79

Pleasure crafts - Non-professionals

M&R, Removal - Dai ly emission 16.48 14 .93 0.87 0.79

M&R, Application - Daily emission 14.76 0.78

WC : worst case I TC: typical case I M&R = Maintenance and repair

Table 0-25: PEC/PNEC ratios for fresh sediment after indirect releases via the STP to the environment - Concentrations on suspended matter considering the background

Exposure Scenario PEC (mg/kg wwt} PEC/PNEC PNECtresh sediment = 18.90 mg/kg wwt WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (M•R} SCENARIOS Pleasure crafts - Professionals New building - Daily emission 16.41 0.87

M&R, Removal - Daily emission 16.01 14.83 0.85 0.78

M&R, Application - Daily emission 15.49 15.03 0.82 0.80

Pleasure crafts - Non-professionals

52 Dicopper oxide PT 21 Product-type 21 January 2016

M&R, Removal - Daily emission 16.53 I14.93 0.87 l o.79

M&R, Application - Da ily emission 14.77 0.78

WC: worst case I TC : typical case I M&R = Maintenance and repair

These results indicate acceptable risks to the freshwater and sediment, with PEC/PNEC ratios < 1, during the application and removal of paint for pleasure crafts by professional and non-professional users, whatever the scenario applied (realistic worst case or typical case), for indirect contamination of the environment via the STP for Intersmooth 360 SPC product and Olympic 86951 product.

2.4.1..7.2.3 Terrestrial compartment (including groundwater)

The proposed uses of copper oxide as antifouling are anticipated to result in direct and indirect (via the STP) exposure of the terrestrial environment (including groundwater) and hence the risk has been assessed for these compartments.

According to the applicants, it should be considered that the majority of the soil emissions are from old paint flakes and not soluble copper emissions directly to soil. It should be noted that, for amateur application and removal of paint, it is recommended that these activities should only be undertaken over a tarpaulin or similar impervious barrier in order to minimise paint loss to the soil. Once the task is completed (either amateur or professional), the remaining paint can be swept up and disposed of in accordance with local and national requirements. This would further ensure that the exposure of bioavailable copper in soil would be minimal. However, typical and worst case exposure values were calculated for the terrestrial compartment from the use of Intersmooth 360 SPC product and Olympic 86951 product and these are discussed below.

Direct releases to the terrestrial compartment

The PEC values for copper and the corresponding PEC/PNEC ratios for the terrestrial environment (soil and groundwater) resulting from the use of Intersmooth 360 SPC product and Olympic 86951 product as antifouling are presented below for new building, maintenance & repair phases of pleasure crafts, leading to direct releases to soil. Tables below present the values for soil and groundwater for both products.

Table 0-26: INTERSMOOTH 360 SPC - PEC/PNEC ratios for soil after direct releases to the environment - Concentrations considering the background

Exposure Scenario PEC (mg/kg wwt) PEC/PNEC

PN EC50;1 = 40.20 mg/kg wwt WC ITC WC ITC NEW BUILDING - MAINTENANCE AND REPAIR (MltR) SCENARIOS Pleasure crafts - Professionals New building Daily - 28.88 0.72 emission New building Cumulative - 458.13 11.40 emission M&R, Removal - Daily 25.06 121.95 0.62 1 o.55 emission

53 Dicopper oxide PT 21 Product-type 21 January 2016

Exposure Scenario PEC (mg/kg wwt) PEC/PNEC M&R, Removal - Cumulative 654.96 84.94 16.29 2.11 emission M&R, Application Daily - 23.68 22.47 0.59 0.56 emission M&R, Application - 401.62 179.94 9.99 4.48 Cu mulative emission Pleasure crafts - Non-Professionals M&R, Removal Daily - 29.37 22.60 0.73 0.56 emission M&R, Removal - Cumulative 60.46 26.60 1.50 0.66 emission M&R, Applicat ion Daily - 21.88 0.54 emission M&R, Application - 22.99 0.57 Cu mulative emission WC : worst case I TC: typical case I M&R = Maintenance and repair

Table 0-27: OLYMPIC 86951 - PEC/PNEC ratios for soil after direct releases to the environment - Concentrations considering the background

Exposure Scenario PEC (mg/kg wwt) PEC/PNEC PNECsoil = 40.20 mg/ kg wwt WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (M8tR) SCENARIOS Pleasure crafts - Professionals New bu ilding Daily - 29.09 0.72 emission New building Cumulative - 470.76 11.71 emission M&R, Removal Daily - 25.16 21.96 0.63 0.55 emission M&R, Removal - Cumulative 673.30 86.77 16.75 2.16 emission M&R, Applicat ion Daily - 23.74 22.49 0.59 0.56 emission M&R, Application - 412.62 184.52 10.26 4.59 Cu mulative emission Pleasure crafts - Non-Professionals M&R, Removal Daily - 29.60 22.63 0.74 0.56 emission M&R, Removal - Cumulative 61.59 26.74 1.53 0.67 emission M&R, Application Daily - 21.89 0.54 emission M&R, Application - 23.03 0.57 Cu mulative emission WC: worst case I TC: typical case I M&R = Maintenance and repair

Table 0-28: INTERSMOOTH 360 SPC - Risk assessment for groundwater after direct releases to the environment - Concentrations considering the background

54 Dicopper oxide PT 21 Product-type 21 January 2016

Exposure Scenario PEC (µg/L} Risk characterization Acceptable concentration according to the drinking water directive : 2000 µg/L WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (M8tR) SCENARIOS Pleasure crafts - Professionals New building Daily - 6.79 Acceptable emission New building Cumulat ive - 236.25 Acceptable emission M&R, Removal Daily - 4.75 3.09 Acceptable Acceptable emission M&R, Removal - Cumulat ive 34 1.47 36.76 Acceptable Acceptable emission M&R, Application Daily - 4.01 3.36 Acceptable Acceptable emission M&R, Application - 206.04 87.54 Acceptable Acceptable Cu mulat ive emission Pleasure crafts - Non-Professionals M&R, Removal Daily - 7.06 3.43 Acceptable Acceptable emission M&R, Removal - Cumulative 23.68 5.57 Acceptable Acceptable emission M&R, Application Daily - 3.05 Acceptable emission M&R, Application - 3.64 Acceptable Cu mulative emission WC : worst case I TC: typical case I M&R = Maintenance and repair

Table 0-29: OLYMPIC 86951 - Risk assessment for groundwater after direct releases to the environment - Concentrations considering the background

Exposure Scenario PEC (µg/L} Risk characterization Acceptable concentration according to the drinking water directive : 2000 µg/L WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (M8tR) SCENARIOS Pleasure crafts - Professionals New building Daily - 6.90 Acceptable em ission New building Cumulat ive - 243.00 Acceptable em ission M&R, Removal Daily - 4.80 3.09 Acceptable Acceptable emission M&R, Removal - Cumulat ive 351.27 37.74 Acceptable Acceptable em ission M&R, Application Daily - 4.04 3.38 Acceptable Acceptable emission M&R, Application - 211.92 89.99 Acceptable Acceptable Cumulative emission Pleasure crafts - Non-Professionals M&R, Removal Daily - 7.18 3.45 Acceptable Acceptable em ission

SS Dicopper oxide PT 21 Product-type 21 January 2016

M&R, Removal - Cumulative 24.28 15.65 Acceptable Acceptable emission I M&R, Application Daily - 3.05 Acceptable emission M&R, Application - 3.66 Acceptable Cumulative emission WC : worst case I TC : typical case I M&R = Ma intenance and repair

Results of the risk assessment are similar for both products. Considering a one-day emission, the results indicate acceptable risks to the terrestrial compartment, with PEC/PNEC ratios < 1, during the application and removal of paint for pleasure crafts by professional and non-professional users, whatever the scenario applied (realistic worst case or typical case). Nevertheless the risks are deemed unacceptable for professional users over the emission period when copper cumulate in soil after multiple applications. The risks are acceptable for non- professional users for a cumulative risk assessment over the emission period for the application phase of M&R and the removal (typica l case only). Concerning groundwater, all the scenarios lead to acceptable level of contamination for Intersmooth 360 SPC product and Olympic 86951 product.

La bels and/ or safety data sheets of product s authorised for professional uses shall indicate that application must be conducted on impermeable hard standing to prevent direct losses to soil and water and that any losses must be collected for disposal.

Indirect releases to the terrestrial compartment

The PEC values for copper and the corresponding PEC/PNEC ratios for the terrestrial environment (soil and groundwater) resulting from t he use of Intersmooth 360 SPC product and Olympic 86951 product as antifouling are presented below for new building, maintenance & repair phases of pleasure crafts, leading to indirect releases to soil via the spreading of STP sludge. Tables below present the values for soil and groundwater for both products. The concentrations in soil do not consider the ageing factor of 2.

Table 0-30: INTERSMOOTH 360 SPC - PEC/PNEC ratios for soil after indirect releases via the STP to the environment - Concentrations considering the background

Exposure Scenario PEC (mg/kg wwt) PEC/PNEC PNECsoil = 40.20 mg/kg wwt WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (M8tR) SCENARIOS Pleasure crafts - Professionals

New building - Daily emission 22.54 0.56

M&R, Removal - Daily emission 22.32 21.67 0.56 0.54

M&R, Application - Daily emission 22.03 21.78 0.55 0.54 Pleasure crafts - Non-professionals

M&R, Removal - Daily emission 22.61 21.73 0.56 0.54

M&R, Application - Daily emission 21.64 0.54

56 Dicopper oxide PT 21 Product-type 21 January 2016

WC : worst case I TC: typical case I M&R = Maintenance and repair

Table 0-31: OLYMPIC 86951 - PEC/PNEC ratios for soil after indirect releases via the STP to the environment - Concentrations considering the background

Exposure Scenario PEC (mg/kg wwt) PEC/PNEC PNECsoil = 40.20 mg/kg wwt WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (M8tR) SCENARIOS Pleasure crafts - Professionals

New building - Daily emission 22.57 0.56

M&R, Removal - Daily emission 22.34 21.67 0.56 0.54

M&R, Application - Daily emission 22.04 21.79 0.55 0.54 Pleasure crafts - Non-professionals

M&R, Removal - Daily emission 22.64 21.73 0.56 0.54

M&R, Application - Daily emission 21.64 0.54

WC : worst case I TC: typical case I M&R = Maintenance and repair

Table 0-32: INTERSMOOTH 360 SPC - Risk assessment for groundwater after direct releases to the environment - Concentrations considering the background

Exposure Scenario PEC (µg/L) Risk characterization Acceptable concentration according to the drinking wat er direct ive : 2000 µg/L WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (M8tR) SCENARIOS Pleasure crafts - Professionals New building - Daily emission 3.40 Acceptable

M&R, Removal - Daily emission 3.29 2.94 Acceptable Acceptable

M&R, Application - Daily emission 3.13 3.00 Acceptable Acceptable

Pleasure crafts - Non-professionals

M&R, Removal - Daily emission 3.29 2.94 Acceptable Acceptable

M&R, Application - Daily emission 2.92 Acceptable

WC : worst case I TC: typical case I M&R = Maintenance and repair

57 Dicopper oxide PT 21 Product-type 21 January 2016

Table 0-33: OLYMPIC 86951 - Risk assessment for groundwater after direct releases to the environment - Concentrations considering the background

Exposure Scenario PEC (µg/L) Risk characterization Acceptable concentration according to the drinking water directive : 2000 µg/L WC TC WC TC NEW BUILDING - MAINTENANCE AND REPAIR (M8tR} SCENARIOS Pleasure crafts - Professionals

New building - Daily emission 3.42 Acceptable

M&R, Removal - Daily emission 3.30 2.94 Acceptable Acceptable

M&R, Application - Daily emission 3.14 3.00 Acceptable Acceptable

Pleasure crafts - Non-professionals

M&R, Removal - Daily em ission 3.45 2.97 Acceptable Acceptable

M&R, Application - Daily emission 2.92 Acceptable

WC : worst case I TC: typical case I M&R = Maintenance and repair

These results indicate acceptable risks to soil and groundwater, during the application and removal of paint for pleasure crafts by professional and non-professional users, whatever t he scenario applied (realistic worst case or typica l case), for indirect contamination of the environment via the STP, for I ntersmooth 360 SPC product and Olympic 86951 product.

2.4.1..7.2.4 Non-compartmental specific effects relevant to the food chain (secondary poisoning)

An in-depth literature search showed the absence of copper biomagnification across the t rophic chain in the aquatic and terrestrial food chains. Differences in sensitivity among species were not related to t he level in the trophic chain but to the capability of internal homeostasis and detoxification. Field evidence had further provided no indicat ions of secondary poisoning.

2.4.1..7.2.5 Atmospheric compartment

Em ission to the air of copper in the I ntersmooth 360 SPC product may occur during the application and removal phases and through spray drift, HP water wash and abrasion and volatilization from paint during drying. However, cuprous oxideis an inorganic compound and as such has negligible volatility. Hence, the amount emitted to air is expected to be very low and no risk assessment is carried out for the atmosphere compartment.

2.4.1..7.2.6 Overall conclusion for the environment

The marine aquat ic compartment can be exposed directly or indirect ly (via the STP) to the product during the phases of application or removal of paint and directly during the service-life of ship hulls. The proposed scenarios led to acceptable risks for commercial vessels and pleasure crafts, when the wider marine environments were considered. In

58 Dicopper oxide PT 21 Product-type 21 January 2016 fact, the risks were not deemed acceptable for the sediment inside commercial harbours or marinas, but are acceptable for the whole aquatic compartment in the adjacent areas of the harbours and marinas. It was considered that the freshwater environment (including the sediment) can also be exposed indirectly via the STP only, during the pleasure crafts application or removal phases. Whatever the scenarios, the risks were considered acceptable for the STP and the freshwater environment. Direct emissions to the freshwater environment have not been assessed due to the lack of a harmonized scenario and should be considered during product assessment, if appropriate.

The terrestrial compartment (including groundwater) can be exposed directly or indirectly via the STP during the pleasure craft application or removal of paint by professionals or non-professionals. The risks for the soil and groundwater were considered acceptable for non-professional activities (leading to direct or indirect soil emission). On the other hand, the releases during application and removal of paint by professionals working on pleasure crafts led to unacceptable risks for soil when a direct exposure of the terrestrial compartment is foreseen. In this case the risk remained acceptable for groundwater or when releases were directed to a STP. Labels and/ or safety data sheets of products authorised for professional uses shall indicate that application must be conducted on impermeable hard standing to prevent direct losses to soil and water and that any losses must be collected for disposal.

The regional copper background concentrations were added to the calculated concentrations of copper issuing from cuprous oxide antifouling paint application, for all the environmental compartments. This has been done to cover all the other possible uses of copper in the calculation of the risk ratios, and in consequence in the assessment of the risk for environment.

2.5 Overall conclusions

The outcome of the assessment for cuprous oxide in product-type 21 is specified in the BPC opinion following discussions at the 13rd meeting of the Biocidal Products Committee (BPC). The BPC opinion is available from the ECHA web-site.

59 Dicopper oxide PT 21 Product - type 21 January 2016

Intersmooth 360 SPC SPC Hu man secondary Human primary exposure Aquatic compartment exposure Terrest r ial Gr oundwat Secondar SCENARIO No n STP compartme Air y Professiona Gener al Surface er professio na Wo r ker Sediment nt poisoning I pu blic wat er I APPLICATION Applicatio Com m e rd a n and Accepta Acceptable NR NR4 NR Acceptable1 Acceptable2 NR NR NR NR I vessel rem oval ble5 of oaint Direct releases: Pleasure Applicatio Non cr afts - n and Accepta 4 Acceptable NR NR Acceptable Acceptable1 Acceptable2 accept able Acceptable NR NR Profession r em oval ble5 I ndirect a ls of paint releases: acce otable Pleasure Applicat io crafts - Acceptable Acceptabl n and No n- only with ea Acceptable Acceptable1 Acceptable2 Acceptable Acceptable rem oval NR NR NR NR PPE6 Profession of paint als Shipping Service- Acceptable1 NR NR NR NR NR Acceptable1 NR NR NR NR lane life Commercia Service- Acceptable1 NR NR NR NR NR Acceptable2 NR NR NR NR I Harbour life Service- Acceptable1 Ma rina NR NR NR NR NR Acceptable2 NR NR NR NR life NR: not relevant 1 Acceptable with MAMPEC modelling 2 Acceptable with MAMPEC modelling, for surrounding areas only 3 Unacceptable but labels and where provided instructions for use shall indicate that children shall be kept away unt il t reated surface are dry. 4 To protect byst anders in the ship yard the area where painting is performed should be labelled with "Unprotected persons should be kept out of t reatment areas" 5Safe operational procedures and appropriate organizational measures shall be established. Where exposure cannot be reduced to an acceptable level by other means, products shall be used with appropriate personal protective equipment. 6The risk for non-professionals is acceptable only when gloves are worn.

60 Dicopper oxide PT 21 Product-type 21 January 2016

H empeI' s A n t"fI OU rm 01IVffiPIC 86951 secondary Human primary exposure Human Aquatic compartment exoosure Terrestrial Secondar SCENARIO STP compartme Groundwat Air y Professiona Non General Surface er professiona Worker Sediment nt poisoning I public water I APPLICATION Applicatio

Commercia n and Accepta 3 1 2 Acceptable NR 3 NR NR Acceptable Acceptable NR NR NR NR I vessel removal ble A of oaint Direct Applicatio releases: Pleasure Non crafts - n and Accepta 3 1 2 Acceptable NR 3 NR Acceptable Acceptable Acceptable accept able Acceptable NR NR Profession removal ble A of paint I ndirect als releases: acceotable Pleasure Applicatio - Unaccept crafts Acceptable Non- n and NR NR able6 Acceptable Acceptable1 Acceptable2 Acceptable Acceptable NR NR removal only with PPE5 Profession of paint als Shipping Service- Acceptable 1 Acceptable1 NR NR lane life NR NR NR NR NR NR NR 1 Commercia Service- NR NR NR NR NR Acceptable Acceptable2 NR NR NR NR I Harbour life Service- Acceptable 1 Marina NR NR NR NR NR Acceptable2 NR NR NR NR life NR: not relevant 1 Acceptable with MAMPEC modelling 2 Accept able w ith MAMPEC modelling, for surrounding areas only 3 To protect bystanders in the ship yard the area where painting is performed should be labelled with "Unprotected persons should be kept out of t reatment areas" 4 Safe operational procedures and appropriate organizational measures shall be established. Where exposure cannot be reduced to an acceptable level by other means, products shall be used with appropriate personal protective equipment. 5The risk for non-professionals is acceptable only when gloves are worn 6 Unacceptable but labels and where provided instructions for use shall indicate t hat children shall be kept away until treated surface are dry.

61 Dicopper oxide PT 21 Product-type 21 January 2016

2.6 Requirement for further information related to the product

Further data on products containing cuprous oxide shall be required as detailed below:

Intersmooth 360 SC:

- The stability at 0°C of the product, the surface tension of the pure product, the flash- point, a long term storage stability study (2 years) with the effect of light, a study to determine true residue level in container after use or a management of the packaging in a specialized processing dedicated circuit, a validated analytical method for the identification and determination of cuprous oxide in the product Intersmooth 360 and further data on specificity for the analytical method for the determination of zinc pyrithione in the product should be provided at the product authorization stage.

- With regard to human health assessment, following information should be provided: A dermal absorption study will be required at product authorisation stage to refine the risk assessment: Because of deficiencies in the available dermal absorption studies, new studies would be needed at product authorisation. However, at this point it would not be reasonable to require new dermal absorption studies before harmonised guidance for PT 21 dermal absorption studies is developed. It was agreed to set a provisional absorption value for each copper compound based on the products tested, and these values would only apply for active substance approval).

Hempel’s Antifouling Olympic 86951:

- The stability at 0°C of the product, the surface tension of the pure product, an accelerated storage stability study14 days at 54°C, a long term storage stability study (2 years) with the effect of light, a pourability test, the flash point (and if necessary the boiling point of the product) and a validated analytical method for the identification and determination of cuprous oxide in the product Olympic should be provided at the product authorization stage.

- With regard to physico-chemical properties, labelling of the product should indicate ‘shake well before use’.

62 Dicopper oxide PT 21 Product-type 21 January 2016

APPENDIX 1: LIST OF ENDPOINTS

Chapter 1: Identity, Physical and Chemical Properties, Details of Uses, Further Information, and Proposed Classification and Labelling

Active substance (ISO Common Name) Cuorous oxide Function (e.g. fungicide) Prevention of foulina bv settlina oraanisms.

Rapporteur Member State I France.

Identity (Annex IIA, point II.)

Chemical name (IUPAC) Coooer ( I) oxide Chemical name (CA) Cuorous oxide, dicoooer oxide CAS No 1317-39-1 EC No 215-270-7 Other substance No. CIPAC 8084 Minimum purity of the active substance 942g/ kg as cuprous oxide as manufactured (g/ kg or g/ I) 837g/ kg as cooper (I) Ident ity of relevant impurities and There are four relevant impurities: additives (substances of concern) in the Arsenic (max 0.009Sg/ kg) active substance as manufactured (g/ kg) Cadmium (max 0.04g/ kg) Lead ( max 1.2g/ kg) Nickel ( max 0.3a/ ka) Molecular formula Cu?O Molecular mass 143.09 a/ mol Structural formula Cu I Cu- 0

63 Dicopper oxide PT 21 Product-type 21 January 2016

Physical and chemical properties (Annex IIA, point III., unless otherwise indicated) Melting point (state purity) >346 °C Purity: 97% Boiling point (state purity) Not necessary as boiling point will occur at temperatures greater than 360 SPC°C based on the melting point Temperature of decomposition >346ºC Appearance (state purity) Easily compactable orange powder. Purity: 97% Relative density (state purity) 5.87 Purity: 97% Surface tension Not applicable due to the low water solubility of cuprous oxide (< 1mg/L) Vapour pressure (in Pa, state Not necessary as the melting point is above temperature) 300°C. Henry’s law constant (Pa m3 mol -1) Not relevant Solubility in water (g/l or mg/l, state pH 4.0: at least 28.6 g/L at 20°C temperature) pH 6.5 to 6.6: 0.639 mg/L at 20°C pH 9.7: < LOQ (0.539 mg/L) at 20°C Solubility in organic solvents (in g/l or Toluene <1.4 × 10-2 g/L mg/l, state temperature) (Annex IIIA, DCM <1.0 × 10-2 g/L point III.1) n-Hexane <1.2 × 10-2 g/L Ethyl acetate <1.2 × 10-2 g/L Methanol <9.8 × 10-3 g/L Acetone <1.3 × 10-2 g/L Stability in organic solvents used in Not required. The active substance as biocidal products including relevant manufactured does not include any organic breakdown products (IIIA, point III.2) solvents. If biocidal products (i.e. antifouling paints) are formulated with organic solvents, the compatibility between dicopper oxide and solvents and the stability of the products will be reported in the product dossier

Partition coefficient (log POW) (state Not relevant for the ecotoxicological risk temperature) assessement, due to the specific absorption mechanism of copper.

Hydrolytic stability (DT50) (state pH and pH______: temperature) (point VII.7.6.2.1) pH______: pH______: Not applicable for metal compounds. Dissociation constant (not stated in Not relevant, cuprous oxide oxide is slightly Annex IIA or IIIA; additional data soluble in water and the solubilisation results requirement from TNsG) of oxido-reduction reaction of the cuprous oxide into ionic copper. Any addition of acid would result in reaction with cuprous oxide UV/VIS absorption (max.) (if absorption Maximal absorption at : > 290 nm state  at wavelength) 260 nm (marginal) for neutral solution 206 nm for alkaline solution 225 nm for acidic solution

Photostability (DT50) (aqueous, sunlight, Not applicable. state pH) (point VII.7.6.2.2)

64 Dicopper oxide PT 21 Product-type 21 January 2016

Quantum yield of direct Not applicable. phototransformation in water at  > 290 nm (point VII.7.6.2.2) Flammability Not highly flammable Explosive properties Not explosive

65 Dicopper oxide PT 21 Product-type 21 January 2016

Summary of validated intended uses

Object Member Product Organisms Remarks: and/or State name controlled Applied amount per (m) Formulation Application situation or (c) treatment (a) Country Type Conc. method number interval g as/L water g (d-f) of as kind min max between min L/m2 min as/m2 (i) (f-h) (k) applications ma max min (min) x max Objects to EU Antifoulin Fouling Antifouli 42.56% Airless Minimum Reapplica Not Not Depends on Antifouling product 1 be g Product organisms ng w/w wet spray, one coat. tion applicabl applicable required should be regarded as a protected 1 – in marine paint. paint brush, Multiple times e film representative include see ans 37.5 % roller. coats may will thickness formulation for the hulls of confidenti freshwater w/w wet be applied depend purpose of supporting commercial, al environme paint to achieve on an application for naval and file nts required mainten cuprous oxide approval. other film ance government thickness schedule vessels, 42.56% dependent of pleasure w/w wet on in- treated craft and paint service vessels. man-made lifetime. structures and objects..

(a) e.g. biting and suckling insects, fungi, molds; (b) e.g. wettable powder (WP), emulsifiable concentrate (EC), granule (GR) (c) GCPF Codes - GIFAP Technical Monograph No 2, 1989 ISBN 3-8263-3152-4); (d) All abbreviations used must be explained (e) g/kg or g/l;(f) Method, e.g. high volume spraying, low volume spraying, spreading, dusting, drench; (g) Kind, e.g. overall, broadcast, aerial spraying, row, bait, crack and crevice equipment used must be indicated; (h) Indicate the minimum and maximum number of application possible under practical conditions of use; (i) Remarks may include: Extent of use/economic importance/restrictions

66 Dicopper oxide PT 21 Product-type 21 January 2016

Classification and proposed labelling (Annex IIA, point IX.)

with regard to physical/chemical data Not classified with regard to toxicological data Acute Tox 4 H302: Harmful if swallowed

Acute Tox 4 H332 Harmful if inhaled

Eye dam. 1 H318: Causes serious eye damage.

with regard to fate and behaviour data R53, May casue long-term adverse effects in the aquatic environment. with regard to ecotoxicological data R50, Very toxic to aquatic organisms

Chapter 2: Methods of Analysis

Analytical methods for the active substance Technical active substance (principle of Determination by conversion of the test method) (Annex IIA, point 4.1) substance batches with iron(III) chloride solution and potentiometric back-titration with cerium(IV) sulfate solution. The determined reducing power allows to obtained cuprous oxide content by calculation after the determination of copper metal content.

Analytical method is validated for Spiess Urania and Nordox. Further validation data would be required for American Chemet for the approval of the active substance Impurities in technical active substance Relevant trace metals can be determined by (principle of method) (Annex IIA, point HPLC –AES (Atomic Emission Spectroscopy), 4.1) ICP-AES (Inductively Coupled Plasma – Atomic Emission Spectroscopy) or by AAS, the samples are previously digested in dilute acid. Complete validation data are missing for Nordox and American Chemet and would be required for the approval of the active substance.

Validated analytical methods have been provided by Spiess Urania for the determination of other impurities. Analytical methods and validation data are missing for Nordox and American Chemet and would be required for the approval of the active substance

Analytical methods for residues

Soil (principle of method and LOQ) Residues of copper may be determined in (Annex IIA, point 4.2) soils using ICP-AES methods (e.g. AOAC official method 990.8). The estimated instrumental limit of determination (LOD) is

67 Dicopper oxide PT 21 Product-type 21 January 2016

6 µg Cu/l. Another suitable method is AAS (e.g. US EPA method 7210), with an LOD of 20 µg Cu/l. For both methods of analysis, the sample must first be digested. Air (principle of method and LOQ) Residues of copper may be determined in air (Annex IIA, point 4.2) using Flame-AAS or ICP-AES methods (e.g. NIOSH methods 7029 or 7300 respectively). The estimated instrumental limits of determination (LOD) are 0.05 and 0.07 µg Cu/filter (LOQ not determined). Water (principle of method and LOQ) In water, trace elements may be (Annex IIA, point 4.2) determined by Inductively Coupled Plasma – Atomic Emission Spectrometric (ICPAES) (e.g. US EPA method 220.7). The LOD for this method was estimated at 3 µg Cu/l and the LOQ was determined at 20 µg Cu/l. Other suitable methods include AAS with direct aspiration (LOD 20 µg/l, LOQ 200 µg/l) (e.g. US EPA method 220.1) and AAS with graphite furnace (LOD 1 µg/l, LOQ 5 µg/l) (e.g. US EPA method 220.2). For all three methods of analysis, the sample must first be digested. Sea water analysis can be performed by a voltammetry method such as Differential Pulse Anodic Stripping Voltammetry at a Hanging Mercury Drop Electrode (DPASV HMDE). The detection limit is dependant on the deposition time. For a typical 300 second deposition time, 0.1 µg/l is achievable. Body fluids and tissues (principle of ICP-AES may also be used for analysing method and LOQ) (Annex IIA, point 4.2) elements in body fluids and tissues following acid digestion of the sample. LOQs are 10 µg/100 g blood, 2 µg/g tissue (e.g. NIOSH method 8005) and 0.1 µ/sample of urine (NIOSH method 8310).

Nevertheless no analytical method is required as the active substance is not classified T or T+. Food/feed of plant origin (principle of Not applicable for antifouling applications method and LOQ for methods for monitoring purposes) (Annex IIIA, point IV.1) Food/feed of animal origin (principle of ICP-AES may be used for analyzing copper in method and LOQ for methods for fresh fish. LOQ is 2.5µg/g wet tissue (US EPA monitoring purposes) (Annex IIIA, point 200.11) IV.1)

68 Dicopper oxide PT 21 Product-type 21 January 2016

Chapter 3: Impact on Human Health

Absorption, distribution, metabolism and excretion in mammals (Annex IIA, point 6.2) Rate and extent of oral absorption: It was agreed during the TMIII08 that an oral absorption of 36% for humans and 25% for animals have to be used. Rate and extent of dermal absorption: By default, a dermal absorption of 5% has to be used for copper compound in solution.

For product, it has been agreed to set provisional absorption values of 0.14% for International paint product and 0.34% for Hempel product, based on the products tested. This value would only apply for active substance approval. Dermal absorption study of copper in formulated product should be provided at the product authorization level. Rate and extent of inhalative absorption: 100 % (default value) Distribution: Once absorbed by oral route, copper is bound to albumin and transcuprein and then rapidly transported to the liver where it is incorporated to ceruloplasmin, a transport protein that circulates in the organism and deliver the copper to other organs. The liver is the main organ involved in copper distribution and plays a crucial role in copper homeostasis by regulating its release. It should be however noted that a minor fraction of the absorbed dose can directly be distributed to peripheral organs. In both humans and animals, copper is tightly regulated at a cellular level, involving metallothionein and metallochaperones. These regulating molecules prevent from the accumulation of potentially toxic, free copper ions within the cell. In addition to the liver, the brain is another organ which contains relatively high concentrations of copper. Potential for accumulation: Mammals have metabolic mechanisms that maintain homeostasis (a balance between metabolic requirements and prevention against toxic accumulation). Because of this regulation of body copper, indices of copper status remain stable except under extreme dietary conditions. This stability was demonstrated in a study in which human volunteers received a diet containing total copper in the range 0.8 to 7.5 mg/d. Under these conditions, there were no significant changes in commonly used indices of copper status, including plasma copper, ceruloplasmin, erythrocyte superoxide dismutase and urinary copper. Rate and extent of excretion: Biliary excretion is quantitatively the most

69 Dicopper oxide PT 21 Product-type 21 January 2016

important route, with a mean copper excretion estimated to be in the order of 1.7 mg Cu/day (24.6  12.8 µg Cu/kg bodyweight). A small amount of copper is also lost in urine and in sweat. Excretion of endogenous copper is influenced by dietary copper intake. When the copper intake is low, turnover is slow and little endogenous copper is excreted and vice versa. Faecal copper losses reflect dietary copper intake with some delay as intake changes and copper balance is achieved. Urinary losses do not contribute to the regulation of copper stores and contribute very little to the overall balance. Toxicologically significant metabolite None

Acute toxicity (Annex IIA, point 6.1)

Rat LD50 oral 1340 mg/kg Rat LD50 dermal >2000 mg/kg Rat LC50 inhalation < 5 mg/l Skin irritation Negative; not classified as irritating to skin. Eye irritation Positive; classified as an eye irritant. Skin sensitization (test method used and Negative; not classified as a skin sensitiser. result)

Repeated dose toxicity (Annex IIA, point 6.3) Species/ target / critical effect The test substance used the following study was copper (II) sulphate.

Rat/ liver/ inflammation Rat/ kidney/ cytoplasmic droplets Rat, mouse/ forestomach/ minimal to moderate hyperplasia of the squamous mucosa Lowest relevant oral NOAEL / LOAEL 16.3 mgCu/mg kg/d Lowest relevant dermal NOAEL / LOAEL Not available Lowest relevant inhalation NOAEL / 0.2 mgCu/m3 LOAEL

Genotoxicity (Annex IIA, point 6.6) The test substance used in each of the following studies was copper (II) sulphate pentahydrate. 1. Ames test in Salmonella typhimurium - negative in both the presence and absence of S9 mix. 2. Bone marrow micronucleus study in the mouse – negative at a dose of 447 mg/kg bw. 3. In vivo/in vitro unscheduled DNA synthesis study in the livers of orally dosed male rats – negative, following treatment with doses of 632.5 or 2000 mg/kg bw. These studies demonstrate that copper is not mutagenic in the in vitro and in vivo test

70 Dicopper oxide PT 21 Product-type 21 January 2016

systems used.

Carcinogenicity (Annex IIA, point 6.4) Species/type of tumour Available studies of the carcinogenicity of copper compounds in rats and mice, although not fully reliable, have given no indication that copper salts are carcinogenic. lowest dose with tumours Not applicable.

Reproductive toxicity (Annex IIA, point 6.8) Species/ Reproduction target / critical The test substance used in the following effect study was copper (II) sulphate pentahydrate. Rat/Two-generation study/No evidence of effects on the fertility potential of either male or female rats. Lowest relevant reproductive NOAEL / Copper sulphate cannot be regarded as LOAEL having adverse effects on fertility in the animals tested. 1500 ppm NOAEL in rat two-generation study = 23.6-43.8 mgCu/kg bw/d (maximal dose tested) Species/Developmental target / critical Mouse/ Developmental toxicity/ effect malformations (study with major methodological deficiencies) Lowest relevant developmental NOAEL / 6 mg Cu/kg bw/d LOAEL (NOAEL maternal toxicity = 6 mg Cu/kg bw/d) However rat two-generation study with copper sulphate pentahydrate does not raise any particular teratogenic concern.

Neurotoxicity / Delayed neurotoxicity (Annex IIIA, point VI.1) Species/ target/critical effect Rat/ CNS/ locomotor activity, learning ability, relearning capacity and memory Lowest relevant developmental NOAEL / No adverse effects for these endpoints. LOAEL.

Other toxicological studies (Annex IIIA, VI/XI) None ......

Medical data (Annex IIA, point 6.9) Direct observation, eg clinical cases, Acute symptoms resulted in metallic taste, poisoning incidents if available; data salivation, epigastric pain, nausea, vomiting point 6.12.2. and diarrhoea. Anatomo-pathological examinations after self-poisoning (ingestion varying between 1 and 100 g of copper dissolved in water) revealed ulcerations of gastro-intestinal mucosa, hepatic damages (dilatation of central vein, cell necrosis and bile thrombi) and kidney lesions (congestion of glomeruli, swelling or necrosis of tubular cells and sometimes haemoglobin casts). Chronic symptoms, occurred in a voluntary intoxication by daily ingestion of 30 mg of

71 Dicopper oxide PT 21 Product-type 21 January 2016

copper for 2 years and 60 mg during the third year, were malaise, jaundice, hepatomegaly and splenomegaly. Liver examination revealed micronodular cirrhosis. In the particular case of vineyard sprayers intoxication by the Bordeaux mixture (unknown doses), lung lesions with focal distribution were observed: alveoli filled with desquamated macrophages, granuloma in the alveoli septa and fibro-hyaline nodules.

72 Dicopper oxide PT 21 Product-type 21 January 2016

Summary (Annex IIA, point 6.10) Value Study Safety factor ADI (if residues in food or feed) 0.15 Not mgCu/kg EFSA (2008) applicable. bw/day Acute-term AEL 0.082 mg/kg MOE ref = 90d in rats bw/d 50 Medium-term AEL 0.082 mg/kg MOE ref = 90d in rats bw/d 50 Long-term AEL 0.041 mg/kg MOE ref = 90d in rats bw/d 100 Drinking water limit Not applicable ARfD (acute reference dose) Not applicable

Acceptable exposure scenarios (including method of calculation) Professional users Acceptable, if professionals wear the following PPE/RPE: (most conservative PPE/RPE): Potman: impermeable coverall, gloves and mask APF 10 during mixing and loading phase,

Sprayer: impermeable coverall, gloves and mask APF 40 during application,

Worker who applies product by roller and brush: an equivalent Tyvek coverall and gloves during mixing and loading of paint into trail and brushing,

Sand blaster: protective protections equivalent to water-proof overalls, an airstream helmet with rubber flaps that covered a large part of their upper body, strong protective gloves and mask APF 10,

Grit filler: coated coverall, gloves and mask APF 40.

Non-professional users Unacceptable Indirect exposure as a result of use Acceptable under conditions mentioned below: Due to application by professionals, no quantitative risk was performed to assess exposure of bystander but the product should be labelled with the phrases “unprotected persons be kept out of treatment areas” Due to application by non professionals, labels and where provided instructions for use shall indicate that children shall be kept away until treated surface are dry. Concerning secondary exposure via food contamination, pending uniform methodology to assess dietary exposure induced by an antifouling treatment, available knowledge

73 Dicopper oxide PT 21 Product-type 21 January 2016

about the natural occurrence of copper, physiological needs, physico-chemical properties and regulations already in force constitute appreciable information to consider as negligible its influence on the consumer.

Chapter 4: Fate and Behaviour in the Environment Route and rate of degradation in water (Annex IIA, point 7.6, IIIA, point XII.2.1, 2.2)

Hydrolysis of active substance and pH______: Not applicable to metals. relevant metabolites (DT50) (state pH and temperature) pH______: pH______: Photolytic / photo-oxidative degradation Not applicable to metals. of active substance and resulting relevant metabolites Readily biodegradable (yes/no) No. Biodegradation in seawater Not applicable to metals. Non-extractable residues Not applicable to metals. Distribution in water / sediment systems The distribution of metals between (active substance) aqueous phase and soil/sediment/suspended matter should preferentially be described on the basis of measured soil/water, sediment/water and suspended matter/water equilibrium distribution coefficient (TECHNICAL GUIDANCE DOCUMENT on Risk Assessment Part II Appendix VIII, 2003; TECHNICAL GUIDANCE DOCUMENT Annex 4-VIII Environmental risk assessment for metals and metal compounds (RIP 3.2- 2). From the literature overview, the following partitioning coefficients have thus been derived for Cu metal and Cu compounds:

Partition coefficient in suspended matter Kpsusp = 30,246 l/kg (log Kp (pm/w) = 4.48) (50th percentile) (Heijerick et al, 2005)

Partition coefficient in sediment Kpsed = 24,409 l/kg (log Kp(sed/w) = 4.39) (50th percentile) (Heijerick et al., 2005)

Distribution in water / sediment systems Not applicable to metals. (metabolites)

Route and rate of degradation in soil (Annex IIIA, point VII.4, XII.1.1, XII.1.4; Annex VI, para. 85)

74 Dicopper oxide PT 21 Product-type 21 January 2016

Mineralization (aerobic) Not applicable to metals.

Laboratory studies (range or median, DT50lab (20C, aerobic): Not applicable to with number of measurements, with metals. regression coefficient)

DT90lab (20C, aerobic): Not applicable to metals.

DT50lab (10C, aerobic): Not applicable to metals.

DT50lab (20C, anaerobic): Not applicable to metals. degradation in the saturated zone: Not applicable to metals.

Field studies (state location, range or DT50f: Not applicable to metals. median with number of measurements)

DT90f: Not applicable to metals. Anaerobic degradation Not applicable to metals. Soil photolysis Not applicable to metals. Non-extractable residues Not applicable to metals. Relevant metabolites - name and/or Not applicable to metals. code, % of applied a.i. (range and maximum) Soil accumulation and plateau Although unable to degrade, the affect of concentration ageing on the distribution of copper in soil results in increased immobilisation by long term adsorption and complexation reactions in the soil.

Adsorption/desorption (Annex IIA, point XII.7.7; Annex IIIA, point XII.1.2) Ka , Kd The distribution of metals between aqueous Kaoc , Kdoc phase and soil/sediment/suspended matter pH dependence (yes / no) (if yes type of should preferentially be described on the dependence) basis of measured soil/water, sediment/water and suspended matter/water equilibrium distribution coefficient (TECHNICAL GUIDANCE DOCUMENT on Risk Assessment Part II Appendix VIII, 2003; TECHNICAL GUIDANCE DOCUMENT Annex 4- VIII Environmental risk assessment for metals and metal compounds (RIP 3.2-2).

From the literature overview, the following partitioning coefficients have thus been derived for Cu metal and Cu compounds:

Partition coefficient in soil th Kd = 2120 l/kg (log Kp = 3.33) (50 percentile) (Sauvé et al. 2000)

Fate and behaviour in air (Annex IIIA, point VII.3, VII.5) Direct photolysis in air Not applicable to metals. Quantum yield of direct photolysis Not applicable to metals.

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Photo-oxidative degradation in air Latitude: ...... Season:

...... DT50 ...... Not applicable to metals. Volatilization The potential for volatilisation of copper under environmentally relevant conditions is considered not to be significant.

Monitoring data, if available (Annex VI, para. 44) Soil (indicate location and type of study) No data available relating to the use of copper in antifouling paints.. Surface water (indicate location and type Two monitoring studies have been conducted of study) in the UK and Finland and have investigated the speciation of copper in the marine environment. The monitoring data of commercial harbours and estuaries in the UK (which did not show any elevated copper concentrations at these sites) also confirm the modelled output data from MAMPEC. The measured water results from marinas compare identically with the modelling data from MAMPEC with values within the marina and as with the modelled data, show that the average concentrations in the marina are within the normal background levels of copper in the marine environment. Samples, taken just outside the marina shows that the copper levels fall even further indicating that if increased copper levels are observed, they are a very localised effect to the actual marina itself. The results of the Finnish monitoring data showed that the boating activity and associated release of Cu2+ from the pleasure craft and no significant effect on the copper levels in the water when comparing the samples taken in the marina and those taken at the entrance and further downstream of the marina. Ground water (indicate location and type No data available relating to the use of of study) copper in antifouling paints. Air (indicate location and type of study) No data available relating to the use of copper in antifouling paints

76 Dicopper oxide PT 21 Product-type 21 January 2016

Chapter 5: Effects on Non-target Species

Toxicity data for aquatic species (most sensitive species of each group) (Annex IIA, Point 8.2, Annex IIIA, Point 10.2)

Acute toxicity to aquatic No acute toxicity data are presented as the toxicity organisms was evaluated using a SSD based on chronic toxicity data. Chronic toxicity to SSD result from 139 individual NOEC/EC10 aquatic organisms in the values: HC5-50 = 7.8 µg Cu / l as reasonable FRESHWATER COMPARTMENT worst case Freshwater algae and higher plants: Lowest NOEC used in the SSD = 15.7 µg Cu /L (growth of Pseudokirchneriella subcapitata) Highest NOEC used in the SSD = 510.2 µg Cu /L (growth of Chlorella vulgaris)

Freshwater Invertebrates: Lowest NOEC used in the SSD = 4 µg Cu /L (mortality and reproduction of Ceriodaphnia dubia) Highest NOEC used in the SSD = 181 µg Cu /L (reproduction of Daphnia magna)

Freshwater Fishes: Lowest NOEC used in the SSD = 2.2 µg Cu /L (growth of Oncorhynchus mykiss) Highest NOEC used in the SSD = 188 µg Cu /L (mortality of Perca fluviatilis)

Chronic toxicity to SSD result from 62 individual NOEC values: aquatic organisms in the HC5-50 = 1741 mg Cu/kg OC, corresponding to FRESHWATER SEDIMENT 87 mg Cu/kg dry weight for a sediment with 5 COMPARTMENT % O.C.(TGD default value) Sediment organisms: Lowest NOEC used in the SSD = 18.3 mg Cu /kg d.w. (growth and reproduction of Tubifex tubifex) Highest NOEC used in the SSD = 580.9 mg Cu /kg d.w. (survival of Tubifex tubifex )

Chronic toxicity to The lowest reliable observed NOEC value was Sewage microorganisms noted for the inhibition of respiration = 0.23 mg/l Chronic toxicity to SSD result from 56 individual NOEC/EC10 values: aquatic organisms in the  HC5-50 = 5.2 µg Cu / 2 for DOC level MARINE WATER typical for harbours and marinas (2 mg/L) COMPARTMENT  HC5-50 = 2.3 µg Cu / 2 for DOC level typical for surrounding waters (0.5 mg/L)  HC5-50 = 1.3 µg Cu / 2 for DOC level typical for sea (0.2 mg/L)

Marine water algae and higher plants: Non normalized lowest NOEC = 2.9 µg Cu /L (growth of Phaeodactylum tricornutum) Non normalized highest NOEC = 50.1 µg Cu /L (germination of Macrocystis pyrifera)

77 Dicopper oxide PT 21 Product-type 21 January 2016

Marine water Invertebrates: Non normalized lowest NOEC = 5.9 µg Cu /L (development of Mytilus galloprovincialis) Non normalized highest NOEC = 145 µg Cu /L (growth of Penaeus monodon)

Marine water Fishes: Non normalized lowest NOEC = 55 µg Cu /L (length and weight of Atherinops affinis) Non normalized highest NOEC = 123 µg Cu /L (hatchability and survival of Atherinops affinis)

Effects on earthworms or other soil non-target organisms

Acute toxicity to soil No acute toxicity data are presented as the toxicity organisms was evaluated using a SSD based on chronic (Annex IIIA, point XIII.3.2) toxicity data. Chronic toxicity to SSD result from 252 individual chronic soil organisms in the NOEC/EC10 values: HC5-50 = 45.6 mg Cu/kg TERRESTRIAL COMPARTMENT dry weight was used as reasonable worst case value for Europe in absence of site- specific information on soil properties.

Terrestrial higher plants: Lowest NOEC used in the SSD = 18 mg Cu /kg d.w. (Hordeum vulgare) Highest NOEC used in the SSD = 698 mg Cu /kg d.w. (Lycopersicon esculentum)

Terrestrial Invertebrates: Lowest NOEC used in the SSD = 8.4 mg Cu /kg d.w. (cocoon production of Eisenia andrei) Highest NOEC used in the SSD = 1460 mg Cu /kg d.w. (reproduction of Falsomia candida)

Soil micro-organisms: Lowest NOEC used in the SSD = 30 mg Cu /kg d.w. (glucose respiration) Highest NOEC used in the SSD = 2402 mg Cu /kg d.w. (maize respiration)

Effects on terrestrial vertebrates Acute toxicity to mammals Not applicable to active substances used in (Annex IIIA, point XIII.3.3) antifouling products Acute toxicity to birds Not applicable to active substances used in (Annex IIIA, point XIII.1.1) antifouling products Dietary toxicity to birds Not applicable to active substances used in (Annex IIIA, point XIII.1.2) antifouling products Reproductive toxicity to birds Not applicable to active substances used in (Annex IIIA, point XIII.1.3) antifouling products

78 Dicopper oxide PT 21 Product-type 21 January 2016

Effects on honeybees (Annex IIIA, point XIII.3.1) Acute oral toxicity Not applicable to active substances used in antifouling products Acute contact toxicity Not applicable to active substances used in antifouling products

Effects on other beneficial arthropods (Annex IIIA, point XIII.3.1) Acute oral toxicity Not applicable to active substances used in antifouling products Acute contact toxicity Not applicable to active substances used in antifouling products Not applicable to active substances used in Acute toxicity to antifouling products

Bioconcentration (Annex IIA, point 7.5) Bioconcentration factor (BCF) For the naturally occurring substances such as essential metals as copper, bioaccumulation is complex, and many processes are available to modulate both accumulation and potential toxic impact. Biota regulates their internal concentrations of essential metals through homeostatic control mechanisms (i.e. active regulation, storage). As a result of these processes, at low metal concentrations, organisms accumulate essential metals more actively in order to meet their metabolic requirements than when they are being exposed at higher metal concentrations. As a consequence of homeostatic processes, and unlike many organic substances, the BCF/BAF is not independent of exposure concentrations for metals and it is inversely related to exposure concentrations. Thus, the use of ratios Cbiota/Cwater or Cbiota/Csediments as an overall approach for estimating copper bioconcentration factors is thus not appropriate.

Depration time (DT50) Not applicable for metals. (DT90) Level of metabolites (%) in organisms Not applicable for metals. accounting for > 10 % of residues

Chapter 6: Other End Points None required

79 Dicopper oxide PT 21 Product-type 21 January 2016

APPENDIX 2: LIST(S) OF ABBREVATIONS

List of standard terms and abbreviations (adapted from: (i) Guidelines and criteria for the preparation of PPP dossiers11; (ii) TNsG on Data Requirements12).

Stand. Explanation Stand. Explanation Term/ Term/ abbreviation abbreviation A ampere Bt Bacillus thuringiensis ACh acetylcholine Bti Bacillus thuringiensis israelensis AChE acetylcholinesterase Btk Bacillus thuringiensis kurstaki ADI acceptable daily intake Btt Bacillus thuringiensis tenebrionis ADME administration distribution BUN blood urea nitrogen metabolism and excretion ADP adenosine diphosphate bw body weight AE acid equivalent c centi- (x 10 –2 ) AF assessment factor °C degrees Celsius (centigrade) AFID alkali flame-ionisation CA controlled atmosphere detector or detection A/G albumin/globulin ratio CAD computer aided design ai active ingredient CADDY computer aided dossier and data supply (an electronic dossier interchange and archiving format) ALT alanine aminotransferase cd candela (SGPT) Ann. Annex CDA controlled drop(let) application AEC acceptable concentration cDNA complementary DANN level AEL acceptable exposure level CEC cation exchange capacity AMD automatic multiple cf confer, compare to development AMD automatic multiple CFU colony forming units development ANOVA analysis of variance ChE cholinesterase AP alkaline phosphatase CI confidence interval approx approximate CL confidence limits ARfD acute reference dose cm centimetre as active substance CNS central nervous system AST aspartate aminotransferase COD chemical oxygen demand (SGOT) ASV air saturation value CPK creatinine phosphatase ATP adenosine triphosphate cv coefficient of variation BAF bioaccumulation factor Cv ceiling value BCF bioconcentration factor d day(s) bfa body fluid assay DCA Dichloroacetaldehyde BOD biological oxygen demand DDVP Dimethyl Dichloro Vinyl Phosphate bp boiling point DIS draft international standard (ISO) BPD Biocidal Products Directive DMSO dimethylsulfoxide BSAF biota-sediment accumulation DNA deoxyribonucleic acid factor BSP bromosulfophthalein dna designated national authority

11 EU (1998a): European Commission: Guidelines and criteria for the preparation of complete dossiers and of summary dossiers for the inclusion of active substances in Annex I of Directive 91/414/EC (Article 5.3 and 8,2). Document 1663/VI/94 Rev 8, 22 April 1998 12 European Chemicals Bureau, ECB (1996) Technical Guidance Documents in support of the Commission Directive 93/67/EEC on risk assessment for new notified substances and the Commission Regulation (EC) 1488/94 for existing substances

80 Dicopper oxide PT 21 Product-type 21 January 2016

Stand. Explanation Stand. Explanation Term/ Term/ abbreviation abbreviation DO dissolved oxygen FOB functional observation battery

DOC dissolved organic carbon foc organic carbon factor (compartment dependent) dpi days post inoculation fp freezing point DRP detailed review paper FPD flame photometric detector (OECD)

DT50(lab) period required for 50 FPLC fast protein liquid percent dissipation (under chromatography laboratory conditions) (define method of estimation)

DT90(field) period required for 90 g gram(s) percent dissipation (under field conditions) (define method of estimation) dw dry weight GC gas chromatography  decadic molar extinction GC-EC gas chromatography with coefficient electron capture detector

EC50 median effective GC-FID gas chromatography with concentration flame ionisation detector ECD electron capture detector GC-MS gas chromatography-mass spectrometry

ED50 median effective dose GC-MSD gas chromatography with mass-selective detection EINECS European inventory of GEP good experimental practice existing commercial substances ELINCS European list of notified GFP good field practice chemical substances ELISA enzyme linked GGT gamma glutamyl transferase immunosorbent assay e-mail electronic mail GI gastro-intestinal EMDI estimated maximum daily GIT gastro-intestinal tract intake EN European norm GL guideline level EPMA electron probe micro- GLC gas liquid chromatography analysis ERL extraneous residue limit GLP good laboratory practice ESPE46/51 evaluation system for GM geometric mean pesticides EUSES European Union system for GMO genetically modified organism the evaluation of substances F field GMM genetically modified micro- organism

F0 parental generation GPC gel-permeation chromatography

F1 filial generation, first GPMT guinea pig maximisation test

F2 filial generation, second GPS global positioning system FBS full base set GSH glutathione FELS fish early-life stage GV granulosevirus FIA fluorescence immuno-assay h hour(s) FID flame ionisation detector H Henry’s Law constant (calculated as a unitless value)

Fmol fractional equivalent of the ha hectare(s) metabolite´s molecular weight compared to the active substance

81 Dicopper oxide PT 21 Product-type 21 January 2016

Stand. Term/ Explanation Stand. Term/ Explanation abbreviation abbreviation Hb haemoglobin ISBN international standard book number HC5 concentration which will be ISSN international standard harmless to at least 95 % of the serial number species present with a given level of confidence (usually 95 %) HCG human chorionic gonadotropin IUCLID International Uniform Chemical Information Database Hct haematocrit iv intravenous HDT highest dose tested IVF in vitro fertilisation hL hectolitre k (in kilo combination) HEED high energy electron diffraction k rate constant for biodegradation HID helium ionisation detector K Kelvin HPAEC high performance anion Ka acid dissociation constant exchange chromatography HPLC high pressure liquid Kb base dissociation constant chromatography or high performance liquid chromatography

HPLC-MS high pressure liquid Kads adsorption constant chromatography - mass spectrometry

HPPLC high pressure planar liquid Kdes apparent desorption chromatography coefficient HPTLC high performance thin layer kg kilogram chromatography

HRGC high resolution gas KH Henry´s Law constant (in chromatography atmosphere per cubic metre per mole)

HS Shannon-Weaver index Koc organic carbon adsorption coefficient

Ht haematocrit Kom organic matter adsorption coefficient

HUSS human and use safety standard Kow octanol-water partition coefficient I indoor Kp solid-water partition coefficient

I50 inhibitory dose, 50% kPa kilopascal(s)

IC50 median immobilisation l, L litre concentration or median inhibitory concentration 1 ICM integrated crop management LAN local area network ID ionisation detector LASER light amplification by stimulated emission of radiation IEDI international estimated daily LBC loosely bound capacity intake

IGR insect growth regulator LC liquid chromatography im intramuscular LC-MS liquid chromatography- mass spectrometry inh inhalation LC50 lethal concentration, median INT 2-p-iodophenyl-3-p-nitrophenyl- LCA life cycle analysis 5-phenyltetrazoliumchloride testing method ip intraperitoneal LC-MS-MS liquid chromatography with tandem mass spectrometry

IPM integrated pest management LD50 lethal dose, median; dosis letalis media IR infrared LDH lactate dehydrogenase IRAC Insecticide resistance action ln natural logarithm committee

82 Dicopper oxide PT 21 Product-type 21 January 2016

Stand. Explanation Stand. Explanation Term/ Term/ abbreviation abbreviation LOAEC lowest observable adverse effect MLD minimum lethal dose concentration LOAEL lowest observable adverse effect level mm millimetre LOD limit of detection MMAD mass median aerodynamic diameter LOEC lowest observable effect concentration mo month(s) LOEL lowest observable effect level MOE margin of exposure log logarithm to the base 10 mol mole(s) LOQ limit of quantification (determination) mp melting point LPLC low pressure liquid chromatography MRE maximum residue expected LSC liquid scintillation counting or counter MRL maximum residue level or limit LSD least squared denominator multiple mRNA messenger ribonucleic acid range test LSS liquid scintillation spectrometry MS mass spectrometry LT lethal threshold MSDS material safety data sheet m metre MTD maximum tolerated dose M molar MT material test µm micrometre (micron) MW molecular weight MAC maximum allowable concentration n.a. not applicable MAK maximum allowable concentration n- normal (defining isomeric configuration) MC moisture content MT material test MCH mean corpuscular haemoglobin MW molecular weight MCHC mean corpuscular haemoglobin n.a. not applicable concentration MCV mean corpuscular volume n number of observations MDL method detection limit NAEL no adverse effect level MFO mixed function oxidase nd not detected

µg microgram NEDI national estimated daily intake mg milligram NEL no effect level

MHC moisture holding capacity NERL no effect residue level MIC minimum inhibitory concentration ng nanogram min minute(s) nm nanometre MKC minimum killing concentration NMR nuclear magnetic resonance mL millilitre no, n° number MLT median lethal time NOAEC no observed adverse effect concentration

Stand. Explanation Stand. Explanation Term/ Term/ abbreviation abbreviation NOAEL no observed adverse effect level PIC prior informed consent NOEC no observed effect concentration pic phage inhibitory capacity NOED no observed effect dose PIXE proton induced X-ray emission NOEL no observed effect level pKa negative logarithm (to the base 10) of the acid dissociation constant NOIS notice of intent to suspend pKb negative logarithm (to the base 10) of the base dissociation constant NPD nitrogen-phosphorus detector or PND post natal day detection NPV nuclear polyhedrosis virus PNEC predicted no effect concentration (compartment to be added as subscript) NR not reported po by mouth NTE neurotoxic target esterase POP persistent organic pollutants OC organic carbon content ppb parts per billion (10 -9 ) OCR optical character recognition PPE personal protective equipment ODP ozone-depleting potential ppm parts per million (10 -6 ) ODS ozone-depleting substances PPP plant protection product

83 Dicopper oxide PT 21 Product-type 21 January 2016

OH hydroxide ppq parts per quadrillion (10 -24 ) OJ Official Journal ppt parts per trillion (10 -12 ) OM organic matter content PSP phenolsulfophthalein OP Organophosphate PrT prothrombin time Pa pascal PRL practical residue limit PAD pulsed amperometric detection PT product type 2-PAM 2-pralidoxime PT(CEN) project team CEN pc paper chromatography PTT partial thromboplastin time PC personal computer QA quality assurance PCV haematocrit (packed corpuscular QAU quality assurance unit volume)

PEC predicted environmental concentration (Q)SAR quantitative structure- activity relationship

PECA predicted environmental concentration r correlation coefficient in air 2 PECS predicted environmental concentration r coefficient of determination in soil

PECSW predicted environmental concentration RA risk assessment in surface water

PECGW predicted environmental concentration RBC red blood cell in ground water PED plasma-emissions-detector REI restricted entry interval pH pH-value RENI Registry Nomenclature Information System PHED pesticide handler’s exposure data Rf retardation factor

84 Dicopper oxide PT 21 Product-type 21 January 2016

Stand. Explanation Stand. Explanation Term/ Term/ abbreviation abbreviation RfD reference dose SPE solid phase extraction RH relative humidity SPF specific pathogen free

RL50 median residual lifetime spp subspecies RNA ribonucleic acid SSD sulphur specific detector RP reversed phase SSMS spark source mass spectrometry rpm revolutions per minute STER smallest toxicity exposure ratio (TER) rRNA ribosomal ribonucleic acid STMR supervised trials median residue RRT relative retention time STP sewage treatment plant RSD relative standard deviation t tonne(s) (metric ton) s second t½ half-life (define method of estimation)

S solubility T3 tri-iodothyroxine

SAC strong adsorption capacity T4 thyroxine

SAP serum alkaline phosphatase T25 tumorigenic dose that causes tumours in 25 % of the test animals SAR structure/activity relationship TADI temporary acceptable daily intake SBLC shallow bed liquid TBC tightly bound capacity chromatography sc subcutaneous TCD thermal conductivity detector sce sister chromatid exchange TG technical guideline, technical group SCAS semi-continous activated sludge TGD Technical guidance document SCTER smallest chronic toxicity TID thermionic detector, alkali exposure ratio (TER) flame detector SD standard deviation TDR time domain reflectrometry se standard error TER toxicity exposure ratio

SEM standard error of the mean TERI toxicity exposure ratio for initial exposure

SEP standard evaluation procedure TERST toxicity exposure ratio following repeated exposure

SF safety factor TERLT toxicity exposure ratio following chronic exposure

SFC supercritical fluid tert tertiary (in a chemical chromatography name)

SFE supercritical fluid extraction TEP typical end-use product SIMS secondary ion mass TGGE temperature gradient gel spectroscopy electrophoresis S/L short term to long term ratio TIFF tag image file format SMEs small and medium sized TLC thin layer chromatography enterprises SOP standard operating procedures Tlm median tolerance limit sp species (only after a generic TLV threshold limit value name)

Stand. Term/ Explanation abbreviation TMDI theoretical maximum daily intake TMRC theoretical maximum residue contribution TMRL temporary maximum residue limit TNsG technical notes for guidance TOC total organic carbon Tremcard transport emergency card tRNA transfer ribonucleic acid TSH thyroid stimulating hormone

85 Dicopper oxide PT 21 Product-type 21 January 2016

(thyrotropin) TTC 2,3,5-triphenylterazoliumchloride testing method TWA time weighted average UDS unscheduled DNA synthesis UF uncertainty factor (safety factor) ULV ultra low volume UR unit risk UV ultraviolet UVC unknown or variable composition, complex reaction products UVCB undefined or variable composition, complex reaction products in biological material v/v volume ratio (volume per volume) vis visible WBC white blood cell wk week wt weight w/v weight per volume ww wet weight w/w weight per weight

XRFA X-ray fluorescence analysis yr year < less than  less than or equal to > greater than  greater than or equal to

86 Dicopper oxide PT 21 Product-type 21 January 2016

APPENDIX 3: LIST OF STUDIES

Reference list of st udies submitted and validated by Section number for the active substance:

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPANY) COMPANY, DATA OWNER Essential Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation ( Yes/ Nol Yes No A 3.1.1 O'Connor, B.J., Mullee, D.M. 2003 Nordox Copper Oxide : Determination of general physico-chemical properties. Yes Nord ox i:gJ SafePharm Laboratories. SPL Report No. 1515/003; GLP; Unpublished A 3.1.3 O'Connor, B.J., Mullee, D.M. 2003 Nordox Copper Oxide : Determination of general physico-chemical properties. Yes Nord ox i:gJ SafePharm Laboratories. SPL Report No. 1515/003; GLP; Unpublished A 3.3. 1 O'Connor, B.J., Mullee, D.M. 2003 Nordox Copper Oxide : Determination of general physico-chemical properties. Yes Nord ox i:gJ SafePharm Laboratories. SPL Report No. 1515/003; GLP; Unpublished A 3.3.2 O'Connor, B.J., Mullee, D.M. 2003 Nordox Copper Oxide: Determination of general physico-chemical properties. Yes Nord ox i:gJ SafePharm Laboratories. SPL Report No. 1515/003; GLP; Unpublished A 3.3.3 O'Connor, B.J., Mullee, D.M. 2003 Nordox Copper Oxide: Determination of general physico-chemical properties. Yes Nord ox 18:1 SafePharm Laboratories. SPL Report No. 1515/003; GLP; Unpublished A 3.4.1 Xu, L., Chen, X., Wu, Y., Chen, c., 2006 Solution-phase synthesis of single-crystal hollow Cu20 spheres with No Public 18:1 Li, W., Pan, W., Wang, Y. nanoholes. Nanotechnology 17; 1501- 1505; Not GLP; Published domain A 3.4.1 Messerschmidt, s. 2006 UV/VIS absorption spectrum of cuprous oxide; study code 20051363/01- Yes Nord ox i:gJ PCSD A 3.4.2 O'Connor, B.J., Mullee, D.M. 2003 Nordox Copper Oxide : Determination of general physico-chemical properties. Yes Nord ox i:gJ SafePharm Laboratories. SPL Report No. 1515/003; GLP; Unpublished A 3.5 O'Connor, B.J., Mullee, D.M. 2003 Nordox Copper Oxide: Determination of general physico-chemical properties. Yes Nord ox 18:1 SafePharm Laboratories. SPL Report No. 1515/003; GLP; Unpublished A 3.7 Messerschmidt, s. 2006 Solubility of Cuprous oxide in organic solvents; GAB Biotechnologie GmbH & Yes EU 18:1 GAB Analytik GmbH. Report No. 20051363/01-PSBO; GLP; Unpublished Antifouli ng Task Force A 3.7 O'Connor, B.J., Mullee, D.M. 2003 Nordox Copper Oxide : Determination of general physico-chemical properties. Yes Nord ox 18:1 SafePharm Laboratories. SPL Report No. 1515/003; GLP; Unpublished A 3.8 Messerschmidt, s. 2006 UV/VIS Absorption Spectrum of Cuprous oxide; GAB Biotechnologie GmbH & Yes EU ~ GAB Analytik GmbH. Report No. 20051363/01-PCSD; GLP; Unpublished Antifouli ng Task Force A 3.8 O'Connor, B.J., Mullee, D.M. 2003 Nordox Copper Oxide: Determination of general physico-chemical properties. Yes Nord ox ~ SafePharm Laboratories. SPL Report No. 1515/003; GLP; Unpublished A4.l Blossom, N. 2006 Copper {I ) oxide : Determination of Purity of Five Technical Batches. Yes America 18:1 American Chemet Corportation, Helena, USA Report No. 42406; April 2006; n GLP; Unpublished Chem et A4.1 Blossom, N. 2012 Copper {I ) oxide: Determination of Purity of Ten Technical Batches. American Yes America 18:1 Chemet Corportation, Helena, USA; February 2012; Not GLP; Unpublished n Chem et A4.l CIPAC - CIPAC method for total copper 44/TC/M/3.2. Volumetric thiosulphate No Public 18:1 method. CIPAC E, Pace 44. Not GLP, oublished. domain

8 7 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No A4.1 CIPAC - CIPAC method for total copper 44/TC/M/3.1. Electrolytic method (Referee No Public ~ method). CI PAC E, Paae 42. Not GLP, oublished. domain A4.1 Kiefer, R. 2004 Cuprous oxide: Determination of Purity of Five Technical Batches. GAB Yes Spiess- ~ Biotechnologie GmbH Report No.20021079/ 01-UCA; September 2004; GLP; Urania Unoublished A4.1 Kreuscher, T 2012 Cuprous oxide technical: Determination of Purity of Five Technical Batches. Yes Spiess- ~ Aurubis AG Report; February 2012; Not GLP; Unpublished Urania A4.1 O'Connor, B.J., Mullee, D.M. 2003 Copper I Oxide: Analytical method validation. SafePharm Laboratories. SPL Yes Nord ox ~ Reoort No. 1515/002· GLP· Unoublished A4.1 O'Connor, B.J., Mullee, D.M. 2003 Copper I Oxide: Analytical profile of batches. SafePharm Laboratories. SPL Yes Nord ox ~ Reoort No. 1515/001 · GLP· Unoublished A4.1 Stromberg, A 2012 5-batch Analysis - Qualitative and Quantitative Profile of the test substance Yes Nord ox ~ NORDOX Cuprous Oxide; Nordox AS Report; Not GLP; Unpublished A4.2 AOAC 1993 AOAC Official Method 990.08,. Metals in Solid Wastes; I nductively Coupled No Public ~ Plasma Atomic Emission Method. AOAC Official Methods of Ana lysis; Metals domain and Other Elements Chanter 9 oaae 31. Not GLP oublished. A4.2 EPA 1983 Methods for Chemical Analysis of Water and Wastes. Method 220.2 (Copper. No Public ~ Atomic Absorption, furnace technique). Wash ington, DC; U.S. Environmental domain Protection Aaencv. Not GLP oublished. A4.2 EPA 1983 Inductively Coupled Plasma - Atomic Emission Spectrometric Method for No Public ~ Trace Element Analysis of Water and Wastes -Method 200.7. Washington, domain DC· U.S. Environmental Protection Aaencv. Not GLP oublished. A4.2 EPA 1986 Test Methods for Evaluating Solid Waste, Physical/Chemical Methods (SW- No Public ~ 846). Method 7210 (Copper. Atomic Absorpt ion, direct aspiration) . domain Washington, DC; U.S. Environmental Protection Agency. Not GLP, published. And appended : EPA, 1986. Test Methods for Evaluating Solid Waste, Physical/Chemical Methods (SW-846). Method 3050B (Acid digestion of sediments, sludges and soils). Washington, DC; U.S. Environmental Protection Aaencv. (published). A4.2 EPA 1986 Methods for Chemical Analysis of Water and Wastes. Method 220.1 (Copper. No Public ~ Atomic Absorption, direct aspiration). Washington, DC; U.S. Environmental domain Protection Aaencv. Not GLP, published. A4.2 NI OSH 1987 Method 8005. NIOSH Manual of Analytical Methods, Fourth Edition, 8/ 15/94. No Public ~ Not GLP, oublished. domain A4.2 NI OSH 1987 Method 8310. NIOSH Manual of Analytical Methods, Fourth Edition, 8/ 15/ 94. No Public ~ Not GLP, published. domain A4.2 NI OSH N/A Method 7029. NIOSH Manual of Analytical Methods, Fourth Edition, 8/ 15/ 94. No Public ~ No GLP, oublished. domain A 4.3 Martin TD, Martin ER, Lobring LB 1991 US EPA Method 200.11, Revision 2.1. Determination of Metals in Fish Tissue No Public ~ and McKee GD. by Inductively Coupled Plasma-Atomic Emission Spectrometry. EPN600/ 4- domain 91-010, nn 177-209; Not GLP; Published A 6.1.1 1984a OECD Acute Oral Toxicity Test: Determination of the Acute Oral Medial Lethal Yes Nord ox ~ Dose (LOSO) of Cuprous Oxide in the Rat. Reoort No. 296/8404 A 6.1.1 Hixson, O.F. 1973 Determination of the Oral Toxicity and Skin Irritat ion Potential of Purple Copp Yes America ~ 97. Rosner Hixson Laboratories. Laboratory No. PT73-40. 27 March 1973 n lunoublishedl. Chem et

88 Dicopper oxide PT 21 Product-type 21 January 2016

T NG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for stu dies for CLAIMED evaluat ion evaluation (Yes/ No l Yes No A 6.1.1 1991a Purple Copp 97N Cuprous Oxide: Acute Oral LOSO in Rats. Yes America ~ Report No. 91048- 2 n Chemet A 6. 1.2 Kukulinski, M. 1976 Acute Dermal Toxicity/ Eye Irritation. Rosner, Hixson Laborat ories. Report Yes America ~ No. PT76-298 n Chemet A 6.1.2 1991b Purple Copp 97N Cuprous Oxide: Acute Dermal Toxicity in Rabbits. Yes America ~ Report No. 91048-1 n Chemet A 6. 1.2 1988 Akute Derma le Toxizitat an Ratten m it. Yes Spiess- ~ Reoort No. 1-4-1602-BB Urania A 6. 1.3 1988a Acute Toxicological Study of Kupfer-1-0xid After I nhalation by the Rat. Yes Spiess- ~ Report No. 1-4-40-88-- Urania A 6.1.3 1991 Acute Inhalation Toxicit y in the Rat Single Level Limit Test Purple Copp Yes America ~ 97N Cuprous Oxide. -· Study No. n 131.003 Chemet A 6.1.3 1985 Cuprous Oxide, Acute Inhalation Toxicity Study in Rats (Lim it Test). Yes Nord ox ~ Reoort No. 3401 A 6.1.3 1985 Cuprous Oxide, Acute I nhalation Toxicity Study in Rats. Yes Bardyke ~ Reoort No. 3398; GLP; Unoublished A 6.1.3 1973 Purple Copp 97: Acute Inhalation Toxicity in Rats. Yes America ~ Report No. PT73-40A n Chemet A 6. 1.4 1984b OECD Skin Irritation Test: Determination of the Degree of Pr--imary Cutaneous Yes Nord ox ~ Irritation Caused by Cuprous Oxide in the Rabbit. Reoort No. 237/8404 A 6.1.4 1984c OECD Eye Irritation Test: Determination of the Degree of Ocular Irritation Yes Nord ox ~ Caused by Cuprous Oxide in the Rabbit. Report No. 105/8404 A 6. 1.4 1988b Irritant Effects of Kupfer-1-0xid on Rabbit Skin Acc. To Draize. Yes Spiess- ~ Reoort No. 1-3-42-88 Urania A 6. 1.4 Dickhaus, s. & Heisler, E. 1988c Eye Irritation Test with Kupfer-I -Oxide Acc. To Draize and OECD Guidelines Yes Spiess- ~ No. 405. Beratung und Forschung GmbH. Report No. 1- 3-4 1-88. Urania A 6.1.4 Hixson, O.F. 1973 To Determine the Oral Toxicity and Skin Irritation Potential for Purple Copp Yes America ~ 97. Rosner Hixson Laboratories. La boratory No. PT73-40. 27 March 1973 n lunoublished). Chemet A 6. 1.4 1994 Primary Eye Irritation Study in Rabbits. Report No. 0634- Yes America ~ 93 n Chemet A 6.1.4 Kukulinski, M. 1980 Low Tint Purple Copp 97N: Eye I rritation. Rosner, Hixson Laborat ories. Yes America ~ Report No. TM 80-373 n Chemet A 6. 1.4 Kukulinski, M. 1976 Acute Dermal Toxicity and Eye Irritation. Rosner, Hixson Laboratories. Yes America ~ Report No. PT76-298 n Chemet A 6.1.5 1993 Guinea Pig Maximisat ion Test of Skin Sensitisation with 'URA 17030'. Yes Spiess- ~ - Report No. 10-05-1961/00-92 Urania

89 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No A 6.1.5 1986 Dermal Sensitization Study in Guinea Pigs with Purple Copp 97N Cuprous Yes America 18] Oxide. Study No. 480-2833 n Chem et A 6.12.2 Chuttani HK, Gupta PS, Gulati S, 1965 Acute Copper Sulfate Poisoning. Am J Med, 39: 849-854; Not GLP; published No Public 18] Gupta DN. domain A 6.12.2 O'Donohue JW, Reid MA, Varghese 1993 Micronodular cirrhosis and acute liver failure due to chronic copper self- No Public 18] A, Partmann B, Williams R intoxication. Eur. J. Gastroenterol. 5:561- 562; Not GLP; published domain

A 6.12.2 O'Connor, J.M., Bonham, M.P., 2003 Copper supplementation has no effect on markers of DNA damage and liver No Public ~ Turley, E., McKeown, A., function in healthy adults (FOODCUE Project). Ann Nutr Metab, 47: 201- domain McKelvey-Martin, V.J., Gilmore, 206. Not GLP, Published w.s. and Strain, J.J. A 6.12.2 Pimentel JC, Marques F 1969 Vineyard sprayer's lung - A new occupational disease. Thorax, 24, 678-688; No Public 18] Not GLP; oublished domain A 6.12.2 Pimentel JC, Menezes AP. 1977 Liver disease in vineyard sprayers. Gastroenterology 72:275-283; Not GLP; No Public 18] published domain A 6.12.2 Pimentel JC, Menezes AP. 1975 Liver granulomas containing copper in vineyard sprayer's lung - A new No Public ~ Etiology of Hepatic Granulomatosis. Am. Rev. Respir. Dis. 111:189-195; Not domain GLP; published A 6.12.2 Pratt, W.B., Omdahl, J.L. and 1985 Lack of Effects of Copper Gluconate Supplementat ion. The American Journal No Public ~ Sorenson, R.J ., of Clinical Nutrition, 42: 681 - 682. Not GLP, Published domain A 6.12.2 Rock, E., Mazur, A., O'Connor, 2000 The Effect of Copper Supplementation on Red Blood Cell Oxidizability and No Public 18] J.M., Bonham, M.P., Rayssiguier, Plasma Antioxidants in Middle-Aged Healthy Volunteers. Free Radical Biology domain Y. & Strain, J .J and Medicine. 28 (3); 324-329. Not GLP, Published

A 6.12.2 Tanner MS, Partmann B, Mowat 1979 Increased hepatic copper concentration in Indian Childhood Cirrhosis. Lancet No Public 18] AP, Williams R, Pandit AN, Mills 1:1203- 5; Not GLP; published domain CF, Bremner I. A 6.12.2 Turley, E., McKeown, A., Bonham, 2000 Copper supplementation in Humans Does Not Affect the Susceptibility of Low No Public 18] M.P., O'Connor, J.M, Chopra, M., Density Upoprotein to In Vitro Induced Oxidation (Foodcue Project). Free domain Harvey, L.J., Majsak-Newman, G., Radical Biology & Medicine, 29: (11); 1129-1134. Not GLP, Published Fairweather-Tait, S.J., Bugel, s., Sandstrom, B. Rock, E. , Mazur, A., Tavssiauier Y. & Strain J.J. A 6.12.4 Plamenac P, Santic z, Nikulin A, 1985 Cytologic changes of the respiratory tract in vineyard spraying workers. Eur No Public 18] Serdarevic H. J Respir Dis, 67: 50-55; Not GLP; published domain A 6.12.4 Scheinberg IH, Sternlieb I. 1994 Is non-I ndian childhood cirrhosis caused by excess dietary copper? Lancet, No Public 18] 344: 1002-1004' Not GLP· oublished domain A 6.12.4 Tanner MS, Kantarjian AH, Bhave 1983 Early introduction of copper-contaminated animal milk feeds as a possible No Public 18] SA, Pandit AN . cause of Indian Childhood Cirrhosis. Lancet 2: 992-995; Not GLP; published domain A 6.12.5 Internationa I Programme on 1990 Poisons Information Monograph (PIM G002) : Copper and copper salts; Not No Public ~ Chemical Safety GLP; Published domain A 6.12.7 Internationa I Programme on 1990 Poisons Information Monograph (PIM G002): Copper and copper salts; Not No Public 18] Chemical Safety GLP; Published domain A 6.12.8 Internationa I Programme on 1990 Poisons Information Monograph (PIM G002) : Copper and copper salts; Not No Public 18] Chemical Safety GLP; Published domain

90 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No A 6.2 Allen, M.M., Barber, R.S., Braude, 1961 Further studies on various aspects of the use of high-copper supplements for No Public ~ R. and Mitchell, K.G. growing pigs. Brit. J. Nutr., 15: 507 - 522, Not GLP Published domain A6.2 Amaravadi, R., Glerum, D.M. and 1997 Isolation of a cDNA encoding the human homolog of COX17, a yeast gene No Public ~ Tzagoloff, A. essential for mitochondrial copper recruitment . Hum Genet. 99: 329-333. domain Not GLP, Published. A 6.2 Aoyagi, s. and Ba ker, D.H. 1993 Bioavailability of Copper in Analytical-Grade and Feed Grade I norganic No Public ~ Copper Sources when Fed to Provide Copper at Levels Below the Chick's domain Reauirement. Poultrv Science. 72: 1075-1083. Not GLP Published A 6.2 Baker, D.H., Odle, J., Funk, M.A. 1991 Research Note: Bioavailability of Copper in Cupric Oxide, Cuprous Oxide, No Public ~ and Wieland, T.M. and in a Copper-Lysine Complex. Poultry Science. 70 : 177-179. Not GLP, domain Published A 6.2 Buescher, R.G., Griffin, S.A. and 1961 Copper Availability to Swine from Cu64 Labelled I norganic Compounds. No Public ~ Bell, M.C. Journal of Animal Science, 20: 529- 531. Not GLP, Published domain A 6.2 Bunch, R.J., Speer, V.C., Hays, 1963 Effects of High Levels of Copper and Chlortetracycline on Performance of No Public ~ v.w. and Mccall, J.T. Pigs. J. An imal Sci. 22: 56-60. Not GLP, Published domain A 6.2 Bunch, R.J., Speer, v.c., Hays, 1961 Effects of copper Sulfate, Copper oxide and Chlortetracycline on Baby Pig No Public ~ V.W., Hawbaker, J.H. and Catron, Performance. J. Animal Sci. 20: 723-726. Not GLP, Published domain D.V. A 6.2 campbell, C.H., Brown, R. and 1981 Circulating Ceruloplasmin is an I mportant Source of Copper for Normal and No Public ~ Linder, M.C. Malignant Animal Cells. Biochim. Biophys. Acta. 678: 27- 38. Not GLP, domain Published. A 6.2 Cromwell, G.L., Stahly, T.S. and 1989 Effects of Source and Level of Copper on Performance and Liver Copper No Public ~ Monegue, H.J. Stores in Wean ling Pigs. J. Animal Sci. 67: 2996-3002. Not GLP, Published domain A6.2 Culotta, V.C., Klomp, J.S., 1997 The Copper Chaperone for Superoxide Dismutase. The Journal of Biological No Public ~ casareno, R.L. B., Krems, B. And chemistry. 272 (38): 23469 - 23472. Not GLP, Published domain Gitlin, J.D A 6.2 Darwish, H.M., Cheney, J.C., 1984 Mobilisation of copper (II) from plasma components and mechanism of No Public ~ Schmitt, R.C. and Ettinger, M.J. hepatic copper transport. Am. J. Physiol., 246 (9):G72-G79. Not GLP, domain Published. A6.2 Gunshin, H., Mackenzie, B, Berger, 1997 Cloning and Cha racterisation of a Mammalian Proton-Coupled Metal-Ion No Public ~ u.v., Gunshin, Y., Romero, M.F., transporter. Nature. 388:482-488. Not GLP, Published. domain Boron, W.F., Nussberger, s., Golian, J.L. & Hediger, M.A.

A6.2 Keg ley, E.B. and Spears, J.W. 1994 Bioavailability of feed-grade copper sources (oxide, sulfate, or lysine) in No Public ~ growing cattle. J. Animal Sci. 72: 2728- 2734. Not GLP, Published domain A 6.2 Klomp, L.W.J., Lin, S.J., Yuan, 1997 Identification and Functional Expression of HAHl, a Novel Human Gene No Public ~ D.S., Klausner, R.D., Culotta, V.C. Involved in Copper Homeostasis. The Journal of Biological Chemistry domain and Gitlin, J.D. 272(14): 9221-9226. Not GLP, Published.

A 6.2 Lee S.H., Lancey R., Montaser A., 1993 Ceruloplasmin and copper transport during the latter part of gestation in the No Public ~ Madani N., Under M.C. rat. Proc Soc Exp Biol Med 203 : 428-39. Not GLP, Published. domain A 6.2 Linder M.C., Weiss K.C. and Hai, 1987 Structure and function of transcuprein in transport of copper by mammalian No Public ~ V.M. blood plasma. In: Hurley L.C., Keen C.L., Lonnerdal, B. and Rucker, R.B. domain (eds). Trace Elements in Man and Animals (TEMA-6). New York: Plenum, 141- 144. Not GLP Published.

9 1 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No A 6.2 McArdle, H.J., Gross S.M., Danks 1990 Role of Albumin's Copper Binding Site in Copper Uptake by Mouse No Public ~ D.M. & Wedd, A.G. Hepatocytes. Am. J. Physiol. 258 (Gastrointest. Liver Physiol. 21}: 988-991. domain Not GLP, Published. A 6.2 McArdle, H.J., Gross, S.M. and 1988 Uptake of Copper by Mouse Hepatocytes. Journal of Cellular Physiology, No Public ~ Danks, D.M. 136: 373- 378. Not GLP, Published. domain A 6.2 Norvell, M.J., Gable, D.A. and 1975 Effects of feeding high levels of various copper salts to broiler ch ickens. In No Public ~ Thomas, M.C., Trace Substances in Environments! Health - 9, (Hemphill, D.D., Ed}. domain Universitv of Missouri, Columbia, MO. Not GLP, Published A 6.2 Pirot, F., Millet, J., Ka lia, Y.N. & 1996 In vitro Study of Percutaneous Absorption, Cutaneous Bioavailability and No Public ~ Humbert, P Bioequivalence of Zinc and Copper from Five Topica l Formulations. Skin domain Pharmacol. 9 : 259-269. Not GLP, Published. A 6.2 Pirot, F., Panisset, F., Agache, P. & 1996 Simultaneous Absorption of Copper and Zinc through Human Skin in vitro. No Public ~ Humbert, P. Skin Pharmacol. 9: 43-52. Not GLP, Published. domain A6.2 Rojas, L.X., McDowell, L R., 1996 Interaction of different organic and inorganic zinc and copper sources fed to No Public ~ Cousins, R.J., Martin, F.G., rats. J. Trace Elements Med. Biol. 10: 139-144. Not GLP, Published domain Wilkinson, N.S., Johnson, A.B. and Velasquez, J.B. A 6.2 Scott, K.C. & Turnlund, J.R., 1994 Compartment Model of Copper Metabolism in Adult Men. J. Nutr. Biochem. No Public ~ 5: 342-350. Not GLP, Published. domain A 6.2 Turnlund, J.R., Keen, C.L. and 1990 Copper status and urinary and salivary copper in young men at three levels No Public ~ Smith, R.G. of dietary copper. Am. J. Clin. Nutr. 51 : 658-64.Not GIP, Published. domain A 6.2 Turnlund, J.R., Ketes, W.R., 1998 Copper absorption, excretion and retention by young men consuming low No Public ~ Peiffer, G.L. and Scott, K.C dietary copper determined using the stable isotope 65Cu. Am. J. Clin. Nutr., domain 67: 1219 - 1225. Not GLP, Published A6.2 Turnlund, J.R., Keyes, W.R., 1989 Copper absorpt ion and retention in young men at three levels of dietary No Public ~ Anderson, H.L and Acord, LL. copper by use of the stable isotope 65Cu. Am. J. Clin. Nutr. 49:870-878.Not domain GLP, Published. A 6.2 Turnlund, J.R., Wada, L., King, 1988 Copper Absorption in Young Men Fed Adequate and Low Zinc Diets. No Public ~ J.C., Keyes, W.R. and Lorra, L.A Biological and Trace Element Research, 17 : 31 - 41. Not GLP, Published domain A 6.2 van Berge Henegouwen, G.P., 1977 Biliary Secretion of Copper in Healthy Man. Quantitation by an intestinal No Public ~ Tangedahl, T.N., Hofmann, A.F., perfusion technique. Gastroenterology, 72: 1228-1231. Not Published. domain Northfield, T.C. La Russo, N.F. and Mccall, J.T.,

A 6.2 Van den Berg, G.J., Van Wouwe, 1990 Ascorbic Acid Supplementation and Copper Status in Rats. Biological Trace No Public ~ J.P and Beynen, A.C., Element Research, 23 : 165-172. Not GLP, Pu blished domain A6.2 Walker, R.W. 1982 The Result of a Copper Bracelet Clinical Trial and Subsequent Studies. p 469 No Public ~ - 478. I n: J. R. J. Sorenson (ed) Inflammatory Diseases and Copper: The domain Metabolic and Therapeutic Roles of Copper and Other Essential Metalloelements in Humans; Humana Press; Clifton N.J .. USA. Not GLP, Published. A 6.2 Weiss K.C. & Linder M.C. 1985 Copper transport in rats involving a new plasma protein. Am. J. Physiol. No Public ~ 249: E77-88. Not GLP, Published. domain A 6.2 Whitaker, P. & McArdle, H.J. 1997 Iron Inhibits Copper Uptake by Rat Hepatocytes by Down-Regulating the No Public ~ Plasma Membrane NADH Oxidase. In. Fisher, P.W., L'Abbe, M.R., Cockell, domain K.A. et al. (Eds}. Trace Elements in Man and Animals. (TEMA9}. NRC Research Press Ottowa nn 237-239

92 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/Nol Yes No A 6.2 Wirth, W.L. and Under, M.M. 1985 Distribution of Copper Among Components of Human Serum. JNCI. 75: 277- No Public ~ 284. Not GLP, Published. domain A 6.2 Xin, Z., Waterman, D.F., Hemken, 1991 Effects of copper sources and dietary cation-anion balance on copper No Public ~ R.W., Harmon, R.J. and Jackson, availability and acid-base status in dietary calves. J. Dairy Sci. 74: 3167- domain J.A 3173. Not GLP, Published A 6.2 Zhou, B. & Gitschier, J. 1997 hCTRl; A Human Gene for Copper Uptake Identified by Complementation in No Public ~ Yeast. Proc. Natl. Acad . Sci USA. 94:7481-7486. Not GLP, Published. domain A 6.4.1 Hebert, C.D., 1993 NTP Technical Report on toxicity studies of cupric sulphate {CAS No. 7758- No Public ~ 99-8) administered in drinking water and feed to F344/N rats and B6C3Fl domain mice. National Toxicology Program, Toxicity Report Series No. 29, United States Department of Health and Human Services {NIH Publication 93-3352). GLP Published A 6.4.1 Hebert, C.D., 1993 NTP Technical Report on toxicity studies of cupric sulphate {CAS No. 7758- No Public ~ 99-8) administered in drinking water and feed to F344/N rats and B6C3Fl domain mice. National Toxicology Program, Toxicity Report Series No. 29, United States Department of Health and Human Services {NIH Publication 93-3352). GLP Published A 6.5 Burki, H.R. and Okita, G.T. 1969 Effect of oral copper sulfate on 7, 12-dimethylbenz(a )anthracene No Public ~ carcinogenesis in mice. Br. J. cancer Sep; 23{3): 591-596. Not GLP, domain Published. A6.5 carlton, W.W. and Price, P.S. 1973 Dietary Copper and the Induction of Neoplasms in the Rat by No Public ~ Acetylaminofluorene and Dimethylnitrosamine. Fd Cosmet. Toxicol. 11: 827- domain 840 foublished\. A 6.5 De Vries, D.J., Sewell, R.B. and 1986 Effects of Copper on Dopaminergic Function in the Rat Corpus Striatum. No Public [81 Beart P.M. Experimental Neurology, 91: 546-558. Not GLP, Published domain A 6.5 Hall, E.M. and Butt, E.M 1928 Experimental Pigment Cirrhosis Due to Copper Poisoning. It's Relation to No Public ~ Hemochromatosis. Archives of Pathology, 6 : 1-25. Not GLP, Published domain A6.5 Hall, E.M. and Mackay, E.M. 1931 Experimental Hepatic Pigmentation and Cirrhosis. I. Does Copper Poisoning No Public ~ Produce Pigmentation and Cirrhosis of the Liver? The American Journal of domain Patholoov, 7: 327-342. Not GLP, Published A 6.5 Harrison, J.W.E., Levin, S.E. and 1954 The Safety and Fate of Potassium Sodium Copper Chlorophyllin and Other No Public ~ Trabin, B. Copper Compounds. Journal of the American Pharmaceutical Association, domain 43(12): 722-737. Not GLP, Published. A6.5 Haywood, S. 1980 The Effect of Excess Dietary Copper on the Liver and Kidney of the Male Rat. No Public ~ Journal of Comparative Pathology, 90: 217-232. Not GLP, Published domain A6.5 Haywood, S. 1985 Copper Toxicosis and Tolerance in the Rat. I - Changes in Copper Content of No Public [81 the Liver and Kidney. Journal of Pathology, 145: 149-158. Not GLP, domain Published A 6.5 Haywood, S. and Comerford, B. 1980 The Effect of Excess Dietary Copper on Plasma Enzyme Activity and on the No Public [81 Copper Content of the Blood of the Male Rat. Journal of Comparative domain Patholonv 90: 233-238. Not GLP Published A6.5 Haywood, S. and Loughran, M. 1985 Copper Toxicosis and Tolerance in the Rat. II. Tolerance - a Liver Protective No Public [81 Adaotation. Liver 5: 267-275. Not GLP Published domain A 6.5 Haywood, s. and Loughran, M. 1985 Copper Toxicosis and Tolerance in the Rat. II. Tolerance - a Liver Protective No Public [81 Adaotation. Liver 5: 267-275. Not GLP Published domain A 6.5 Liu, c .-C.F. and Medeiros, D.M. 1986 Excess Diet Copper Increases Systolic Blood Pressure in Rats. Biological No Public [81 Trace Element Research 9 : 15-24. Not GLP Published domain

93 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/Nol Yes No A 6.5 Tachibana, K. 1952 Pathological Transition and Functional Vicissitude of liver During Formation No Public ~ of Cirrhosis by Copper. The Nagoya Journal of Medical Science, 15: 108-114. domain Not GLP, Published A 6.5 Wiederanders, M.D. and Wasdahl, 1968 Acute and Chronic Copper Poisoning in the Rat. The Journal-Lancet, Minneap, No Public ~ W.W. 88: 286-291. Not GLP, Published domain A 6.6.4 Agarwal, K., Sharma, A. and 1990 Clastogenic effects of copper sulphate on the bone marrow chromosomes of No Public ~ Talukder, G., mice in vivo. Mutation Research, 243 :1-6. Not GLP, Published domain A 6.6.4 Bhunya, S.P. & Pati, P.C. 1987 Genotoxicity of an Inorganic Pesticide, Copper Sulpahte in Mouse in vivo Test No Public ~ svstem. Cvtoloaia. 52: 801-808. Not GLP Published. domain A 6.6.4 Tinwell, H. & Ashby, J. 1990 Inactivity of Copper Sulphate in a Bone-Marrow Micronucleus Assay. Mutat. No Public ~ Res . 245 : 223-226. Not GLP Published. domain A 6.7 Burki, H.R. and Okita, G.T. 1969 Effect of oral copper sulfate on 7, 12-dimethylbenz{ a )anthracene No Public ~ carcinogenesis in mice. Br. J. Cancer Sep; 23{3): 591-596. Not GLP, domain Published A 6.7 carlton, W.W. and Price, P.S., 1973 Dietary Copper and the Induction of Neoplasms in the Rat by No Public ~ Acetylaminofluorene and Dimethylnitrosamine. Fd Cosmet. Toxicol. 11: 827- domain 840. Not GLP Published. A 6.7 Harrison, J. W.E., Levin, S.E. and 1954 The Safety and Fate of Potassium Sodium Copper Chlorophyllin and Other No Public ~ Trabin, B., Copper Compounds. Journal of the American Pharmaceutical Association, domain 43112): 722-737. Not GLP Published A 6.8.1 Au lerich, R.J., Ringer, R.K., 1982 Effects of Supplemental Dietary Copper on Growth, Reproductive No Public ~ Bleavins, M.R. and Napolitano, A. Performance and Kit Survival of Standard Dark Mink and the Acute Toxicity domain of Conner to Mink 5512\: 337 - 343. Not GLP Published A 6.8.1 Barash, A., Shoham {Schwartz), 1990 Development of Human Embryos in the Presence of a Copper Intrauterine No Public ~ z., Borenstein, R. and Nebel, L. Device. Gynecol. Obstet. Invest., 29:203-206. Not GLP, Published domain

A6.8.1 Barlow, S.M., Knight, A.F. and 1981 Intrauterine exposure to copper IUDs and prenatal development in the rat. No Public ~ House, I. J. Reo. Fert. , 62: 123 - 130 domain A 6.8.1 Chang, c.c. And Tatum, H.J. 1973 Absence of teratogenicity of intrauterine copper wire in rats, hamsters and No Public ~ rabbits. Contraceotion, 7(5): 413 - 434 domain A 6.8.1 Dicarlo, F.J 1980 Syndromes of Ca rdiovascular Malformations Induced by Copper Citrate in No Public ~ Ha msters. Teratoloav 21: 89-101. Not GLP, Published domain A 6.8.1 Ferm, V.H. and Hanlon, D.P. 1974 Toxicity of Copper Salts in Hamster Embryonic Development. Biology of No Public ~ Reoroduction, 11: 97-101. Not GLP, Published domain A 6.8.1 Haddad, D.S., Al-Alousi, L.A. and 1991 The Effect of Copper Loading on Pregnant Rats and Their Offspring. No Public ~ Kantarjian, A.H. Functional and Developmental Morphology 1{3): 17-22. Not GLP, Published domain A 6.8.1 Kasama, T. and Tanaka, H 1988 Effects of copper administration on fetal and neonatal mice. J. Nutr. Sci. No Public ~ Vitaminol. 34: 595-605. Not GLP Published domain A 6.8.1 Lecyk, M. 1980 Toxicity of CuS04 in mice embryonic development. Zoologica Poloniae, No Public ~ 28(2): 101-105. Not GLP Published domain A 6.8.2 Au lerich, R.J., Ringer, R.K., 1982 Effects of Supplemental Dietary Copper on Growth, Reproductive No Public ~ Bleavins, M.R. and Napolitano, A. Performance and Kit Survival of Standard Dark Mink and the Acute Toxicity domain of Conner to Mink 55(2): 337 - 343. Not GLP Published A 6.8.2 Chang, c.c. And Tatum, H.J. 1973 Absence of teratogenicity of intrauterine copper wire in rats, hamsters and No Public ~ rabbits. Contraceotion 715): 413 - 434 domain A6.8.2 Cromwell, G.L., Monegue, H.J. and 1993 Long-term effects of feeding a high copper diet to sows during gestation and No Public ~ Stahly, T.S. lactation. J. Anim. Sci. 71: 2996-3002. Not GLP, Published domain

94 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No A 6.8.2 Hebert, c.o., 1993 NTP Technical Report on toxicity studies of cupric sulphate (CAS No. 7758- No Public ~ 99-8) administered in drinking water and feed to F344/N rats and B6C3Fl domain mice. National Toxicology Program, Toxicity Report Series No. 29, United States Department of Health and Human Services (NIH Publication 93-3352). GLP, Published A6.8.2 Hebert, c.o., 1993 NTP Technical Report on toxicity studies of cupric sulphate (CAS No. 7758- No Public ~ 99-8) administered in drinking water and feed to F344/N rats and B6C3Fl domain mice. National Toxicology Program, Toxicity Report Series No. 29, United States Department of Health and Human Services (NIH Publication 93 -3352). GLP, Published A 6.8.2 Lecyk, M. 1980 Toxicity of CuS04 in mice embryonic development . Zoologica Poloniae, No Public ~ 28(2): 101-105. Not GLP, Published domain A 6.8.2 Llewellyn, G.C., Floyd, E.A., Hoke, 1985 Influence of dietary aflatoxin, zinc and copper on bone size, organ weight, No Public ~ G.D., Weekley, L.B. and and body weight in hamsters and rats. Bull. Environ. Contam. Toxicol., 35: domain Kimbrouah T.D. 149-156. Not GLP Published A 6.8.2 2005 Copper Sulfate Pentahydrate : Multigenerat ion Reproduction Study in Rats. Yes Europea ~ n GLP;l!lpubHshed Copper Institute A 6.9 Murthy, R.C., La l, s., Saxena, - Effect of Manganese and Copper Interaction on Behaviour and Biogenic No Public ~ D.K., Shukla, G.S., Mohd Ali, M Amines in Rats Fed a 10% Casein Diet. Chem. Biol. Interactions, 37: 299 - domain and Chandra S.V. 308. Not GLP Published A Brooks, s. 2006 Copper speciat ion in samples collected from a Finnish marina. Cefas contract Yes EU ~ 7.1.1.2.3.1 report CEFAS/PRO/C2415 Antifouli ng Task Force A Jones, B., Bolam, T., Waldock, M. 2005 The Speciation of Copper in samples collected from the Marine Environment. Yes EU ~ 7.1.1.2.3.1 Cefas contract report Cl 385 Antifouli ng Task Force A 7.1.4 Bessinger, B., Cooke, T., Forman, 2006 A Kinetic model of Copper cycling in San Francisco Bay. San Francisco No Public ~ B., Lee, v., Mineart, P., Estuary and Watershed Science Vol. 4, Iss. 1 [February 2006], Art. 4; Not domain Armstrona L. GLP· Published A 7.1.4 Comber sow, Gunn AM, Whalley 1995 Comparison of the partitioning of trace metals in the Humber and Mersey No Public ~ c, Estuaries. Marine Pollution Bu lletin 30, 12, 851-860. domain A 7.1.4 Helmers E, 1996 Trace metals in suspended particu late matter of Atlantic Ocean surface water No Public ~ (40°N to 20°S). Marine Chemistrv 53, 51-67. domain A 7.1.4 Lin, C-F., Houng, L-M., Lo, K.S., 1994 Kinetics of copper complexation with dissolved organic matter using stopped- No Public ~ Lee, D-Y. flow fluorescence technique; Toxicological and Environmental Chemistry, Vol. domain 43 nn. 1-12· Not GLP· Published A 7.1.4 McManus JP, Prandle D, 1996 Determination of source concentrations of dissolved and particu late trace No Public ~ metals in the southern North Sea. Marine Pollution Bulletin 32, 504-512. domain A 7.1.4 Munksgaard NC, Parry DL, 2001 Trace metals, arsenic and lead isotopes in dissolved and particulate phases of No Public ~ North Australian coastal and estuarine seawater. Marine Chemistry, 75, 165- domain 184. A 7.1.4 Nolting RF, Helder w, de Baar 1999 Contrasting behaviour of trace metals in the Scheidt estuary in 1978 No Public ~ HJW, Gerringa U A, compared to recent years. Journal of Sea Research, Volume 42, Number 4, domain December 1999 , nn. 275-290(16)

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TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPANY) COMPANY, DATA OWNER Essential Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation ( Yes/Nol Yes No A 7.1.4 Owens RE, Balls PW, Price NB, 1997 Physicochemical processes and their effects on the composition of suspended No Public ~ particulate material in estuaries : implications for monitoring and modelling. domain Marine Pollution Bulletin 34, 51 -60. A 7.1.4 Paucot H, Wollast R, 1997 Transport and transformation of trace metals in the Scheidt Estuary. Mar. No Public ~ Chem. 58, 229-244. domain A 7.1.4 Pohl C, Hennings U, 1999 The effect of redox processes on the partitioning of Cd, Pb, Cu and Mn No Public ~ between dissolved and particulate phases in the Ba ltic Sea. Marine Chemistry domain 65, 41-53. A 7.1.4 Safiudo-Wilhelmy SA, Rivera- 1996 Distribution of colloidal trace metals in the San Francisco Bay estuary. No Public ~ Duarte I, Flegal AR, Geochimica et Cosmochimica Acta 60, 4933-4944. domain A 7.1.4 Tappin AD, Millward GE, Statham 1995 Trace metals in the Central and Southern North Sea. Estuarine, Coastal and No Public ~ PJ, Burton JD, Morris AW, Shelf Science 41, 275-323. domain A 7.1.4 Vasconcelos MTSD, Leal MFC, 1997 Speciation of Cu, Pb, Cd and Hg in waters of the Oporto coast in Portugal, No Public ~ using pre-concentration in a Chelamine resin column. Ana lytica Chimica Acta domain 353 189-198 A 7.1.4 Zhou JL, Liu VP, Abrahams PW, 2003 Trace metal behaviour in the Conwy estuary, North Wales. Chemosphere 51, No Public ~ 429-440. domain A 7.4.1.1 Buhl, P.C., & Steven, J.H. 1990 Comparative toxicity of inorganic contaminants released by placer mining to No Public ~ early life stages of sa lmonids. Ecotoxicol. Environ. Saf. Vol. 20, 325-342. domain Not GLP Published A 7.4.1.1 Howarth, R. S. & Sprague, J. B. 1978 Copper lethality to rainbow trout in waters of various hardness and pH. No Public ~ Water Res . Vol. 12 455-462. Not GLP Published domain A 7.4.1.1 1973 To determine the toxicity of Chem Copp Spray Grade 75 (EPA #26883) to Yes America ~ bluegill; II I I Report No. 040260; Not n GLP; Unpublished Chem et A 7.4.1.1 1991 Acute toxicity of purple copp 97N to the sheepshead minnow (cyprinodon Yes America ~ variegatus); II I I Project ID ESE No. 3913022- n 0200-3140; GLP; Unpublished Chem et A 7.4.1.2 Baird, D. J. et al. 1991 A comparative study of genotype sensitivity to acute toxic stress using clones No Public ~ of Daphnia magna. Ecotoxicol Envrion. Saf. Vol. 21, 257-265. Not GLP, domain Published A 7.4.1.2 Dave, G. 1984 Effects of copper on growth, reproduction, survival and haemoglobin in No Public ~ Daphnia magna. Comp. Biochem. Physiol. Vol. 78C (2) 439-443. Not GLP, domain Published A 7.4.1.2 Le Blanc, G. A. 1982 Laboratory investigation into the development of resistance of Daphnia No Public ~ magna to environmental pollutants. Environ. Poll. Vol. A27, 309-322. Not domain GLP, Publ ished A 7.4.1.2 Noack, M. 1993 Acute immobilisation test (48 hour) to Daphnia magna Straus according to Yes Spiess- ~ OECD 202 I of URA-17030; Dr U Noack-Laboratorium fur angewandte Urania biologie, Proiect No. 921027NH, Study No. DAI33241; GLP; Unpublished A 7.4.1.2 Oikari, A. et al. 1992 Acute toxicities of chemicals to Daphnia magna in humic waters. Sci. Total. No Public ~ Environ. Vol. 117/118, 367-377. Not GLP, Published domain A 7.4.1.2 Wade, B. A. 1991 Acute toxicity of purple copp 97N to the mysid shrimp (mysidopsis bahia); Yes America ~ ESE Laboratories, Gainesville, FL, Project ID ESE No. 3913022-0600-3140; n GLP; Unoublished Chem et A 7.4.1.3 De Schamphelaere KAC, Janssen 2005 A unified bioavailability model for predicting copper toxicity to freshwater No Public ~ CR green micro-algae; Un iversity of Gent; Draft report - not yet published; not domain

96 Dicopper oxide PT 21 Product-type 21 January 2016

A 7.4.1.3 Dickhaus, s. & Heisler, E. 1988 Algal growth inhibition test with copper-I-oxide (OECD guideline 201); Yes Spiess- ~ Pharmatox Gmbh reoort No. 1-7-44-88; GLP; unoublished Urania A 7.4.1.3 Garvey, J.E. et al.* 1991 Toxicity of C-Opper to the Green Alga Chlamydomonas reinhardt ii No Public ~ (Chlorophyceae) as Affected by Humic Substances of Terrestrial and domain Freshwater Oriain. Aauatic Toxicoloav. Vol. 19 89-96. Not GLP Published A 7.4.1.3 Ghent University.* 2002 Chronic algae testing of copper with Chlamydomonas reinhardtii and No Public ~ Chlorella vulaaris. Unoublished data domain A 7.4.1.3 Heijerick D., Bossuyt B. and 2001 EURO-ECOLE Assessment of the Bioavailability and Potential Ecological No Europea ~ Janssen c. Effects of Copper in European Surface Waters - Subproject 4 :Evaluation and n improvement of the ecological relevance of laboratory generated toxicity Copper data· no reoort number· not GLP· Unoublished Institute A 7.4.1.3 Heijerick* 2002 Heijerick DG, Bossuyt BTA, Indeherberg M, Mingazinni M, Janssen CR, 2002. No Public ~ Effects of varying physico-chemistry of European surface waters on the domain copper toxicity to the green algae Pseudokirchneriella subcapitata. Not GLP, Not Published I submitted). A 7.4.1.3 Nyholm, N. * 1990 Expression of results from growth inhibition toxicity tests with algae. Arch. No Public ~ Environ Contam. Toxicol. Vol 19 (4) 518- 522. Not GLP, Published domain A 7.4.1.3 Schafer, H. et al.* 1994 Biotests using unicellular algae and ciliates for predicting long-term effects of No Public ~ toxicant. Ecotoxicol. Enviorn. Safe. Vol. 27, 64-81. Not GLP, Published domain A 7.4.1.3 Simpson, s et al 2003 Effect of declining toxicant concentrations on algal bioassay endpoints; No Public ~ Environmental Toxicology and Chemistry, Vol. 22, No. 9, pp. 2073- 2079; domain Not GLP; Published A 7.4.1.3 Smyth, D.V., Kent, s. 2006 Copper: toxicity to the marine alga Skeletonema costatum; BEL report no. Yes EU ~ BL8337/ B; GLP; Unpublished Antifouli ng Task Force A 7.4.1.3 Smyth, D.V., Kent, s. 2006 Copper: toxicity to the marine alga Phaeodactylum tricornutum; BEL report Yes EU ~ no. BL8338/B; GLP; Unpublished Antifouli ng Task Force A 7.4.1.3 Teisseire, H. et al.* 1998 Toxic Responses and Catalase Activity of Lemna minor Exposed to Folpet, No Public ~ Copper and their Combination. Ecotoxicol. Environ. Saf. 40, 194-200. Not domain GLP, Published A 7.4.1.4 Cha, D.K., Allen, H.E. & Song, J.S. - Effect of C-Opper on Nitrifying and Heterotrophic Populations in Activated Yes Europea ~ Sludge. Department of Civil and Environmental Engineering, University of n Delaware, USA. Not GLP, Unpublished Copper Institute A 7.4.1.4 Codina, J.C., Munoz, M.A., 1998 The Inhibition of Methanogenic Activity from Anaerobic Domestic Sludges as No Public ~ cazorla, F.M., Perez-Garcia, A., a Simple Toxicity Bioassay. Water Research. 32 (4) 1338-1342. Not GLP, domain Morifiigo, M.A. & De Vicente, A. Published

A 7.4.1.4 Madoni, P., Davole, D., Gorbim G. 1996 Toxic Effect of Heavy Metals on the Activated Sludge Protozoan Community. No Public ~ & Vescovi, L. Water Research. 30 (1) 135-141. Not GLP, Published domain A 7.4.1.4 Madoni, P., Davoli, D. & Guglielmi, 1999 Response of Sour and Aur to Heavy Metal Contamination in Activated Sludge. No Public ~ L. Water Research. 33 {10): 2459-2464. Not GLP, Published domain

97 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/Nol Yes No A 7.4.2 Ahsanulla, M. & Williams, A.R. 1991 Sublethal Effects and Bioaccumulation of Cadmium, Chromium, Copper and No Public ~ Zinc in the Marine Amphipod, Allorchestes compressa. Mar. Biol. Not GLP, domain Published. A 7.4.2 Amiard, J.C., Amiard-Triquet, C. & 1985 Experimental Study of Bioaccumulation, Toxicity and Regulation of Some No Public ~ Metayer, c. Trace Metals in Various Estuarine and Coastal Organisms. Symp. Biologica. domain Huna. 29; 313-323 (published). A 7.4.2 Benoit, D .A. 1975 Chronic Effects of Copper on Survival, Growth and Reproduction of the No Public ~ Bluegill (Lepomis macrochirus). Trans. Am. Fish. Soc. 104 (2). 353-358. Not domain GLP, Published. A 7.4.2 Borgmann, u., Norwood, W.P. & 1993 Accumulation, Regulation and Toxicity of Copper, Zinc, Lead and Mercury in No Public ~ Clarke, c. Hyalella azteca. Hydrobiologica . 259: 79-89. Not GLP, Published. domain A 7.4.2 Brown, B. E 1977 Uptake of Copper and Lead by a Metal Tolerant Isopod Asellus meridianus. No Public ~ Freshwater Biol. 7: 235-244. Not GLP Published. domain A 7.4.2 Brungs, W. A. Leonard, E.N., 1973 Acute and Long Term Accumulation of Copper by the Brown Bullhead, No Public ~ McKim, J.M. Ictalurus nebulosus. J. Fish Res. Board. Can. 30 : 583-586. Not GLP, domain Published. A 7.4.2 calabrese, A., Maci nnes, Nelson, 1984 Effects of Long-Term Exposure to Silver or Copper on Growth, No Public ~ D.A, Greig, R.A. & Yevich, P.P. Bioaccumulation and Histopathology in the Blue Mussel, Mytilus edulis. Mar. domain Environ. Res . 11 : 253-274. Not GLP Published. A 7.4.2 canterford, G.S., Buchanan, A.S. 1978 Accumulation of Heavy Metals by the Marine Diatom Ditylum brightwelli No Public ~ & Ducker, s.c. {West) Grunow. Aust. J. Freshwater Res. 29: 613-22. Not GLP, Published domain A 7.4.2 Djangmah, J.S. & Grove, D.J. 1970 Blood and Hepatopancreas Copper in Crangon vulgaris {Fabricius) . No Public ~ Comoarative Biochemistrv and Phvsioloav (oublished). domain A 7.4.2 Engel, D.W. & Brouwer, M. 1985 Cadmium and Copper Metallothioneins in the American Lobster, Homarus No Public ~ americanus. Environ. Health. Perspect. 66; 87-92 (published). domain A 7.4.2 George, S.G., Pirie, B.J.S., 1978 Detoxication of Metals by Marine Bivalves. An Ultrastrutural Study of the No Public ~ Cheyne, A.R., Coombs, T.L. & Compartmentation of Copper and Zinc in the Oyster Ostrea edulis. Marine domain Grant, P.T. Bioloav, 45; 147-156 Polychaete Phyllodoce maculata. Estuarine & No Public ~ Coastal Mar. Sci. 3: 103-108. Not GLP Published. domain A 7.4.2 Mersch, J., Morhain, E. & Mouvet, 1993 Laboratory Accumulation and Depuration of Copper and cadmium in the No Public ~ c. Freshwater Mussel Dreissena polymorpha and the Aquatic Moss domain Rhynchostegium riparioides. Chemosphere. 27 (8): 1475-1485. Not GLP, Published. A 7.4.2 Millanovich, F.P., Spies, R., 1976 Uptake of Copper by the Polychaete Cirriformia spirabrancha in the Presence No Public ~ Guram, M.S. & Sykes, E.E. of Dissolved Yellow Organic Matter of Natural Origin. Estuarine and Coastal domain Mar. Sci. 4: 585-588. Not GLP Published.

98 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/Nol Yes No A 7.4.2 Pesch, C.E. & Morgan, D 1978 Influence of Sediment in Copper Toxicity Tests with the Polychaete Neanthes No Public 18] arenaceodentata. Water Research. 12: 747-751. Not GLP, Published domain A 7.4.2 Phillips, D. J. H. 1976 The Common Mussel Mytilus edulis as an Indicator of Pollution by Zinc, No Public 18] Cadmium, Lead and Copper. I. Effects of Environmental Variables on Uptake domain of Metals. Mar. Biol. 38: 59-69. Not GLP, Published. A 7.4.2 Rainbow, P.S. 1985 Acaimulation of Zn, Cu and Cd by Crabs and Barnacles. Estuarine, Coastal No Public 18] Shelf Science. 21 · 669-686 foublished). domain A 7.4.2 Rainbow, P.S. & White, s. L 1989 Comparative Strategies of Heavy Metal Accumulation by Crustaceans: Zinc, No Public 18] Copper and Cadmium in a Decapod and Am phi pod and a Barnacle. domain Hvdrobioloaia 174· 245-262 foublishedl. A 7.4.2 Rainbow, P.S. & White, S. L 1989 Comparative Strategies of Heavy Metal Accumulation by Crustaceans: Zinc, No Public 18] Copper and Cadmium in a Decapod and Amphipod and a Barnacle. domain Hvdrobioloaia 174· 245-262 foublishedl. A 7.4.2 Rainbow, P.S. & White, s. L 1989 Comparative Strategies of Heavy Metal Accumulation by Crustaceans: Zinc, No Public 18] Copper and Cadmium in a Decapod and Amphipod and a Barnacle. domain Hvdrobioloaia 174· 245-262 foublishedl. A 7.4.2 Rainbow, P.S., Scott, A.G., 1980 Effect of Chelating Agents on the Accumulation of Cadmium by the Barnacle No Public 18] Wiggins, E.S. & Jackson, R.W. Semibalanus balanoides, and Complexation of Soluble Cd, Zn and Cu . domain Marine Ecoloav. 2· 143-152 foublishedl. A 7.4.2 Riley, J.P. & Roth, I. 1971 The Distribution of Trace Elements in Some Species of Phytoplankton Grown No Public 18] in Culture. J. Mar. Biol. Ass. UK. 51: 63-72. Not GLP, Published domain A 7.4.2 Roesijadi, G 1980 Influence of Copper on the Clam Protothaca staminea: effects on Gills and No Public 18] Occurrence of Copper Binding Proteins. Biol. Bull. 158: 233-247. Not GLP, domain Published. A 7.4.2 Shuster, c. N. & B.H. Pringle 1969 Trace Metal Accumulation by the American Eastern Oyster, Crassostrea No Public ~ virginica. Proc. Nat. Shellfish. Ass. 59: 91-103. Not GLP, Published. domain A 7.4.2 Shuster, C.N and Pringle, B.H. 1969 Effects of Trace Metals on Estuarine Molluscs. Proceedings of the 1st Mid- No Public ~ Atlantic Industrial Waste Conference. November 13-15, 197. Not GLP, domain Published A 7.4.2 Solbe, J.F. de LG. & Cooper, V.A. 1976 Studies on the Toxicity of Copper Sulphate to Stone Loach Neomacheilus No Public 18] Barbatulus (L.) in Hard Water. Wat. Res . 10: 523-527. Not GLP, Published. domain A 7.4.2 Timmermans, K. R. & Walker, P.A. 1989 The Fate of Trace Metals During Metamorphosis of Chrionomids (Diptera, No Public 18] Chironomidae). Environmental Pollution. 62; 73-85 (published). domain A 7.4.2 White, S.L. & Rainbow, P.S. 1982 Regulation and Accumulation of Copper, Zinc and cadmium by the Shrimp No Public 18] Pa laemon elegans. Marine Ecology Progress Series. 8; 95-101 (published). domain A 7.4.2 Winner, R.W. 1984 The Toxicity and Bioaccumulation of cadmium and Copper as Affected by No Public l8J Humic Acid. Aquatic Toxicology. 5: 267-274. Not GLP, Published. domain A 7.4.2 Young, J.S., Buschbom, R.L., 1979 Effects of Copper on the Sabel lid Polychaete, Eudistylia vancouveri: I No Public 18] Gurtisen, J.M. & Joyce, S.P. Concentration Limits for Copper Accumulation. Archives of Environmental domain Contamination and Toxicoloav. 8: 97-106. Not GLP. Published A 7.4.2 Zaroogian, G.E. & Johnston, M. 1983 Copper Accumulation in the Bay Scallop, Argopecten irradians. Arch. Environ. No Public 18] Contam. Toxicol. 12: 127-133. Not GLP, Published. domain A 7.4.3 Foekema E.M., Kramer K.J.M., 2010 Determination of the biological effects and fate of dissolved copper in Yes EU ~ Kaag N.H.M.B., Sneekes A.C., outdoor marine mesocosms; !MARES Wageningen UR Report No. C105/ 10; Antifouli Hoornsman G., Lewis W.E., van Not GLP; Unpublished ng Task der Vlies E.M. Force

99 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/Nol Yes No A 7.4.3.1 Collvin, L.* 1984 The effect of copper on growth, food consumption and food conversion of No Public ~ perch Perea fluviatilis L. offered maximal food rations. Aquatic Toxicology domain (Amsterdam) 6 : 105-113. Not GLP, Publ ished A 7.4.3.1 Scudder, B. c., J. L. carter and H. 1988 Effects of copper on development of the fathead minnow, Pimephales No Public ~ v. Leland* promelas Rafinesque. Aquatic Toxicology (Amsterdam) 12: 107-124. Not domain GLP, Published A 7.4.3.1 Solbe, J. F. d. L. G. and v. A. 1976 Studies on the toxicity of copper sulphate to stone loach Noemacheilus No Public ~ Cooper* barbatulus (L.) in hard water. Water Research 10: 523-527. Not GLP, domain Published A 7.4.3.1/ Job, K.M., A.M. Askew and R.B. 1995 Development of a water-effect-ratio for copper, cadmium and lead for the No Public ~ 7.4.3.2 Foster.* Great Works River in Maine using Ceriodaphnia dubia and Salvelinus domain fontinalis. Bulletin of Environmental Contamination and Toxicology. 54: 29- 35. Not GLP, Published A 7.4.3.1/ Mount, D. I.* 1968 Chronic toxicity of copper to fathead minnows {Pimephales promelas No Public ~ 7.4.3.2 Rafinesque). Water Research 2 : 215-223. Not GLP, Published domain A 7.4.3.1/ Spehar, R. L. and J. T. Fiandt* 1985 Acute and chronic effects of water quality criteria based metal mixtures on No Public ~ 7.4.3.2 three aquatic species. Project Summary EPN6000/S3-85/074. u. s . domain Environmenta I Protection Agency, Environmental Research Laboratory, Duluth Minnesota. Not GLP Published A 7.4.3.1/ Mount, D. I. and c. E. Stephan.* 1969 Chronic toxicity of copper to the fathead minnow {Pimephales promelas) in No Public ~ 7.4.3.2 soft water. Journal of the Fisheries Research Board of canada 26: 2449- domain 2457. Not GLP Publ ished A 7.4.3.1/ Mudge, J. E., N. T. E., G. s . Jeane, 1993 Effect of varying environmental conditions on the toxicity of copper to No Public ~ 7.4.3.2 W. Davis and J. L. Hickam* salmon. pp. 19-33. In: J. W. Gorsuch, F. J. Dwyer, C. G. Ingersoll and T. W. domain L. Point (eds.). Environmental Toxicology and Risk Assessment: 2nd Volume, ASTM STP 1216. American Society for Testing Materials, Philadelphia, Pennsvlvania. Not GLP Published A 7.4.3.1/ McKim, J.M. and D. A. Benoit.* 1971 Effects of long-term exposures to copper on survival, growth, and No Public ~ 7.4.3.2 reproduction of brook trout {Salvelinus fontinalis). Journal of the Fisheries domain Research Board of Canada 28: 655-662. Not GLP Published A 7.4.3.1/ Horning, w. B. and T. w. 1979 Chronic effect of copper on the bluntnose minnow, Pimephales notatus No Public ~ 7.4.3.2 Neiheisel* {Rafinesque). Archives of Environmental Contamination and Toxicology 8: domain 545-552. Not GLP, Published A 7.4.3.1/ Sauter, s., K. s . Buxton, K. J. 1976 Effects of exposure to heavy metals on selected freshwater fish. Toxicity of No Public ~ 7.4.3.2 Macek ands. R. Petrocelli* copper, cadmium, chromium and lead to eggs and fry of seven fish species. domain Ecological Reseach Series EPA-600/3-76-105. U.S. Environmental Protection Agency, Environmental Research Laboratory, Duluth, Minnesota. Not GLP, Published A 7.4.3.2 Anderson, B.S., Middaugh, D.P., 1991 Copper toxicity to sperm, embryos, and larvae of topsmelt Atherinops affinis, No Public ~ Hunt, J.W., and Turpen, S.L. with notes on induced spawning. Mar. Environ. Res. 31: 17-35 domain A 7.4.3.2 Belanger, S. E. and D. S. Cherry.* 1990 Interacting effects of pH acclimation, pH, and heavy metals on acute and No Public ~ chronic toxicity to Ceriodaphnia dubia {Cladocera). Journal of Crustacean domain Bioloav 1012): 225-235. Not GLP, Published A 7.4.3.2 Brungs, w. A., J. R. Geekier and 1976 Acute and chronic toxicity of copper to the fathead minnow in a surface No Public ~ M. Gast.* water of variable quality. Water Research 10: 37-43. Not GLP, Published. domain A 7.4.3.2 Collvin, L* 1985 The effects of copper on maximum respiration rate and growth rate of perch, No Public ~ Perea fluviatilis L. Water Research 18{2): 139-144. Not GLP, Published domain

100 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No A 7.4.3.2 2006 Copper: Determination of the effects on the embryo larval development of Yes EU ~ the Sheepshead Minnow {Cyprinodon variegates). Report No. BL8353/ B Antifouli ng Task Force A 7.4.3.2 2006 Copper: Determination of the effects on the embryo larval development of Yes EU ~ the Sheepshead Minnow {Cyprinodon variegates). Report No. BL8353/ B Antifouli ng Task Force A 7.4.3.2 Marr, J. c. A., J. Upton, D. cacela, 1996 Relationship between copper exposure duration, tissue copper concentration, No Public ~ J. A. Hansen, H. L. Bergman, J. s. and ra inbow trout growth. Aquatic Toxicology 36: 17-30. Not GLP, Published domain Meyer and c. Hogstrand. *

A 7.4.3.2 Pickering, Q., W. Brungs and M. 1977 Effect of exposure time and copper concentration on reproduction of the No Public ~ Gast.* fathead minnow {Pimephales promelas). Water Research 11{12): 1079-1083. domain Not GLP, Published A 7.4.3.2 Seim, W. K., L. R. Curtis, S. W. 1984 Growth and survival of developing steelhead trout {Sa l mo gairdneri) No Public ~ Glenn and G. A. Chapman.* continuously or intermittently exposed to copper. Canadian Journal of domain Fisheries and Aauatic Sciences 4H3l: 433-438. Not GLP, Published A 7.4.3.4 Ahsanullah, M., Ying, W. 1995 Toxic Effects of Dissolved Copper on Penaeus mergulensis and Penaeus No Public ~ monodon. Bull. Environ. Contain. Toxicol. {1995) 55 :81-88; Not GLP; domain Published A 7.4.3.4 Arthur, J. W. and E. N. Leonard.* 1970 Effects of copper on Gammarus pseudolimnaeus, Physa integra, and No Public ~ Campeloma decisum in soft water. Journal of the Fisheries Research Board of domain Canada 27171: 1277-1283. Not GLP Published A 7.4.3.4 Bechmann R.K. 1994 Use of life tables and LC50 tests to evaluate chronic and acute toxicity effects No Public ~ of copper on the marine copepod Tisbe furcata {Baird), Environmental domain Toxicoloav and Chemistrv Vol.13 No. 9 nn. 1509-1517. A 7.4.3.4 Belanger, S. E., J. L. Fanris and D. 1989 Effects of diet, water hardness, and population source on acute and chronic No Public ~ S. Cherry* copper toxicity to Ceriodaphnia dubia. Archives of Environmental domain Contamination and Toxicoloav 18: 601-611. Not GLP, oublished A 7.4.3.4 Brix, K.V. , Gerdes, R.M., Adams, 2006 Effects of Copper, Cadmium, and Zinc on the Hatching Success of Brine No Public ~ W.J., Grosel, M Shrimp {Artemia franciscana). Arch. Environ. Contam. Toxicol. 51, 580- 583; domain Not GLP· Published A 7.4.3.4 Cerda, Band Olive, J.H. 1993 Effects of Diet on Seven-Day Ceriodaphnia dubia Toxicity Tests; Ohio J. Sci. No Public ~ 93 (3): 44-47, 1993; no report number; not GLP; Published domain A 7.4.3.4 Deaver, E. and J. H. Rodgers, Jr.* 1996 Measuring bioavailable copper using anodic stripping voltammetry. No Public ~ Environmental Toxicology and Chemistry 15(11): 1925-1930. Not GLP, domain Unoublished A 7.4.3.4 Gould E. ,Thompson R. J., Buckley 1988 Uptake and effects of copper and cadmium in the gonad of the scallop No Public ~ L.J ., Rusanowsky D., Sennefelder Placopecten magellanicus: concurrent metal exposure; Marine Biology {97) domain G.R. 212-233; Not GLP; Published

A 7.4.3.4 Hall, L W.Jr, Anderson, R.D., 1997 Acute and chronic toxicity of copper to the estuarine copepod eurytemora No Public ~ Kilian, J.V. affinis: influence of organic complexation and speciation. Chemosphere, Vol. domain 35 No. 7 nn. 1567-1597 A 7.4.3.4 Hatakeyama, s. and M. Yasuno.* 1981 A method for assessing chronic effects of toxic substances on the midge, No Public ~ Paratanytarsus parthenogeneticus-effects of copper. Archives of domain Environmental Contamination and Toxicoloav 10: 705-713. Not GLP,

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A 7.4.3.4 Heijerick D., Bossuyt B. and 2001 EURO-ECOLE Assessment of the Bioavailability and Potential Ecolog ical No Europea ~ Janssen c . Effects of Copper in European Surface Waters - Subproject 4 :Evaluation and n improvement of the ecological relevance of laboratory generated toxicity Copper data· no reoort number· not GLP· Unoublished Institute A 7.4.3.4 Heijerick DG, Bossuyt BTA, 2002 Effects of varying physico-chemistry of European surface waters on the No Public ~ Indeherberg M, Mingazinni M, copper toxicity to the green algae Pseudokirchneriella subcapitata. Not GLP, domain Janssen CR,* Not Published (submitted). A 7.4.3.4 Jop, K.M., A.M. Askew and R.B. 1995 Development of a water-effect-ratio for copper, cadmium and lead for the No Public ~ Foster.* Great Works River in Maine using Ceriodaphnia dubia and Salvelinus domain fontinalis. Bulletin of Environmental Contaminat ion and Toxicology. 54: 29- 35. Not GLP Published A 7.4.3.4 LaBreche T.M.C., Dietrich A.M., 2002 Copper Toxicity to Larval Mercenaria mercenaria (hard clam), Environmental No Public ~ Gallagher D.L., Shepherd N. Toxicology and Chemistry, Vol. 21, No. 4, pp 760-766. domain

A 7.4.3.4 Maund S.J., E.J. Taylor and D. 1992 Population responses of the freshwater amphipod crustacean Gammarus No Public igJ Pascoe.* pulex to copper. Freshwater Biology 28: 29-36. Not GLP, Published domain A 7.4.3.4 Nebeker, A. V., A. Stinchfield, c. 1986 1986; Effects of copper, nickel and zinc on three species of Oregon No Public ~ Savonen and G. A. Chapman freshwater snails; Environmental Toxicology and Chemistry 5(9): 807-811; domain not GLP· Published A 7.4.3.4 Nebeker, A. V., c. Savonen, R. J. 1984 Effects of copper, nickel and zinc on the life cycle of the caddisfly Clistoronia No Public ~ Baker and J. K. Mccrady.* magnifica {Limnephilidae). Environmental Toxicology and Chemistry 3 : 645- domain 649. Not GLP Published A 7.4.3.4 Reichelt-Brushett A. J., Michalek- 2005 Effects of Copper on the fertilisation success of the soft coral Lobophytum No Public ~ Wagner, K compactum, Aquatic Toxicology 74 {2005) 280- 284. domain A 7.4.3.4 Reichelt-Brushett A.J, Harrison 2000 The Effect of Copper on the Settlement Success of Larvae from the No Public ~ P.L. Scleractinian Coral Acropora tenuis, Marine Pollution Bulletin Vol. 41, Nos. domain 7±12, DD . 385± 391. A 7.4.3.4 Reichelt-Brushett A.J, Harrison 2004 Development of a Sublethal Test to Determine the Effects of Copper and No Public ~ P. L. Lead on Scleractinian Cora l Larvae, Arch. Environ. Contam. Toxicol. 47, 40- domain 55 A 7.4.3.4 Rosen G., Rivera-Duarte I., and 2004 Sinclair Inlet Toxicity Assessment: Puget Sound Naval Shipyard & No Public igJ Johnston, R.K. Intermediate Maintenance Facility Surface Water Copper Bioavailability and domain Toxicity Study. Environmental Sciences & Applied Systems Branch, Code 2375 Space and Naval Warfare Systems Center, U.S. Navy San Diego, CA. Draft Report. A 7.4.3.4 Spehar, R. L. and J. T. Fiandt* 1985 Acute and chronic effects of water quality criteria based metal mixtures on No Public ~ three aquatic species. Project Summary EPN6000/S3-85/074. u. s. domain Environmental Protection Agency, Environmental Research Laboratory, Duluth, Minnesota. Not GLP, Published A 7.4.3.4 Taylor E.J., S. J. Maund and D. 1991 Evaluation of a chronic toxicity test using growth of the insect Chironomus No Public igJ Pascoe.* riparius Meigen. In: Bioindicators and Environmental Management . Eds. D.W. domain Jeffrey and B. Madden. Academic Press, United Kingdom, pp. 343-352. Not GLP, Published

102 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No A 7.4.3.4 Van Leeuwen, c. J., J. L. Buchner 1988 Intermittent flow system for population toxicity studies demonstrated with No Public ~ and H. Van Dijk.* Daphnia and copper. Bulletin of Environmental Contaminat ion and Toxicology domain 40(4): 496-502. Not GLP, Published A 7.4.3.4 Williams, T.D., Hayfield, A.J. 2006 Copper: effects on the survival, development and reproduction of the marine Yes EU ~ copepod Tisbe battagliai; BEL report no. BL8295/B; GLP; Unpublished Antifouli ng Task Force A 7.4.3.4 Williams, T.D., Hayfield, A.J. 2006 Copper: effects on the survival, development and reproduction of the marine Yes EU ~ copepod Tisbe battagliai; BEL report no. BL8295/B; GLP; Unpublished Antifouli ng Task Force A 7.4.3.4 Winner, R. W.* 1985 Bioaccumulation and toxicity of copper as affected by interactions between No Public ~ humic acid and water hardness. Water Research 19(4): 449-455. Not GLP, domain Published A 7.4.3.4 Young, J.S., Gurtisen, J.M., Apts, 1979 The Relationship Between the Copper Complexing Capacity of Sea Water and No Public ~ c.w., Crecelius, E.A. Copper Toxicity in Shrimp Zoeae. Mar. Environ. Res. 2: 344-348 domain A 7.4.3.4 Young, J.S., Gurtisen, J.M., Apts, 1979 The Relationship Between the Copper Complexing capacity of Sea Water and No Public ~ C.W., Crecelius, E.A. Copper Toxicity in Shrimp Zoeae. Mar. Environ. Res. 2: 344-348 domain A 7.4.3.5 Belanger, S.E., Farris, J.L., Cherry, 1990 Va lidation of Corbicula fluminea Growth Reductions Induced by Copper in No Public ~ D.S., & cairns, Jr., J. Artificia l Streams and River Systems. Can. J. Fish. Aquat. Sci. 47: 904-914. domain Not GLP, Published A 7.4.3.5 Borgmann, u., Cover, R. & 1980 Effects of Metals on the Biomass Production Kinetics of Freshwater Copepods. No Public ~ Loveridge, c. Can. J. Fish. Aquat. Sci. 37: 567-575. Not GLP, Published . domain A 7.4.3.5 Brooks, s. 2006 The effects of dissolved organic carbon on the toxicity of Copper to the Yes EU ~ embryo of the pacific oyster. Cefas contract report C2548-1 Antifouli ng Task Force A 7.4.3.5 Brooks, s. 2006 Copper speciation and toxicity to the development of the mussel embryo. Yes EU ~ Cefas contract report CEFAS/PRO/ C1921 Antifouli ng Task Force A 7.4.3.5 Brooks, s. 2006 The effects of dissolved organic carbon on the toxicity of Copper to the Yes EU ~ embryo of the pacific oyster. Cefas contract report C2548-1 Antifouli ng Task Force A 7.4.3.5 Clements, W.H., Cherry, D.S. & 1988 Structural Alterations in Aquatic Insect Communities Exposed to Copper in No Public ~ cairns Jr., J. Laboratory Streams. Environ. Toxicol. Chem. 7: 715-722. Not GLP, Published domain A 7.4.3.5 Clements, W.H., Cherry, D.S. & 1989b The Influence of Copper Exposure on Predator-Prey Interactions in Aquatic No Public ~ cairns, Jr., J. Insect Communities. Freshwater Biology. 21 : 483-488. Not GLP, Published. domain A 7.4.3.5 Clements, W.H., Farris, J.L. , 1989a The Influence of Water Quality on Macroinvertebrate Community Responses No Public ~ Cherry, D.S. & cairns Jr., J. to Copper in Outdoor Experimental Strea ms. Aquatic Toxicol. 14: 249-262. domain Not GLP, Published

103 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No A 7.4.3.5 Girling, A.E., Pascoe, s., Janssen, 2000 Development of Methods for Eva luating Toxicity in Freshwater Ecosystems. No Public ~ C.R., Peither, A. Wenzel, A., Ecotoxicol. Environ. Safe. 45, 148-176. Not GLP, Published domain Schafer, H., Neumeier, B., Mitchell, G.C., Taylor, E.J., Maund, S.J., Lay, J.P., Juttner, I., Crossland, N.O., Stephenson, & Persoone, G. A 7.4.3.5 Hart, B.T., Currey, N.A. & Jones, 1992 Biogeochemistry and Effects of Copper, Manganese and Zinc Added to No Public ~ M.J. Endosures in Island Billa bong, Magela Creek, Northern Australia. domain Hvdrobioloaica . 230: 93-134. Not GLP, Published A 7.4.3.5 Havens, K. E 1994b Structural and Functional Responses of Freshwater Plankton Community to No Public ~ Acute Copper Stress. Environmental Pollution. 86 (3); 259-266. Not GLP, domain Published A 7.4.3.5 Havens, K.E. 1994a An Experimental Comparison of the Effects of Two Chemica l Stressor on a No Public ~ Freshwater Zooplankton Assemblage. Environmental Pollution. 84: 245-251. domain Not GLP, Published A 7.4.3.5 Hedtke, s. F. 1984 Structure and Function of Copper-Stressed Aquatic Microcosms. Aquatic No Public ~ Toxicoloav. 5: 227-244. Not GLP, Published domain A 7.4.3.5 Hurd, K. 2006 Copper: Determination of the toxicity to the larvae of the Sea Urchin Yes EU ~ (Paracentrotus lividus). Report No. BL8354/B Antifouli ng Task Force A 7.4.3.5 Hurd, K. 2006 Copper: Determination of the toxicity to the larvae of the Sea Urchin Yes EU ~ (Paracentrotus lividus). Report No. BL8354/B Antifouli ng Task Force A 7.4.3.5 Leland, H.V. & Carter, J.L 1985 Effects of Copper on Production of Periphyton, Nitrogen Fixation and No Public ~ Processing of Leaf Litter Sierra Nevada california, Stream. Freshwater domain Bioloav. 15: 155-173. Not GLP Published A 7.4.3.5 Leland, H.V. & Garter, J.L 1984 Effects of copper on Species Composition of Periphyton in a Sierra Nevada, No Public ~ California, Strea m. Freshwater Biology. 14: 281-296. Not GLP, Published domain A 7.4.3.5 Leland, H.V. & Kent, E. 1981 Effects of Copper on Microfaunal Species Composition in a Sierra Nevada, No Public ~ California Stream. Verh. Internat. Verein. Liminol. 21 : 819-829. Not GLP, domain Published A 7.4.3.5 Leland, H.V., Fend, s.v., Dudley, 1989 Effects of Copper on Species Composition of Benthic Insects in a Sierra No Public ~ T.L & Carter, J.L Nevada, Ca lifornia Stream. Freshwater Biology. 21: 163-179. Not GLP, domain Published A 7.4.3.5 Lorenzo, J.I., Nieto, o., Beiras, R. 2006 Anodic stripping voltammetry measures copper bioavailability for sea urchin No Public ~ larvae in the presence of fulvic acids. Environmenta I Toxicology and domain Chemistrv. Volume 25 Number 1 A 7.4.3.5 Moore, M.V. & Winner, R.W 1989 Relative Sensitivity of Cerodaphnia dubia Laboratory Tests and Pond No Public ~ Communities of Zooplankton and Benthos to Chronic Copper Stress. Aquatic domain Toxicoloav. 15 : 311-330. Not GLP Published A 7.4.3.5 Pesch c. E., Schauer, P.S., 1986 Effect of diet on copper toxicity to Neanthes arenaceodentata.NTIS PB 87- No Public ~ Balboni, M.A. 167128. pp. 369-383. In: T.M. Poston and R. Purdy (eds.). ASTM Special domain Technical Publication N°921: Aquatic Toxicology and Environmental Fate, Vol. 9. A Symposium Amer. Soc. Test. Mater. Philadelphia, PA, USA, 530 p.

104 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No A 7.4.3.5 Redpath, K. J. 1985 Growth Inhibition and Recovery in Mussels (Mytilus edulis) Exposed to Low No Public ~ Copper Concentrations. Journal of the Marine Biological Association of the domain United Kinadom, 65(2):421-31; Not GLP; Published A 7.4.3.5 Roesijadi, G. 1980 Influence of copper on the clam Protothaca staminea: effects on gills and No Public ~ occurrence of copper-binding proteins. Biol. Bull., 158: 233-247 domain A 7.4.3.5 Roesijadi, G. 1980 Influence of copper on the clam Protothaca staminea: effects on gills and No Public ~ occurrence of copper-binding proteins. Biol. Bull., 158: 233-247 domain A 7.4.3.5 Schafers, c. 2003 Community Level Study with Copper in Aquatic Microcosms. Fraunhofer Yes Europea ~ Institute for Molecular Biology and Applied Ecology {IME}. Fraunhofer Study n Number EECU 01. Not GLP, Unpublished Copper Institute A 7.4.3.5 Taub, F.B., Kindig, A.C., Meador, 1991 Effects of 'Seasonal Succession' and Grazing on Copper Toxicity in Aquatic No Public ~ J.P. & Swartzman, G.L. Microcosms. Verh. Internat. Verein. Limnol. 24: 2205- 2214. domain A 7.4.3.5 Winner, R.W. & Owen, H.A. 1991 Seasonal Variability in the Sensitivity of Freshwater Phytoplankton No Public ~ Communities to a Chronic Copper Stress. Aquatic. Toxicol. 19: 73-88. Not domain GLP, Published. A 7.4.3.5 Winner, R.W., Owen, H.A. & 1990 Seasonal Varia bility in the Sensitivity of Freshwater Lentic Communities to a No Public ~ Moore, M.V. Chronic Copper Stress. Aquatic Toxicology. 17: 75-92. Not GLP, Published domain A 7.4.3.5 Winner, R.W., Van Dyke, J.S., 1975 Response of the Macroinvertebrate Fauna to a Copper Gradient in an No Public ~ Garis, N. & Farrel, M.P. Experimentally Polluted Stream. Verh. I nternat . Verein. Liminol. 19: 2121- domain 2127. Not GLP, Published A 7.4.3.5.1 Torp, U.M. 1994 Assessment of sed iment-phase toxicity to the sediment reworker Corophium Yes Nord ox ~ volutator (Pa llas); TERRA Milj0-laboratorium NS Report No. 60169.sft\tm.003; GLP; Unpublished A 7.4.3.5.2 Anderson, B.S., Hunt, J.W., 1990 Copper toxicity to microscopic stages of giant kelp Macrocystis pyrifera: No Public ~ Turpen, S.L., Cou lon, A.R., Martin, interpopulation comparisons and temporal variability. Mar. Ecol. Prog. Ser. domain M. 68: 147 - 156 A 7.4.3.5.2 Brooks, s. 2006 The effects of dissolved organic carbon on the toxicity of Copper to the Yes EU ~ marine macroalgae Fucus vesiculosus. Cefas contract report C2548- 2 Antifouli ng Task Force A 7.4.3.5.2 Brooks, s. 2006 The effects of dissolved organic carbon on the toxicity of Copper to the Yes EU ~ marine macroalgae Fucus vesiculosus. Cefas contract report C2548- 2 Antifouli ng Task Force A Ahsanullah, M., Ying, w. 1995 Toxic Effects of Dissolved Copper on Penaeus mergulensis and Penaeus No Public ~ 7.4.3.5.2{2} monodon. Bull. Environ. Contain. Toxicol. {1995} 55:81-88; Not GLP; domain Published A 7.4.3.6 De Schamphelaere K., Roman, 2004 Bioavailability and ecotoxicity of copper in sediments. Ghent University Yes Europea ~ Y.E., Nguyen, L.H. and Ja nssen, Report prepared for ECI. Report Ref. PRP ENV-05-59; not GLP; Unpublished. n C.R. Copper Institute A 7.4.3.6 Milani D., T.B. Reynoldson, u. 2003 The relative sensitivity of four benthic invertebrates to metals in spiked No Public ~ Borgmann and J. Kolasa. sediment exposures and application to contaminated field sediment. Env. Tox domain and Chem 22 4 845-854· not GLP· Published.

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TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No A 7.4.3.6 Vecchi M., T.B. Reynoldson, A. 1999 Toxicity of Copper Spiked Sediments to Tubifex tubifex : Comparison of the No Public ~ Pasteris and D. Bonomi. 28-day reproductive bioassay with an early life stage bioassay. Env. Tox and domain Chem, 18, 6, 1173-1179; not GLP; Published A 7.5.1.1 Arshad, M. & Frankenberger, 1991 Effects of Soil Properties and Trace Elements on Ethylene Production in Soils. No Public ~ W.T.* Soil Science. 151, 5 : 377-386. Not GLP, Published domain A 7.5.1.1 Arshad, M. & Frankenberger, 1991 Effects of Soil Properties and Trace Elements on Ethylene Production in Soils. No Public ~ W.T.* Soil Science. 151, 5: 377-386. Not GLP, Published domain A 7.5.1.1 Bogomolov, D.M., Chen, S.K., 1996 An Ecosystem Approach to Soil Toxicity Testing: A Study of Copper No Public ~ Parmalee, R.W, Subler, s. & Contamination in Laboratory Soil Microcosms. Applied Soil Ecology. 4 : 95- domain Edwards C.A. * 105. Not GLP Published A 7.5.1.1 Bogomolov, D.M., Chen, S.K., 1996 An Ecosystem Approach to Soil Toxicity Testing : A Study of Copper No Public ~ Parmalee, R.W, Subler, s. & Contamination in Laboratory Soil Microcosms. Applied Soil Ecology. 4: 95- domain Edwards C.A. * 105. Not GLP Published A 7.5.1.1 Bollag, J-M, Barabasz, W.* 1979 Effect of Heavy Metals on the Denitrification Process in Soil. J. Environ. Qual. No Public ~ 8: (2) · 196- 201. Not GLP Published domain A 7.5.1.1 Bollag, J-M, Barabasz, W.* 1979 Effect of Heavy Metals on the Denitrification Process in Soil. J. Environ. Qual. No Public ~ 8 : (2) · 196- 201. Not GLP Published domain A 7.5.1.1 Chang, F-H. & Broadbent, F.E* 1981 Influence of Trace Metals on Carbon Dioxide Evolution from a Yolo Soil. Soil No Public ~ Science. 132: 6· 416-421. Not GLP Published. domain A 7.5.1.1 Chang, F-H. & Broadbent, F.E* 1981 Influence of Trace Metals on carbon Dioxide Evolution from a Yolo Soil. Soil No Public ~ Science. 132: 6· 416-421. Not GLP Published. domain A 7.5.1.1 Chang, F-H. & Broadbent, F.E* 1982 Influence of Trace Metals on Some Soil Nitrogen Transformations. J. Environ. No Public ~ oual. 11: 1 · 1-4. Not GLP Published. domain A 7.5.1.1 Chang, F-H. & Broadbent, F.E* 1982 Influence of Trace Metals on Some Soil Nitrogen Transformations. J. Environ. No Public ~ oual. 11: 1; 1-4 . Not GLP, Published. domain A 7.5.1.1 Doelman, P. & Haanstra, L* 1984 Short Term and Long Term Effects of cadmium, Chromium, Copper, Nickel, No Public ~ Lead and Zinc on Soil Microbial Respiration in Relation to Abiotic Soil Factors. domain Plant and Soil. 79; 317-327. Not GLP, Published. A 7.5.1.1 Doelman, P. & Haanstra, L* 1984 Short Term and Long Term Effects of cadmium, Chromium, Copper, Nickel, No Public ~ Lead and Zinc on Soil Microbial Respiration in Relation to Abiotic Soil Factors. domain Plant and Soil. 79; 317-327. Not GLP, Published. A 7.5.1.1 Doelman, P. & Haanstra, L* 1986 Short and Long Term Effects of Heavy Metals on Urease Activity in Soils. No Public ~ Biol. Fertil. Soils. 2; 213-218. Not GLP, Published. domain A 7.5.1.1 Doelman, P. & Haanstra, L* 1986 Short and Long Term Effects of Heavy Metals on Urease Activity in Soils. No Public ~ Biol. Fertil. Soils. 2; 213-218. Not GLP, Published. domain A 7.5.1.1 Doelman, P. & Haanstra, L.* 1989 Short and Long Term Effects of Heavy Metals on Phosphatase Activity in No Public ~ Soils: An Ecological Dose-Response Model Approach. Biol. Fertil. Soils. 8; domain 235- 241.Not GLP, Published. A 7.5.1.1 Doelman, P. & Haanstra, L.* 1989 Short and Long Term Effects of Heavy Metals on Phosphatase Activity in No Public ~ Soils: An Ecological Dose-Response Model Approach. Biol. Fertil. Soils. 8; domain 235- 241.Not GLP, Published. A 7.5.1.1 E. Smolders, Oorts, K 2004 Development of a predicitive model of bioavailability and toxicity of copper in Yes Europea ~ soils: microbial toxicity; Laboratory of Soil and Water Management, n Katholieke Universiteit Leuven; No report number; not GLP; Unpublished Copper Institute

106 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/Nol Yes No A 7.5.1.1 Frostegard, A, Tunlid, A. & Baath, 1993 Phospholipid Fatty Acid Composition, Biomass and Activity of Microbial No Public ~ E.* Communities from Two Different Soil Types Experimentally Exposed to domain Different Heavy Metals. App. Environ. Microbiol. 59 (11): 3605- 3617. Not GLP, Publ ished A 7.5.1.1 Frostegard, A, Tunlid, A. & Baath, 1993 Phospholipid Fatty Acid Composition, Biomass and Activity of Microbial No Public ~ E.* Communities from Two Different Soil Types Experimentally Exposed to domain Different Heavy Metals. App. Environ. Microbiol. 59 (11): 3605- 3617. Not GLP, Publ ished A 7.5.1.1 Haanstra, L. & Doelman, P.* 1984 Glutamic Acid Decomposition as a Sensitive Measure of Heavy Metal Pollution No Public ~ in Soil. Soil Biol. Biochem. 16; 595-600. Not GLP, Publ ished. domain A 7.5.1.1 Haanstra, L. & Doelman, P. * 1984 Glutamic Acid Decomposition as a Sensitive Measure of Heavy Metal Pollution No Public ~ in Soil. Soil Biol. Biochem. 16; 595-600. Not GLP, Published. domain A 7 .5.1.1 Haanstra, L. & Doelman, P. * 1991 An Ecological Dose-Response Model Approach to Short and Long Term Effects No Public l8J of Heavy Metals on Arylsulphatase Activity in Soil. Biol. Fert. Soils. 11; 18- domain 23. Not GLP Published. A 7 .5.1.1 Haanstra, L. & Doelman, P.* 1991 An Ecological Dose-Response Model Approach to Short and Long Term Effects No Public l8J of Heavy Metals on Arylsulphatase Activity in Soil. Biol. Fert. Soils. 11; 18- domain 23. Not GLP Published. A 7 .5.1.1 Hemida, S.K., Omar, S.A. & Abdel- 1995 Microbial Populations and Enzyme Activity in Soil Treated with Heavy Metals. No Public l8J Mallek, A.Y.* Water, Air. Soil Poll. 95: 13-22. Not GLP, Published . domain A 7.5.1.1 Hemida, S.K., Omar, S.A. & Abdel- 1995 Microbial Populations and Enzyme Activity in Soil Treated with Heavy Metals. No Public ~ Mallek, A.Y.* Water, Air. Soil Poll. 95: 13-22. Not GLP, Published. domain A 7 .5.1.1 Khan, M. and Scullion, J. 2002 Effects of metal (Cd, Cu, Ni, Pb or Zn) enrichment of sewage-sludge on soil No Public ~ micro-organisms and their activities. Applied Soil Ecology, 20, 145-155; not domain GLP; Published A 7 .5.1.1 Maliszewska, w., Dec, s., 1985 The Influence of Various Heavy Metal Compounds on the Development and No Public ~ Wierzbicka, H. & Wozniakowska, Activity of Soil Micro-Organisms. Environ. Poll. (Series A). 37; 195-215. Not domain A.* GLP, Publ ished A 7 .5.1.1 Maliszewska, W., Dec, s., 1985 The Influence of Various Heavy Metal Compounds on the Development and No Public ~ Wierzbicka, H. & Wozniakowska, Activity of Soil Micro-Organisms. Environ. Poll. (Series A). 37; 195-215. Not domain A.* GLP, Publ ished A 7 .5.1.1 Premi, P.R. & Cornfield, A.H.* 1969 Effects of Addition of Copper, Manganese, Zinc and Chromium Compounds on No Public ~ Ammonification and Nitrification During Incubation of Soil. Plant and Soil. domain 31: 12) ' 345-352. Not GLP Published. A 7.5.1.1 Premi, P.R. & Cornfield, A.H.* 1969 Effects of Addition of Copper, Manganese, Zinc and Chromium Compounds on No Public l8J Ammonification and Nitrification During Incubation of Soil. Plant and Soil. domain 31: 12) ' 345-352. Not GLP Published. A 7.5.1.1 Quraishi, M.S.I & Cornfield, A.H.* 1973 Incubation Study of Nitrogen Mineralisation and Nitrification in Relation to No Public l8J Soil pH and Level of Copper (II) Addition. Environ. Poll. 4; 159-163. Not GLP, domain Published. A 7.5.1.1 Quraishi, M.S.I & Cornfield, A.H .* 1973 Incubation Study of Nitrogen Mineralisation and Nitrification in Relation to No Public l8J Soil pH and Level of Copper (II) Addition. Environ. Poll. 4; 159-163. Not GLP, domain Publ ished. A 7.5.1.1 Saviozzi, A., Levi-Minzi, R., 1997 The Influence of Heavy Metals on Carbon Dioxide Evolution from A Typic No Public l8J cardelli, R. & Riffaldi, R* Xerochrept Soil. Water, Air Soil Poll. 93: 409-417 (published) . domain A 7.5.1.1 Saviozzi, A., Levi-Minzi, R., 1997 The Influence of Heavy Metals on Carbon Dioxide Evolution from A Typic No Public l8J cardelli, R. & Riffaldi, R* Xerochrept Soil. Water, Air Soil Poll. 93: 409-417 (published). domain

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TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No A 7.5.1.1 Skujins, J., Nohrstedt, H-0., Oden, 1986 Development of a Sensitive Biological Method for the Determination of a No Public ~ S.* Low-Level Toxic Contamination in Soils. Swedish J. Agric. Res . 16; 113- domain 118.Not GLP, Published A 7.5.1.1 Skujins, J., Nohrstedt, H-0., Oden, 1986 Development of a Sensitive Biological Method for the Determination of a No Public ~ S.* Low-Level Toxic Contamination in Soils. Swedish J. Agric. Res. 16; 113- domain 118.Not GLP, Published A 7.5.1.1 Speir, T.W., Kettles, H.A., Percival, 1999 Is Soil Acidification the Cause of Biochemical Response when Soils are No Public ~ H.J. & Parshotam, A* Amended with Heavy Metal Sa lts? Soil Biology and Biochemistry. 31: 1953- domain 1961. Not GLP, Published A 7.5. 1.1 Speir, T.W., Kettles, H.A., Percival, 1999 Is Soil Acidificat ion the Cause of Biochemical Response when Soils are No Public ~ H.J. & Parshotam, A* Amended with Heavy Metal Salts? Soil Biology and Biochemistry. 31: 1953- domain 1961. Not GLP, Published A 7.5.1.2/ van Gestel, C.A.M., van Dis, W.A., 1991 Influence of Cadmium, Copper and Pentachlorophenol on Growth and Sexual No Public ~ 7.5.6 Dirven-van Breeman, E.M., Development of Eisenia andrei {O ligochaeta; Annelida). Biology and Fertility domain Sparenburg, P.M. & Baerselman, of Soils. 12; 117-121. Not GLP, Published. R.* A 7.5.1.2/ van Gestel, C.A.M., van Dis, W.A., 1991 Influence of Cadmium, Copper and Pentachlorophenol on Growth and Sexual No Public ~ 7.5.6 Dirven-van Breeman, E.M., Development of Eisenia andrei {Oligochaeta; Annelida). Biology and Fertility domain Sparenburg, P.M. & Baerselman, of Soils. 12; 117-121. Not GLP, Published. R.* A 7 .5.1.2/ Spurgeon, D.J. & Hopkin, S.P.* 1995 Extrapolation of the Laboratory-Based OECD Earthworm Toxicity Test to No Public ~ 7.5.6/ Metal-Contaminated Field Sites. Ecotoxicity. 4; 190-205 domain 7.5.2.1 A 7 .5.1.2/ Spurgeon, D.J. & Hopkin, S.P.* 1995 Extrapolation of the Laboratory-Based OECD Earthworm Toxicity Test to No Public ~ 7.5.6/ Metal-Contaminated Field Sites. Ecotoxicity. 4; 190- 205 domain 7.5.2.1 A 7 .5.1.2/ Svendsen, C. & Weeks, J.M* 1997a Relevance and Applicability of a Simple Earthworm Biomarker of Copper No Public ~ 7.5.6 Exposure. I. Links to Ecological Effects in a Laboratory Study with Eisenia domain andrei. Ecotoxicolonv and Environmental Safetv. 36' 72-79 A 7 .5.1.2/ Svendsen, c. & Weeks, J.M* 1997a Relevance and Applicability of a Simple Earthworm Biomarker of Copper No Public ~ 7.5.6 Exposure. I. Links to Ecological Effects in a Laboratory Study with Eisenia domain andrei. Ecotoxicolonv and Environmental Safetv. 36' 72-79 A 7 .5.1.2/ Martin, N.A.,* 1986 Toxicity of Pesticides to Allolobophora caliginosa {Oligochaeta: Lumbricidae) . No Public ~ 7.5.2.1 New Zealand Journal of Agricultural Research. 29; 699-706. Not GLP, domain Published. A 7 .5.1.2/ Martin, N.A.,* 1986 Toxicity of Pesticides to Allolobophora ca liginosa {Oligochaeta: Lumbricidae) . No Public ~ 7.5.2.1 New Zealand Journal of Agricultural Research. 29; 699-706. Not GLP, domain Published. A 7.5.2.1 Herbert IN, Svendsen C, Hankard 2004 Comparison of instantaneous rate of population increase and critical-effect No Public ~ PK and Spurgeon DJ estimates in Folsomia candida exposed to four toxicants. Ecotox. Environ. domain Safetv 57 :175-183' not GLP· Published A 7.5.2.1 Kammenga, J.E., Van Koe rt, 1996 A Toxicity Test in Artificial Soil based on the Life History Strategy of the No Public ~ P.H.G., Riksen, J.A.G., Korthals, Nematode Plectus acuminatus. Environmental Toxicology and Chemistry. domain G.W. & Bakker, J.* 15; 722-727. Not GLP, Published. A 7.5.2.1 Kammenga, J.E., Van Koe rt, 1996 A Toxicity Test in Artificial Soil based on the Life History Strategy of the No Public ~ P.H.G., Riksen, J.A.G., Korthals, Nematode Plectus acuminatus. Environmental Toxicology and Chemistry. domain G.W. & Bakker, J.* 15; 722-727. Not GLP, Published.

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TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/Nol Yes No A 7.5.2.1 Lock, K., Janssen, C.R. 2001 Test designs to assess the influence of Soil Characteristics on the Toxicity of No Public ~ Copper and Lead to the Oligochaete Enchytraeus albidus; Ecotoxicology, 10, domain 137-144; not GLP; Published A 7.5.2.1 Ma, W-C.,* 1988 Toxicity of Copper to Lumbricid Earthworms in Sandy Agricultural Soils No Public ~ Amended with cu-Enriched Organic Waste Materials. Ecological Bulletins. 39; domain 53-56. Not GLP, Published. A 7.5.2.1 Ma, W-C.,* 1988 Toxicity of Copper to Lumbricid Earthworms in Sandy Agricultural Soils No Public ~ Amended with cu-Enriched Organic Waste Materials. Ecological Bulletins. 39; domain 53-56. Not GLP, Published. A 7.5.2.1 P. Criel, K.A.C. De Schamphelaere 2005 Development of a predictive model of bioavailability and toxicity of copper in Yes Europea ~ and C. R. Janssen soils Invertebrate toxicity; Laboratory of Environmental Toxicology and n Aquatic Ecology, Ghent University; No Report number; not GLP; Unpublished Copper Institute A 7.5.2.1 Pedersen, M. B., van Gestel, 2001 Toxicity of copper to the collembolan Folsomia fimetaria in relation to the age No Public ~ C.A.M. of soil contamination; Ecotoxicology and Environmental Safety, 49, 54-59; domain not GLP· Published A 7.5.2.1 Pedersen, M. B., van Gestel, 2000 Effects of copper on reproduction of two collembolan species exposed No Public ~ C.A.M ., Elmegaard, N. through soil, food and water. Environmental Toxicology and Chemistry, 19, domain 10 2579-2588' not GLP· Published A 7.5.2.1 Rundgren s. & Van Gestel, C.A.M. 1988 Comparison of Species Sensitivity. In: Handbook of Soil Invertebrate No Public ~ Toxicity Tests. pp 41-55 Ed. H. Lokke and C.A.M. Van Gestel. J. Wiley and domain Sons Ltd Chichester UK· not GLP· Published. A 7.5.2.1 Sandifer, R.D & Hopkin, S.P. 1997 Effects of Temperature on the Relative Toxicities of Cd, Cu, Pb and Zn to No Public ~ Folsomia candida (Collembola). Ecotoxicology and Environmental Safety. 37; domain 125-130' not GLP· Published A 7.5.2.1 Spurgeon DJ, Svendsen C, Kille P, 2004 Responses of earthworms {Lumbricus rubellus) to copper and cadmium as No Public ~ Morgan AJ, Weeks JM. determined by measurement of juvenile traits in a specifically designed test domain svstem. Ecotoxicol Environ Saf. 57 fl) 54-64' not GLP· Published A 7.5.2.1 van Dis, W.A., Van Gestel, C.A.M., 1988 Ontwikkeling van een toets ter bepaling van sublethale effecten van No Public ~ and Sparenburg, P.M. chemische stoffen op regenwormen; RIVM expert report 718480002; not domain GLP· Published A 7.5.2.1 Van Gestel, C.A.M. & Doornekamp, 1998 Tests of the Oribatid mite Playnothrus peltifer. In Handbook of Soil No Public ~ A.* Invertebrate Toxicity Tests. Ed. H. Lokke and C.A.M. Van Gestel. J. Wiley and domain Sons Ltd Chichester UK. Not GLP Published. A 7.5.2.1 Van Gestel, C.A.M. & Doornekamp, 1998 Tests of the Oribatid mite Playnothrus peltifer. In Handbook of Soil No Public ~ A.* Invertebrate Toxicity Tests. Ed. H. Lokke and C.A.M. Van Gestel. J. Wiley and domain Sons Ltd, Chichester, UK. Not GLP, Published. A 7.5.2.1 van Gestel, C.A.M., Van Dis, W.A., 1989 Development of a Standardised Reproduction Toxicity Test with the No Public 18] Breemen, E.M. & Sparenburg, P.M. Earthworm Species Eisenia fetida andrei Using Copper, Pentachlorophenol domain and 2, 4-Dichloroaniline. Ecotoxicol. Environ. Safety. 18: 305-312; not GLP; Published. A 7.5.2.1 Van Gestel, C.A.M., Van Dis, W.A., 1989 Development of a Standardised Reproduction Toxicity Test with the No Public ~ Breemen, E.M. & Sparenburg, Earthworm Species Eisenia fetida andrei Using Copper, Pentachlorophenol domain P.M .* and 2, 4-Dichloroaniline. Ecotoxicol. Environ. Safety. 18: 305-312. Not GLP, Published. A 7.5.2.1 Van Gestel, C.A.M., Van Dis, W.A., 1989 Development of a Standardised Reproduction Toxicity Test with the No Public 18] Breemen, E.M. & Sparenburg, Earthworm Species Eisenia fetida andrei Using Copper, Pentachlorophenol domain P.M.* and 2, 4-Dichloroaniline. Ecotoxicol. Environ. Safety. 18: 305-312. Not GLP,

109 Dicopper oxide PT 21 Product-type 21 January 2016

A 7.5.2.2 Ali, N. A., Ater, M., Sunahara, G., 2004 Phytotoxicity and bioaccumulation of copper and chromium using barley No Public ~ Robidoux, P.Y. (Hordeum vulgare L.) in spiked artificial and natural forest soils. domain Ecotoxicology and Environmental Safety Volume 57, Issue 3 , March 2004, Paaes 363-374· not GLP· Published A 7.5.2.2 Alva, A.K., Graham, J.H. & Tucker, 1993 Role of Calcium in Amelioration of Copper Phytotoxicity for Citrus. Soil No Public ~ D.P.H.* Science. 155· 3· 211-218. Not GLP Published. domain A 7.5.2.2 Belanger, A., Levesque, M.P. & 1987 The Influence of Variation in Soil Copper on the Yei ld and Nutrition of No Public ~ Mathur, S.P.* Rad ishes Grown in Microplots on Two Peat Soils. International Peat Journal. domain 2; 65-73.Not GLP, Published. A 7.5.2.2 Belanger, A., Levesque, M.P., 1987 The influence of variation in soil copper on the yield and nutrition of radishes No Public ~ Mathur, S.P. grown in microplots on two peat soils. International Peat Journal, 2, 65-73; domain not GLP· Publ ished A 7.5.2.2 Brun LA, Le Corff J, Maillet J. 2003 Effects of elevated soil copper on phenology, growth and reproduction of five No Public ~ ruderal plant species. Environ Pollut. 2003;122(3): 361-8; not GLP; Published domain A 7.5.2.2 Chhibba, I. M. Nayyar, V.K. & 1994 Upper Critical Level of Copper in Wheat (Triticum aestivum) Raised on Typic No Public ~ Takkar, P.N.* Ustipsamment Soil. Indian Journal of Agricultural Sciences. 64 (5); 285-289 domain Not GLP, Published. A 7.5.2.2 de Haan, s., Rethfeld, H. & van 1985 Acceptable Levels of Heavy Metals (Cd, Cr, Cu, Ni, Pb, Zn) in Soils, No Public ~ Oriel, w. Depending on their Clay and Human Content and Cation-Exchange Capacity. domain Instituut Voor Bodemvruchtbaarheid Haren-Gr. Report No. 0434-6793 (published). A 7.5.2.2 de Haan, s., Rethfeld, H. & van 1985 Acceptable Levels of Heavy Metals (Cd, Cr, Cu, Ni, Pb, Zn) in Soils, No Public ~ Oriel, W.* Depending on their Clay and Human Content and Cation-Exchange Capacity. domain Instituut Voor Bodemvruchtbaarheid Haren-Gr. Report No. 0434-6793. Not GLP, Publ ished A 7.5.2.2 Jarvis, S.C. 1978 Copper Uptake and Accumulation by Perennial Ryegrass Grown in Soil and No Public ~ Solution Culture. J. Sci. Fd. Aoric. 29 : 12-18 (published). domain A 7.5.2.2 Jarvis, s.c. * 1978 Copper Uptake and Accumulation by Perennial Ryegrass Growth in Soil and No Public ~ Solution culture. J. Sci. Food. Agric. 29: 12-18. Not GLP, Published . domain A 7.5.2.2 Kalyanaraman, S.B. & 1993 Effect of cadmium, Copper and Zinc on the Growth of Blackgram. Journal of No Public ~ Sivaaurunathan P. * Plant Nutrition. 16 110) 2029-2042. Not GLP Published. domain A 7.5.2.2 Kjcer, c. & Elmegaard. N. 1996 Effects of Copper Sulphate on Black Bindweed (Polygonum convolvulus L.) No Public ~ Ectoxicology and Environmental Safety. 33; 110-117 (published). domain A 7.5.2.2 Kjcer, C. & Elmegaard. N.* 1996 Effects of Copper Sulphate on Black Bindweed (Polygonum convolvulus L.) No Public ~ Ectoxicology and Environmental Safety. 33; 110-117. Not GLP, Published domain A 7.5.2.2 Korthals, G.W., Alexiev, A.D., 1996a Long Term Effects of Copper and pH on the Nematode Community in an No Public ~ Lexmond, T.M., Kammenga, J.E. & Agrosystem. Environ. Toxicol. Chem. 15 (6): 979-985. Not GLP, Published. domain Bongers, T.*

A 7.5.2.2 Lexmond, T. M.* 1980 The Effect of Soil pH on Copper Toxicity to Forage Maize Grown Under Field No Public ~ Conditions. Neth. J. Agric. Sci. 28: 164-183. Not GLP, Published. domain A 7.5.2.2 Lexmond, T.M. 1980 The effect of soil pH on copper toxicity to forage maize grown under field No Public ~ conditions. Neth. J. Agric. Science 28, 164-183; not GLP; Published domain A 7.5.2.2 McBride, M.B.* 2001 Cupric Ion Activity in Peat Soil as a Toxicity Indicator for Maize. Journal of No Public ~

110 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No Environmental Quality. 30; 78-84. Not GLP, Published domain A 7.5.2.2 Pedersen, M. B., Kjcer, c. 2000 Toxicity and Bioaccumulation of Copper to Black Bindweed (Fallopia No Public 18] Elmegaard, N. convolvulus) in Relation to Bioavailability and the Age of Soil Contamination. domain Archives of Environmental Contamination and Toxicology. 39; 431 -439 loublishedl. A 7.5.2.2 Pedersen, M. B., Kjcer, c. 2000 Toxicity and Bioaccumulation of Copper to Black Bindweed (Fallopia No Public 181 Elmegaard, N.* convolvulus) in Relation to Bioavailability and the Age of Soil Contamination. domain Archives of Environmental Contamination and Toxicology. 39; 431-439. Not GLP, Published. A 7.5.2.2 Rhoads, F.M., Barnett, R.D. & 1992 Copper Toxicity and Phosphorus Concentration in 'Florida 502' Oats. Soil No Public 181 Olson, S.M.* Crop Science Society Florida Proceedings. 51; 18-20. Not GLP, Published. domain A 7.5.2.2 Rhoads, F. M., Barnett, R.D., 1992 Copper toxicity and phosphorous concentration in "Florida 502" oats. Soil and No Public 181 Olson, S.M Crop Science of Florida, 51 :18-20; not GLP; Published domain A 7.5.2.2 Rooney, C.P, McGrath, S.P, Zhao, 2004 Development of a predicitive model of bioavailability and toxicity of copper in Yes Europea 18] F.J., Davis, M.R.H., Zhang, H. soils: biological endpoints: Plant toxicity and effects of shock on microbial n communities; Agricu ltural and Environment Division, Rothamsted Research; Copper No reoort number· not GLP· Unoublished Institute A 7.5.2.2 Roth, J.A., Wallihan, E.F. & 1971 Uptake by Oats and Soybeans of Copper and Nickel Added to a Peat Soil. Soil No Public 18] Sharpless, R.G* Science. 112; 5; 338-342. Not GLP, Published domain A 7.5.2/ Sandifer, R.D. & Hopkin, s. P.* 1996 Effects of pH on the Toxicity of Cadmium, Copper, Lead and Zinc to Folsomia No Public 18] 7.5.2.1 candida Willem, 1902 (Collembola) in a Standard La boratory Test System. domain Chemosohere. 33: 12; 2475-2486. Not GLP, Published. A 7.5.2/ Sandifer, R.D. & Hopkin, s. P. * 1996 Effects of pH on the Toxicity of Cadmium, Copper, Lead and Zinc to Folsomia No Public ~ 7.5.2.1 candida Willem, 1902 (Collembola) in a Standard Laboratory Test System. domain Chemosohere. 33: 12; 2475-2486. Not GLP, Published. A 7.5.3.1.1 Dickhaus, s. 1988 Acute Toxicologica l Study of Kupfer-I-Oxid After Oral Application to the Yes Spiess- ~ Quail; Pharmatox GmbH, project no. 1-8-43-88; GLP; Unpublished Urania A 7.5.4.1 Hoxter, K.A., Lynn, S.P. 1991 Cuprous oxide - Agro grade: An acute contact toxicity study with the honey Yes Nord ox 18] bee; Wildlife International Ltd. Project No. 303-lOl B; GLP; Unpublished A 7.5.6 Augustsson, A. K., & Rundgren, S* 1998 The Enchytraeid Cognettia sphagnetorum in Risk Assessment: Advantages No Public 181 and Disadvantages. Ambio. 27; 62-69. Not GLP, Published. domain A 7.5.6 Bogomolov, D.M., Chen, S.K., 1996 An Ecosystem Approach to Soil Toxicity Testing: A Study of Copper No Public 181 Parmalee, R.W, Subler, s. & Contamination in Laboratory Soil Microcosms. Applied Soil Ecology. 4; 95- domain Edwards C.A. * 105. Not GLP Published. A 7.5.6 Jaggy, A. & Streit, B. * 1982 Toxic Effects of Soluble Copper on Octolasium cyaneum sav. ( lumbricidae). No Public 18] Rev. Suisse De Zoologie. 89; 4: 881-889. Not GLP, Published. domain A 7.5.6 Kah ii, M.A., Abdel-Lateif, H.M., 1996b Effects of Metals and Metal Mixtures on Survival and Cocoon Production of No Public 18] Bayoumi, B.M, van Straalen, N.M. the Earthworm Aporrectodea ca liginosa. Pedobiology. 40; 548- 556 .Not GLP, domain & van Gestel, C.A.M.* Published. A 7.5.6 Khalil, M.A., Abdel-Lateif, H.M., 1996a Analysis of Separate and Combined Effects of Heavy Metals on the Growth of No Public 18] Bayou mi, B. M. & van Straalen, Aporrectodea caliginosa (Oligochaeta; Annelida), Using the Toxic Unit domain N.M.* Annroach. Annlied Soil Ecoloav. 4 ' 213-219.Not GLP Published. A 7.5.6 Korthals, G.W, Van de Ende, A., 1996b Short-Term Effects of Cadmium, Copper, Nickel and Zinc on Soil Nematodes No Public 18] Van Megen, H., Lexmond, T.M., from Different Feeding and Life-History Strategy Groups. App. Soil. Ecology. domain Kammenga, J.E. & Bongers, T. 4, 107-117. GLP, published

111 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No A 7.5.6 Korthals, G.W., Alexiev, A.O., 1996a Long Term Effects of Copper and pH on the Nematode Community in an No Public ~ Lexmond, T.M., Kammenga, J.E. & Agrosystem. Environ. Toxicol. Chem. 15 (6): 979-985. Not GLP, Published. domain Bongers, T.*

A 7.5.6 Korthals, G.W., van de Ende, A., 1996 Short-Term Effects of cadmium, Copper, Nickel and Zinc on Soil Nemat odes No Public ~ van Megen, H., Lexmond, T.M., from Different Feed ing and Life History Strategy Groups. Applied Soil. domain Kammenga, J. & Bongers, T. * Ecology. 4; 107- 117. Not GLP, Published.

A 7.5.6 Ma, W.C. * 1982 The I nfluence of Soil Properties and Worm Related Factors on the No Public ~ Concentration of Heavy Metals in Earthworms. Pedobiologica . 24; 109-119. domain Not GLP, Published. A 7.5.6 Parmalee, R. w., Wentsel, R.S., 1993 Soil Microcosm for Testing the Effects of Chemical Pollutants on Soil Fauna No Public ~ Phillips, C.T., Simini, M. & Checkai, Communities and Trophic Structure. Environ. Toxicol. Chem. 12; 1477- domain R.T.* 1486. Not GLP, Published. A 7.5.6 Scott-Fordsmand, J.J., Krogh P.H. 1997 Sublethal Toxicity of Copper to a Soil-Dwelling Springtail {Folsomia fimetaria) No Public ~ & Weeks, J.M.* {Collembola: Isotomidae). Environmental Toxicology and Chemistry, 16: 12; domain 2538- 2542.Not GLP, Published. A 7.5.6 Svendsen, C. & Weeks, J. M.* 1997b Relevance and Applicability of a Simple Earthworm Biomarker of Copper No Public ~ Exposure. II Validation and Applicability Under Field Conditions in a domain Mesocosm Experiment with Lumbricus rubellus. Ecotoxicol. Environ. Saf. 36, 80-88. Not GLP, Published. A 7.5.6/ Kula, H. & Larink, O.* 1997 Development and Standardisation of Test Methods for the Prediction of No Public ~ 7.5.2.1 Sublethal Effects of Chemicals on Earthworms. Soil Biology and Biochemistry. domain 29: 3/ 4; 635-639. Not GLP, Published. A 7.5.6/ Spurgeon, D.J., Hopkin, S.P. & 1994 Effects of Cadmium, Copper, Lead and Zinc on Growth, Reproduction and No Public ~ 7.5.2.1 Jones, D.T.* Survival of the Earthworm Eisenia fetida {Savigny): Assessing the domain Environmental Impact of Point-Source Metal Contamination in Terrestrial Ecosystems. Environmental Pollution. 84; 123-130. Not GLP, Published. A 7.5.6/ Bengtsson G., Gunnarsson, T. & 1986 Effects of Metal Pollution on the Earthworm Dendrobaena rubida {Sav) in No Public ~ 7.5.2.1 Rundgren, S. * Acified Soils. Water, Air and Soil Pollution. 28; 361-383 domain A 7.5.6/ Krogh, P.H. & Axelsen, J.A.* 1998 Test on the Predatory Mite Hypoaspis aculeifer Preying on the Collembolan No Public ~ 7.5.2.1 Folsomia fimetaria. In: Handbook of Soil I nvertebrate Toxicity Tests. pp domain 239- 251. Ed. H. Lokke and C.A.M. Van Gestel. J. Wiley and Sons Ltd, Chichester UK. Not GLP Published. A 7.5.6/ Rundgren S. & Van Gestel, C.A.M 1998 Comparison of Species Sensitivity. I n : Handbook of Soil Invertebrate No Public ~ 7.5.2.1 Toxicity Tests. pp 95-112 Ed. H. Lokke and C.A.M. Van Gestel. J. Wiley and domain Sons Ltd Chichester UK. Not GLP.

112 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No A 7.5.6/ Ma, W-C.* 1984 Sublethal Toxic Effects of Copper on Growth, Reproduction and litter No Public ~ 7.5.2.1 Breakdown Activity in the Earthworm Lumbricus rubellus, with Observations domain on the Influence of Temperature and Soil pH. Environmental Pollution {Series Al. 33; 207- 219. Not GLP, Published. A 7.5.6/ Scott-Fordsmand, J.J., Krogh, P.H 2oooa Responses of Folsomia fimetaria {Collembola : Isotomidae) to Copper Under No Public ~ 7.5.2.1 & Weeks, J.M.* Different Soil Copper Contamination Histories in Relation to Risk Assessment. domain Environmental Toxicology and Chemistry. 19: 5; 1297-1303 Not GLP, Published A 7.5.6/ Scott-Fordsmand, J.J., Weeks, J.M 2000b Importance of Contamination History for Understanding Toxicity of Copper to No Public ~ 7.5.2.1 & Hopkins, S.P.* Earthworm Eisenia fetica (Oligochaeta: Annelida), Using Neutral Red domain Retention Assay. Environmental Toxicology and Chemistry. 19: 7; 1774- 1780. Not GLP, Published. IIA Abril, G., Nogueira, M., Etcheber, 2002 Behaviour of Organic Carbon in Nine Contrasting European Estuaries. No Public ~ H., Cabe~adas, G., Lemaire, E., Estuarine, Coastal and Shelf Science, 54, 2002, 241-262 domain Brogueira, M.J.

IIA Ahner, B. A. and F. M. M. Morel 1995 Phytochelat in production in marine algae: I. An intraspecies comparison. No Public ~ Limnoloov and Oceanoaraohv 40. domain IIA Ahner, B. A. and F. M. M. Morel 1995 Phytochelat in production in marine algae: II. I nduction by various metals. No Public ~ Limnoloov and Oceanoaraohv 40 : 658-665. domain IIA Ahner, B. A., Morel, F. M. M., 1997 Trace metal control of phytochelatin production in coastal waters. limnol. No Public ~ Moffett, J.W. Oceanoar., 42131, 601-608 domain IIA Ahsanullah M, Negilski D S and 1981 Toxicity of Zinc, Cadmium and Copper to the Shrimp Callianassa No Public ~ Mobley M c australiensis. I. Effects of Individual Metals. Marine Biology 64, 299-304. domain IIA Ahsanullah, M. & Williams, A.R. 1991 Sublethal Effects and Bioaccumulation of Cadmium, Chromium, Copper and No Public ~ Zinc in the Marine Amphipod, Allorchestes compressa . Mar. Biol; Not GLP; domain Published IIA Aldenberg T. RIVM Bilthoven NL 2007 Technical memo NickelGOFOl.doc, 1st Draft, Dec. 2007 "Comments on No Public ~ Distribution Fitting of Species Sensitivity Distributions in EU Risk Assessment domain Reoorts lwith soecial emohasis on Nickel comooundsl" IIA Aldenberg T. RIVM Bilthoven NL 2007 Technical memo NickelGOFOl.doc, 1st Draft, Dec. 2007 "Comments on No Public ~ Distribution Fitting of Species Sensitivity Distributions in EU Risk Assessment domain Reoorts lwith soecial emohasis on Nickel comooundsl" IIA Aldenberg T., Slob W. 1993 Confidence limits for hazardous concentrations based on logistically No Public [81 distributed NOEC toxicity data. Ecotox. Environ. Saf. 25, 48-63. domain IIA Aldenberg T., Jaworska J.S. 2000 Uncertainty of the hazardous concentration and fraction affected to normal No Public ~ species sensitivity distributions. Ecotoxicol. and Environ. Saf. 46:1-18. domain IIA Al len, H.E. et al 1999 Integrated Approach to Assessing The Bioavailability and Toxicity of Metals in No Public ~ Surface Waters and Sediments - Addendum & Appendices. US EPA, USA domain IIA Alutoin, s, Boberg, J, Nystrom, M, 2001 Effects of the multiple stressors copper and reduced sa linity on the No Public ~ Tedengren, M metabolism of the hermatypic coral Porites lutea domain IIA American Society for Testing an d 2003 ASTM E1218 - 04e1 Standard Guide for Conducting Static Toxicity Tests with No Public [81 Materials Microalgae. In: ASTM Volume 11.06, August 2007. Biological Effects and domain Environmental Fate · Biotechnolnnv IIA Anderson B., J. Hunt, W. Piekarski, 1995 Influence of sa linity on copper and azide toxicity to larval Topsmelt No Public [81 B. Phillips, M. Englund, {Atherinopsis affinis). Arch. Env. Contam.Toxicol. 29, 366-372 domain R.Tieerdena J. Goetz!

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TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPANY) COMPANY, DATA OWNER Essential Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation ( Yes/ Nol Yes No IIA Anderson, s and Kausky, L. 1996 Copper effects on reproductive stages of Baltic Sea Fucus vesiculosus; No Public ~ Marine Biolocv 125:171-176 domain IIA Apte SC, Ga rdner MJ, Ravenscroft 1990 Examination of the range of copper complexing ligands in natural waters No Public ~ JE, Turrell JA, using a combination of cathodic stripping voltammetry and computer domain simulation. Analvtica Ch imica Acta 235, 287-297. IIA Arnold, W. R. 2005 Effects of Dissolved Organic Carbon on Copper Toxicity: Implications for No Public ~ Saltwater Copper Criteria. Integrated Environ mental Assessment and domain Manacement, Volume: 1 I ssue: 1 Paces: 34- 39 IIA Arnold, W. R. 2005 Effects of Dissolved Organic carbon on Copper Toxicity: Implications for No Public ~ Saltwater Copper Criteria. Integrated Environ mental Assessment and domain Manacement, Volume : 1 I ssue: 1 Paces: 34-39 IIA Arnold, W. R. 2007 pers comm Public ~ domain IIA Arnold, w. R. et. al. 2007 Effects of using synthetic sea salts when measuring and modeling copper No Public ~ toxicity in sa ltwater toxicity tests. Env. Tox. & Chem., Vol. 26, No. 5, pp. domain 935- 943 IIA Baeyens et al 1987 Trace metals in the eastern part of the North Sea : 1: Analyses and short- No Public ~ term distributions. Oceanol. Acta 1012\: 169-179 domain IIA Baeyens et al 1987 Trace metals in the eastern part of the North Sea : 2. Flows of Cd, Cu, Hg, Pb No Public ~ and Zn through the coastal area . Oceanol. Acta 10{3): 301- 309 domain IIA Baker, A., Spencer R.G.M., 2004 Characterization of dissolved organic matter from source to sea using No Public ~ fluorescence and absorbance spectroscopy. Science of t he Total domain Environment 33 217-232 IIA Balls PW, 1986 Composition of suspended particulate matter from Scottish coastal waters - No Public ~ geochemical implications for the transport of metal contaminants. Sci.Total domain Environ. 57 174-180. IIA Balls PW, 1988 The control of trace metal concentrations in coastal seawater through No Public ~ partition onto suspended particu lar matter. Neth.J. Sea Res. 22, 2 13- 218. domain IIA Balls PW, 1989 The pa rtition of trace metals between dissolved and particulate phases in No Public ~ European coastal waters: a compilation of field data and comparison with domain laboratory studies. Neth.i.Sea Res. 23, 7-14; IIA Beaumont A.R., Tserpes, G., Budd, 1987 Some effects of copper on the veliger larvae of the mussel Mytilus edulis and No Public ~ M.D. the scallop Pecten maximus. Mar. Environ. Res., 21: 299-309. domain IIA Bellas, J., Beiras, R., Vazquez, E. 2004 Sublethal Effects of Trace Metals {Cd, Cr, Cu, Hg) on Embryogenesis and No Public ~ Larval Settlement of the Ascidian Ciona intestinalis Arch. Environ. Contam. domain Toxicol. 46, 61- 66 (2004) IIA Benoit G, Oktay-Marshall SD, 1994 Partitioning of Cu, Pb, Ag, Zn, Fe, Al and Mn between filtered-retained No Public ~ cantu II A, Hood EM, Coleman CH, particles, colloids and solution in six Texas estuaries. Marine Chemistry 45, domain Corapciog lu MO, Santschi PH, 307-336.

IIA Betzer S.B., Yevich, P.P. 1975 Copper toxicity in Busycon canaliculatum. Biol. Bull., 148 :16-25. No Public ~ domain IIA Blanchard, J., Grosell, M. 2006 Copper toxicity across salinities from freshwater to seawater in the No Public ~ euryhaline fish Fundulus heteroclitus: Is copper an ionoregulatory toxicant in domain hiah salinities? Aauatic Toxicoloav 80 (2006) 131- 13 IIA Blanck H. 2002 A critical review of procedures and approaches used for assessing Pollutant No Public ~ Induced Community Tolerance {PICT) in biotic communities. Human and domain

114 Dicopper oxide PT 21 Product-type 21 January 2016

IIA Blust, R., Kockelbergh, E., 1992 Effect of salinity on the uptake of cadmium by the brine shrimp Artemia No Public ~ Baillieu l, M., franciscana. Mar. Ecol. Prog. Ser. 84, 245- 254. domain IIA Brand L E., Sunda, W.G., Guillard, 1986 Reduction of marine phytoplankton reproduction rates by copper and No Public ~ R.R.L cadmium. Journal of experimental marine biology and ecology 96: 225-250. domain IIA Brand L E., Sunda, W.G., Guillard, 1986 Reduction of marine phytoplankton reproduction rates by copper and No Public ~ R.R.L cadmium. Journal of experimental marine biology and ecology 96: 225-250. domain IIA Bryan G.W. & Hummerstone LG. 1971 Adaptation of the Polychaete Nereis diversicolor to Estuarine Sediments No Public ~ Containing High Concentrations of Heavy Metals. I. General Observations and domain Adaotation to Coooer. J. Mar. Biol. Assoc. U.K. 51, 845-863. IIA Buck, K. N. and K.W. Bruland, K. W. 2005 Copper speciation in San Francisco Bay: a novel approach using multiple No Public ~ analvtical windows. Marine Chemistrv, 96: 185-198 domain IIA Buck, K.N. and K.W. Bruland, K.W. 2005 Copper speciation in San Francisco Bay: a novel approach using multiple No Public ~ analvtical windows. Marine Chemistrv, 96: 185-198 domain IIA Burton JD, Althaus M, Millward GE, 1993 Processes influencing the fate of trace metals in the North Sea. No Public ~ Morris AW, Statham PJ, Tappin Phil.Trans.R.Soc.Lond.A 343, 557- 568. domain AD, Turner A, IIA cadee, G.c., 1982 Tidal and seasonal variation in particulate and dissolved organic carbon in No Public ~ the Western Dutch Wadden Sea and Marsdiep Tidal inlet . Netherlands domain Journal of Sea Research 1512) 1982 228-249 IIA calabrese A., Maci nnes, J.R., 1977 Survival and growth of bivalve larvae under heavy metal stress. Mar. Biol., No Public ~ Nelson, D.A., Miller, J.E. 41:179- 184. domain

IIA calabrese, A., Macinnes, Nelson, 1984 Effects of Long-Term Exposure to Silver or Copper on Growth, No Public ~ D.A, Greig, R.A. & Yevich, P.P. Bioaccumulation and Histopathology in the Blue Mussel, Mytilus edulis. Mar. domain Environ. Res . 11: 253-274; Not GLP; Published IIA canterford, G.S., Buchanan, A.S. 1978 Accumulation of Heavy Metals by the Marine Diatom Ditylum brightwelli No Public ~ & Ducker, s .c . {West) Grunow. Aust. J. Freshwater Res. 29: 613-22; Not GLP; Published domain IIA cauwet G, Miller A, Brasse s, 1997 Dissolved and particulate organic carbon in the western Mediterranean Sea. No Public ~ Fengler G, Mantoura RFC, Spitzy Deep Sea Research II, 44, 3-4, 769-779. domain A, IIA CDA 2007 pers comm No Public ~ domain IIA Cervantes c, Gutierrez-Corona F. 1994 Copper resistance mechanisms in bacteria and fungi. FEMS Microbial Rev. No Public ~ 14(2):121-37. domain IIA Chiffoleau J-F, Cossa D, Auger D, 1994 Trace metal distribution, partition and fluxes in the Seine estuary {France) in No Public ~ Truauet I, low discharae reaime. Marine Chemistrv 47, 145-158. domain IIA Chung l .K., Brinkhuis, B.H. 1986 Copper effects in early stages of the kelp Laminaria saccharina. Mar. Pol. No Public ~ Bull., 17:213-218. domain IIA Cid, A., C. Herrero, et al. 1995 Copper toxicity on the marine microalga Phaeodactylum tricornutum: effects No Public ~ on phytosynthesis and related parameters. Aquatic Toxicology 3 1: 165-174. domain IIA Clarke, A.K., Campbell, D. 1996 Inactivation of the petE Gene for Plastocyanin Lowers Photosynthetic No Public ~ Capacity and Exacerbates Chilling-Induced Photoinhibition in the domain cvanobacterium Svnechococcus. Plant Phvsiol 112 : 1551-1561

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TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/Nol Yes No IIA Conrad, G. w. 1988 Heavy metal effects on cellular shape, cleavage and larval development of No Public ~ the marine gastropod mollusc (llyanassa obsoleta Say). Bull. Environ. domain Contain. Toxicol. 41, 79-85. IIA Croot P.L., Moffett, J., Brand, L. 2000 Production of extracellular Cu complexing ligands by eucaryotic No Public ~ phytoplankton in response to cu stress. limnol. Oceanogr.• 45(3), 2000, domain 619- 627 IIA Croot, P.L., Karlson, B., van 2003 Uptake and efflux of 64Cu by the marine cyanobacterium Synechococcus No Public ~ Elteren, J. T. , Kroon, J.J. WH7803. Limnol. Oceanogr .• 48{1), 2003, 179-188 domain IIA Cullen A.C. ' Frey H.C. 1999 Probabilistic techniques in exposure assessment. A handbook for dealing with No Public ~ variability and uncertainty in models and inputs. Plenum Press, New York & domain London. 335 p, IIA De Boeck G., J. Hattink, N.M. 2007 Metal toxicity in spiny dogfish {Squalus acanthus) : urea loss contributes to No Public ~ Franklin, C.P. Bucking, s. Wood, the osmoregulatoery disturbace. Aquatic toxicity 84, 133-141. domain P.J . Walsh, C.M. Wood.

IIA De Boeck G., J. Hattink, N.M. 2007 Metal toxicity in spiny dogfish {Squalus acanthus) : urea loss contributes to No Public ~ Franklin, C.P. Bucking, s. Wood, the osmoregulatoery disturbace. Aquatic toxicity 84, 133-141. domain P.J. Walsh, C.M. Wood.

IIA Di Toro TM, Mahoney JD, 1986 Effects of nonreversibility, particle concentration and ionic strength on heavy No Public ~ Kirchgraber PR, O'Bryne OL, metal sorption. Environ.Sci.Tech. 20, 55-61. domain Pascuale LR, Piccirilli DC, IIA Di Toro, D.M., McGrath, J.A., 2002 Predicting the Acute and Chronic Toxicity of Metals in Sediments using No Public ~ Hansen, D.J., Berry, W.J. Organic carbon Normalized SEM and AVS . USEPA Publication; Not GLP; domain Published IIA Doval, M. D., Perez, F.F., Berdalet, 1999 Dissolved and particulate organic carbon and nitrogen in the Northwestern No Public ~ E., Mediterranean. Deep-Sea Resea rch I, 46,1999, 511-527 domain IIA Doval, M. D., Perez, F.F., Berdalet, 1999 Dissolved and particulate organic carbon and nitrogen in the Northwestern No Public ~ E., Mediterranean. Deep-Sea Research I, 46,1999, 511-527 domain IIA Druffel ERM, Williams PM, Bauer 1992 Cycling of dissolved and particulate organic matter in the ocean. J Geophys No Public ~ JE, Ertel JR. Res 1992;97:15639- 59. {Cited in Baker & Spencer 2004) domain IIA Dryden, C.L., Gordon, A.S., Donat, 2004 Interactive regulation of dissolved copper toxicity by an estuarine microbial No Public ~ J.R. community. limnol. Oceanoor., 49(4), 2004, 1115- 1122 domain IIA ECETOC 2001 Technical report nr 82. Risk assessment of marine environments. ISSN- No Public ~ 0773-8072-82 domain IIA Eklund, B., Borg, H., Karlsson, J., 2007 Effects and uptake of copper by species ecologically relevant to the Baltic No Public ~ lithner, G., Ndung'u, K. Sea in natural sea water. Kemi report File number 805-6477-05Nv; domain Unoublished IIA Elbaz-Poulichet F, Martin JM, 1987 Dissolved cadmium behaviour in some selected French and Chinese No Public ~ Huang WW, Zhu JX, estuaries, consequences on Cd supply to the ocean. Marine Chemistry 22, domain 125-136. IIA Ferrari, G. M., 2000 The relationship between chromophoric dissolved organic matter and No Public ~ dissolved organic carbon in the European Atlantic coastal area and in the domain West Mediterranean Sea {Gulf of lions). Ma rine Chemistry, 70, 2000, 339- 357 IIA Ferrari, G. M., 2000 The relationship between chromophoric dissolved organic matter and No Public ~ dissolved organic carbon in the European Atlantic coastal area and in the domain West Mediterranean Sea (Gulf of lions). Ma rine Chemistrv, 70, 2000, 339-

116 Dicopper oxide PT 21 Product-type 21 January 2016

IIA Ferrari, G.M., Dowell, M.D., 1996 Relationship between the optical properties of chromophoric dissolved No Public ~ Grossi, s., Targa, c., organic matter and total concentration of dissolved organic carbon in the domain southern Baltic Sea region. Marine Chemistry 55, 299-316. Cited in K&P 2008 IIA Foster, P. L. 1982 Metal resistances of Chlorophyta from rivers polluted by heavy metals. No Public ~ Freshwater Bioloav Volume 12 o 41 domain IIA Gibson, v., Grice, G. 1977 Response of macro- zooplankton to copper : Controlled Ecosystem Pollution No Public ~ Exoeriment. Bull. Mar. Sci. 27(1) 85-91 domain IIA Glover, C.N., Balesaria, S., Mayer, 2003 Intestinal zinc uptake in two marine teleosts, squirrelfish ( Holocentrus No Public ~ G.D., Thompson, E. D., Walsh, P.J., adscensionis) and gulf toadfish {Opsanus beta). Physiolog ical and domain and Hogstrand, c. Biochemical Zoology 76, 321- 330 IIA Golimowski J, Merks AGA, Valenta 1990 Trends in heavy metal levels in the dissolved and particu late phase in the No Public ~ P, Dutch Rhine-Meuse {MAAS) delta. Sci.Total Environ. 92, 113-127. domain IIA Granger, J., Wards, B. 2003 Accumulation of nitrogen oxides in copper-limited cultures of denitrifying No Public ~ bacteria. Umnol. Oceanoar., 48(1), 2003, 313- 318 domain IIA Grosell et al. 2004 Effects of prolonged copper exposure in the marine gulf toadfish {Opsanus No Public ~ beta) I. Hydromineral ba lance and plasma nitrogenous waste products. domain Aquatic Toxicoloav 68 (2004) 249- 262 IIA Grose II, M., Blanchard, J., Brix 2007 Physiology is pivotal for interactions between salinity and acute copper No Public ~ K.V., Gerdes, R. toxicity to fish and invertebrates. Aquatic Toxicology {in press) domain IIA Grzybowski, W. 2002 The significance of dissolved organic matter photodegradation as a source of No Public ~ ammonium in natural waters. Oceanologia 44 (3), 355-365. Cited in K&P domain 2008 IIA Grzybowski, W., Pempkowiak, J. 2003 Preliminary results on low molecular weight organic substances dissolved in No Public ~ the waters of the Gulf of Gdan'sk. Oceanologia 45 (4), 693-704. Cited in domain K&P 2008 IIA Gustavson, K., et al 1999 Pollution-Induced Community Tolerance {PICT) in coastal phytoplankton No Public ~ communities exposure to copper. Hydrobiologia, 4 16, 125-138 domain IIA Hiemstra, T., van Riemsdijk, W.H ., 2006 Biogeochemical speciation of Fe in ocean water. Marine Chemistry, 102, No Public ~ 2006 181-197 domain IIA Hoare, K., Davenport, J,, 1995 Effects of exposure and previous exposure to copper on growth of veliger No Public ~ Beaumont, A.R. larvae and survivorship of Mytilus edulis juveniles. Mar. Ecol. Prog. Ser. 120: domain 163-168 IIA Howard, L. S., D. G. Crosby and P. 1986 Evaluation of some methods for quantitatively assessing the toxicity of heavy No Public ~ Ali no metals to corals. In: Technical Report {Hawaii Institute of Marine Biology), domain No. 37. Coral Reef Population Biology. Eds. P. L. Jokiel, R. H. Richmond, and R. A. Roaers IIA Hughes, R., Reichelt-Brushett, A. 2005 Identifying suitable invertebrate species from a unique habitat for No Public ~ J., and Newman, L. J. ecotoxicological testing. Australasian Journal of Ecotoxicology 11{2): 85-92 domain IIA Hutchinson TH, Scholz N, Guhl W. 1998 Analysis of the ECETOC aquatic toxicity {EAT) database IV - Comparative No Public ~ toxicity of chemicals substances to freshwater versus sa ltwater organisms. domain Chemosohere 36 143-153.

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TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/Nol Yes No IIA Huthnance JM, Allen J, Davies 1994 Towards water quality models. In: Charnock H, Dyer KR, Huthnance JM, Liss No Public ~ !AM, Hydes DJ, James ID, Jones PS, Simpson JH, Tett PB (Eds), Understanding the North Sea System, domain JE, Millward GE, Prandle D, Proctor Chapman and Hall, Cambridge, UK, pp. 191-206 .. R, Purdie DA, Statham PJ, Tett PB, Thomson s, Wood RG,

IIA JaTry, A. et al. 1999 Speciation of Organic Carbon, Cu and Mn in the River Mame {France): The No Public ~ Role of Colloids. Hydrological Process. Vol. 13, 223-237 domain IIA Johnston, E.L., Webb, A.J., 2003 Pulse Disturbances to the Colonization of Hard-substrates and in situ No Public ~ Keough, M.J. Determination of Copper using Diffusive Gradients in Thin-films {DGT): domain Ouantifvina Dose and Response in the Field. Biofoulina, 19:5, 335 - 345 IIA Johnston, E.L., Webb, A.J., 2003 Pulse Disturbances to the Colonization of Hard-substrates and in situ No Public ~ Keough, M.J. Determination of Copper using Diffusive Gradients in Thin-films {DGT): domain Quantifvina Dose and Response in the Field. Biofoulina, 19:5, 335 - 345 IIA Jouanneau JM, Etcheber H, 1983 Impoverishment and decrease of metallic elements associated with No Public ~ Latouche C; suspended matter in the Gironde estuary. In: Wong CS, Boyle E, Bruland domain KW, Burton JD, Goldberg ED {Eds), Trace metals in sea water. Plenum Press, New York o 245-264. !IA Jurkowskis, A.K., Formych, T.A., 1976 Cikl izmienienij fosfora, azota i organiczeski swiazannogo uglieroda w No Public ~ Grotanie, B.J. Baltijskom Morie. Okieanologia 16, 79-86. Cited in K&P 2008 domain IIA Kaiser, H., Chalmers, R., and 2003 The relationship between copper-related damage and population growth of No Public ~ Oellermann, L. K. the rock anemone, Aiptasia spp. Journal of Applied Aquaculture 14(1-2): 53- domain 67 IIA Kaiser, H., Chalmers, R., and 2003 The relationship between copper-related damage and population growth of No Public [81 Oellermann, L. K. the rock anemone, Aiptasia spp. Journal of Applied Aquaculture 14(1-2): 53- domain 67 IIA Karbe, L. 1972 Marine Hybrids as Test Organisms for Assessing the Toxicity of Water No Public ~ Pollutants. The Effect of Heavy Metals on Colonies of Eirene Viridula . Ma r. domain Biol. 12, 316-328 IIA Karman, c.c., Kramer, K.J.M., 1999 Determinisitic model for the prediction of the bioavailable copper No Public ~ Jak, R.G. concentration in a marine environment. TNO report TNO-MEP-R98/382. domain !IA Kennish, M.J. 1989 CRC Practical Handbook of Marine Science, CRC Press, Boca Raton, Florida No Public ~ domain IIA Kosakowska A., Falkowski, L., 1988 Effect of amino acids on the toxicity of heavy metals to phytoplankton. Bull. No Public ~ Lewandowska, J. Environ. Contam. Toxicol., 40 :532-538. domain IIA Kremling K, Petersen H, 1978 The distribution of Mn, Fe, Zn, Cd and Cu in Baltic seawater: a study on the No Public ~ basis of one anchor station. Mar.Chem. 6, 155-170. domain IIA Kulinski and Pempkowiak 2008 Dissolved organic carbon in the southern Baltic Sea: Quantification of factors No Public ~ affecting its distribution; Estuarine, Coastal and Shelf Science xx {2008) 1-7 domain (Article in Press) IIA Kupper H, Setlik I, setlikova E, 2003 Copper-induced inhibition of photosynthesis: limiting steps of in vivo copper No Public [81 Ferimazova N, Spiller M, Kupper chlorophyll formation in Scenedesmus quadricauda. Functional Plant Biology domain FC 30(12). 1187-1196 !IA Lage, O.M., Soares, H.M., 1996 Toxicity Effects of Copper{Il) on the Marine Dinoflagellate Amphidinium No Public [81 Vasconcelos, M.T., Parente, A.M., caterae - Influence of Metal Speciation. Europ.J.Phycol., 31, 341/348; Not domain Salema, R. GLP, Published IIA Landner L, Lindestrom L 1999 Copper in society and in the environment. Vasteras, Swedish Environmental No Public [81

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TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No Research Group (M FG) (SCDA S-721 88). domain IIA Larsen, B.K., Portner, H.0 ., 1997 Extra- and intra-cellular acid-base balance and ionic regulation in cod (Gadus No Public 18] Jensen, F.B. morhua) during combined and isolated exposures to hypercapnia and copper. domain Marine Bioloav 128, 337-346. IIA Lawrence A.J., Poulter, C. 1998 Development of a sub-lethal pollution bioassay using the estuarine amphipod No Public ~ Gammarus duebeni. Water Research, 32:569-578. domain IIA Lea l, M., Vasconcelos, M., van den 1999 Copper-induced release of complexing ligands similar to thiols by Emiliania No Public 1:81 Berg, c. huxleyi in seawater cultures. limnol. Oceanogr., 44(7), 1750- 1762 domain IIA Lee, M.R., Correa, J.A. 2005 Effects of copper mine tailings disposal on littoral meiofaunal assemblages in No Public 1:81 the Atacama region of northern Chile; Marine Environmental Research 59 domain 12005) 1- 18 IIA Lehman, J.T., Bazzi, A., Nosher, T, 2004 Copper inhibition of phytoplankton in Saginaw Bay, Lake Huron. can. J. Fish. No Public 1:81 Nriagu, J.O. Aquat. Sci. 61(10): 1871-1880 domain IIA Leung KMY, Morritt D, Wheeler JR, 2001 Can saltwater toxicity be predicted from freshwater data? Marine Pollution No Public 1:81 Whitehouse P, Sorokin N, Toy R, Bulletin, 42, 1007- 1013. domain Holt M, Crane M IIA Lundebye A.K., Depledge, M.H. 1998 Automated interpulse duration assessment (AIDA) in the shore crab Carcinus No Public 1:81 maenas in response to copper exposure. Mar. Biol., 130:613-620. domain IIA Lussier, s. M., Gentile, J. H. 1985 Acute and chronic effects of heavy metals and cyanide on Mysidopsis bahia No Public 18] Walker, J. (Crustacea : Mysidacea). Aquat. Toxicol. 7:25-35. domain IIA MacDonald J.M., Shields J.D., 1988 Acute toxicities of eleven metals to early life history stages of the yellow crab No Public 18] Zimmer-Faust, R.K. Cancer anthonyi. Mar. Biol., 98:201-207. domain IIA Maldonado, M.T., et al 2006 Copper-dependent iron transport in coastal and oceanic diatoms. limnol. No Public 1:81 Oceanoar., 51(4), 2006, 1729- 1743 domain IIA Mann, E. L. et al 2002 Copper toxicity and cyanobacteria ecology in the Sargasso Sea. limnol. No Public ~ Oceanoar., 4714), 2002, 976- 988 domain IIA Martin JM, Guan OM, El baz- 1993 Preliminary assessment of the distributions of some trace elements (As, Cd, No Public 1:81 Poulichet F, Thomas AJ, Gordeev Cu, Fe, Ni, Pb, and Zn) in a pristine aquat ic environment: the Lena river domain w, estuarv ! Russia). Mar.Chem. 43, 185-199 IIA Martin J-M, Whitfield M, 1983 The significance of the river input of chemical elements to the ocean. In: No Public 1:81 Wong SC et al (Ed), Trace Metals in Sea Water. Plenum Press, New York, pp. domain 265-296. IIA Matthiessen, P 2008 Review of the validity, and implications for the environmental risk No Public 1:81 assessment of copper, of St n11mgren, T. and Nielsen, M.V. (1991). Spawning domain frequency, growth and mortality of Mytilus edulis larvae exposed to copper and diesel oil. Aauatic Toxicoloav 21, 171-180. IIA Melusky, D.S. & Phillips, c. N. K. 1975 Some Effects of Copper on the Polychaete Phyllodoce maculata. Estuarine & No Public 1:81 Coastal Mar. Sci. 3: 103-108; Not GLP; Published domain IIA Metaxas, A. and A. G. Lewis 1991 Copper tolerance of Skeletonema costatum and Nitzschia thermalis. Aquatic No Public 1:81 Toxicoloav 19: 265-280. domain IIA Metaxas, A. and A. G. Lewis 1991 Interactions between two species of marine diatoms: effects on their No Public 1:81 individual coooer tolerance. Marine Biolonv 109: 407-415. domain IIA Miao, A.-J., w.-X. Wang, et al. 2005 Comparison of Cd, Cu, and Zn toxic effects on four marine phytoplankton by No Public 1:81 pulse-amplitude-modulated fluorometry. Environmental Toxicology and domain Chemistrv 24110) : 2603-2611.

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TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No IIA Millanovich, F.P., Spies, R., 1976 Uptake of Copper by the Polychaete Cirriformia spirabrancha in the Presence No Public ~ Guram, M.S. & Sykes, E.E. of Dissolved Yellow Organic Matter of Natural Origin. Estuarine and Coastal domain Mar. Sci. 4 : 585-588; Not GLP; Published IIA Miller, M. 1946 Toxic Effects of Copper on Attachment and Growth of Bugula Neritina. No Public ~ Biological Bulletin, Vol. 90, No. 2. (Apr., 1946), pp. 122-140 domain IIA Millward GE, Glegg GA, 1997 Fluxes and retention of trace metals in the Humber estuary. Estuarine No Public ~ Coastal Shelf Sci. 44 97-105. domain IIA Milne, C.J., Kinniburgh, D.G., Van 2003 Generic NICA- Donnan model parameters for metal-ion binding by humic No Public ~ Riemsdijk, W.H., Tipping, E. substances. Environ. Sci. Technol. 37 (5),958- 971. Cited in Hiemstra 2006 domain

IIA Milne, C.J., Kinniburgh, D.G., Van 2003 Generic NICA- Donnan model parameters for metal-ion binding by humic No Public ~ Riemsd ijk, W.H., Tipping, E. substances. Environ. Sci. Technol. 37 (5),958- 971. Cited in Hiemstra 2006 domain

IIA Mitchelmore, C.L. et al. 2003 Differential accumulation of heavy metals in the sea anemone Anthopleura No Public ~ elegantissima as a function of symbiotic state. Aquatic Toxicology 64 {2003) domain 317 /329 IIA Mitchelmore, C.L. et al. 2003 Differential accumulat ion of heavy metals in the sea anemone Anthopleura No Public ~ elegantissima as a function of symbiotic state. Aquatic Toxicology 64 {2003) domain 317 /329 IIA Moffett, J. W. and L E. Brand 1996 Production of strong, extracellular Cu chelators by marine cyanobacteria in No Public ~ response to cu stress. Umnology and Oceanography 41(3): 388-395. domain IIA Moffett, J. W., L. E. Brand, et al. 1997 Cu speciation and cyanobacterial distribution in harbors subject to No Public ~ anthropogenic Cu inputs. Limnology and Oceanography 42(5): 789-799. domain IIA Monteny F, El skens M, Baeyens W, 1993 The behaviour of copper and zinc in the Scheidt Estuary. No Public ~ Nertherl.J.Aqua .Ecol. 27, 279-286. domain IIA Morel, F.M.M., Price, N.M. 2003 The Biogeochemical Cycles of Trace Metals in the Oceans. Science 9 May No Public ~ 2003: 944 domain IIA Mouneyrac, c., Mastain, 0 ., 2003 Trace-metal detoxification and tolerance of the estuarine worm Hediste No Public ~ Amiard, J.C., Amiard-Triquet, C., diversicolor chronically exposed in their environment . Marine Biology 143, domain Beaunier, P., Jeantet, A.Y., Smith, 731-744. B.D., and Ra inbow, P.S.

IIA Mwanuzi F, De Smedt F, 1999 Heavy metal distribution model under estuarine mixing. Hydro!. Process. 13, No Public ~ 789-804. domain IIA Negri A. P. Heyward A. J 2001 Inhibition of coral fertilisation and larval metamorphosis by tributyltin and No Public ~ copper. Marine Environmental Research 51 {2001) 17-27 domain IIA Nell J.A., Holliday, J.E 1986 Effects of potassium and copper on the settling rate of Sydney rock oyster No Public ~ (Saccostrea commercialis). Aauaculture, 58:263-267. domain IIA Nelson D.A.,Miller, J.E., Ga labrese, 1988 Effect of heavy metals on bay scallops, surf clams and blue mussels in acute No Public ~ A. and long-term exposures. Arch. Environ. Contam. Toxicol., 17:595- 600. domain IIA Ng and Keough 2003 Delayed effects of larval exposure to Cu in the bryozoan Watersipora No Public ~ subtorquata. Mar Ecol Proo Ser 257: 77- 85, 2003 domain IIA Noriki s, Ishimori N, Harada K, 1985 Removal of trace metals from seawater during a phytoplankton bloom as No Public ~ Tsunogai s, studied with sediment traps from seawater during a phytoplankton bloom as domain studied with sediment traps in Funka Bay, Japan. Marine Chemistry 17, 75- 89.

120 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No IIA Nystrom M., Moberg, F. and 1997 Natural and anthropogenic disturbance on reef corals in the Inner Gulf of No Public ~ Tedengren, M. Tha iland: Physiological effects of reduced sa linity, copper, and siltation. domain Chapter pp.: 1893-1898 In: Proceedings of the 8th International Cora l Reef Svmoosium, Panama, June 24-29, 1996 IIA Nystrom, M., Nordemar, I., and 2001 Simultaneous and sequential stress from increased temperature and copper No Public ~ Tedengren, M. on the metabolism of the hermatypic coral Porites cylindrica. Marine Biology domain 138(6): 1225-1231 IIA Obernosterer, I., Herndl, G.J. 2000 Differences in the optical and biological reactivity of the humic and nonhumic No Public ~ dissolved organic carbon component in two contrasting coastal marine domain environments. Umnol. Oceanoar., 45(5), 2000, 1120-1129 IIA Obernosterer, I., Herndl, G.J. 2000 Differences in the optical and biological reactivity of the humic and nonhumic No Public ~ dissolved organic carbon component in two contrasting coastal marine domain environments. Umnol. Oceanoar., 45(5), 2000, 1120-1129 IIA OECD 2002 Draft Revised Gu ideline 201 : Freshwater Alga and Cyanobacteria, Growth No Public ~ Inhibition Test. Guidelines for the testina of chemicals domain IIA Ogle, R. S. 2008 Review of article by Stromgren and Nielsen {1991) on copper toxicity to No Public ~ Mvtilus edulis soawnina and larval survival and arowth. domain IIA OSPAR 2001 Data Report on the Comprehensive Study of Riverine Inputs and Direct No Public ~ Discharaes (RID) in 2001 domain IIA Paulsson M, Nystrom B, and 2000 Long-term toxicity of zinc to bacteria and algae in periphyton communities No Public ~ Blanck H. from the river Gota alv, based on a microcosm study. Aquatic Toxicol domain 47 :243-57 IIA Peers, G., Price, N.M. 2006 Copper-containing plastocyanin used for electron transport by an oceanic No Public ~ diatom. Nature fLond.) 4417091 : 341-344 domain IIA Peers, G., Quesnel, S-A., Price, 2005 Copper requirements for iron acquisition and growth of coastal and oceanic No Public ~ N.M. diatoms. Umnol. Oceanoar. 50(4) 2005 1149- 1158 domain IIA Pempkowiak, J., Widrowski, M., 1984 Dissolved organic carbon and particulate carbon in the Southern Baltic in No Public ~ Kulinski,W., September, 1983. Proceedings XIV Conference of Ba ltic Oceanographers, domain IMGW Gdvnia 699-713. Cited in K&P 2008 IIA Pettine, M., Patrolecco, L, 1999 Seasonal variations of dissolved organic matter in the northern Adriatic Sea. No Public ~ Manganelli, M., Capri, s., Farrace, Marine Chemistry, 64,1999, 153-169 domain M.G. IIA Piola and Johnston 2006 Differential resistance to extended copper exposure in four introduced No Public ~ brvozoans. Mar Ecol Proa Ser 311 : 103- 114 2006 domain IIA Piola and Johnston 2006 Differential tolerance to metals among populations of the introduced No Public ~ bryozoan Bugula neritina. Marine Biology {2006) 148: 997- 1010 domain IIA Piola and Johnston 2006 Differential resistance to extended copper exposure in four introduced No Public ~ brvozoans. Mar Ecol Proa Ser 311 : 103- 114, 2006 domain IIA Rainbow, P.S. 1985 Accumulation of Zn, Cu and Cd by Crabs and Barnacles. Estuarine, Coastal No Public ~ Shelf Science. 21; 669-686; Not GLP; Published domain IIA Rainbow, P.S. 2002 Trace metal concentrations in aquatic invertebrates: why and so what ? No Public ~ Environmental Pollution 120, 497-507. domain IIA Rainbow, P.S. & White, S. L 1989 Comparative Strategies of Heavy Metal Accumulation by Crustaceans: Zinc, No Public ~ Copper and Cadmium in a Decapod and Am phi pod and a Barnacle. domain Hvdrobioloa ia 174; 245-262; Not GLP; Published IIA Rao V.N.R., Latheef, G.M. 1989 Effect of Copper on Artemia salina Linn. and of Skeletonema costatum No Public ~ {Grev.) Cleve as Feed. Comp. Physiol. Ecol., 14(2):41-48. domain

121 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No IIA Rao V.N.R., Latheef, G.M. 1989 Effect of Copper on Artemia salina Linn. and of Skeletonema costatum No Public ~ {Grev.) Cleve as Feed. Comp. Physiol. Ecol., 14(2):4 1-48. domain IIA Rayburn J.R., Fisher, w.s. 1999 Developmental toxicity of copper chloride, methylene ch loride and 6- No Public ~ aminonicotinamide to embryos of the grass shrimp Palaemonetes pugio. domain Environ. Toxicol. Chem., 18:950-957. IIA Regnier P, Hoenig M, Chou L, 1990 Trace metals in the suspended matter collected in the mixing zone of the No Public ~ Wollast R Rhone estuarv. Water Pollut. Res.Rea. 20 385-396. domain IIA Reichelt-Brushett 1999 The Efect of Copper, Zinc and cadmium on Fertilization Success of Gametes No Public ~ from Scleractinian Reef Corals. Marine Pollution Bulletin Vol. 38, No. 3, pp. domain 182-187 1999 IIA Reish D.J., Martin, J.M., Piltz, F.M., 1976 The effect of heavy metals on laboratory populations of two polychaetes with No Public ~ Word, J.Q. comparisons to the water quality conditions and standards in southern domain California marine waters. Water Research 10:299-302. IIA Reish, D.J., carr, R.S. 1978 The effect of heavy metals on the surviva l, reproduction, development and No Public ~ life cycles for two species of polychaetous annelids. Mar. Pollut. Bull., 9, 24- domain 27 IIA Ringwood AH 1992 Comparative sensitivity of gametes and early developmental stages of a sea No Public ~ urchin species {Echinometra mathaei) and a bivalve species {I sognomon domain californicum) during metal exposures. Arch Environ Contam Toxicol, 22: 288- 295. IIA Saifullah, S.M. 1978 Inhibitory Effects of Copper on Marine Dinoflagellates. Mar. Biol. Vol.44; 299. No Public ~ domain IIA Scott 1992 Flexible Kernel Density Estimation reference No Public ~ domain IIA Scott 1992 Flexible Kernel Density Estimation reference No Public ~ domain IIA Scoullos, M., Plavsic, M., 2006 Partitioning and distribution of dissolved copper, cadmium and organic No Public ~ Karavoltsos, S., Sakellari, A., matter in Mediterranean marine coastal areas: The case of a mucilage event . domain Estuarine, Coastal, and Shelf Science 67, 2006, 484-490 IIA Shcolnick, s., Keren, N. 2006 Metal Homeostasis in Cyanobacteria and Chloroplasts. Balancing Benefits and No Public ~ Risks to the Photosynthetic Apparatus. Plant Physiol. Vol. 141, pp 805-810 domain IIA Sholkovitz ER, 1983 The geochemistry of plutonium in fresh and marine water environments. No Public ~ Earth Sci.Rev. 19, 95 -161. domain IIA Shuster, C.N and Pringle, B.H. 1969 Effects of Trace Metals on Estuarine Molluscs. Proceedings of the 1st Mid- No Public ~ Atlant ic Industrial Waste Conference. November 13-15, 197; Not GLP; domain Published IIA Silva, S. 2006 Effects of Diesel fuel and copper contaminants on benthic macroalgae. PhD No Public ~ dissertation. domain IIA Silverman 1986 Flexible Kernel Density Estimation reference No Public ~ domain IIA Silverman 1986 Flexible Kernel Density Estimation reference No Public ~ domain IIA Skraba l, S.A. et al. 1997 Fluxes of Copper-Complexing ligands from Estuarine Sediments. limnol. No Public ~ Ocean. Vol. 42 (5) 992-996 domain IIA Smith, s . D., DePalma, S.G.S., 2008 Natural Organic and Inorganic Matter Quality and Copper Toxicity to Mytilus No Public ~ Arnold W.R. galloprovincialis. Abstract and presentation at SETAC Europe Conference, domain 2007

122 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No IIA Smolders R, Vlaeminck A, Blust R. 2005 Comparative toxicity of metals to freshwater and saltwater organisms. No Public ~ DRAFT version 1.1 - Aoril 2005. domain IIA Smyth, D.V., Kent, s. 2006 Copper: toxicity to the marine algae Skeletonema costatum; BEL report no. Yes EU ~ BL8243/B; GLP; Unpublished Antifouli ng Task Force IIA Soria-Dengg, s., Reissbrodt, R., 2001 Siderophores in marine coastal waters and their relevance for iron uptake by No Public ~ Horstmann, U. phytoplankton: experiments with the diatom Phaeodactylum tricornutum. domain Mar Ecol Proa Ser. Vol. 220: 73- 82, 2001 IIA Stagg, R.M., Shuttleworth, T.J. 1982 The accumulation of copper in Platichthys flesus L. and its effect on plasma No Public ~ electrolvte concentration. J. Flsh Biol. 20, 491-500. domain IIA Stagg, R.M., Shuttleworth, T.J. 1982 The effects of copper on ionic regulation by the gills of the seawater adapted No Public ~ flounder {Platichthys flesus L.). J. Comp. Physiol. 149: 83-90. domain IIA Stark J.S. 1998 Effects of copper on macrobenthic assemblages in soft sediments: a No Public ~ laboratory experimental study. Ecotoxicology, 7, 163-171 domain IIA Stark J.S. 1998 Effects of copper on macrobenthic assemblages in soft sediments: a No Public ~ laboratory experimental study. Ecotoxicology, 7, 163-171 domain IIA Stebbing, A. 1976 The effects of low metal levels on a clonal hydroid. J. Mar. Biol. Ass . {U .K), No Public ~ 56:977-994. domain IIA Stebbing, A., Pomroy, A. 1978 A sublethal technique for assessing the effects of contaminants using Hydra No Public ~ littoralis. Water Research, 12:631-635. domain IIA Steele, c .w . 1983 Acute toxicity of copper to sea catfish. Mar. Pollut. Bull. 14 : 168-170. No Public ~ domain IIA Steele, c .w. 1983 Comparison of the behavioural and acute toxicity of copper to sheepshead, No Public ~ Atlantic croacker and pinfish. Mar. Pollut. Bull. 14 : 425-428. domain IIA Steele, c .w . 1983 Acute toxicity of copper to sea catfish. Mar. Pollut. Bull. 14 : 168-170. No Public ~ domain IIA Steele, c .w . 1983 Comparison of the behavioural and acute toxicity of copper to sheepshead, No Public ~ Atlant ic croacker and pinfish. Mar. Pollut. Bull. 14: 425-428. domain IIA Stephens M.A. 1982 Andersen-Darling test for goodness-of-fit. In Kots S. and N.L. Johnson, Eds. No Public ~ Encyclopedia of Statistical Sciences, Vol. 1, Wiley, New York. domain IIA Stromgren T., Nielsen, M.V. 1991 Spawning frequency, growth and mortality of Mytilus edulus larvae, exposed No Public ~ to copper and diesel oil. Aquatic Toxiciology, 171-179. domain IIA Stumm, W. and J.J. Morgan 1981 Aquatic Chemistry: An Introduction Emphasizing Chemica l Equilibra In No Public ~ Natural Waters. John Wiley & Sons, NY, 780 DD. domain IIA Subrahmanyam 1990 Concentration of Mn, cu, Ni, Cd and Co and toxicity of Mn and Ni in No Public ~ zoopla nkton from Visakhapatnam harbour {Bay of Bengal). Indian j ournal of domain marine sciences 1990, vol. 19, no4, DD. 297-299 IIA Tipping E, Lofts S, Lawlor AJ, 1998 Modelling the chemical speciation of trace metals in the surface waters of the No Public ~ Humber svstem. Sci.Total Environ. 210, 211, 63-77. domain IIA Torres et al. 1987 Acute toxicity of copper to Mediterranean dogfish. Comp Biochem Physiol; No Public ~ 86C: 169-171 domain IIA Turner A, 1996 Trace-metal partitioning in estuaries: importance of sa linity and particle No Public ~ concentration. Marine Chemistrv 54, 27-39. domain

123 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No IIA Turner A, Millward GE, Schuchard 1992 Trace metal distribution coefficients in the Weser Estuary (Germany). No Public ~ B, Schirmer M, Prange A, Cont.Shelf Res. 12, 1277-1292. domain

IIA Valenta P, Duursma EK, Merks 1986 Distribution of Cd, Pb and Cu between the dissolved and particu late phases in No Public ~ AGA, rutzel H, Nurnberg HW, the Eastern and Western Scheidt estuary. Sci.Total Environ. 53, 41-76. domain

IIA van den Berg, C.M.G., A.G. Merks 1987 Organic complexation and its control of the dissolved concentrations of No Public ~ and E. K. Duursma copper and zinc in the Scheidt estuary. Estuarine, Coastal and Shelf Science, domain 24: 785- 797. IIA Vignudelli, s., Santinelli, c., 2004 Distribution of dissolved organic ca rbon {DOC) and chromophoric dissolved No Public ~ Murru, E., Nannicini, L , Seritti A., organic matter {CDOM) in coastal waters of the northern Tyrrhenian Sea domain (ltalv). Estuarine, Coastal and Shelf Science 60, 2004, 133-149 IIA Visviki I & Rachlin JW 1991 The toxic action and interactions of copper and cadmium to the marine alga No Public ~ Dunaliella minuta, in both acute and chronic exposure. Arch Environ Contam domain Toxicol, 20: 271- 275. IIA Visviki I & Rachlin JW 1994 Acute and chronic exposure of Dunaliella sa lina and Chlamydomonas No Public ~ bullosa to copper and cadmium: Effects on growth. Arch Environ Contam domain Toxicol, 26: 149-153. IIA Visviki I & Rachlin JW 1994 Acute and chronic exposure of Dunaliella salina and Chlamydomonas No Public ~ bullosa to copper and cadmium: Effects on ultrastructure. Arch Environ domain Contam Toxicol 26: 154-162. IIA Wagner c., Lokke H. 1991 Estimation of ecotoxicological protection levels for NOEC toxicity data. Water No Public ~ Research 25: 1237-1242. domain IIA Wang, W-X, and Flsher, N.S. 1998 Accumulation of trace elements in a marine copepod. Limnol Oceanogr. No Public ~ 1998 Vol 43 Issue 2 0273-283 domain IIA Wangberg S-A, Heyman u, Blanck 1991 Long-term and short-term arsenate toxicity to freshwater phytoplankton and No Public ~ H. periphyton in limnocorrals. Can J Fish Aquat Sci 48:173-82 domain IIA Wangberg, S-A., Alexandersson, 1995 Rapport fran projektet: Batbottentargernas bidrag till kopparforekomsten I No Public ~ s., Hellgren, M. den akvatiska miljon. Uppfoljning av Keml's beslut om batbottenfarger, med domain hjalp av en PI CT-undersokning pa mikroalgsamhallen. Delprojekt 1 och 2. 95-01-10 IIA Webster, N.S, Webb, R.I., Ridd, 2001 The effects of copper on the microbial community of a coral reef sponge. No Public ~ M.J., Hill, R.T, Negri, A.P. Environmental Microbiology {2001) 3(1), 19-31 domain IIA Webster, N.S, Webb, R.I., Ridd, 2001 The effects of copper on the microbial community of a coral reef sponge. No Public ~ M.J., Hill, R.T, Negri, A.P. Environmental Microbiology {2001) 3(1), 19-31 domain IIA Wells, M.L. et al. 2005 Domoic acid : The synergy of iron, copper, and the toxicity of diatoms. No Public ~ Limnol. Oceanoar., 50(6), 2005,1908- 1917 domain IIA Wheeler, J.R., Leung, K.M.Y., 2002 Freshwater to Saltwater toxicity extrapolation using Species Sensitivity No Public ~ Morritt, D., Sorokin, N., Rogers, Distribution,s Environmental Toxicology and Chemistry, Vol. 21, No. 11, pp. domain H., Toy, R., Holt, M., Whitehouse, 24 59- 2467 P., Crane, M. IIA White, S.L. & Rainbow, P.S. 1982 Regulation and Accumulation of Copper, Zinc and cadmium by the Shrimp No Public ~ Palaemon elegans. Marine Ecology Progress Series. 8; 95-101; Not GLP; domain Published IIA Wright, D.A. 1995 Trace metal and major ion interactions in aquatic animals. Mar Pollut Bull; No Public ~ 3Hl-3): 8-18. domain

124 Dicopper oxide PT 21 Product-type 21 January 2016

TNG AUTHOR(S) YEAR TITLE SOURCE ( WHERE DIFFERENT FOR COMPA NY) COMPANY, DATA OWNER Essent ial Essential SECTION REPORT NO. PROTECT studies for studies for CLAIMED evaluat ion evaluation (Yes/ Nol Yes No IIA Young, J.S., Buschbom, R.L , 1979 Effects of Copper on the Sabellid Polychaete, Eudistylia vancouveri: I No Public ~ Gurtisen, J.M. & Joyce, S.P. Concentration Limits for Copper Accumulation. Archives of Environmental domain Contamination and Toxicoloav. 8 : 97- 106 IIA Zaroogian, G.E. & Johnston, M. 1983 Copper Accumulation in the Bay Scallop, Argopecten irradians. Arch. Environ. No Public ~ Contam. Toxicol. 12: 127-133; Not GLP; Published domain IIA Zhang M., Wang, J., Bao, J. 1992 Study on the relationship between speciation of heavy metals and their No Public ~ ecotoxicity. I. Toxicity of Cu, Cd, Pb and Zn in sea water to three marine domain algae in the presence of different complexation agents. Chin J. Oceanol. Limnol., 10:215-222.

125 Dicopper oxide PT 21 Product-type 21 January 2016

Intersmooth 360 SPC

Reference list of studies submitted and validated by Section number for the representative product Intersmooth 360 SPC:

Section No / Reference Author (s) Year Title Source (where different from company) Data Prot ection Owner Essential Essent ial No Company, Report No. GLP ( where r elevant) I Claim ed studies for studies for (Un)Published (Yes/ No) evaluation evaluat ion Yes No Section 1 No study reports submitted ~ Section 2 No study reports submitted ~ Section 3 Greenwood J, Wright E 2002 Intersmooth 360 Ecoloflex Antifouling Paint: Evaluation Yes Internation [8J of Physical Properties and Storage Stability (New First) al Paint Covance Laboratories Ltd Report Number 1485-12-02149 GLP/Unoublished Section 4 4.1/01 Wright E., Ristorcelli D 2001 Copper Compounds:Validation of the Analytical Method Yes Internation 1:8:1 for the Analysis in Antifouling Pa ints (New First) al Paint Covance Laboratories Ltd Report Number 1485/010-02149 GLP/Unoublished Section 4 4.1/02 Wright E. , Ristorcelli D 2001 Zinc Pyrithione:Va lidat ion of the Analytical Method for Yes Internation ~ the Analysis in Antifouling Pa ints (New First) al Paint Covance Laboratories Ltd Report Number 1485/009-02149 GLP/Unoublished Section 5 5.1-5.11 Shilton c, Green G 2001 Antifouling Efficacy Report; Intersmooth 360 Yes Internation [8J B5.10.2/0l (New First) al Paint Section 5 5.1-5.11 Callow ME 2005 Toxicity of Copper to Algae University of Yes Internation [8J B5.10.2/02 Birmingham Report number not (First New) al Paint soecified Unoublished Section 5 5.1-5.11 Callow ME 2005 Toxicity of Zinc Pyrithione to Algae Yes Internation 1:8:1 B5.10.2/03 University of Birmingham Report (First New) al Paint number not soecified Unoublished Section 5 5.1-5.11 Prowse, G. and 2006 Antifouling paint efficacy report, Intersmooth type zinc Yes Internation [8J B5.10.2/03 Solomon, T. pyrithione free formulation (First New) al Paint International Paint Ltd Report number not soecified Unoublished Section 5 5.1-5.11 Prowse G.M. 2009 The Efficacy of Copper in Antifouling Paints Yes Internation ~ B5.10.2/04 International Paint Ltd Report (First New) al Paint number not soecified Unoublished Section 6 B6.1.1 2003 Intersmooth 360 Ecoloflex SPC Antifouling BEA368 Dark Yes Internation 181 Brown : Acute Oral Toxicity in Rats (New First) al Paint

1 leoo~ ~u mbe r 7432-03 G LP/Unou ~l 1s~e~

126 Dicopper oxide PT 21 Product-type 21 January 2016

Section No I Reference Author(s) Year Title Sour ce (where different from company) Data Pr ot ection Owner Essential Essent ial No Com pany, Report No. GLP ( w her e relevant ) I Claimed studies for studies for {Un)Published { Yes/ No) evaluat io n evaluat ion Yes No Section 6 B6.1.2 2001 Intersmooth 365 Ecoloflex {BEA363) Acute Dermal Yes Intemation IZI iiiiii Toxicity {Limit) Test in Rats {New First) al Paint Report Number 17983 Gl9,~npu ~ l 1s~e~ Section 6 B6.1.3 2003 Intersmooth 360 Ecoloflex SPC Antifouling BEA368 Dark Yes Intemation IZI Brown : Acute Inhalation Toxicity Study in Rats {New First) al Paint - leoo~ ~umbe r 7433-03 GLP/Unouti l 1 s ~ e~ Section 6 B6.2/0l 2001 Intersmooth 365 Ecoloflex {BEA363) Acute Dermal Yes Intemation IZI Irritat ion Test in Rabbits {New First) al Paint Repo~ ~ u m~er H~H l!J1unpublished Section 6 B6.2/02 1997 Intersmooth 360 Ecoloflex Dermal I rritation Test in Yes Intemation IZI iiiiii Rabbits {New First) al Paint Report 1 ~um~er IHl6 GLP/Unoublished Section 6 B6.2/03 1998 Intersmooth 460 Ecoloflex Primary Eye Yes Intemation IZI Irritat ion/Corrosion in Rabbits {New First) al Paint Report Numberl !1-HIUI !~9,~ npublished Section 6 B6.3 1994 Ecoloflex Paint Buehler Sensitisation Test in Gu inea Yes Intemation IZI liiiiiiiiiiiiii PigsTest in Rabbits {New First) al Paint Reoort Number 9979 GLP/Unout>lisheel Section 6 B6.4/0l Roper c s, Sherratt R 2003 The In Vitro Percutaneous Absorption of Copper in Two Yes Intemation ~ Paint Preparations Through Human Skin {New First) al Paint Inveresk Research, UK. Reoort Number 23056 GLP/Unoublished Section 6 B6.4/02 Roper cs 2005 The In Vitro Percutaneous Absorption of Copper in Two Yes Intemation ~ Paint Preparations Through Human Skin - Dermal {New First) al Paint Delivery Inveresk Research, UK. Report Number 24740 GLP/Unoublished Section 6 B6.4/03 Roper cs 2005 The In Vitro Percutaneous Absorption of Copper in Two Yes Intemation ~ Paint Preparations Through Human Skin - An Expert {New First) al Paint Report Inveresk Research, UK. Report Number 25631 GLP/Unoublished Section B6.4/04 Roper cs 2002· The In Vitro Percutaneous Absorption of Radiolabelled Yes Intemation ~ Zinc Pyrithione in Two Antifouling Paint Test Preparations {New First) al Paint Through Human Skin Inveresk Research, UK. Report Number 20499 GLP/Unpublished Section 6.4/ McGurk c 2014 Dermal Penetration of Copper Compounds from Biocidal Yes Inernationa IZI Supplimentary Antifouling Paints Product Type 21 {PT21) {New First) I Paint International Paint Ltd Report number not soecified Unoublished

127 Dicopper oxide PT 21 Product-type 21 January 2016

Section No I Reference Author(s) Year Title Source (where different from company) Data Protection Owner Essential Essential No Company, Report No. GLP ( where relevant) I Claimed studies for studies for {Un)Published {Yes/ No) evaluation evaluation Yes No Section 6.4/ Roper cs, Sheratt R. 2003 The In Vitro Percutaneous Absorption of Copper in Two Yes Intemation IZI Supplimentary Paint Test Preparations Through Human Skin, Inveresk (New First) al Paint Study number 203927, Inveresk Report Number 23056, Inveresk Research. GLP/Unoublished Section 6.4/ Toner F. 2009 The In Vitro Percutaneous Absorption of Radiolabelled Yes Intemation IZI Supplimentary Zinc Pyrithione in an Antifouling Paint Through Human (New First) al Paint Skin, Charles River Study number 785726, Report number 30556, Charles River. GLP/Unoublished Section 6.4/ Roper C, 2006 The In Vitro Percutaneous Absorption of Radiolabelled Yes Intemation IZI Supplimentary Toner F, Biocide in a Single Solvent-Based Paint Formulation (New First) al Paint Prowse G, Hunter ], through Human Skin. Charles River Laboratories Maddens. Preclinica l Services. GLP/Published Section 6.4/ Toner F. 2012 The In Vitro Assessment of Different Methods for Yes Intemation IZI Supplimentary Removal of Zinc Pyrithione in Paint from Human Skin, (New First) al Paint Charles River Study number 785380, Report Number 30557, Charles River Laboratories. GLP/Unoublished. Section 6.4/ Toner F. 2008 The I n Vitro Percutaneous Absorption of Zinc Through Yes Intemation IZI Supplimentary Human Skin Following Application of Three Paints (New First) al Paint Containing Zinc Oxide to Human Skin, Charles River Study Number 779529, Report number 28075, Charles River GLP/Unpublished. Section 6.4/ Toner F, 2005 The In Vitro Percutaneous Absorption of Rad iolabelled Yes Intemation [gJ Supplimentary Crow LF, Econ ea 028 in a Single Paint Formulation Through (New First) al Paint Roper cs. Human Skin, Inveresk Study Number 775566, Inveresk Report Number 25468, I nveresk Research. GLP/Unoublished Section 7 No study reports submitted

Section 8 No study reports submitted

Section 9 No study reports submitted

Section 10 No study reports submitted

128 Dicopper oxide PT 21 Product-type 21 January 2016

Hempel's Antifouling Olympic 86951

Reference list of studies submitted and validated by Section number for the representative product Olympic 86951 :

Section No / Refer ence Author (s) Year Title Data protection Owner Essential Essential No. Source Claimed (Yes/ No) stud ies for studies for Company evaluation evaluation Report No. Yes GLP No (Un )Published 62.2.2 Guldberg et al 2002 High-Alumina Low-Silica HT Stone Wool Flbres - A No - llSI Chemica l Compositiona I Range with High Biosolubility. Regulatory Toxicology and Pharmacology 35, pp 1- 10. Published 62.2.2 HempelA/S 2005b Safety Data Sheet for Hempel's Antifouling Olympic No - llSI 86951. 26/07-2005 Published 63.1 Ra msay N 2005 Olympic 86951 Physico-Chemical testing of Olympic Yes Hempel A/S ~ 86951. (first) Inveresk Research, Tranent, Ed inburgh, Inveresk Study No : 207298, Inveresk Report No : 24516 GLP Unpublished 63.4 Ramsay N 2005 Olympic 86951 Physico-Chemical testing of Olympic Yes Hempel A/S ~ 86951. (first) Inveresk Research, Tranent, Ed inburgh, I nveresk Study No: 207298, Inveresk Report No : 24516 GLP Unpublished 63.6 Ramsay N 2005 Olympic 86951 Physico-Chemical testing of Olympic Yes Hempel A/S ~ 86951. (first) Inveresk Research, Tranent, Ed inburgh, Inveresk Study No : 207298, Inveresk Report No: 24516 GLP Unpublished 63.7 Soria M 2003 Storage Stability Test: Hempel's Antifouling Olympic Yes Hempel A/S ~ 86951-50220 (first) Project number A2931PES. February 2003. Unpublished

129 Dicopper oxide PT 21 Product-type 21 January 2016

Section No/ Reference Author(s) Year Title Data protection Owner Essential Esse ntial No. Source Claimed ( Yes/No) studies for studies for Company evaluation evaluation Report No. Yes GLP No ( Un )Published B3.8 Soria M 2003 Storage Stability Test: Hempel's Antifouling Olympic Yes Hempel A/S ~ 86951-50220 (first) Project number A2931PES. February 2003. Unpublished B3.8 PSD 2002 Pesticides Safety Directorate No - ~ Data requirements handbook Published B3.10.2 Ramsay N 2005 Olympic 86951 Physico-Chemical testing of Oly mpic Yes Hempel A/S ~ 86951. (first) Inveresk Research, Tranent, Edinburgh, Inveresk Study No : 207298, Inveresk Report No : 24516 GLP Unoublished 84.1 Eng K 1999 Qua litative and Quantitative Determination of Yes Hempel A/S ~ Cuprous Oxide in Antifouling Paints. Hempel's (first) Analytica l Laboratories. Report number A99044. February 1999 Unoublished 84.1 Lykke S E 1999 Quantitative Determination of Cuprous Oxide in Yes Hempel A/S ~ Antifouling Paints, Method Validation. AnalyTech (first) Milj0laboratorium ApS Unoublished 84.1 ASTM 1999 Standard Test Method for Chemical Ana lysis of No ~ Cuprous Oxide and Copper Pigments

B5.2 Hempel A/S 2005a Product data Sheet for Hempel's Antifouling No - ~ Olympic 86950 Tin-free. February 2005 Published B5.3 Hempel A/S 2005a Product data Sheet for Hempel's Antifouling No - ~ Olympic 86950 Tin-free. February 2005 Published B5.6.1 Little & DePa lma 1988 Marine Biofouling No - ~ Treatise on Materials Science and Technology 28, pp 89-119. Published B5.10.2 Soria M 2006 Efficacy report for Hempel's Antifouling Olympic Yes Hempel A/S ~ 86951, Barcelona - Lab R&D, Report number (first) A1440RES, Project number PR99070A, March 2006 Unpublished B5.10.2 Soria M 2008 Efficacy report of Hempel's Antifouling Olympic Yes Hempel A/S ~ 86951, Barcelona - Lab R&D, Report number (first) A4050RES, Project number A7836PES, April 2008 Unoublished

130 Dicopper oxide PT 21 Product-type 21 January 2016

Section No/ Reference Author(s) Year Title Data protection Owner Essential Essential No. Source Claimed ( Yes/ No) studies for studies for Company evaluation evaluation Report No. Yes GLP No Un Published 85.10.2 Willeboordse s 2008 Hempel Marine Maintenance Report, Project number Yes Hempel A/S NLSTW000008, March 2008 (first) Un ublished 85.10.2 Wright R 2005 Hempel's Ship Data, Sand Heron, April 2005 Yes Hempel A/S Un ublished first 86.1.1 2005a Hempel's Antifouling Olympic 86951 Acute Oral Yes Hempel A/S Toxicity (Acute Toxic Class) Test in Rats. (first) MLJYMo ~epok Mo : ;41;215•• GLP Unpublished 86.1.2 2005b Hempel's Antifouling Olympic 86951 Acute Dermal Yes Hempel A/S Toxicity ( Limit) Test in Rats (first)

Stu y No : 506944, Report No :

GLP unpublished 86.1.3 Anderson B 2002 Statement on acute inhalation testing with paint Yes Hempel A/S mixes. (first) Inveresk Research, Tranent, Edinburgh 07/05- 2002 Un ublished 86.2.1 2005c Hempel's Antifouling Olympic 86951 Acute Dermal Yes Hempel A/S Skin Irritation Test in Rabbits. (first)

stuay No : 506970, Report No:

86.2.2 2005d 86951 Acute Eye Yes Hempel A/S (first)

No : 506965, Report No: 24267 GLP Un ublished 86.3 Pritchard J D 2005e Hempel's Antifouling Olympic 86951 Loca l Lymph Yes Hempel A/S Node Assay. (first) Inveresk Research, Tranent, Edinburgh, Inveresk Study No : 506923, Inveresk Report No: 24264 GLP Un ublished

13 1 Dicopper oxide PT 21 Product-type 21 January 2016

Section No / Refer ence Author(s) Year Title Dat a protection Owner Essential Essential No. Source Claimed ( Yes/No) studies for studies for Company evaluatio n evaluation Report No. Yes GLP No Un Published 66.4 Roper c s 2006 The In Vitro Percutaneous Absorption of Copper in a Yes Hempel A/S Single Commercial Paint Formulation Through (first) Human Skin. Inveresk Research, Tranent, Edinburgh, Inveresk Study No : 777359, Inveresk Report No: 25983 GLP Un ublished 67.7.2 OECD 2004 Harmonisation of Environmental Emission No Scenarios. An Emission Scenario Document for Antifouling Products in OECD countries - ESD PT21. Project number 9M2892.0l. September - 2004 Published 69/ 01 2005a Hempel's Antifouling Olympic 86951 Acute Oral Yes Hempel A/S Toxicity (Acute Toxic Class) Test in Rats. (first) MLJYMo ~epok Mo: ;41;215•• GLP Unpublished 69/ 02 2005b Hempel's Antifouling Olympic 86951 Acute Dermal Yes Hempel A/S Toxicity ( Limit) Test in Rats (first)

stuay No: 506944, Report No:

69/ 03 2005c Yes Hempel A/S (first)

No : 506970, Report No:

69/ 04 2005d 86951 Acute Eye Yes Hempel A/S (first)

No: 506965, Report No: 24267 GLP un ublished 69/ 05 Hempel NS 2005b Safety Data Sheet for Hempel's Antifouling Olympic No 86951. 26/07-2005 Published

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