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

Evaluation of active substances

Assessment Report

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Active chlorine released from hypochlorous acid

Product-type 1 (Human hygiene)

July 2020

Slovak Republic Active chlorine released from Product-type 1 July 2020 hypochlorous acid

CONTENTS

1. STATEMENT OF SUBJECT MATTER AND PURPOSE...... 4

1.1. Procedure followed...... 4

1.2. Purpose of the assessment report...... 4

2. OVERALL SUMMARY AND CONCLUSIONS...... 5

2.1. Presentation of the Active Substance...... 5 2.1.1. Identity, Physico-Chemical Properties & Methods of Analysis...... 5 2.1.2. Intended Uses and Efficacy...... 9 2.1.3. Classification and Labelling...... 10

2.2. Summary of the Risk Assessment...... 10 2.2.1. Human Health Risk Assessment...... 10 2.2.1.1. Hazard identification and effects assessment...... 10 2.2.1.2. Exposure assessment and risk characterisation...... 14 2.2.1.3. Preliminary risk assessment for disinfection by-products (DBPs)...... 15 2.2.2. Environmental Risk Assessment...... 16 2.2.2.1. Hazard identification and effects assessment...... 16 2.2.2.2. Exposure assessment and risk characterisation...... 19 2.2.2.3. Fate and distribution in the environment...... 22 2.2.2.4. PBT and POP assessment...... 22 2.2.3. Assessment of endocrine disruptor properties...... 22

2.3. Overall conclusions...... 24 2.3.1. Overall conclusion of the evaluation including need for risk management measures ... 24

2.4. Requirement for further information related to the reference biocidal product ....24

2.5. List of endpoints...... 24

APPENDIX I: LIST OF ENDPOINTS...... 25

Chapter 1: Identity, Physical and Chemical Properties, Classification and Labelling ....25

Chapter 2: Methods of Analysis...... 30

Chapter 3: Impact on Human Health...... 32

Chapter 4: Fate and Behaviour in the Environment...... 41

Chapter 5: Effects on Non-target Species...... 43

Chapter 6: Other End Points...... 45

APPENDIX II: LIST OF INTENDED USES...... 46

APPENDIX III: LIST OF STUDIES...... 47

2 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

APPENDIX IV: LIST OF ABBREVIATIONS...... 77

3 Active chlorine generated from Product-type 1 July 2020 sodium chloride by electrolysis

1. STATEMENT OF SUBJECT MATTER AND PURPOSE

1.1. Procedure followed

This assessment report has been established as a result of the evaluation of the active substance Active chlorine released from hypochlorous acid as product-type 1 (Human hygiene), carried out in accordance with Article 90(2) of Regulation (EU) No 528/2012, with a view to the possible approval of this substance.

Active chlorine released from hypochlorous acid (CAS no. not applicable) was notified by PuriCore International Ltd, UK (Puricore International Ltd. transfers to PuriCore Europe Limited. PuriCore Europe Limited is a subsidiary of Realm Therapeutics PLC) and Forum Bioscience Holdings Ltd UK, (the subsequent change in the body of the applicant to company Aqualution Systems Ltd, UK because of the change of ownership), hereafter referred to as the applicants, in product-type 1.

On 31st July 2007, SK competent authority received a dossier from PuriCore International Ltd, UK (Puricore International Ltd. transfers to PuriCore Europe Limited. PuriCore Europe Limited is a subsidiary of Realm Therapeutics PLC) and Forum Bioscience Holdings Ltd UK, (the subsequent change in the body of the applicant to company Aqualution Systems Ltd, UK because of the change of ownership). The Rapporteur Member State accepted the dossier as complete for the purpose of the evaluation on 31st January 2008.

On 19st November 2010, the Rapporteur Member State submitted to the Commission and the applicants a copy of the evaluation report, hereafter referred to as the competent authority report.

In 2019 PuriCore Europe Limited sold and transferred rights in the dossier to Aqualution Systems Ltd.

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" (ECHA). 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 report

The aim of the assessment report is to support the opinion of the Biocidal Products Committee and a decision on the approval of Active chlorine released from hypochlorous acid 1, and, should it be approved, to facilitate the authorisation of individual biocidal products. 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.

For the implementation of the common principles of Annex VI, the content and conclusions of this assessment report, which is available from the Agency web-site, 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 for that purpose has been granted to that applicant.

4 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

2. OVERALL SUMMARY AND CONCLUSIONS

2.1. Presentation of the Active Substance

2.1.1. Identity, Physico-Chemical Properties & Methods of Analysis

Active chlorine released from hypochlorous acid is an equilibrium mixture, with the exact composition dependent on pH.

The active substance is generated by the electrolysis of a dilute aqueous solution of sodium chloride (NaCl). The passage of an electric current through sodium chloride in the electrolytic cell causes oxidation of the chloride ions (Cl-) to chlorine (Cl2). The chlorine undergoes rapid hydrolysis to form a range of different chlorine based constituents: hypochlorous acid (HOCl), chloride ions and hypochlorite ion (OCl-).

2 Cl- ^ Cl 2 + 2 e-

Cl2 + H2O ^ HOCl + H+ + Cl-

HOCl ^ H+ + OCl-

Chlorine is available in three different forms: OCl-, HOCl and Cl2 . Thus, the term "Active Chlorine" covers all three forms of available chlorine.

The precise concentration of the individual forms of available chlorine strongly depends on a number of parameters such as background electrolyte concentration, temperature and pH. Typically, at pH 6 - 8 the solution would contain primarily NaCl (not all the NaCl is converted to Active Chlorine), sodium hypochlorite (NaOCl), HOCl and other minor forms. HOCl is predominant between pH 3 and 7. At pH 7.5 the ratio OCl-/HOCl is in the proportion of one to one. At pH values higher than 10 the only constituent present is the OCl- .

The generated solution is bottled and forms the product.

Originally, the dossier for active chlorine released from hypochlorous acid was submitted under the Biocidal Products Directive as part of the dossier on active chlorine generated from sodium chloride by electrolysis. During the peer review it was conclude however that these are distinct active substances. Consequently, the original dossier was split in two: active chlorine generated from sodium chloride by electrolysis and active chlorine released from hypochlorous acid.

Minimum content of hypochlorous acid (predominant in pH 3.0-7.4) is 0.0255% w/w (as dry weight min 90.87% w/w) 1.

The individual chlorine based constituents are never isolated. Therefore, details on the constituents are presented for information only.

Chlorine:

CAS-No. 7782-50-5

EINECS-No. 231-959-5

Other No. (CIPAC, ELINCS) Not applicable

1 Reference specification is derived from the 5-batch analysis of the company Puricore Europe Ltd (a subsidiary of Realm Therapeutics PLC). Analytical results are by convention expressed as available (active) chlorine using the molecular weight of chlorine. The reported values have been converted into hypochlorous acid by applying a conversion factor of 0.74 (Mw HOCl/Mw Cl2 = 52.45/70.91) Active chlorine released from Product-type 1 July 2020 hypochlorous acid

IUPAC Name Chlorine

Common name, synonyms Chlorine

Molecular formula Cl 2

Structural formula Cl — Cl

Molecular weight (g/mol) 35.453 for atomic chlorine, 70.906 for molecular chlorine

Hypochlorous acid:

CAS-No. 7790-92-3

EINECS-No. 232-232-5

Other No. (CIPAC, ELINCS) Not available

IUPAC Name Hypochlorous acid

Common name, synonyms Hypochlorous acid

Molecular formula HOCl

Structural formula H-O-Cl

Molecular weight (g/mol) 52.5

Sodium hypochlorite:

CAS-No. 7681-52-9

EINECS-No. 231-668-3

Other No. (CIPAC, ELINCS Not applicable

IUPAC Name Sodium hypochlorite

Common name, synonyms Sodium hypochlorite

Molecular formula NaClO

Structural formula Na+ Cl — O-

Molecular weight (g/mol) 74.4

Identification of the representative products

• Aqualution® 70 is used to refer to the solution (at approximately pH 7) produced when the active substance is generated by the electrolysis of a sodium chloride solution at the Applicant's manufacturing site and then supplied in containers to the client. The concentration of available chlorine is approximately 200 mg/L. Any containerised product with mode of manufacture and composition equivalent to Aqualution® 70 is also covered by the Aqualution® 70 assessment.

6 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

• Puricide refers to the aqueous solution (at approximately pH 5-6) produced by electrolysis of a sodium chloride solution and contains available chlorine at approximately 300 mg/L. Puricide® solution is generated using the systems supplied by Puricore International Ltd. It is produced at the Applicant's manufacturing site and then supplied in containers to the client.

Physico-Chemical Properties

Hypochlorous acid is very weak acid. Hypochlorous acid is known only in aqueous solution, formed by the action of water on chlorine. HOCl cannot be isolated in its pure form and it is technically not feasible to determine most of the physico-chemical properties.

Data on hypochlorous acid are mainly based on data of recently performed studies on a 24% available chlorine solution (Cl2 + hypochlorous acid + sodium hypochlorite) and on literature data, which also addresses those physical-chemical parameters which are meaningful for hypochlorous acid.

The tested solution is a yellow limpid liquid, with faint chlorinous odour and melting point of -28.9 ± 0.5 °C; relative density (D2 1 2 /4 ) is 1.300 ± 0.001.

The vapour pressure of sodium hypochlorite solutions is reported by EN 901:2013 to be approximately 2.5 kPa at 20°C, due to water2.

Solubility in water of HOCl is 25 g/100 g H2O. Temperature is not stated3. The dissociation constant for HOCl is 7.53. For HOCl a log Pow was calculated to be - 0.87. The value was calculated using KOWWIN v1.67. Henry's Law Constant for HOCl4 is determined as 0.110 Pa m3/mol. The aqueous solution of HOCl is not considered to be flammable, auto- flammable or explosive. HOCl has oxidizing properties, but solutions of HOCl at relevant concentrations do not need to be classified as an oxidiser.

Certain studies can be performed and these are included below:

• UV-Vis absorption of Aqualution 70 at pH 7: Absorbance A = 0.154 at Amax = 291.5 nm

• Raman Infra-red: HOCl: 728 cm-1 : v(Cl-O)

Hypochlorous acid is not currently listed in Annex VI of Regulation 1272/2008. The concentration of available chlorine in aqueous solution (HOCl is predominant in pH range 3-7) is approximately 300 mg/L and therefore would not be classified.

Analytical Methods

Analysis of active substance as manufactured:

Active Chlorine solution is an equilibrium mixture of chlorine, hypochlorous acid and hypochlorite, composition is dependent on pH. It is generated by the electrolysis of sodium chloride solution.

Analysis of hypochlorite will be applicable for assessment of the available chlorine present in the Active Chlorine solution.

• Sodium hypochlorite: Sodium hypochlorite reacts with potassium iodide to release iodine in the presence of acetic acid. The iodine is titrated with sodium thiosulphate solution in the presence of starch indicator solution.

2 The vapour pressure of pure water, as given in different handbooks, is 2.34 kPa at 20°C. 3 The Merck index: an encyclopedia of chemicals, drugs, and biologicals (2013) 15th edition. ISBN 9781849736701. 4 Setting a value for the Henry's Law Constant of Hypochlorous Acid by 'weight of evidence' approach based on available literature data" (2015).

7 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Hypochlorite is degraded with hydrogen peroxide and the total chloride content is determined by titration with silver nitrate solution. The amount of chloride resulting from hypochlorite has to be subtracted from the total chloride content to obtain the sodium chloride content.

• Available chlorine: Available chlorine is the sum of Cl2 + HOCl + ClO- . It is expressed as the equivalent content of Cl2, based on the oxidising capacity. A spectrometric and a titrimetric method for the determination of available chlorine are described.

Spectrometric method: Direct reaction between available chlorine and N,N-diethyl-1,4- phenylenediamine (DPD) and formation of a red compound at pH 6.2 to 6.5. Colour intensity determination was performed by visual comparison of the colour, with a scale of permanent glass standards, or by spectrometry.

Titrimetric method: Direct reaction of free chlorine with N,N-diethyl-1,4-phenylenediamine (DPD) and formation of a red compound at pH 6.2 to 6.5. Titration is by means of a standard solution of ammonium iron(II)sulphate, to the disappearance of the red colour.

The limit of determination for both methods is 0.0004 mmol/L (0.03 mg/L) Cl2. The methods are applicable to concentrations in terms of chlorine from 0.0004 to 0.07 mmol/L (0.03 to 5 mg/L) total chlorine and at higher concentrations by dilution of samples. These methods have been considered acceptable.

Further information on the above methods can be found in Doc. IIIA4.1.

Formulation analysis:

Active Chlorine cannot be isolated as such. It is generated through electrolysis of aqueous sodium chloride solution to make a biocidal product. The methods described in above section are therefore applicable.

Residue analysis:

• Residues in soil: In soil, available chlorine reacts very rapidly with organic material. Thus, justification for non-submission of analytical method for residues in soil was considered acceptable.

• Residues in water: A spectrometric and a titrimetric method for the determination of available chlorine are described.

Spectrometric method: Direct reaction between available chlorine and N,N-diethyl-1,4- phenylenediamine (DPD) and formation of a red compound at pH 6.2 to 6.5. Measurement of the colour intensity is by visual comparison of the colour, with a scale of permanent glass standards, or by spectrometry.

Titrimetric method: Direct reaction of available chlorine with N,N-diethyl-1,4-phenylenediamine (DPD) and formation of a red compound at pH 6.2 to 6.5. Titration is by means of a standard solution of ammonium iron (II) sulphate, to the disappearance of the red colour.

The limit of determination with both methods is 0.0004 mmol/L (0.03 mg/L) Cl2. The methods are applicable to concentrations in terms of chlorine from 0.0004 to 0.07 mmol/L (0.03 to 5 mg/L) total chlorine and at higher concentrations by dilution of samples. These methods have been considered acceptable.

Further information on the above methods can be found in Doc. IIIA4.1.

• Residues in air: Exposure to chlorine is only accidental. Chlorine can be formed and released when hypochlorite products or solutions are mixed with strong acids. Sampling is performed by passing a measured volume of air through a sulphamic acid solution, trapping the chlorine as stable chloramines. The subsequent analytical determination is 8 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

based on the reaction of chloramines and iodide in slightly acidic solution with the formation of a tri-iodide species. Spectrophotometric measurement of the tri-iodide is made at 288 nm. It could also be based on the reaction of chloramines with iodide, in slightly acidic solution, producing free iodine which oxidises DPD (N,N-diethyl-1,4- phenylenediamine sulphate) forming a red coloured diimine. Spectrophotometric measurement of the red coloured solution is made at 510 nm. The method was considered acceptable.

• Residues in body fluids and tissues: Available chlorine will degrade very rapidly when in contact with skin or body fluids. Justifications for non-submission of analytical methods for residues in body fluids and tissues were considered acceptable.

• Residues in food and feeding stuffs and other products where relevant: Secondary exposure of food and feed with available chlorine, e.g. upon contact with treated surfaces or equipment, is considered to be not relevant, since available chlorine is highly unstable and will rapidly degrade upon contact with organic matter. Consequently, the justifications for non-submission of analytical methods for residues in food and feeding stuffs and other products were considered acceptable.

At the Human Health WG IV 2017 it was concluded, that measurements of chlorate as representative DBP within in use situations shall be provided at product authorisation stage. Also other potentially critical DBP should be identified, measured and assessed at product authorisation stage.

2.1.2. Intended Uses and Efficacy

In spite of the efficacy data presented in IIIA document that deals with the individual forms of available chlorine, a specific approach has to be applied for the evaluation of the efficacy of the individual biocidal products. The efficacy of the biocidal product has to be evaluated as a complex mixture manufactured by the electrolysis of the sodium chloride. The biocidal product represents equilibrium of hypochlorous acid, chlorine gas and sodium hypochlorite depending on the pH value and temperature.

Field of use envisaged The uses assessed belong to the product-type 1:

• Skin disinfection of the hands in healthcare (200-300 mg/L available chlorine). The "organism to be protected" is man. The aim of the treatments is to control spreading of infectious diseases.

Professional and non-professional use is envisaged.

• Skin disinfection of the feet in healthcare (200-300 mg/L available chlorine). The "organism to be protected" is man. The aim of the treatments is to control spreading of infectious diseases.

Professional use is envisaged.

The participants provided data on the biocidal activity of the active substance against following target organism(s):

• Bacteria: Clostridium difficile, Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella enterica, Escherichia coli, Campylobacter jejuni, Enterococcus hirae, Mycobacterium tuberculosis and other Mycobacterium species, Enterococcus faecalis

• Virus: infectious bronchitis virus, adenovirus type 5, human immunodeficiency virus 1, influenza A (H1N1) virus, orthopoxvirus, poliovirus 9 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

• Fungi: Aspergillus brasiliensis

• Yeast: Candida albicans

• Spores: Bacillus cereus, Bacillus subtilis var. niger, Clostridium sporogenes

The above list of microorganisms is a non-exhaustive list. Available chlorine at the levels tested in the Active Chlorine solution (120-220 mg/L as available chlorine) has been shown to be efficacious against an even wider range of microorganisms (refer to section B5 in doc. IIIB). The effective doses lay in the scope of the doses of the intended uses.

Provided data are sufficient at active substance approval stage. However, at product authorisation efficacy studies according to the relevant guidance documents which appropriately simulate the applied in- use situation have to be submitted for organisms representative for the application area. For final and unequivocal conclusion on the efficacy of individual biocidal products under product authorisation stage, information on pH range and organic load is required.

Based on non-specific mode of action, the resistance of pathogens to Active Chlorine is not very probable, but cannot be excluded. Some of the mechanisms like clonal selection from the population of the cells exposed to some of the forms of available chlorine may contribute to the drop of the chlorine efficacy. The basic mechanisms contributing to the chlorine resistance most probably are based on an increased production (with the genetic background) of proteins exported to the vicinity of the cell surface and thus protecting the cell against the relevant form of the available chlorine. The capacity to produce biofilm is one of the factors which substantially increase resistance of the bacteria and fungi against biocidal products.

Based on current knowledge the resistance of pathogens to Active Chlorine is not higher than that of other active substances with a general mode of action (oxidation). There is no need for specific resistance management strategies for Active Chlorine based disinfectants. They do not differ from those that have already been proposed for other disinfectants with general mode of action, i.e. strict respect for recommended concentration use, strict respect for expiration time period, rotation of disinfectants.

In addition, in order to facilitate the work of Member States in granting or reviewing authorisations, the intended uses of the active substance Active chlorine released from hypochlorous acid, as identified during the evaluation process, are listed in Appendix II. The list of intended uses provided for this product type is not necessarily the final list.

2.1.3. Classification and Labelling

Hypochlorous acid is not currently listed in Annex VI of Regulation 1272/2008. A classification proposal is currently not available and needs to be considered.

2.2. Summary of the Risk Assessment

2.2.1. Human Health Risk Assessment

2.2.1.1. Hazard identification and effects assessment

The only evident toxicological concern is the eye, skin and respiratory tract irritating potential of sodium hypochlorite solutions. However, the concentration of available chlorine in the Active Chlorine solutions (~0.03%) is far below the concentrations triggering classification for skin or eye irritation. Consequently, though exposure should be limited for precautionary reasons no major concern is expected for irritation of Active Chlorine.

The toxicological profile of Active Chlorine (as an equilibrium of chlorine, hypochlorous acid and sodium hypochlorite) generated through electrolysis is linked to that of sodium hypochlorite,

10 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

hypochlorous acid and chlorine gas. Therefore, all studies investigating these species of available chlorine can be used for evaluation and assessment of Active Chlorine.

The available human toxicokinetic data for respiratory exposure indicated that more than 95 % of inspired chlorine was absorbed in the upper airways of all subjects. Nevertheless, where risk assessment for systemic effects is required a respiratory absorption rate of 100% may be used considering that with the reaction of Active Chlorine with mucosa disinfection by-products (DBPs) are produced and subsequently minimal levels of Active Chlorine as well as DBPs may become systemically available.

The available animal toxicokinetic data for oral exposure had a low recovery rate, but with the worst case assumption that the non-recovered part (about 70% or 50% in the two available studies) was not absorbed a worst case estimate of 36% 36Cl oral absorption was derived. No differentiation between hypochlorite, chloride or disinfection by-products was possible. Considering the high reactivity of hypochlorite, it is expected that the major part of hypochlorite reacted at the site of contact to DBPs and chloride and only a minor part of hypochlorite was systemically absorbed. However, where risk assessment for systemic effects is required, e.g. in the context of toxicological evaluation DBPs a 36% absorption rate of the total 36Cl may be taken into consideration.

The metabolism data supported that HO36Cl is converted and eliminated in the chloride form. 36Cl was widely distributed in the body with highest values in plasma, followed by bone marrow, kidney, testes, lung, skin, duodenum, spleen, stomach, liver, carcass and ileum. The distribution scheme of 36Cl after HO36Cl administration revealed the highest 36Cl activity in the plasma and whole blood, while the lowest activity was measured in the liver, ileum and adipose tissue. The plasma carried four times the activity of 36Cl compared to packed cells. The decrease of total 36Cl after washing packed cells with cold saline suggested that a high percentage of total 36Cl was loosely bound to the erythrocyte membrane or exchangeable with the chloride in saline. Approximately 20 % of the 36Cl in the plasma was bound to protein and in the same time this concentration was higher (five-fold) than the amount which was bound to the liver protein.

No specific dermal absorption data were available. However, within Active Chlorine hypochlorite is present only at non irritant concentrations and at these non irritant concentrations the potential of hypochlorite solutions to penetrate the skin is expected to be low, given its ionic character and its reactivity with proteinaceous material. Where risk assessment for systemic effects is required, 10 % dermal absorption may be assumed for exposure calculations.

No specific data were available for bioaccumulation. However, the fat tissue presented very low content after exposure to a single dose, thus indicating a negligible potential for bioaccumulation. Sequestration by breast milk also seemed not likely, due to the high reactivity of the active substance with organic molecules.

The acute systemic toxicity of tested hypochlorite solutions by oral route is low. In addition, the data available indicates very low acute dermal toxicity of sodium hypochlorite. The only acute inhalation toxicity study with sodium hypochlorite did not show an effect on rat. In an acute inhalation study in Wistar rats conducted with chlorine clinical signs of eye and respiratory tract irritation were observed. Human data are available for accidental ingestion and accidental parenteral exposure. Clearly local effects are dominant and dependent not only on the dose but also on the concentration and acute lethal effects are to be expected, if at all as a consequence of local corrosion. However, the available chlorine is approximately 300 mg/L (0.03%) within Active Chlorine. Therefore, there is no concern for acute systemic effects from Active Chlorine.

With regard to skin and eye irritation, available animal data supports current EU classification for sodium hypochlorite solutions as skin corrosive category 1B. In the absence of specific classification limits the general classification limits need to be applied: 1% to 3% for eye irritation, > 3% for eye corrosion; 1% to 5% skin irritation, > 5% skin corrosion. Since within 11 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Active Chlorine the available chlorine is approximately 300 mg/L (~0.03%) no classification for skin or eye irritation is necessary for Active Chlorine. The irritant effect of sodium hypochlorite is caused by its oxidative property and generation of OH- ions in contact with water or wet surroundings which create a high pH on exposed skin/tissues.

Due to the skin and eye irritant properties of sodium hypochlorite solutions they may be also considered as comparably irritant in the respiratory tract. However, the concentration of available chlorine in the Active Chlorine solutions (~0.03%) is far below the concentrations triggering classification for skin or eye irritation. Consequently, though respiratory exposure should be limited for precautionary reasons no major concern is expected for respiratory irritation of Active Chlorine.

Based on available animal data tested sodium hypochlorite solutions do not pose a skin sensitization hazard. In view of the known irritant and corrosive properties of sodium hypochlorite, the effects reported in humans suggest an irritation rather than a sensitising potential.

The dermal repeated dose NOAEC depends on exposure time, frequency, concentration and quantity. However, it is experimentally difficult to cover all these variability and no fully reliable study for the derivation of a dermal repeated dose NOAEC is available: Concentration of 0.125% in daily exposures for 8 weeks did not lead to adverse local effects in guinea pigs. Concentration of 1% twice weekly exposure for 51 weeks did not lead to adverse local effects in mice, but dosing may be considered to be not frequent enough. Exposure to 1% once for 24 hours in 20 humans did not lead to effects. Continuous skin exposure to solutions of 0.5% for more than 7 days lowered the viability of basal cells. From the available information on irritation it appears that the minimal concentration for irritation is 5% in rabbits (4.75% for 25 hours showed no effects, whereas 5 to 5.25% in 4 hour patch testing including abraded skin resulted in slightly irritating effects). In summary dermal NOECs for local effects were observed in the range of 0.1% to 1% for various exposure regimes, animal species and humans. It was agreed that a NOAEC of 1% available chlorine shall be used for a semi­ quantitative risk assessment.

There is no repeated dose/subchronic inhalation toxicity study on sodium hypochlorite available either in animals and humans. Therefore, studies investigating chlorine gas can be used for evaluation of repeated inhalation exposure to Active Chlorine. Although it is recognised that this data will be derived following exposure to gas and not to an aerosol which may affect qualitative and quantitative aspects of the findings. From a 6 week rat study a NOAEC of 2.9 mg/m3 is available, from the 1 year monkey study a NOAEC of 1.5 mg/m3 and from the 2 year rat and mouse study a NOAEC of < 1.2 mg/m3. In addition, data from groups of 8 human volunteers are available for exposures up to 6 hours per day, for 3 consecutive days indicating a NOAEC of 1.5 mg/m3. Having considered all available data the human NOAEC of 0.5 ppm (1.5 mg/m3) was used as a point of departure and an inter-species toxicodynamic factor of 3.2. was applied to derive an AECinhalation of 0.5 mg available Cl/m3 for a quantitative risk assessment for local effects.

With regard to genotoxicity sodium hypochlorite showed positive results in one of three available in vitro tests in bacteria, but only in strain TA100. In the two other tests, negative results were obtained in all strains used, including TA100. Equivocal or positive results were found in cytogenetic tests in mammalian cells. However, all in vivo tests (two micronucleus tests and one cytogenetic test) were clearly negative. Equivocal results were obtained in the germ cell assay. Based on the total weight of evidence and taking into account the results of the negative carcinogenicity studies in rats and mice and the negative reprotoxicity studies in rats sodium hypochlorite/hypochlorous acid is not considered to be genotoxic/mutagenic or clastogenic.

No adverse effects on development or reproduction were observed in the developmental rat study, the 1 generation rat study and the 7 generation rat study up to doses of 6.8 mg/kg bw day or respective concentrations of 500 mg/L in water. Since also no adverse parental effects were observed at these concentrations there is uncertainty if at higher concentrations specific 12 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

reproductive adverse effects may be observed. However, palatability problems and gastric irritation may be expected from higher doses. Moreover, the concentrations tested were at least 20 fold (in the 1-generation study even 100 fold) above the maximal concentrations of 5 mg/L considered for animal drinking water. Concentrations in swimming pools or human drinking water are usually even lower (below 2 or 1 mg/L).

The toxicity of sodium hypochlorite was investigated in several studies with repeat administration via oral route (drinking water and feeding) up to 104 weeks studies in mouse and rats. The only adverse effects observed were reduced chlorinated drinking water consumption and/ or body weight reduction and biochemical liver effects. The overall critical NOAEC was 1000 mg/L or 0.1% available chlorine (corresponding to a NOAEL of 50 mg/kg bw day) from a 2 year rat study (Hasegawa et al. 1986). The corresponding LOAEC was 2000 mg/L or 0.2% available chlorine.

Summary of reference values for active chlorine:

AELlong-term, medium term, short term and ADI, ARfD : Not derived due to dominant local effects Dermal, oral, inhalation absorption values: Not derived due to dominant local effects

NOAECdermal (to be used for semi-quantitative MOE approach)= 1% available chlorine, based on various exposure regimes, animal species and humans NOAEC oral (to be used for semi-quantitative MOE approach)=0.1% available chlorine, based on Hasegawa et al. 1986 studies (90 day rat and 104 weeks rat)

AEC respiratory = 0.5 mg av. chlorine/m3 based on subchronic inhalation toxicity values from human and rhesus monkey.

Chlorate Due to the high reactivity of chlorine species, residues on surfaces degrade very rapidly (decomposition to physiological sodium/calcium and chloride). Hence, residue formation is assumed to be negligible for aqueous solutions of active chlorine species. This conclusion is further supported by the conclusions drawn in the ENV risk assessment. Finally, no systemic assessment is required for active chlorine species which act by a local mode of action only.

The BPC APCP WGII-2016 concluded that chlorate residues may still be relevant as chlorate is considered a stable metabolite. Chlorate can be formed from hypochlorite in aqueous chlorine solutions during storage. Thus, chlorate may represent a worst-case for active chlorine residues.

In the absence of data, the WGIII-2016 agreed on the ADI and ARfD values proposed by the EFSA Panel on Contaminants in the Food Chain (Scientific Opinion on risks for public health related to the presence of chlorate in food. EFSA Journal 2015;13(6):4135,103 pp).

ARfD and ADI to be used for risk characterization of chlorate:

ARfD = 36 |jg chlorate/kg bw

ADI = 3 ^g chlorate/kg bw

In addition to the EFSA Opinion, the following data sources are available including but not limited to the "Chlorite and Chlorate in Drinking-water" background document of the WHO (2005) in which a TDI (equivalent to ADI) of 3 |jg/kg bw and a provisional guideline value of 0.7 mg/litre was derived for chlorate.

The WHO drinking water limit of 0.7 mg chlorate/L is also mentioned in the draft Guidance on Disinfection By-Products (vers. 1, April 2016) which is currently undergoing a PEG process.

13 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

2.2.I.2. Exposure assessment and risk characterisation

Human exposure to active substance from its manufacture/formulation and use in biocidal product can take place via inhalation and dermal routes (see table 2.2.1.2-1).

Table 2.2.1.2-1: Main paths of human exposure to Active Chlorine from use in PT 1.

Exposure Industrial Professional General Via the path use use public environment

Inhalation No No Yes No

Dermal No Yes Yes No

Oral No No No No

The assessment of human exposure follows the recommendations of "Technical Notes for Guidance on Human Exposure to Biocidal Products (European Commission, 2002)" and "Human Exposure to Biocidal Products (TNsG June 2002) User guidance version 1".

The human exposure assessment is carried out for local effects only, as local effects are dominant compared to potential systemic effects. As the relevant use concentrations are below the reference values for local dermal and local oral effects, risks via the dermal and oral route can be excluded independent from use pattern. Consequently for these routes no detailed exposure assessment is provided. Nevertheless, calculations estimating air concentrations of available chlorine in air are derived for estimating risks related to local inhalation effects due to the intended uses.

At the in-use pH values under PTs 1-2-3-4-5, exposure to gaseous chlorine is not expected, but through accidental events (chlorine can be formed and released when the Active Chlorine equilibrium is shifted to low pHs by strong acids, e.g. by mixing hypochlorite-based solutions with acidic cleaning agents).

The manufacture/formulation of active substance is essentially carried out in an enclosed system; therefore, EASE predicts very low dermal prediction (effectively zero) and very low inhalation exposure.

The applicant has chosen a representative product for PT 1 human hygiene products intended for professional use for hand and foot washing. Most of the applicant's proposed uses cover disinfection of medical personnel and patients and hospital visitors as well. Therefore, the primary exposure of non-professional users was considered during the risk assessment (for details on the intended uses, please see Appendix II of this document).

No secondary human exposure is thought to occur due to the rapid decay of available chlorine under use of the Active Chlorine solution.

The risk assessment is carried out for local effects only, as local effects are dominant compared to potential systemic effects. Since the active substance does not need to be classified for skin or eye corrosion or irritation, no detailed risk assessment for local skin and eye effects is necessary. A semi-quantitative risk assessment is provided for oral, dermal and respiratory exposure.

Table 2.2.1.2.-2 Risk for local effects for professionals using the product for human hygiene purposes

Exposure Route of Reference Value Potential Exposure Exposure to Concentration of 14 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Local Effects available Cl

inhalation 0.5 mg/m3 0.14 mg/m3 Hand washing from dispenser dermal 1% 0.03%

inhalation 0.5 mg/m3 0.38 mg/m3 Feet-treatment dermal 1% 0.03%

inhalation 0.5 mg/m3 < 0.38 mg/m3 Filling of foot baths and dispensers dermal 1% 0.03%

Oral exposure is not considered likely if good hygiene practice is maintained.

The risk can be considered acceptable since the reference values established for relevant dermal and respiratory local effects are not reached in any use patterns.

The exposure concentrations for non-professional users for relevant use patterns are identical to those for professional uses with the exception of filling foot baths and dispensers not being relevant. Consequently, there is no concern for the non-professionals (patients, visitors) for all use-patterns presented in this part of document.

No secondary human exposure is thought to occur due to the rapid decay of available chlorine under use of the Active Chlorine solution presented in this document.

2.2.1.3. Preliminary risk assessment for disinfection by-products (DBPs)

The risk assessment from potential exposure to DBPs was based on chlorate as representative DBP and its EFSA agreed ADI of 3 pg/kg bw day and reverse exposure scenarios for which the range for the chlorate content in the exposure volume was fixed (between full conversion of active chlorine to chlorate and no conversion, just impurity) and the ranges for maximal acceptable exposure volumes calculated.

Considering only the amount of chlorate as given in the identity of the bottled substance all scenarios appear acceptable. The chlorate content in the in situ substance contains 2.3 fold less chlorate, therefore this is true also for the in situ generated substance. The following values were calculated for the bottled substance.

26 ml product exposure (oral, dermal, inhalation) or dermal exposure to a surface film of 0.31 mm on 820cm2 (complete surface of both hands) or more (for PT3 8.6 fold lower concentrated foot/hoof product is used) and complete uptake of all the chlorate content from this volume would be necessary per human and day in order to achieve the TDI of 0.003 mg/kg bw day. With regard to dermal exposure a limited dermal flux needs to be assumed, but no data are available for this. However for situations where only hand exposure and some respiratory or oral exposure to the product is possible (all scenarios with product exposure for PT 1, PT2, PT3, PT4, PT5) this is an unlikely exposure value for unintentional uptake and therefore the respective risk is considered acceptable.

However assuming that all of the active chlorine is converted to chlorate as representative DBP would lead to an unacceptable risk: Just 0.3 ml/day of unintentional (oral, dermal, inhalation) exposure or dermal exposure to a surface film of 0.003 mm on 820cm2 (complete surface of both hands) and complete uptake of all the chlorate content from this volume would suffice in order to achieve the ADI of 0.003 mg/kg bw day.

Since these reverse scenarios indicate potential unacceptable risks it is suggested that respective measurements of chlorate as representative DBP within in use situations shall be 15 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

provided at product authorisation stage. Also other potentially critical DBP should be identified, measured and assessed at product authorisation stage. In addition, estimates or studies for dermal flux of DBPs may be considered to refine the risk assessment. Alternatively reverse exposure scenarios may be developed on the basis of expected exposure for products or in use solutions and available ADIs for critical DBPs so that maximum acceptable concentration of the DBPs within the products or in use solutions can be determined and monitored.

2.2.2. Environmental Risk Assessment

Active Chlorine is a mixture of chlorine, hypochlorous acid and sodium hypochlorite, released from hypochlorous acid. The hypochlorous acid (HOCl) is in equilibrium with hypochlorite anion (OCl-) and chlorine. The equilibrium depends on the pH value: below pH 4, chlorine is available, in the neutral pH range hypochlorous acid is the predominant species and at pH values higher then 10, the only species present is the hypochlorite ion, see diagram below.

PH

Calculated variation in composition of a chlorine solution, with degree of acidity or alkalinity for 0.1 M Cl 2 in water at standard temperature and pressure.

Therefore, for aqueous solutions with the same available chlorine concentrations and the same pH conditions, it is irrelevant whether the available chlorine was generated from chlorine gas, calcium hypochlorite, sodium hypochlorite or the electrolysis of sodium chloride. Therefore, all studies investigating aqueous solutions of available chlorine can be used for evaluation and assessment of Active Chlorine.

2.2.2.I. Hazard identification and effects assessment

Summary table on compartments exposed and assessed

Compartment Exposed (Y/N) Assessed (Y/N)

STPYY

Surface water Y Y

Sedim ent Y Y

Soil Y Y

Groundwater Y Y

Air Y Y

16 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Summary table on relevant physico-chemical and fate and behaviour parameter of the active substance

Value Unit Remarks

Molecular weight 52.5

Value for HOCL as used in the environmental exposure assessment Vapour pressure at 25°C 276 Pa for Active chlorine released from calcium hypochlorite

Log Octanol/water partition -0.87 Log 10 QSAR estimate* coefficient

Derived from DT50 of 20 sec in the sewer as 56 sec (at 12°C) given in the ESD for DT50 for STP 0.0157 h (at 12°C) PT 5. This is a purely 6.55E-04 d (at 12°C) chemical process, no biodegradation occurs.

* KOWWIN v1.68 estimate. This value is used for consistency with the CARs for Active chlorine released from calcium hypochlorite and Active chlorine released from sodium hypochlorite noting that the QSAR is in fact not appropriate to be applied for ionisable substances

The application of halogen-containing biocides leads to the formation of disinfection by­ products (DBPs). These DBPs have been shown to include hazardous substances that may pose a risk to human health or the environment. For environmental DBP assessment, the participants to a dedicated Workshop organized by ECHA on 25 June 2015 agreed that for Active Chlorine the issue had been sufficiently covered by the EU RAR document for sodium hypochlorite. Experts also recognised, however, that where usage scenarios deviated significantly from those present in the EU RAR document for sodium hypochlorite, additional data could be generated at a product level. The use of Active Chlorine in PT 1 is not specifically addressed in the EU RAR document for sodium hypochlorite and additional data may be required at a product level. Doc. IIA, Section 1.6 FORMATION OF DISINFECTION BY­ PRODUCTS highlights the potential relevance of the formation of disinfection by-products for the environmental risk assessment in case of the uses of Active Chlorine in PT 1—5. During the discussion on NaOCl, CaOCl and Chlorine in WGII2016 it was confirmed that the risk assessment of the disinfection by-products will be included in the assessment at the renewal stage of the active substances.

Effects assessment

Short and long-term toxicity data from literature are available for fish, invertebrates, algae and micro-organisms. Only flow-through tests or static test with a reliable analytical monitoring of the test concentration over the test duration should be used for the effects assessment and as a basis for the environmental risk assessments. Most tests with a static test design result in by a factor of 100 - 500 higher end-points (NOEC, LC50) than studies performed according to a flow-through design. Due to the very fast hypochlorite decay, the static test system is not exposed during the complete test duration to the same hypochlorite concentration. When data from literature were considered not valid or incomplete for the risk assessment, new toxicity laboratory studies were performed and included in the CAR.

The evaluation and comparison of toxicity data is complicated by the complexity of the Active Chlorine chemistry in water and by the different analytical methods used in the tests performed for the monitoring of the test item concentration in the test medium. TRC (total residual chlorine) is a measurement of both free and combined chlorine (such as chloramines). It is difficult to separate the contribution to toxicity of the FAC (free available chlorine) such as

17 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

HClO/ClO_ from that of the combined chlorine species. In addition, the relative amounts of the different chlorine species vary from test to test, depending on test duration, pH and other medium related effects such as ammonium level and others. For those studies where the percentage of FAC (free available chlorine) from TRC (total residual chlorine) was measured, the toxicity endpoints were expressed also as FAC/L. In the tests with chlorinated seawater, test-item concentrations were expressed as TRO (total residual oxidant) or CPO (chlorine produced oxidants), which include, in addition to free and combined chlorine, also other oxidative species, such as bromine species.

The PNECaquatic is derived as agreed in the WGII2016 Ad Hoc Follow up for NaOCl, CaOCl and Chlorine.

PNECaquatic

As reported in the TGD, use of pooled data deriving from the freshwater effects endpoints in addition to saltwater effect endpoints is possible and PNEC values should be derived from the most sensitive endpoint regardless the medium. Where differences in the apparent sensitivity of freshwater and marine species are observed for individual compounds, such differences are generally comprised within a factor of 10. Data on freshwater or marine fish, crustacean and algae can be used interchangeably for evaluation of the risk assessment to either compartment.

The available NOECs for hypochlorite spread over one order of magnitude and confirm the observations reported in the TGD. Short- and long-term toxicity data for fresh and seawater organisms are available on three trophic levels. NOEC values were defined for each trophic level: fish, invertebrates (molluscs) and algae.

From the available NOEC dataset, the lowest endpoint is derived from algae with a NOEC = 2.1 pg FAC/L (7d NOEC, Cairns, 1990), which was selected as reference value for the risk assessment.

For the deduction of the aquatic PNEC an Assessment Factor (AF) of 50 is used. This is justified because, according to the TGD on Risk Assessment, an AF of 50 can be used when two long­ term NOECs from fresh- or saltwater species representing two trophic levels and one long-term NOEC from an additional marine taxonomic group (molluscs) are available (EU TGD, 2003).

After WGII2016 an Ad hoc follow-up was launched: comments from FR, NL and DE were received. NL pointed out that differences in water characteristics will influence the chemical equilibria. The presence of bromide in seawater will lead to a shift towards bromine species instead of chlorine, and HOBr will be formed. It is noted that in the EU RAR on hypochlorite, the datasets for freshwater and marine species have been kept separately but in the CAR for fish a comparison between freshwater and marine tests is not possible due to lack of reliable data. For now, the lack of data makes a proper comparison of data impossible. Therefore, it is considered appropriate to keep the AF of 50 as proposed by the eCA. If at product authorisation additional information is provided it could become possible to lower the assessment factor.

PNECaquatic = 2.1 pg FAC/L : 50 = 0.042 p g FAC/L

PNECsediment

The PNECsediment was calculated to be 0.045 pg FAC/kg ww on the basis of the PNECaquatic, using the equilibrium partitioning method according to the TGD.

PNECs tp

The lowest available EC50 and NOEC value for micro-organisms in the activated sludge is 77.1 mg available chlorine/L and 41.1 mg available chlorine/L, respectively. The WGII2016 agreed that the PNECs tp should be derived in accordance to previous agreements (TAB entry ENV-4). 18 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

and that an AF 10 to the NOEC (or EC10) should be applied. An assessment factor of 10 was applied to the NOEC value (lowest available endpoint), resulting in a PNEC of 4.11 mg available chlorine/L.

PNECterrestrial

The PNECterrestrial was calculated to be 0.015 M9 FAC/kg ww on the basis of the PNECaquatic, using the equilibrium partitioning method according to the TGD.

2.2.2.2. Exposure assessment and risk characterisation

Emission and exposure resulting from all stages of the life-cycle of Active Chlorine released from hypochlorous acid have to be assessed in the exposure and risk assessments. The risk from exposure to chloride as degradation product is considered acceptable based on the risk characterisation for chloride from residual sodium chloride (see assessment for precursor). The calculated PEC values, according to the ESD PT 1, are reported in the tables below.

Aquatic compartment (incl. sediment)

Surface water

In Doc. IIA, Chapter 4, a PNEC of 0.042 qg/L (i.e. 4.2 x 10-5 mg/L) was derived from a long­ term toxicity study in algae (most sensitive species). The risk assessment for surface water was calculated on the basis of this PNEC and the product type specific PEC for surface water as calculated in the exposure assessment (see Doc. IIB, Chapter 3.3).

An overview on the results of the aquatic risk assessment for Active Chlorine released from hypochlorous acid is provided in the tables below.

Overview on the calculated PEC/PNEC for the aquatic compartment (incl. sediment)

PNECsw = 4.2 x 10-5 mg/L PNECsed = 4.5 x 10-5 mg/kg Exposure scenario PECsw PECsed PEC/PNECsw PEC/PNECsed [mg/L] [mg/kg ww] PT 1 5.54E-26 4.23E-26 1.3E-21 9.7E-22 Manufacture/formulation

Disinfectant for hand 4.16E-25 3.26E-25 7.3E-22 7.3E-22 application in hospitals 1.92E-24 1.51E-24 4.6E-20 3.3E-20 Disinfectant for feet treatment 8.01E-26 6.28E-26 1.9E-21 1.4E-21 Disposal of packaging

As shown in the table above, the PEC/PNEC values calculated for manufacture/formulation, the proposed use of Active Chlorine as disinfectant in product type 1 as well disposal of packaging are below 1, indicating acceptable risks from exposure to available chlorine organisms in the water column and sediment organisms.

Sewage treatment plant

In Doc. IIA, Chapter 4, a PNEC of 4.11 mg/L for Active Chlorine was derived from an activated sludge respiration inhibition test. The risk assessment for the STP was calculated on the basis of this PNEC and the product type specific PEC for STP as calculated in the exposure assessment (see Doc. IIB, Chapter 3.3).

Overview on the calculated PEC/PNEC for sewage treatment plant (STP)

19 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

PNECs t p = 4.11 mg/L Exposure Scenario PECs t p [mg/L] PEC/PNECs tp

PT 1 5.54E-25 1.3E-25 Manufacture/formulation

Disinfectant for hand application in hospitals 4.16E-24 7.5E-26 1.92E-23 4.7E-24 Disinfectant for feet treatment 8.01E-25 1.9E-25 Disposal of packaging

As shown in the table above, the PEC/PNEC values calculated for manufacture/formulation, the proposed use of Active Chlorine as disinfectant in product type 1 as well disposal of packaging are below 1, indicating acceptable risks from exposure to available chlorine to microorganisms in the STP.

Atmosphere

Following proposed biocidal use disinfectant in product type 1, there will be negligible emission of available chlorine to the atmosphere. It was outlined in Doc. IIA, chapter 4.1.2, that the adsorption of hypochlorite to aerosol particles, the volatilisation from water into air and the adsorption of hypochlorite onto soil is very low. Thus, hypochlorite will remain in the aqueous phase and degrade very rapidly. There is no concern for this compartment.

Terrestrial compartment

There will effectively be no exposure of soil or groundwater resulting from the manufacture/formulation phase, use phase and disposal phase. Degradation of the miniscule amount left at the end of the sewer line will be completed in the STP. There is no concern from exposure to available chlorine for this compartment.

Aggregated risk assessment

Biocidal active substances are used in various applications and are often contained in many different products. The exposure assessment of single uses may therefore underestimate the actual concentrations of the active substance to be found in the environment. Article 19(2) of the new Biocidal Products Regulation (BPR, 528/2012 EU) states that "the evaluation [...] shall take into account the following factors: [...] (d) cumulative effects, (e) synergistic effects." This is further elaborated in Annex VI (common principles for the evaluation of biocidal products) which states that the risks associated with the relevant individual components of the biocidal product shall be assessed, taking into account any cumulative and synergistic effects. This refers to the environmental risk assessment of an active substance contained in different products of the same Product Type (PT) or of different PTs. Active chlorine generated from sodium chloride by electrolysis was notified as active chlorine releaser in PTs 1-5. The main entry pathways into the environment are equal for all applications mentioned above (via STP), thus a combination of exposures to active chlorine released from Active chlorine generated from sodium chloride by electrolysis for all affected environmental compartments is both possible and realistic. As a first tier, combined exposure of surface water and STP from all applications was assumed without further consideration whether combination of exposure is likely for all assessed uses.

Aggregated risk assessment for surface water considering all PTs PEC/PNECsw PT1 Disinfectant for hand application in hospitals 7.3E-22 PT1 Disinfectant for feet treatment 4.6E-20 PT2 Disinfectant for hard surfaces 2.7E-21

20 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

PT2 Disinfectant for contaminated instruments 6.4E-19 PT2 Disinfectant for public swimming pool, acute 4.0E-19 PT2 Disinfectant for public swimming pool, chronic 1.0E-20 PT2 Disinfectant for private swimming pools 1.9E-19 PT3 Disinfectant for animal housing 1.8E-20 PT3 Disinfectant for teat-dips 6.4E-22 PT3 Disinfectant for animal feet 1.6E-20 PT4 Disinfectant for slaughterhouses and butcheries 4.6E-20 PT4 Disinfectant for large scale catering kitchen 9.1E-21 PT4 Disinfectant for CIP 2.5E-19 PT5 Drinking water disinfectant 1.9E-21 Z PEC/PNECsw 1.7E-18

Aggregated risk assessment for sediment considering all PTs PEC/PNECsed PT1 Disinfectant for hand application in hospitals 5.4E-22 PT1 Disinfectant for feet treatment 3.3E-20 PT2 Disinfectant for hard surfaces 2.0E-21 PT2 Disinfectant for contaminated instruments 4.7E-19 PT2 Disinfectant for public swimming pool, acute 2.9E-19 PT2 Disinfectant for public swimming pool, chronic 7.4E-21 PT2 Disinfectant for private swimming pools 1.4E-19 PT3 Disinfectant for animal housing 1.3E-20 PT3 Disinfectant for teat-dips 4.7E-22 PT3 Disinfectant for animal feet 1.2E-20 PT4 Disinfectant for slaughterhouses and butcheries 3.3E-20 PT4 Disinfectant for large scale catering kitchen 6.7E-21 PT4 Disinfectant for CIP 1.8E-19 PT5 Drinking water disinfectant 1.4E-21 Z PEC/PNECsed 1.2E-18

Aggregated risk assessment for STP considering all PTs

PEC/PNECs t p PT1 Disinfectant for hand application in hospitals 7.5E-26 PT1 Disinfectant for feet treatment 4.7E-24 PT2 Disinfectant for hard surfaces 2.7E-25 PT2 Disinfectant for contaminated instruments 6.5E-23 PT2 Disinfectant for public swimming pool, acute 4.1E-23 PT2 Disinfectant for public swimming pool, chronic 1.0E-24 PT2 Disinfectant for private swimming pools 2.0E-23 PT3 Disinfectant for animal housing 1.9E-24 PT3 Disinfectant for teat-dips 6.5E-26 PT3 Disinfectant for animal feet 1.7E-24 PT4 Disinfectant for slaughterhouses and butcheries 4.7E-24 PT4 Disinfectant for large scale catering kitchen 9.3E-25 PT4 Disinfectant for CIP 2.6E-23 PT5 Drinking water disinfectant 1.9E-25 Z PEC/PNECstp 1.7E-22

The Tier 1 aggregated risk assessment indicates acceptable risk from combined exposure of surface water, sediment and STP following applications as disinfectant in PT1, PT2, PT3, PT4 and PT5.

21 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

2.2.2.3. Fate and distribution in the environment

The fate of available chlorine in the environment, in the sewer and during sewage treatment, is modelled by Vandepitte and Schowanek (as HOCl) (Doc IIIA, Section A7.1.2) and is calculated to be "zero" after the first minutes in the sewer.

In soil, available chlorine reacts rapidly with organic matter. The ultimate fate of available chlorine in soil is its reduction to chloride.

In the atmosphere, chlorine degrades during daylight, with a half-life of 2-4 hours. Available chlorine (as HOCl) is removed from the atmosphere by wet and dry deposition processes and washout by rain. The major sources of reactive chlorine are volatilisation from seasalt, marine algae, volcanoes and coal combustion.

The volatilisation of chlorine, hypochlorous acid and hypochlorite from water into air is very low. The adsorption of chlorine, hypochlorous acid and hypochlorite to aerosol particles and to soil particles is also very low. Thus, Active Chlorine (an equilibrium mixture of these three components) remains in the aqueous phase where it degrades very rapidly in the environment. Substances with a Log Pow less than 3 like chlorine and hypochlorous acid have a low potential to bioaccumulate.

2.2.2.4. PBT and POP assessment

The criteria for PBT assessment are specified in the Annex XIII of Regulation (EC) No 1907/2006 (REACH). A substance is identified as a PBT substance if it fulfils the persistence, bioaccumulation and toxicity criteria of sections 1.1.1, 1.1.2 and 1.1.3 or very persistence and very bioaccumulation (vPvB) if it fulfils criteria of sections 1.2.1 and 1.2.2. The PBT and vPvB criteria of Annex XIII to the Regulation does not apply to inorganic substances as Active Chlorine but apply to all organics substances, including organo-metals.

POP assessment

POP criteria are not applicable to Active chlorine released from hypochlorous acid as mixture is inorganic.

2.2.3. Assessment of endocrine disruptor properties

Human Health There are no studies available specifically addressing the endocrine disrupting potential of Active chlorine solution. All studies used for evaluation endocrine activity are non-GLP and methods used are comparable to OECD guidelines. According to the draft minutes of the BPC HH WGII2016 meeting the toxicity of chlorine solution in the risk assessments is performed on local effects (with secondary systemic effects at high doses). The toxicity of sodium hypochlorite was investigated in several studies with repeat administration via oral route (drinking water and feeding). All the in vivo tests (Level 4 and one study from Level 5) submitted in the data package for this active substance were evaluated. No relevant observed adverse effects except reduced chlorinated drinking water consumption and/ or body weight reduction were identified under the experimental conditions of the submitted studies. EAS-mediated adverse effects are not sufficiently investigated, and no dossier studies measured EATS-mediated endocrine activity. From the available studies it is not possible to know if the impurities of the active substance have been tested. When revising the ED assessment according to the EFSA/ECHA guidance at the renewal stage, the eCA will assess whether the impurities of the active substances are covered by the revised ED assessment. Chlorate is considered as a relevant impurity for active chlorine generated from sodium chloride by electrolysis and active chlorine released from hypochlorous acid. An ED assessment

22 Active chlorine released from Product-type 1 July 2020 hypochlorous acid of chlorate was not performed as the necessary data was not submitted and the available data is not sufficient for concluding. The EFSA Scientific Opinion "Risks for public health related to the presence of chlorate in food" (EFSA Journal 2015; 13:4135) considers inhibition of iodine uptake in humans as the critical effect for chronic exposure to chlorate, especially among infants and children. The most sensitive effects were changes to the thyroid gland of male rats, noting that rats are highly sensitive to the effects of agents that disrupt thyroid hormone homeostasis. No conclusion can be drawn on the ED properties for HH, based on the currently available data. Since this is a backlog dossier, no new studies can be requested at this stage. The revised ED assessment (according to the ED guidance) would have to be provided at the renewal stage. WGI2020 conclusion The WG agrees that no conclusion can be drawn on the ED properties of these active substances in respect to human health. Please refer to Doc IIA for the complete assessment of endocrine disrupting properties of active chlorine solution with respect to human health organisms. Non-target organisms We summarise the data of active chlorine on non-target organisms available in the dossier provided by the applicant and as well as results from literature screening which was performed according to the ED GD. It should be noted, that neither the dossier nor the literature data were designed to specifically answer the question whether active chlorine has endocrine disrupting properties or not. No relevant data available from level 2-5. With regard to non-target organisms no relevant test information is available in the dossier that could be used for assessment of active chlorine as a substance having endocrine disrupting properties. The Guidance states that information on other taxa (invertebrates) should be considered if available. EATS- mediated adverse effects are not sufficiently investigated for non-target organisms (only short-term studies presented with survival, behavioural and abnormal morphology as observed endpoints available, majority of studies is non-GLP and non-OECD TG). Observed abnormalities are connected with toxicity of active chlorine as were reported in studies. There is no endpoint declaring that the active substance could be potentially an endocrine disruptor, however majority of all provided studies have lower reliability. It is also important to notice, that many reported studies are old dated and majority of them are not GLP and non- OECD TG studies. Only several endpoints were observed with focus on mortality, behaviour and malformations without focus on ED-relevant endpoints. There was also no relevant level 2­ 5 study for active chlorine for the environment according to ED GD requirements. All adverse effects reported in the provided studies were linked with toxicity of the active substance. WGI2020 conclusion The WG agreed that it is not possible to conclude on the ED properties for non-target organisms with the information available. Please refer to Doc IIA for the complete assessment of endocrine disrupting properties of active chlorine solution with respect to non-target organisms. Overall conclusion regarding endocrine disrupting properties For the endocrine-disrupting properties as defined in Regulation (EU) No 2017/2100, the necessary data was not submitted and no conclusion can be drawn on the available data. The EFSA Scientific Opinion "Risks for public health related to the presence of chlorate in food"; (EFSA Journal 2015; 13:4135) suggests that chlorate may disrupt the thyroid hormone homeostasis. An ED assessment of chlorate was not performed as the necessary data was not submitted and the available data is not sufficient for concluding. According to the CA meeting note mentioned above, for reports submitted before 1 September 2013, the evaluating 23 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Competent Authority has to conclude based on the already available data and/or the data provided by the applicant. In case the data is insufficient to reach a conclusion, the BPC may conclude in its opinion that no conclusion could be drawn. As the evaluation of active chlorine released from hypochlorous acid for PT 1 was submitted before 1 September 2013, no conclusion is drawn whether active chlorine released from hypochlorous acid meets the conditions laid down in Article 5(1)(d) based on the available data.

2.3. Overall conclusions

2.3.1. Overall conclusion of the evaluation including need for risk management measures

The outcome of the assessment for Active chlorine released from hypochlorous acid product- type 1 is specified in the BPC opinion following discussions at the 25th and 35th meeting of the Biocidal Products Committee (BPC). The BPC opinion is available from the ECHA web-site.

2.4. Requirement for further information related to the reference biocidal product

None.

2.5. List of endpoints

The most important endpoints, as identified during the evaluation process, are listed in Appendix I.

24 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Appendix I: List of endpoints

Chapter 1: Identity, Physical and Chemical Properties, Classification and Labelling

Active substance (ISO Name) Active chlorine released from hypochlorous acid (ISO Common Name of the active substance is not applicable) Product-type PT1 Human hygiene biocidal product

Identity Chemical name (IUPAC) Hypochlorous acid Chemical name (CA) Hypochlorous acid CAS No 7790-92-3 EC No 232-232-5 Other substance No. Not yet assigned Minimum purity of the active substance Reference specification for Active Chlorine as manufactured (g/kg or g/L) which is placed on the market as biocidal product (bottled) is derived from 5-batch analysis of the company Puricore Europe Ltd (a subsidiary of Realm Therapeutics PLC). Hypochlorous acid is expected to be the predominant species in Active Chlorine solution at pH 3.0 - 7.4 Minimum content of hypochlorous acid is 0.0255% w/w (as dry weight min 90.87% w/w). Analytical results are by convention expressed as available (active) chlorine using the molecular weight of chlorine. The reported values have been converted into hypochlorous acid by applying a conversion factor of 0.74 (Mw HOCl/Mw Cl2 = 52.45/70.91) Identity of relevant impurities and Chlorate: < 0.0007% w/w (as dry weight additives (substances of concern) in the max 2.96% w/w) active substance as manufactured (g/kg) Molecular formula HOCl Molecular mass 52.46 g/mol Structural formula Hypochlorous acid : H-O-Cl

Physical and chemical properties

25 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Melting point (state purity) Hypochlorous acid5: -28.9 +/- 0.5 °C (purity: 24.3% available chlorine) Boiling point (state purity) Hypochlorous acid 6: 60.4 - 64.1 °C (purity: 24.3% available chlorine)

Thermal stability / Temperature of Hypochlorous acid6: decomposition Half-life of a 10% av. Cl solution at different temperatures:

800 days at 15 °C 220 days at 25 °C 3.5 days at 60 °C 0.079 day at 100 °C

Half-life of a 5% av. Cl solution at different temperatures:

5000 days at 15 °C 790 days at 25 °C 13.5 days at 60 °C 0.25 day at 100 °C

Appearance (state purity) Hypochlorous acid6 : At room temperature a yellow and limpid liquid with a chlorinated odour. Relative density (state purity) Hypochlorous acid6 : D (21.2 °C/4 °C) = 1.300 +/- 0.001 (purity: 24.3% available chlorine)

Surface tension (state temperature and Hypochlorous acid6 : concentration of the test solution) 82.4 mN/m +/- 0.8 mN/m (n = 3, at 20.2 - 20.3 °C) (purity: 24.3% available chlorine) Vapour pressure (in Pa, state Hypochlorous acid6: temperature) Approximately 2.5 kPa at 20°C Henry's law constant (Pa m3 mol -1) Hypochlorous acid:

0.11 Pa m3 mol -1at 20 °C Solubility in water (g/L or mg/L, state Hypochlorous acid:

temperature) 25 g hypochlorous acid/100 g H2O. Temperature not stated in literature

5Hypochlorous acid does not exist as a pure salt at room temperature. It is produced and handled in form of aqueous solutions. Data on hypochlorous acid is mainly based on data of recently performed studies on a 24% available chlorine solution (as this is the highest technically feasible concentration) and on literature data, which also addresses those physical- chemical parameters which are meaningful for hypochlorous acid. Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Solubility in organic solvents (in g/L or Hypochlorous acid: mg/L, state temperature) Active Chlorine in the form of hypochlorous acid is not isolated, but always produced and handled as an aqueous solution. Therefore, data on solubility in organic solvents is not considered relevant. Stability in organic solvents used in Not relevant; no organic solvents are used in biocidal products including relevant the biocidal product. breakdown products

Partition coefficient (log Po w ) (state Hypochlorous acid: temperature) A log Po w value calculated for hypochlorous acid is: - 0.87

All values were calculated using KOWWIN v1.67.

Not required for inorganic substances such as hypochlorous acid. Dissociation constant The hydrolysis reaction of chlorine dissolved in water is: Cl2 + H2O <-> HOCl + HCl (K1)

The hypochlorous acid formed is also hydrolysed: HOCl <-> ClO- + H+ (K2)

Thus, the equilibrium constant for the reaction of chlorine and water is: K = (H+)(Cl-)(HOCl)(Cl2)-1

The equilibrium constants of the above reactions in pure water are as follows:

At 10 °C: K1 : 2.2 x 10-4 mol/dm3 K2 : 2.7 x 10-8 mol/dm3

At 20 °C: K1 : 3.2 x 10-4 mol/dm3 K2 : 3.5 x 10-8 mol/dm3

At 30 °C: K1 : 4.4 x 10-4 mol/dm3

K2 : 4.3 x 10-8 mol/dm3 UV/VIS absorption (max.) (if absorption Hypochlorous acid: > 290 nm state e at wavelength) Not determined, as hypochlorous acid cannot be isolated in its pure form. Flammability or flash point Hypochlorous acid: Not flammable or auto-flammable. Explosive properties Hypochlorous acid: Not explosive.

27 Active chlorine released from Product-type l July 2G2G hypochlorous acid

Oxidising properties Hypochlorous acid: Hypochlorous acid is a strong oxidising agent. Active Chlorine is formed and exists in aqueous solution. It consists of more than 99.5% water; amount of available chlorine is approximately 300 mg/L. The substance generated can reasonably be expected not be an oxidising hazard due to the dominance of water's properties. Auto-ignition or relative self-ignition Not auto-ignitable substance temperature

Classification and proposed labelling Hypochlorous acid is not currently listed in Annex VI of Regulation 1272/2008. A classification proposal is currently not available and needs to be considered.

The data (according to Regulation 1272/2008/EC) in the tables below are introduced for informative purposes only.

with regard to physical hazards Chlorine:

Hazard Class Hazard Pictogram and Category Statement Signal Word Code(s) Code(s) Code (s)

Danger

Ox. Gas 1 H270 May GHS03 cause or Press Gas intensify fire, GHS04 oxidiser

with regard to human health hazards Skin Irrit. 2 H315 Causes skin irritation

H319 Causes Eye Irrit. 2 serious eye irritation

Acute Tox. 3 H331 Toxic if GHS06 inhaled

H335 May cause STOT SE 3 respiratory irritation

with regard to environmental hazards H400 Very Aquatic G HS 09toxic to GHS09toxic Acute 1 aquatic life

28 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Sodium hypochlorite

Danger with regard to human health hazards H314 Causes severe skin Skin Corr 1B GHS05 burns and eye damage

H400 Very Aquatic toxic to GHS09 Acute 1 aquatic life with regard to environmental hazards H410 Very toxic to Aquatic aquatic life Chronic 1 with long lasting effects

29 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Chapter 2: Methods of Analysis

Analytical methods for the active substance Technical active substance (principle of Available chlorine:

method) Available chlorine is the sum of Cl2 + HOCl + ClO- . It is expressed as the equivalent content of Cl2, based on the oxidising capacity. A spectrometric and a titrimetric method for the determination of available chlorine are described.

Spectrometric method: Direct reaction between available chlorine and N,N-diethyl- 1,4-phenylenediamine (DPD) yielding a red compound at pH 6.2 to 6.5. Measurement of the colour intensity by visual comparison of the colour, with a scale of permanent glass standards, or by spectrometry.

Titrimetric method: Direct reaction of free chlorine with N,N-diethyl-1,4- phenylenediamine (DPD) yielding a red compound at pH 6.2 to 6.5. Titration is by means of a standard solution of ammonium iron(II)sulphate, to the disappearance of the red colour.

The limit of determination for both methods is 0.0004 mmol/L (0.03 mg/L) Cl2. The methods are applicable to concentrations in terms of chlorine from 0.0004 to 0.07 mmol/L (0.03 to 5 mg/L) total chlorine and at higher concentrations by dilution of samples.

Sodium hypochlorite: Sodium hypochlorite reacts with potassium iodide to release iodine in the presence of acetic acid. The iodine is titrated with sodium thiosulphate solution in the presence of starch indicator solution. Hypochlorite is degraded with hydrogen peroxide and the total chloride content is determined by titration with silver nitrate solution. The amount of chloride resulting from hypochlorite has to be subtracted from the total chloride content to obtain the sodium chloride content.

Impurities in technical active substance Chlorate: ion chromatography (IC) with (principle of method) conductivity detection

Analytical methods for residues 3Q Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Soil (principle of method and LOQ) Not relevant Air (principle of method and LOQ) Sampling is performed by passing a measured volume of air through a sulphamic acid solution, trapping the chlorine as stable chloramines. The subsequent analytical determination is based on the reaction of chloramines and iodide in slightly acidic solution with the formation of a tri-iodide species. Spectrophotometric measurement of the tri-iodide is made at 288 nm. It could also be based on the reaction of chloramines with iodide, in slightly acidic solution, producing free iodine which oxidises DPD (N,N-diethyl-1,4-phenylenediamine sulphate) forming a red coloured diimine. Spectrophotometric measurement of the red coloured solution is made at 510 nm. Water (principle of method and LOQ) A spectrometric and a titrimetric method for the determination of available chlorine are described.

Spectrometric method: Direct reaction between available chlorine and N,N-diethyl- 1,4-phenylenediamine (DPD) and formation of a red compound at pH 6.2 to 6.5. Measurement of the colour intensity is by visual comparison of the colour, with a scale of permanent glass standards, or by spectrometry.

Titrimetric method: Direct reaction of available chlorine with N,N-diethyl-1,4- phenylenediamine (DPD) and formation of a red compound at pH 6.2 to 6.5. Titration is by means of a standard solution of ammonium iron (II) sulphate, to the disappearance of the red colour.

The limit of determination with both methods is 0.0004 mmol/L (0.03 mg/L) Cl2 . The methods are applicable to concentrations in terms of chlorine from 0.0004 to 0.07 mmol/L (0.03 to 5 mg/L) total chlorine and at higher concentrations by dilution of samples. Body fluids and tissues (principle of Not relevant method and LOQ)

Food/feed of plant origin (principle of Not relevant method and LOQ for methods for monitoring purposes) Food/feed of animal origin (principle of Not relevant method and LOQ for methods for monitoring purposes)

31 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Chapter 3:Impact on Human Health

Absorption, distribution, metabolism and excretion in mammals

Rate and extent of oral absorption: 36%(36Cl, in the form of hypochlorite, chloride or DBPs)

Rate and extent of dermal absorption*: where needed: 10% assumption based on reactivity of hypochlorite solutions to proteinaceous material and ionic nature Distribution: Mainly in plasma and whole blood (HOCl) Potential for accumulation: No evidence of bioaccumulation

Rate and extent of excretion: Elimination: Rate constant: 0.009 h-1, half-life: 77.0 h mainly via urine (based on results obtained with HOCl) Toxicologically significant metabolite(s) In vitro data If amino acids (present in the stomach fluid recovered from rats) were chlorinated by hypochlorite solution, the corresponding chloramines were identified: N-chloroglycine, either N-chloroleucine or N-chloroisoleucine, and N-chlorophenylalanine.

* the dermal absorption value is applicable for the active substance and might not be usable in product authorization

Acute toxicity

Rat LD50 oral 8830 mg /kg bw of hypochlorite-based bleach with 12,2% Active Chlorine

Rat LD50 dermal 10.0 g NaOCl/kg bw (approx. 9.5 g available chlorine) However, concentration of sodium hypochlorite was not reported and the methodology was not fully explained. Therefore, the value was not considered to be relevant for the risk assessment

Rat LC50 inhalation 209 mg/m3 -extrapolated value from LC50 of 834 mg/m3 for 60 min. exposure to chlorine (legal classification: Acute Tox. 3, H331)

Skin corrosion/irritation Sodium hypochlorite solutions are classified as follows: • Solution with concentration of available chlorine from 1% to lower than 5%: Skin Irrit. 2 • Solutions with concentration of available chlorine of 5% or higher: Skin corrosion 1B

Eye irritation Sodium hypochlorite solutions are classified as follows: • Solution with concentration of available 32 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

chlorine from 1% to lower than 3%: Eye Irrit. 2 • Solution with concentration of available chlorine at 3% or higher: Eye damage 1

Respiratory tract irritation No data available

Skin sensitisation (test method used Non sensitising (based on results obtained and result) with tested sodium hypochlorite solutions, Buehler method)

Respiratory sensitisation (test No data available method used and result) Repeated dose toxicity Short term

Species / target / critical effect Rat / no specific changes Relevant oral NOAEL / LOAEL Only limited data, Available studies with lower reliability

Relevant dermal NOAEL / LOAEL overall NOAEC = 1% based on WoE from several, also longer term studies: With a concentration of 0.125% in daily exposures of guinea pigs for 8 weeks no adverse local effects were observed (Wohlrab et al. 1982). With a concentration of 1% twice weekly for 51 weeks no adverse local effects were observed in mice (Kurokawa 1984). Exposure to 1% once for 24 hours in 20 humans did not lead to adverse local effects (Habets et al. 1986). Continuous skin exposure to solutions of 0.5% for more than 7 days seems to lower viability of basal cells in guinea pigs (Cotter et al. 1985). Relevant inhalation NOAEL / LOAEL Not available

Subchronic

Species/ target / critical effect Rat, mouse / reduced body weight No toxicologically relevant and/or adverse effects were observed in most of the subchronic rat and mouse studies

Relevant oral NOAEL / LOAEL Different NOAELs were derived from studies Relevant dermal NOAEL / LOAEL Not available Relevant inhalation NOAEL / LOAEL Human and Rhesus Monkey, inhalation, chlorine: NOAEC 0.5 ppm corresponding to 1.5 mg av. chlorine/m3 33 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Long term

Species/ target / critical effect Rat, mouse / reduced body weight, clinical signs Relevant oral NOAEL / LOAEL Rat, via drinking water: NOAEC (top concentration) 1000 mg/L (based on results obtained from a 104 weeks drinking water study in rats with sodium hypochlorite, Hasegawa 1986) Relevant dermal NOAEL / LOAEL Mouse NOAEC (top concentration) 9500 mg/L (1%) based on results obtained from a 51 week study in mice with sodium hypochlorite, Kurokawa 1984). Relevant inhalation NOAEL / LOAEL LOAEC 0.4 ppm (corresponding to 0.35 mg/kg bw/d) based on damage of olfactory epithelium in mice and rats (two years studies)

Genotoxicity In vitro (AMES and in cytogenicity tests): inconsistent results In vivo (mouse micronucleus and cytogenicity tests): negative Overall (weight of evidence): no genotoxic potential (based on results obtained with sodium hypochlorite)

Carcinogenicity Species/type of tumour Non-carcinogenic in rats and mice (based on results obtained with chlorine and sodium hypochlorite in drinking water)

Relevant NOAEL/LOAEL Not applicable

Reproductive toxicity Developmental toxicity Species/ Developmental target / critical Rat, via chlorinated drinking water effect No effects observed Relevant maternal NOAEL > 5.7 mg/kg bw/d; NOAEC = 100 mg/L Relevant developmental NOAEL > 5.7 mg/kg bw/d; NOAEC = 100 mg/L Fertility Species/critical effect Rat, via chlorinated drinking water No effects observed Relevant parental NOAEL > 6.8 mg/kg bw/d; NOAEC > 500 mg/L

34 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Relevant offspring NOAEL > 6.8 mg/kg bw/d; NOAEC > 500 mg/L Relevant fertility NOAEL > 6.8 mg/kg bw/d; NOAEC > 500 mg/L

Neurotoxicity Species/ target/critical effect No indicative signs from acute and repeated dose studies; no structural alerts (based on results obtained with chlorine and sodium hypochlorite) Developmental Neurotoxicity Species/ target/critical effect Not available

Immunotoxicity Species/ target/critical effect Not available

Developmental Immunotoxicity Species/ target/critical effect Not available

Other toxicological studies Neurotoxicity No indicative signs from acute and repeated dose studies; no structural alerts (based on results obtained chlorine and sodium hypochlorite) Toxic effects on livestock and pets Not determined since the mode of action is not species specific Studies related to the exposure of the a.s. Studies related to human exposure to humans demonstrated an irritation rather than a sensitising potential of sodium hypochlorite. Food and feeding stuffs No specific studies available. Other tests related to exposure of the a.s. Results obtained from studies with sodium to human considered to be necessary hypochlorite: - Skin thickness (interfollicular epidermis) and the number of cells (total and basal) of female SENCAR mice were increased after treatment with 100 ppm hypochlorous acid. The treatment of the skin of female guinea pigs showed concluded that a 0.1% solution of sodium hypochlorite could be used for long-term maintenance of the wound due to the relatively low toxicity. Tests to assess toxic effects from Not relevant because chlorine based metabolites of treated plants products are not used on plants. Mechanistic studies No studies necessary to clarify effects reported in toxicity studies

35 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Further human health related studies Not required

Medical data Medical surveillance data on manufacturing Chlorine: no data available plant personnel Sodium hypochlorite: no data available

36 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Direct observations, e.g. clinical cases, Chlorine: poisoning incidents Several accidental exposures to chlorine are described: - The outcome in individuals exposed to chlorine/ chloramine gases produced at home due to mixing cleaning products was determined. Most symptoms resolved within 6 hours. - The accidental exposure of workers to chlorine (> 100 ppm) led to airflow obstruction. These changes gradually resolved as after two years. No significant changes were noted in total lung capacity, functional residual capacity and vital capacity. - Symptoms after accidental exposure to chlorine in a swimming pool were eye irritation (children: 50%; adults: 61.9%), throat irritation (children: 54.5%; adults: 73.0%) and cough, wheezing and shortness of breath (children: 71.6%; adults: 66.7%). The effect of exposure on lung function tended to be higher among smokers and ex­ smokers than among never smokers. Persistent symptoms and lung function impairment were found up to 1 month after the incident.

- The accidental exposure of 88 workers to chlorine gas (66 ppm) caused dyspnea and coughing, eye and throat irritation, headache and giddiness, chest pain and abdominal discomfort. The most significant cytopathologic feature on postexposure day 5 was the appearance of "irritation forms" of bronchial epithelial cells. Basal-cell and goblet-cell hyperplasia, acute inflammation and chromatolysis of columnar epithelial cells. Information on pulmonary function seven years after accidental exposure to 400 ppm chlorine gas was provided. The results demonstrate that significant permanent lung damage does not result from acute exposure to chlorine gas.

Sodium hypochlorite: Case 1:accidentally injecting sodium hypochlorite beyond the root apex; clinical signs: severe pain, oedema and eye and face swelling Case 2: two single incidental infusions of sodium hypochlorite solution on continuous ambulatory peritoneal dialysis of one patient; clinical signs: abdominal pain, nausea and abdominal discomfort for several days, decreased serum levels of urea nitrogen and creatinine Case 3:exposure of the eye to 0.5% NaOCl; clinical signs: burning discomfort, treatment: washing with water; recovery within two days Further investigations are available and results are in accordance with irritating/corrosive properties of NaOCl at the site of first contact (e.g. skin, eyes, and respiratory tract).

37 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Health records, both form industry and any Results obtained from observations with other sources sodium hypochlorite: - An 18-year-old girl developed onycholysis of all fingernails after an exposure period of several weeks. Termination of the procedure resulted in total recovery of the fingernails with one or two months. According to illness/injury type 41 of 149 reported cases were systemic while in 85 cases eyes and in 22 cases skin was affected. In one case eyes and skin were affected. Epidemiological studies on the general No data available population Diagnosis of poisoning including specific Results obtained from observations with signs of poisoning and clinical tests sodium hypochlorite: Study 1: Direct examination of the oesophagus is not indicated following Clorox® ingestion as no significant oesophageal injury was observed in 129 cases of ingestion. Study 2: The ingestion of chlorine bleaches containing 5.5% sodium hypochlorite and 0.5% sodium hydroxide resulted in caustic oesophageal burns and oesophageal strictures, emetic and pulmonary effects. Study 3: After ingestion of Clorox® marked constriction of the stomach due to scarring and fibrosis occurred. Oesophagus appeared normal; a small contracted stomach was found; gross and histological examination showed extensive scarring in the stomach wall due to fibrosis. After total gastrectomy the patient was able to take a soft diet within one week. Study 4: Sodium hypochlorite has not caused severe damage in any of the 27 patients. Vomiting and visible reddening in mouth and throat observed in a few cases. One single case remained doubtful. Study 5: In cases of ingestion of large amounts of bleach treatment should include estimation of serum sodium and acid-base-balance. Sensitization/allergenicity observations In view of the known irritant and corrosive properties of sodium hypochlorite, the effects reported in humans suggest an irritation rather than a sensitising potential.

38 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Specific treatment in case of an accident or Chlorine: poisoning: first aid measures and medial Inhalation: treatment • Remove the subject from the contaminated area as soon as possible; transport him/her lying down, with the head higher than the body, to a quiet, uncontaminated and well-ventilated location. • Oxygen or cardiopulmonary resuscitation if necessary. • Consult with a physician immediately in all cases. • Take to hospital immediately. • Keep warm (blanket). Eyes contact: • Flush eyes as soon as possible with running water for 15 minutes, while keeping the eyelids wide open. • In the case of difficulty of opening the lids, administer an analgesic eye wash (oxybuprocaine). • Consult with an ophthalmologist and physician immediately in all cases. • Take to hospital immediately. Skin contact: • Immediately bring the clothed subject under the shower. • Remove contaminated shoes, socks and clothing; wash the affected skin with running water. • Consult with a physician immediately in all cases. • Keep warm (blanket), provide clean clothing.

Ingestion: not applicable

Sodium hypochlorite: Eye contact: • Rinse thoroughly with plenty of water for several minutes. If symptoms persist, seek medical advice. Skin contact: • Rinse affected area with water. If needed apply cold compress to relieve irritation. If symptoms persist, discontinue use of product and seek medical advice. Ingestion: • Drink a glass of water to dilute product, Do not induce vomiting. Act immediately in order to prevent further irritation of mouth, throat and stomach mucosa. If symptoms persist, if persistent vomiting occurs or if blood tinged vomitus is present, seek medical advice. Inhalation: • Go in open air and ventilate suspected area. If irritation is experienced, mouth and throat may be rinsed with water. Aerosolised product adhering to the nasal cavity may be rinsed/diluted with saline/plain water. If irritation or asthma-like symptoms persist, seek medical advice.

Prognosis following poisoning Depending on severity of effects.

39 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Summary Value Study Safety factor

AELlong -term Not derived due to

AELmedium-term dominant local effects --

AELshort -term ADI Not derived for active -- chlorine due to dominant ARfD local effects (however dietary RA for chlorate as DPB is basd on ARfD of 36 pg/kg bw, ADI 3 pg/kg bw) Dermal absorption -- Oral absorption Not derived due to -- dominant local effects Inhalation -- absorption

NOAECdermal (to be overall NOAEC = 1% Various exposure regimes, used for semi­ animal species and humans available chlorine - quantitative MOE approach) NOAEC oral (to be overall NOAEC = 0.1% Hasegawa et al. 1986 used for semi­ available chlorine studies (90 day rat and 104 - quantitative MOE weeks rat) approach)

AEC respiratory AEC = 0.5 mg av. Subchronic inhalation chlorine/m3 toxicity - Human and Rhesus Monkey, for chlorate as relatively stable reaction product

MRL 0.01 mg chlorate/kg food (Scientific Opinion on risks for public health related to the presence of chlorate in food. EFSA Journal 2015;13(6):4135,103 pp) ARfD 36 pg chlorate/kg bw Based on human 12-wks repeated dose oral (drinking water) clinical study according to EFSA CONTAM Panel (EFSA Journal 2015; 13(6):4135) ADI 3 pg chlorate/kg bw Based on the TDI for perchlorate (derived from human observations) according to EFSA CONTAM Panel (EFSA Journal 2015; 13(6):4135) Human drinking water limit 0.7 mg/L (WHO Guidelines for Drinking-water 40 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Quality, FOURTH EDITION, 2011)

Reference value for groundwater

According to BPR Annex VI, point 68

Chapter 4: Fate and Behaviour in the Environment

Route and rate of degradation in water

Hydrolysis of active substance and Hypochlorite degrades very rapidly (~ relevant metabolites (DT50) (state pH 300sec) in the presence of organic matter. and temperature)

Photolytic / photo-oxidative degradation Hypochlorite is very sensitive to light. The of active substance and resulting half-life of a solution with 10 - 15% available relevant metabolites chlorine at 25 °C is 220 days. The influence of light causes a 3 - 4 fold reduction. Direct sunlight causes decomposition and results in the formation of chlorate, chloride and oxygen.

Readily biodegradable (yes/no) Not applicable, hypochlorite is an inorganic substance. Inherent biodegradable (yes/no) Not applicable, hypochlorite is an inorganic substance. Biodegradation in freshwater Not applicable, hypochlorite is an inorganic substance. Biodegradation in seawater Not applicable, hypochlorite is an inorganic substance. Non-extractable residues Not applicable, hypochlorite is degraded to chloride. Distribution in water / sediment systems Hypochlorite degrades very rapidly (~ (active substance) 300sec) in the presence of organic matter. Distribution in water / sediment systems Not applicable, hypochlorite is degraded to (metabolites) chloride.

Route and rate of degradation in soil

Mineralization (aerobic) Not applicable, hypochlorite is an inorganic substance. Laboratory studies (range or median, Not applicable due to the very rapid with number of measurements, with degradation of hypochlorite regression coefficient)

DT50lab (20°C, aerobic): Not applicable, see above DTgdab (20°C, aerobic): Not applicable, see above DT50lab (10°C, aerobic): Not applicable, see above DT50lab (20°C, anaerobic): Not applicable, see above

41 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

degradation in the saturated zone: Not applicable, see above Field studies (state location, range or Not applicable, see above median with number of measurements)

DT50f : Not applicable, see above

DTg0 f: Not applicable, see above Anaerobic degradation Not applicable, see above Soil photolysis Not applicable, see above Non-extractable residues Not applicable, see above Relevant metabolites - name and/or Not applicable, see above code, % of applied a.i. (range and maximum)

Soil accumulation and plateau Not applicable, see above concentration

Adsorption/desorption

Ka , Kd Not relevant, hypochlorite is degraded to

Ka oc , Kd oc chloride. pH dependence (yes / no) (if yes type of dependence)

Fate and behaviour in air

Direct photolysis in air Chlorine:

The half-life is 2 - 4 hours (during day light) main reaction product is atomic chlorine which could react with saturated and unsaturated hydrocarbons and ozone to form HCl. The HCl is removed from the atmosphere by other removal processes, such as rainfall.

Sodium hypochlorite: not applicable; no absorption of light in the visible wavelength range Quantum yield of direct photolysis No data available Photo-oxidative degradation in air No data available Volatilization Chlorine and sodium hypochlorite:

As the concentration of chlorine gas in water is low at environmentally relevant pH, the amount of chlorine that could volatilise from water into air is expected to be very low.

Reference value for groundwater

42 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

According to BPR Annex VI, point 68

Monitoring data, if available Soil (indicate location and type of study) Surface water (indicate location and type of study) Ground water (indicate location and type of study) Air (indicate location and type of study)

Chapter 5: Effects on Non-target Species

Toxicity data for aquatic species (most sensitive species of each group) Species Time­ Endpoint Toxicity scale Fish

Tidewater Silverside Chronic Mortality LOEC (28 days) = fry (Menidia 28 days 0.210 mg CPO/L peninsulae) (mm) sea water NOEC (28 days) = 0.040 mg CPO/L (mm)

Invertebrates

Ceriodaphnia dubia Acute Immobility EC50 = 0.014 mg 48 hours FAC/L (mm)

Daphnia magna Acute Immobility EC50 = 0.028 mg 48 hours FAC/L (mm)

Oysters (Crassostrea Chronic Mortality NOEC (15 days) = virginica) shell 15 -19 0.007 mg TRO/L deposition days (mm) sea water Algae

43 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Pseudokirchneriella Acute Inhibition ErC50 = 0.0365 subcapitata 72 hours concentration FAC/L (init. m.) EbC50 = 0.0183FAC/L (init. m.)

NOErC = 0.0054 mg/FAC/L (init. m.) LOEC (yield) = 0.0054 mg/FAC/L (init. m.)

Peryphytic community Chronic Inhibition IC80 (7 days) = fresh water 7 days concentration 0.358 mg FAC/L (mm) IC50 (7 days) = 0.023 mg FAC/L (mm) NOEC (7 days) = 0.0021 mg FAC/L (mm)

Microorganisms Activated sludge 3 hours Respiration rate NOEC = 41.1mg FAC/L (nom)

ECio = 46.9 mg FAC/L (nom)

EC50 = 77.1 mg FAC/L (nom)

Effects on earthworms or other soil non-target organisms No data available, not required due to lack of Acute toxicity to earthworms exposure

No data available, not required due to lack of Reproductive toxicity to earthworms exposure

Effects on soil micro-organisms

Nitrogen mineralization No data available, not required due to lack of exposure Carbon mineralization No data available, not required due to lack of exposure

Effects on terrestrial vertebrates Acute toxicity to mammals Acute toxicity to birds Dietary toxicity to birds Reproductive toxicity to birds

Effects on honeybees 44 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Acute oral toxicity No data available Acute contact toxicity No data available

Effects on other beneficial arthropods

Acute oral toxicity No data available Acute contact toxicity No data available

Acute toxicity t o ...... No data available

Bioconcentration

Bioconcentration factor (BCF) The low logPow (- 0.87) indicates that hypochlorite has no potential for bio­ concentration and bioaccumulation

(according to guideline OECD 117, log Po w values below 3 are regarded to be indicators of low accumulation potential). Moreover, hypochlorite dissipates very rapidly in the environment.

Depration time (DT50) Not applicable Uptake of hypochlorite into the organism of fish can be excluded due the instantaneous degradation of hypochlorite in contact with organic material.

Depration time (DT90) Not applicable, see above

Level of metabolites (%) in organisms Not applicable, see above accounting for > 10 % of residues

Chapter 6: O ther End Points

45 Active chlorine released from hypochlorous Product-type 1 acid July 2020

Appendix II: List of Intended Uses

Object and/or Product Organisms Applied amount per Formulation Application Remarks: situation Name controlled treatment Type Conc. of method number interval g a.s./L water g a.s. kind min max between min L/m2 a.s./m2 applications max min min (min) max max Hand wash/Skin Aqualution® Bacteria; Aqueous 0.02% Directly on 32/day 0.2 g/L disinfection in 70 Viruses; solution skin (professional) healthcare Fungi; (Mechanical Puricide 0.03% 0.3 g/L (professional Yeast; dispenser 4/day (non­ and non­ Spores provides professional) professional 1.5 mL use) solution per application) Foot wash/Skin Aqualution® Bacteria; Aqueous 0.02% Directly on 2/day 0.2 g/L 70 disinfection in Viruses; solution skin (professional) healthcare Fungi; (Footbath Puricide 0.03% 0.3 g/L (professional Yeast; with use) Spores 20 minutes application)

46 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Appendix III: List of studies

Data protection is claimed by the applicant in accordance with Article 60 of Regulation (EU) No 528/2012.

Section Author(s) Year Title Data Owner No / Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published A3, Gest 2002 Physical, Thermodynamic NO n/a A3.1.1/01 and Selected Chemical Properties of Chlorine - Chapter 1 - Basic Properties, Euro Chlor Publication, Gest 91/168, Chapter 1, 1st Edition, September 2002, Report no. GEST 91/168

A3, ...... ​.. 2007 Melting Point and Boiling YES Euro Chlor A3.1.1(3) Point of Liquids (BS DSC) on the Sodium Hypochlorite 24 %, Defitrates, Report no. 07-905015-001, GLP, (Un)

A3, Gest 2002 Physical, Thermodynamic NO n/a A3.2/01, and Selected Chemical A3.2(1) Properties of Chlorine - Chapter 6 - Thermodynamic Properties, Euro Chlor Publication, Gest 91/168, Chapter 6, 1st Edition, September 2002, Report no. GEST 91/168

A3, Holzwarth 1984 The Fate of Chlorine and NO n/a A3.2.1/01 G., et al. Chloramines in Cooling A3.2.1(2) towers, Water Res., Vol. 18, No. 11, pp. 1421-1427

A3, Gest 2002 Physical, Thermodynamic NO n/a A3.4/01, and Selected Chemical A3.4.1 Properties of Chlorine - Chapter 2 - Optical Properties, Euro Chlor Publication, Gest 91/168, Chapter 2, 1st Edition, September 2002, Report

47 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s) Year Title Data Owner No / Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published no. GEST 91/168

A3, A3.4.2 Nakagawara 1998 Spectroscopic NO n/a S., et al. Characterisation and the pH Dependence of Bactericidal Activity of the Aqueous Chlorine Solution, Analytical Sciences, 14, 691-698

A3, Gest 2002 Physical, Thermodynamic NO n/a A3.5/01, and Selected Chemical A3.5(1) Properties of Chlorine - Chapter 7 - Physico­ Chemical Properties, Euro Chlor Publication, Gest 91/168, Chapter 7, 1st Edition, September 2002, Report no. GEST 91/168

A3, A3.6(2) Pinto G. and 2003 Use of Chloroisocyanurates NO n/a Rohrig B. for Disinfection of Water, J. Chem. Ed., Jan 2003, 80, 1, 41-44

A3, Anonymous 2007 Log Kow calculation YES Euro Chlor A3.9/01, Hypochlorous Acid, (Un) A3.9(1a) A3, Anonymous 2007 Log Kow calculation YES Euro Chlor A3.9/02, Chlorine, (Un) A3.9(1b) A3, White G.C. 1972 Handbook of Chlorination, , NO n/a A3.10/01, pp. 627-675 A3.10(1) A3, ...... ​... 2007 Flash Point on the Sodium YES Euro Chlor A3.12/02, Hypochlorite 24 %, A3.12(2) Defitrates, Report no. 07­ 905015-003, GLP, (Un)

A3, ...... ​... 2007 Surface Tension on the YES Euro Chlor A3.13/01, Sodium Hypochlorite 5 %, A3.13(1) Defitrates, Report no. 07­ 905015-012, GLP, (Un)

A3, ...... ​... 2007 Surface Tension on the YES Euro Chlor A3.13(2) Sodium Hypochlorite 24 %, Defitrates, Report no. 07­ 905015-004, GLP, (Un)

48 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s) Year Title Data Owner No I Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published A3, Gest 2002 Physical, Thermodynamic NO n/a A3.14(1) and Selected Chemical Properties of Chlorine - Chapter 5 - Mechanical Properties, Euro Chlor Publication, Gest 91/168, Chapter 5, 1st Edition, September 2002, Report no. GEST 91/168

A3, ...... ​.. 2007 Viscosity on the Sodium YES Euro Chlor A3.14(2) Hypochlorite 24 %, Defitrates, Report no. 07­ 905015-005, GLP, (Un)

A3, Gest 2004 Materials of Construction NO n/a A3.17(1) for Use in Contact with Chlorine, Euro Chlor Publication, Gest 79/82, 8th Edition, June 2004, Report no. GEST 79/82

A4.1(1) Anonymous 1972 Liquid Chlorine for NO n/a Industrial Use - Determination of the Content of Chlorine by Volume in the Vaporised Product, International Organisation for Standardisation, International Standard ISO 2120

A4.1(2), Anonymous 1999 NF EN 901 European NO n/a A3, A3.2(2) Standard Chemicals Used for Treatment of Water Intended for Human Consumption Sodium Hypochlorite, Association Francaise de Normalisation, Not applicable, (Un)

A4.1(3), Anonymous 2000 Water Quality - NO n/a A4.1(4), Determination of Free A4.2c(1), Chlorine and Total Chlorine, A4.2c(2) ISO 7393-1: 1985, ISO 7393-2: 1985, Januray 2000 and April 2000

49 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s) Year Title Data Owner No / Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published A4.2b(1), Anonymous 1988 Determination of Chlorine NO n/a A4.2b(2) in Workplace Air - Analytical 8, Euro Chlor Publication, Analytical 8, 1st Edition 1988

Supporting Saad B., et 2006 Sequential Flow Injection NO n/a information al. Deetermination of Chlorine for A4.1(1) Species Using a Triiodide- selective Electrode Detector, Analytical Sciences, 22, 45-50

A5.3.1(1) Gutierrez 1995 Efficacy of a Variety of NO n/a C.B. Disinfectants against Actinobacillus Pleuropneumoniae Serotype 1, Am. J. Vet. Res., 56(8), 1025-1029

A5.3.1(2) Babb J.R., 1980 Sporicidal Activity of NO n/a et al. Gluaraldehydes and Hypochlorites and Other Factors Influencing their Selection for the Treatment of Medical Equipment, Journal of Hospital Infection, 1, 63-75

A5.3.1(3) Bloomfield 1985 The Antibacterial Properties NO n/a S.F. and of Sodium Hypochlorite and Uso E.E. Sodium Dichloroisocyanurates as Hospital Disinfectants, Journal of Hospital Infection, 6, 20-30

A5.3.1(4) Bloomfield 1992 Interaction of Bacillus NO n/a S.F. and Subtilis Spores with Sodium Arthur M. Hypochlorite, Sodium Dichloroisocyanurate and Chloramine-T, Journal of Applies Bacteriology, 72, 166-172

A5.3.1(5) Best M., et 1994 Feasibility of a Combined NO n/a al. Carrier Test for Disinfectants - Studies with a Mixture of Five Types of

50 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s) Year Title Data Owner No / Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published Micro-organisms, Am. J. Infect. Control, 22, 152­ 162

A5.3.1(6) Sagripanti 1996 Comparative Sporicidal NO n/a J.-L. and Effects of Liquid Chemical Bonifacino Agents, Applied and A. Environmental Microbiology, 62(2), 545­ 551

A5.3.1(7) Grönholm 1999 Screening of Antimicrobial NO n/a L., et al. Activities of Disinfectants and Cleaning Agents Against Foodborne Spoilage Microbes, Z. Lebensm. Unters. Forsch. A., 289-298

A5.3.1(8) Blaser M.J., 1986 Inactivation of NO n/a et al. Campylobacter Jejuni by Chlorine and Monochloramine, Applied and Environmental Microbiology, 51(2), 307­ 311

A5.3.1(9) Wirtanen G. 1992 Removal of Foodborne NO n/a and Martilla- Biofilms - Comparison of Sandholm T. Surface and Suspension Tests. Part I., Lebensm. Wiss. U. Technol., 25, 43­ 49

A5.3.1(10) Orth R. and 1989 Is the Control of Listeria, NO n/a Mrozek H. Campylobacter and Yersinia A Disinfection Problem, Fleischwirtsch, 69(10), 1575-1578

A5.3.1(11) Berman D., 1988 Inactivation of Particle- NO n/a et al. Associated Coliforms by Chlorine and Monochloramine, Applied and Environmental Microbiology, 54(2), 507­ 512

51 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s) Year Title Data Owner No / Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published A5.3.1(12) Bloomfield 1993 Comparative Testing of NO n/a S.F., et al. Disinfectants using Proposed European Surface Test Methods, Letters in Applied Microbiology, 17, 119-125

A5.3.1(13) Maris P. 1992 Biofilms and Disinfection - NO n/a Development of a Micro­ organisms Carrier-Surface Method, Science des Alments, 12, 721-728

A5.3.1(14) Parnes C.A. 1997 Efficacy of Sodium NO n/a Hypochlorite Bleach and "Alternative" Products, Environmental Health, 14­ 19

A5.3.1(15) Jones M.V., 1992 Comparative Sensitivity of NO n/a et al. Vibrio Cholerae 01 El Tor and Escherichia Coli to Disinfectants, Letters in Applied Microbiology, 14, 51-53

A5.3.1(16) ...... ​.. 1986 Clorox Vol II, EPA NO Euro Chlor Registration No. 5813-1, Your Amendment Application Dated February 1, 1985, (Un)

A5.3.1(17) Kuchta J.M., 1985 Enhanced Chlorine NO n/a et al. Resistance of Tap Water- Adapted Legionella Pneumophila as Compared with Agar Medium- Passaged Strains, Applied and Environmental Microbiology, 50(1), 21-26

A5.3.1(18) Muraca P., 1987 Comparative Assessment of NO n/a et al. Chlorine, Heat, Ozone, and UV Light for Killing Legionella Pneumophila within a Model Plumbing System, Applied and Environmental Microbiology, 52(2), 447-

52 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s) Year Title Data Owner No / Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published 453

A5.3.1(19) Lopes J.A. 1986 Evaluation of Dairy and NO n/a Food Plant Sanitizers Against - Salmonella Typhimurium and Listeria Monocytogenes, J Dairy Sci., 69(11), 2791-2796

A5.3.1(20) El-Kest S.E. 1988 Inactivation of Listeria NO n/a and Marth Monocytogenes by E.H. Chlorine, Journal of Food Protection, 51, 520-524

A5.3.1(21) EPA List B 2006 List B - EPA Registered NO Euro Chlor January Tuberculocide Products Effective Against Mycobacterium Tuberculosis, Environmental Protection Agency, USA, 1-12(Un)

A5.3.1(22) Rutala W.A., 1991 Inactivation of NO n/a et al. Mycobacterium Tuberculosis and Mycobacterium Bovis by 14 Hospital Disinfectants, The American Journal of Medicine, 91(38), 267-271

A5.3.1(23) Best M., et 1990 Efficacies of Selected NO n/a al. Disinfectants Against Mycobacterium Tuberculosis, Journal of Clinical Microbiology, 28(10), 2234-2239

A5.3.1(24) Anderson 1990 Effect of Disinfectants on NO n/a R.L., et al. Pseudomonas Colonised on the Interior Surface of PVC Pipes, AJPH, 80(1), 17-21

A5.3.1(25) Tanner R.S. 1989 Comparative Testing and NO n/a Evaluation of Hard Surface Disinfectants, Journal of Industrial Microbiology, 4, 145-154

53 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s) Year Title Data Owner No / Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published A5.3.1(26) Peter J. and 1998 Model Tests for the Efficacy NO n/a Spicher G. of Disinfectants on Surfaces IV. Communication - Dependence of Test Results on the Amount of Contamination and the Kind of Active Substance, Zent. Bl. Hyg. Umweltmed., 201, 311-323

A5.3.1(27) Bungaard- 1995 Fungicidal Effect of 15 NO n/a Nielsen K. Disinfectants Against 25 and Nielsen Fungal Contaminants V. Commonly Found in Bread and Cheese Manufacturing, Journal of Food Protection, 59(3), 268-275

A5.3.1(28) Shaheen 1996 Public Health Benefits of NO n/a E.A. and Bleach - A Critical Review, Ikawa J.Y. The Clorox Company, 23­ 71

A5.3.1(29) Sattar S.A., 1989 Chemical Disinfection of NO n/a et al. Non-Porous Inanimate Surfaces Experimentally Contaminated with Four Human Pathogenic Viruses, Epidem. Inf., 102, 492-505

A5.3.1(31) Centers for 2006 Interim Guidance about NO n/a Disease Ebola Virus infection for Control Airline Flight Crews, Cargo and Cleaning Personnel, and Personnel Interacting with Arriving Passengers, CDS, 39173

A5.3.1(32) Grabow 1983 Inactivation of Hepatitis A NO n/a W.O.K., et Virus and Indicator al. Organisms in Water by Free Chlorine Residuals, Applied and Environmental Microbiology, 46(3), 619­ 624

A5.3.1(33) Bond W.W., 1983 Inactivation of Hepatitis B NO n/a et al. Virus by Intermediate-to- High-Level Disinfectant

54 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s) Year Title Data Owner No / Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published Chemicals, Journal of Clinical Microbiology, 18(3), 535-538

A5.3.1(34) Prince H.N., 1991 Principles of Viral Control NO n/a et al. and Transmission, Disinfectants and Antiseptics B., by Type of Microorganisms, Chapter 25, 25, 411-444

A5.3.1(35) Prince D.L., 1990 Inactivation of Human NO n/a et al. Immunodeficiency Virus Type 1 and Herpes Simplex Virus Type 2 by Commercial Hospital Disinfectants, Chemical Times and Trends, 14-16, 54

A5.3.1(36) Grouse L. 1985 HTLV-III Transmission, NO n/a JAMA, 254(15), 2130-2131

A5.3.1(37) Gustafson 1986 Precautions for Health Care NO n/a P.R. and Workers of AIDS Patients, Andres N. Texas Medicine, 82, 28-31

A5.3.1(38) Centers for 1987 Recommendations for NO n/a Disease Prevention of HIV Control Transmission in Health­ Care Settings, MMWR, Supplements, 36, 1-11

A5.3.1(39) Sattar S.A. 1991 Survival and Disinfection NO n/a and Inactivation of the Human Springthorp Immunodeficiency Virus - A e V.S. Critical Review, Reviews of Infectious Diseases, 13, 430-447

A5.3.1(40) Brown T.T. 1981 Laboratory Evaluation of NO n/a Selected Disinfectants as Virucidal Agents against Porcine Parvovirus, Pseudorabies virus and Transmissible Gastroenteritis Virus, Am. J. Vet. Res., 42(6), 1033-

55 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s) Year Title Data Owner No / Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published 1036

A5.3.1(41) Lloyd-Evans 1986 Chemical Disinfection of NO n/a N., et al. Human Rotavirus- Contaminated Inanimate Surfaces, J. Hyg. Camb., 91, 163-173

A6.1.1, Anonymous 1970 Bio - Fax - Sodium YES Euro Chlor A6.1.2 Hypochlorite, Industrial A6.1.3(3), Bio-Test Laboratories Inc., A6.3.1(1) (Un)

A6.1.1(2) ...... 1981 Chlorbleichlauge (12,2% YES ...... ​.....​...​... Aktivchlor) - Bestimmung der akuten Toxizität, ZR- FE/Toxikologie, ...... ​...... ​...... ​.....​...... ​..... (Un) Conf

A6.1.3(1), ...... ​.. 1987 Acute Inhalation Toxicity of YES Euro Chlor A6.1.3(2) Chlorine in Rats and Mice, ​...... ​...... ​...... ​...... ​...... ​...... ​...... ​...... ​...... ​...... ​...... (Un)

A6.1.4(1) Pashley, 1985 Cytotoxic Effects of NaOCl NO n/a E.L., et al. on Vital Tissue, Journal of Endodontists, Vol. 11, No. 12, pp. 525-528

A6.1.4(2) Carter R.O. 1965 Experimental Bases for the NO n/a and Griffin Realistic Assessment of J.F. Safety of Topical Agents, Toxicology and Applied Pharmacology, 7, p. 60-73

A6.1.4(3), Nixon G.A., 1975 Interspecies Comparison of NO n/a A6.12.6(2) et al. Skin Irritancy, Toxicology and Applied Pharmacology, 31, pp. 481-490

A6.1.5(1) ...... ​..... 1982 ECM BTS 730 E2050.01 YES Euro Chlor Delayed Contact Hypersensitivity in Guinea Pigs, . .... ​ ...... ​...... ​...... ​.....

56 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s) Year Title Data Owner No / Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published ...... (Un)

A6.1.5(2) ...... ​... 1985 Guinea Pigs Sensitisation YES Euro Chlor Testing By Ritz H.L. and Buchler E.V. on E-2707.01, ​.....​...... ​...... ​...... ​...... ​...... ​...​... ​...... ​.....(Un)

A6.1.5(3) ...... ​... 1985 Guinea Pigs Sensitisation YES Euro Chlor Testing By Ritz H.L. and Buchler E.V. on E-2707.01, ​.....​...... ​...... ​...... ​...... ​...... ​...​... ​...... ​.... (Un)

A6.2(1) Nodelman 1999 Longitudinal Distribution of NO n/a V. and Chlorine Absorption in Ultman J.S. Human Airways - Comparison of Nasal and Oral Quiet Breathing, Journal of Applied Physiology, 86(6), p. 1984­ 1993

A6.2(2) Scully F.E., 1990 Identification of Organic N- NO n/a et al. Chloramines in vitro in Stomach Fluid from the Rat after Chlorination, Chem. Res. Toxicol., 3, pp. 301 - 306

A6.2(3) Abdel- 1982 Metabolism and NO n/a Rahman Pharmacokinetics of M.S., et al. Alternate Drinking Water Disinfectants, Environmental Health Perspectives, Vol. 46, pp. 19-23

A6.2(4) Abdel - 1983 A Comparative Kinetics NO n/a Rahman Study of Monochloramine M.S., et al. and Hypochlorous Acid in Rat, Journal of Applied Toxicology, Vol. 3, No. 4, p. 175-179

57 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s) Year Title Data Owner No / Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published A6.3.1(2) Cunningham 1980 Effect of Sodium NO n/a H.M., et al. Hypochlorite on the Growth of Rats and Guinea pigs, American Journal of Veterinary Research. 41 (2), 295-7

A6.3.3 Barrow C.S., 1979 An Inhalation Toxicity NO n/a et al. Study of Chlorine in Fischer 344 Rats Following 30 Days of Exposure, Toxicology and Applied Pharmacology, 49, pp. 77-88

A6.4.1(1) Hasegawa 1986 Carcinogenicity Study of NO n/a R., et al. Sodium Hypochlorite in F344 Rats, Fd. Chem. Toxic., Vol. 24, No. 12, pp. 1295-1302

A6.4.1(2) Daniel F.B., 1990 Comparative Subchronic NO n/a et al. Toxicity Studies of Three Disinfectants, Research and Technology, Journal AWWA, October 1990, p. 61-69

A6.4.1(3) Daniel F.B., 1991 Comparative Subchronic NO n/a et al. Toxicity of Chlorine and Monochloramine in the B6C3F1 Mouse, Research and Technology, Journal AWWA, November 1991, pp. 68-75

A6.4.3 Klonne D.R., 1987 One-Year Inhalation NO n/a et al. Toxicity Study of Chlorine in Rhesus Monkeys (Macaca mulatta), Fundamental and Applied Toxicology, 9, 557­ 572

A6.5(1), Wolf D.C., 1995 Chlorine Gas Induces Nasal NO n/a A6.5(2) et al. Lesions but Does Not Cause Cancer in Mice or Rats, Chemical Industry Institute of Toxicology (CIT), Vol. 15, No. 3, pp. 1-12

58 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s) Year Title Data Owner No / Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published A6.5(3), Wolf D.C., 1995 Two-year Inhalation NO n/a A6.5(4) et al. Exposure of Female and Male B6C3F1 Mice and F344 Rats to Chlorine Gas Induces Lesions Confined to the Nose, Fundamental and Applied Toxicology, 24, pp. 111-131

A6.5(5) Hasegawa 1986 Carcinogenicity Study of NO n/a R., et al. Sodium Hypochlorite in F344 Rats, Fd. Chem. Toxic., Vol. 24, No. 12, pp. 1295-1302

A6.5(6), NTP-TR 1992 Toxicology and NO n/a A6.5(7) Carcinogenesis Studies of Chlorinated Water (CAS Nos. 7782-50-5 and 7681­ 52-9) and Chloraminated Water (Cas No. 10599-90­ 3), National Toxicology Program, Technical Report Series, No. 392

A6.6.1(1), Ishidate M., 1984 Primary Mutagenicity NO n/a A6.6.2(1) et al. Screening of Food Additives Currently Used in Japan, Fd. Chem. Toxic., Vol. 22, No. 8, pp. 623-636

A6.6.1(2) Kawachi T., 1980 Results of Recent Studies NO n/a et al. on the Relevance of Various Short-Term Screening Tests in Japan, Applied Methods in Oncology, Bd. 3, pp. 253-267

A6.6.1(3) Le Curieux 1993 Comparison of Three Short­ NO n/a F., et al. Term Assays - Results on Seven Chemicals, Mutation Research, Vol. 319, pp. 223-236

A6.6.2(2) Matsuoka 1979 Chromosomal Aberration NO n/a A., et al. Tests on 29 Chemicals Combined with S9 Mix In Vitro, Mutation Research,

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Section Author(s) Year Title Data Owner No I Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published Vol. 66, pp. 277-290

A6.6.2(3) Sasaki M., 1980 Cytogenic Effects of 60 NO n/a et al. Chemicals on Cultured Human and Chinese Hamster Cells, La Kromosomo II-20, 31.12.1980, pp. 574-584

A6.6.4(1) Hayashi M., 1988 Micronucleus Tests in Mice NO n/a et al. on 39 Food Additives and Eight Miscellaneous Chemicals, Fd. Chem. Toxic., Vol. 26, No. 6, pp. 287-500

A6.6.4(2), Meier J.R., 1985 Evaluation of Chemicals NO n/a A6.6.6(1) et al. used for Drinking Water Disinfection for Production of Chromosomal Damage and Sperm-Head Abnormalities in Mice, Environmental Mutagenesis, 7:201-211

A6.6.5(1) Kasai Y., et 1987 Oral Administration of the NO n/a al. Renal Carcinogen, Potassium Bromate, Specifically produces 8- Hydroxydeoxyguanosine in Rat Target Organ DNA, Carcinogenesis, Vol. 9, No. 12, pp. 1959-1961

A6.7(1) Soffritti M., 1997 Results of Long-Term NO n/a et al. Carcinogenicity Studies of Chlorine in Rats, Annals New York Academy of Sciences, pp. 189-208

A6.7(2) Kurokawa 1986 Long-Term in Vivo NO n/a Y., et al. Carcinogenicity Tests of Potassium Bromate, Sodium Hypochlorite and Sodium Chlorite Conducted in Japan, Environmental Health Perspectives, Vol. 69, pp. 221-235

60 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s) Year Title Data Owner No / Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published A6.8.1 Abdel- 1982 Effect of Chlorine and NO n/a Rahman monochloraminine in M.S., et al. Drinking Water on the Developing Rat Fetus, Journal of Applied Toxicology, Vol. 2, No. 3, 156-159

A6.8.2(1) Carlton 1986 Reproductive Effects of NO n/a B.D., et al. Alternative Disinfectants, Environmental Health Perspectives, Vol. 69, pp. 237-241

A6.8.2(2) Druckrey H. 1968 Chloriertes Trinkwasser, NO n/a Toxizitats-Prufungen an Ratten Uber Sieben Generationen, Fd. Cosmet. Toxicol., Vol. 6, pp. 147­ 154

A6.8.2(3) Les E.P. 1968 Effects of Acidified NO n/a Chlorinated Water on Reproduction in C3H/HEJ and C57BL/6J Mice, Laboratory Animal Care, Vol. 18, No. 2, pp. 210-213

A6.12.2(1) Mrvos R., et 1991 Home Exposures to NO n/a al. Chlorine/Chloramine Gas - A Review of 216 Cases, Vet. Hum. Toxicol., 33(4), p. 1

A6.12.2(2) Charan 1985 Effects of Accidental NO n/a N.B., et al. Chlorine inhalation on Pulmonary Function, The Journal of Medicine Clinical Investigation, 143, 3, p. 333-336

A6.12.2(3) Agabiti N., 2001 Short-Term Respiratory NO n/a et al. Effects of Acute Exposure to Chlorine Due to a Swimming Pool Accident, Occup. Environ. Med., 58, 399-404

61 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s) Year Title Data Owner No / Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published A6.12.2(4) Shroff C.P. 1988 Respiratory Cytopathology NO n/a in Chlorine Gas Toxicity - A Study in 28 Subjects, Diagnostic Cytopathology, 4, 1, p.28-32

A6.12.2(5) Weill H., et 1969 Late Evaluation of NO n/a al. Pulmonary Function After Acute Exposure to Chlorine Gas, American Review of Respiratory Disease, 99, 374-379

A6.12.2(6) Becker G.L., 1974 The Sequelae of NO n/a et al. Accidentally Injecting Sodium Hypochlorite Beyond the Root Apex, Oral Surg, Oral Med, Oral Pathol., 38, pp. 633-638

A6.12.2(7) Dedhia 1989 Long-Term Increase in NO n/a N.M., et al. Peritoneal Membrane Transport Rates Following Incidental Intraperitoneal Sodium Hypochlorite Infusion, The Journal of Artificial Organs, Vol. 12, No. 11, pp. 711-714

A6.12.2(8) Grant W.M. 1974 Toxicology of the Eye, NO n/a Charles C Thomas Publishers, pp. 222-259, 571-573, 852 and 932-934

A6.12.2(9) Bibra 1990 Toxicity Profile - Sodium NO n/a Hypochlorite, Bibra Toxicology International, p. 1-11

A6.12.3(1) Coskey R.J. 1974 Onycholysis from Sodium NO n/a Hypochlorite, Arch. Dermatol., Vol. 109, p. 96

A6.12.3(2) Maddy K.T., 1990 Illness Injuries and Death NO n/a et al. from Pesticide Exposure in California 1949 - 1988, Reviews of Environmental Contamination and

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Section Author(s) Year Title Data Owner No / Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published Toxicology, Vol. 114, pp. 57-124

A6.12.5(1) Pike D.G., 1963 A Re-evaluation of the NO n/a et al. Dangers of Clorox Ingestion, The Journal of Pediatrics, Vol. 63, No. 2, pp. 303-305

A6.12.5(2) Tanyel F.C., 1988 Chlorine Bleach Ingestion in NO n/a et al. Children - A Review of 80 Cases, Inc. Turkish Journal of Pediatrics, 30, pp. 105­ 108

A6.12.5(3) Strange 1951 Corrosive Injury of the NO n/a D.C., et al. Stomach, A.M.A. Archives of Surgery, 62, pp. 350­ 257

A6.12.5(4) Mühlendahl 1978 Local Injuries by Accidental NO n/a K.E., et al. Ingestion of Corrosive Substances by Children, Arch Toxicol., 39, pp. 299­ 314

A6.12.5(5) Ward M.J. 1988 Hypernatremia and NO n/a and Hyperchloraemic Acidosis Routledge after Bleach Ingestion, P.A. Human Toxicol., 7, pp. 37­ 38

A6.12.6(1) Eun H.C., et 1984 Sodium Hypochlorite NO n/a al. Dermatitis, Cont. Derm., 11, p. 45

A6.12.6(2) Nixon G.A., 1975 Interspecies Comparisons NO n/a et al. of Skin Irritancy, Toxicology and Applied Pharmacology, 31, 481-490

A6.12.6(3) Hostynek 1990 Irritation Factors of Sodium NO n/a J.J., et al. Hypochlorite Solutions in Human Skin, Contact Dermatitis, 23, p. 316-324

A6.16(1) Cotter J.L., 1985 Chemical Parameters, NO n/a Antimicrobial Activities, and

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Section Author(s) Year Title Data Owner No / Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published et al. Tissue Toxicity of 0.1 and 0.5% Sodium Hypochlorite Solutions, Antimicrobial Agents and Chemotherapy, Vol. 28, No. 1, pp. 118-122

A6.16(2) Robinson 1986 Epidermal Hyperplasia in NO n/a M., et al. Mouse Skin Following Treatment with Alternative Drinking Water Disinfectants, Environmental Health Perspectives, Vol. 69, pp. 293-300

A6.16(3) Wohlrab W. 1982 Untersuchungen zu NO n/a and Wirkung von Wozniak Natriumhypochlorit als K.D. Modellsubstanz auf die Haut und Verschiedene Zellsysteme, Dermatosen, Vol. 30, No. 3, pp. 79-83

A6.18 Aqualution 2018 Literature Review related to YES Aqualution Systems an ED assessment Systems Ltd. Ltd.

Supporting 2007 EU RAR for Sodium NO n/a Hypochlorite. Information https://echa.eu ropa.eu/doc for A6 uments/10162/330fee6d- 3220-4db1-add3- 3df9bbc2e5e5

Supporting Kurokawa 1984 Studies on the Promoting NO n/a Y., et al. and complete Carcinogenic Information activities of some oxidizing for A6 chemicals in skin carcinogenesis. Cancer Lett. 24, 299-304.

A7.1.2 Vandepitte 1997 Sodium Hypochlorite - NO n/a V. and Kinetic Model on the Long Schowanek Term Hypochlorite Decay in D. the Environment - A Specific Model for Use in the HOCl Risk Assessment,

64 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s) Year Title Data Owner No / Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published (Un)

A7.3.1 ...... ​...​..... 2007 Estimation of the YES Euro Chlor ​...... ​.. Atmospheric Residence Time of Sodium Hypochlorite using the Atkinson Method, Scientific Consulting Company, Report no. 832-005, (Un)

A7.3.2(1) Anonymous 1990 Atmospheric Chemistry of NO n/a Chlorine, Section 3, and Environmental Effects, Section 4 of Environmental Fate of Chlorine in the Atmosphere, Edition 1, The Chlorine Institute, Washington, Doc. No.: 792­ 019 and 792-020 (published)

A7.3.2(2) Graedel T.E. 1995 Tropospheric Budget of NO n/a and Keene Reactive Chlorine, Global W.C. Biogeochemical cycles, 9, 1, 47-77

A7.4.1.1(1) Heath J. 1977 Toxicity of Intermittent NO n/a Chlorination to Freshwater Fish - Influence of Temperature and Chlorine Form, Hydrobiologia, Bvol. 56, 39-47

A7.4.1.1(1) Heath A.G. 1978 Influence of Chlorine Form NO n/a and Ambient Temperature on the Toxicity of Intermittent Chlorination to Freshwater Fish, Environmental Effects in Freshwater Systems, pp. 123-133

A7.4.1.1(2) Bellanca 1977 Effects of Chlorinated NO n/a M.A. and Effluents on Aquatic Bailey D.S. Ecosystems in the Lower James River, Journal WPCF, April 1977, 639-645

65 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s) Year Title Data Owner No / Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published A7.4.1.1(3) Thatcher 1978 The Relative Sensitivity of NO n/a T.O. Pacific Northwest Fishes and Invertebrates to Chlorinated Sea Water, Environmental Effects in Marine Systems, Water Chlorination, p. 341-350

A7.4.1.2(1) Taylor P.A. 1993 An Evaluation of the NO n/a Toxicity of Various Forms of Chlorine to Ceriodaphnia Dubia, Environmental Toxicology and Chemistry, Vol. 12, pp. 925-930

A7.4.1.2(2) Roberts Jr. 1978 Acute Toxicity of NO n/a M.H. and Bromochlorinated Seawater Gleeson to Selected Estuarine R.A. Species with a Comparison to Chlorinated Seawater Toxicity, Marine Environ. Res., 1, 19-29

A7.4.1.2(3) ...... 2009 Sodium hypochlorite: a 48- YES Euro Chlor ​...... ​...​... hour flow-through acute toxicity test with the cladoceran (Daphnia magna); Wildlife International Ltd, Easton, Maryland, USA; Study- No.: 676A-101; 2009-03-26; Doc. No. 822-001; (unpublished)

A7.4.1.2(4) ...... 2011 Sodium hypochlorite: a 48- YES Euro Chlor ​...... ​...​... hour flow-through acute toxicity test with the cladoceran (Ceriodaphnia dubia); Wildlife International Ltd, Easton, Maryland, USA; Study- No.: 676A-102; 2011-07-15; Doc. No. 822-002; (unpublished)

A7.4.1.3(1) Cairns J., et 1990 Evaluation of Joint Toxicity NO n/a al. of Chlorine and Ammonia to Aquatic Communities, Aquatic Toxicology, 16, pp.

66 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s) Year Title Data Owner No / Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published 87-100

A7.4.1.3(2) Videau C., 1979 Preliminary Results NO n/a et al. Concerning Effects of Chlorine on Monospecific Marine Phytoplankton, J. Exp. Mar. Biol. Ecol., Vol. 36, pp. 111-123

A7.4.1.4 Raff J., et 1987 Versuche zum Verhalten NO n/a al. Mikrobizider Verbindungen in Klaranlagen - including English Translation, GWF Wasser Abwasser, 6, 319­ 323

A7.4.3.2 Goodman 1983 Early Life-Stage Toxicity NO n/a L.R., et al. Test with tidewater silversides (Menidia Peninsulae) and Chlorine- Produced Oxidants, Environmental Toxicology and Chemistry, Vol. 2, pp. 337-342

A7.4.3.4 Liden L.H. 1980 Effects of Chlorobrominated NO n/a and Burton and Chlorinated Cooling D.T. Waters on Estuarine Organisms, Journal WPCF, Vol. 52, No. 1, pp. 173-182

Supporting Anonymous 2001 Reference Document on YES Euro Chlor Information Best Available Techniques for Doc.IIIA in the Chlor-alkali Manufacturing Industry, EC, Not indicated, (Un)

Doc IIIB Active Chlorine Solution: References listed by section number

67 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s Year Title Data Owner No / ) Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published B3 Lide D.R. 2006 CRC Handbook of Chemistry NO n/a (Editor) and Physics, CRC Press Inc., USA, 87th Edition, ISBN 0­ 8493-0487-3

B3.7 ...... ​. 2009 DCR 805 -Vashe 90 Day YES Aqualution Shelf Life Report Puricore Systems International Ltd, Report No. Ltd. 1400-0027

B5.10(1) ...... 2005 Evaluation of the YES Aqualution .. mycobacterial activity of the Systems disinfectant "Sterilox®" Ltd. against Mycobacterium terrae according to PR EN 14348 (clean conditions), Biotech-Germande, Study No. 312STE.05, (Un)

B5.10(2) ...... 2005 Evaluation of the YES Aqualution .. mycobacterial activity of the Systems disinfectant "Sterilox®" Ltd. according to PR EN 14348 (clean conditions). , Biotech- Germande , Study No. 312.STE.05. , (Un)

B5.10(3) ...... 2005 Evaluation of bactericidal YES Aqualution .. activity of the disinfectant Systems "Sterilox®" according to NF Ltd. EN 13727 (Clean conditions), Biotech- Germande , Study No. 286.STE.04, (Un)

B5.10(4) ...... ​.. 2000 Evaluation of the sporicidal YES Aqualution activity of Sterilox® Systems disinfectant in accordance Ltd. with the NF T 72-230 AFNOR Standard. , Biotech- Germande , Study No. 0027.STE.00.3, (Un)

B5.10(5) ...... ​.. 2000 Evaluation of the bactericidal YES Aqualution activity of Sterilox® Systems disinfectant in accordance Ltd. with the NF EN 1040 Standard, Biotech-

68 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s Year Title Data Owner No / ) Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published Germande, Study No. 0027.SOL.00, (Un)

B5.10(6) ...... ​.. 2000 Evaluation of the fungicidal YES Aqualution activity of Sterilox® in Systems accordance with the NF EN Ltd. 1275 Standard. , Biotech- Germande, Study No. 0027.STE.00.2., (Un)

B5.10(7) ...... ​.. 2000 Evaluation of the virucidal YES Aqualution activity of Sterilox® Systems disinfectant in accordance Ltd. with the NF T 72-180 AFNOR, Biotech-Germande, Study No. 00-E-422, (Un)

B5.10(8) ...... 2001 Sterilox clinical in use YES Aqualution ... studies, Sterilox Systems Technologies, Study No. Ltd. 0091-2, (Un)

B5.10(9) Selkon 1999 Evaluation o the NO n/a J.B., et antimicrobial activity of a al. new super-oxidized water, Sterilox®, for the disinfection of endoscopes., Journal of Hospital Infection, 41, pp. 59 - 70

B5.10(10) Shetty 1999 Evaluation of microbiocidal NO n/a N., et al. activity of a new disinfectant: Sterilox® 2500 against Clostridium difficile spores, Helicobacter pylori, vancomycin resistant Enterococcus species, Candida albicans and several mycobacterium species, Journal of Hospital Infection, 41(2), 101-105

B5.10(11) Clark J., 2006 Efficacy of super-oxidized NO n/a et al. water fogging in environmental decontamination, Journal of Hospital Infection, 1-5

69 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s Year Title Data Owner No / ) Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published B5.10(12) Middleton 2000 Comparison of a solution of NO n/a A.M., et super-oxidized water al. (Sterilox®) with glutaraldehyde for the disinfection of bronchoscopes, contaminated in vitro with Mycobacterium tuberculosis and Mycobacterium avium- intracellulare in sputum., Journal of Hospital Infection

B5.10(13) ...... 2005 Hydroactive: Validation of a YES Aqualution ...... disinfectant for bactericidal Systems ..... activity. Phase II, Ltd...... Huntingdon Life Sciences ...... Ltd, FPD 012/042595, GLP, (Un)

B5.10(14) ...... 2006 Aqualution: validation of a YES Aqualution ​...... ​.. disinfectant for bactericidal Systems ​... activity when tested against Ltd. MRSA and Clostridium difficile. Phase I. , Huntingdon Life Sciences Ltd, Report No. FPD008/033625, GLP, (Un)

B5.10(15) ...... ​.. 2004 Hydroactive: Determination YES Aqualution of virucidal efficacy against Systems Influenza A virus, Ltd. Huntingdon Life Sciences Ltd, Study No. FPD 006/033813., GLP, (Un)

B5.10(16) ...... ​.. 2004 Determination of virucidal YES Aqualution efficacy against infectious Systems bronchitis virus, Huntingdon Ltd. Life Sciences Ltd, Study No. FPD 013/41008., GLP, (Un)

B5.10(17) ...... 2005 Long term microbial efficacy YES Aqualution ​...... ​.. trial at different pH values of Systems ​... Aqualution. , Huntingdon Ltd. Life Sciences Ltd, Study No. FPD 017/053007, GLP, (Un)

B5.10(18) ...... 2005 Hydroactive: validation of a YES Aqualution ​...... ​.. disinfectant for bactericidal Systems

70 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s Year Title Data Owner No / ) Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published ... activity., Huntingdon Life Ltd. Sciences Ltd, Study No. FPD 008/033625, GLP, (Un)

B6.1.1(1) ...... 1999 Sterilox Liquid: Acute Oral YES Aqualution ..... Toxicity in Rats (Fixed Dose Systems Method), ...... ​.... Ltd. ​...... ​...... ​...... ​ ...... ​ ...... ​...... GLP, (Un)

B6.1.1(2) ...... 2006 Aqualution 30: Acute Oral YES Aqualution ..... Toxicity in Rats. , Systems ​...... ​.....​...... Ltd. ​...... ​...... ​...... ​...... ​...... GLP, (Un)

B6.1.2 ...... 2006 Aqualution 30: Acute Dermal YES Aqualution ​...​... Toxicity to the Rat. Systems ​...... ​...... Ltd. ​...... ​.....​...... ​...... ​...... ​...... ​...... ​...... GLP, (Un)

B6.2i(1) ...... 1999 Sterilox Liquid: Skin YES Aqualution ..... irritation to the rabbit, Systems ​...... ​.....​...... Ltd. ​...... ​...... ​...... ​...... ​...... GLP, (Un)

B6.2i(2) ...... ​.. 2003 Primary dermal irritation in YES Aqualution Rabbits, .....​...... Systems ​...... ​ ...... Ltd. ​...... ​.....​....​...... GLP, (Un)

B6.2ii(1) ...... 1999 Sterilox Liquid: Eye Irritation YES Aqualution ..... in the Rabbit. .​...... Systems ​.....​...... ​.....​...... Ltd. ​ ...... ​ ...... ​...... GLP, (Un)

B6.2ii(2) ...... 2002 Primary Eye Irritation Study YES Aqualution ..... in Rabbits. , .....​...... Systems ​...... ​...... Ltd. ​...... ​.....​....​...... GLP, (Un)

71 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s Year Title Data Owner No / ) Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published B6.3(1) ...... 1999 Sterilox Liquid: Skin YES Aqualution ...... Sensitisation to the Guinea- Systems Pig: Magnusson and Kligman Ltd. method, ...... ​.... ​...... ​...... ​...... ​ ...... ​ ...... ​...... GLP, (Un)

B6.3(2) ...... 2006 Draft Report: Aqualution 30: YES Aqualution ... Delayed dermal sensitisation Systems study in guinea pigs: Ltd. Magnusson and Kligman Test., ...... ​...... ​...... ​...... ​...... ​...... ​.....​...... GLP, (Un)

Doc IIIB precursor: References listed by section number

Section Author(s Year Title Data Owner No / ) Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published B7.2(1) Khangaro 1989 Investigation of Correlation NO n/a t B.S. and between Physicochemical Ray P.K. Properties of Metals and Their Toxicity to the Water Flea Daphnia magna Straus, Ecotoxicology and Environmental Safety, 18, pp. 109-120

B7.2(2) Reynoso 1982 Induction of Resistance to NO n/a G.T. et al. Salinity in the Freshwater Alga Chlamydomonas Reinhardtii, Environ. Sci. Res., 23, pp. 531-534

B7.2(3) Mount 1997 Statistical Models to Predict NO n/a D.R., et the Toxicity of Major Ions to Ceriodaphnia dubia, Daphnia

72 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s Year Title Data Owner No / ) Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published al. magna, and Pimephales promelas (Fathead minnows), Environmental Toxicology and Chemistry, Vol. 16, No. 10, pp. 2009­ 2019

B7.2(4) Hoke 1992 Bicarbonate as a Potential NO n/a R.A., et Confounding Factor in al. Cladoceran Toxicity Assessments of Pore Water from Contaminated Sediments, Canadian Journal of Fish, Aquat. Science, Vol. 49, pp.1633-1640

B7.2(5) Cowgill 1991 The Response of the Three NO n/a U.M and Brood Ceriodaphnia Test to Milazzo Fifteen Formulations and D.P. Pure Compounds in Common Use, Arch. Environ. Contam. Toxicol., Vol. 21, pp. 35-40

B7.2(6) Pickering 1996 Subchronic Sensitivity of NO n/a Q.H., et One-, Four- and Seven-day- al. old Fathead Minnow (Pimephales promelas) larvae to Five Toxicants. Environmental Toxicology and Chemistry, Vol. 15(3), pp. 353-359

B7.2(7) Trama 1954 The Acute Toxicity of Some NO n/a F.B. Common Salts of Sodium, Potassium and Calcium to the Common Bluegill (Lepomis macrochirus Bafinesque), Proceedings of the Academy of Natural Sciences of Philadelphia, 106, pp. 185-205

B7.2(8) Khangaro 1989 Investigation of Correlation NO n/a t B.S. and Between Physiological Ray P.K. Properties of Metals and their Toxicity to the Water Flea Daphnia magna Straus. Ecotoxicology and Environmental Safety, 18,

73 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Section Author(s Year Title Data Owner No / ) Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published pp. 109-120

B7.2(9a) Anderson 1948 The Apparent Thresholds of NO n/a B.G. Toxicity to Daphnia magna for Chlorides of Various Metals When Added to Lake Erie water. Trans. Am. Fish Soc., 78, pp. 96-113

B7.2(9b) Anderson 1946 The Toxicity Thresholds of NO n/a B.G. Various Sodium Salts Determined by the Use of Daphnia magna, Sewage Works Journal, Vol. 18, pp. 82-87.

B7.2(10) Kalinkina 1978 Effects of Different NO n/a L.G. and Concentrations of NaCl on Spektoro Growth and Development of v K.S. Chlorella pyrenoidosa, Plant Physiol. (Eng. Transl. Fiziol Rast) / Russ. J. Plant Physiol., 25, pp. 16-20.

B7.2(11) Kalinkina 1979 Growth and Biomass NO n/a L.G. Accumulation in Marine and Freshwater Algae of the Genus Chlorella as a Function of NaCl Concentration in the Medium, Plant Physiol. (Eng. Transl. Fiziol Rast) / Russ. J. Plant Physiol., 26, pp. 320­ 325

Supporting Council of 2006 European Pharmacopoeia, NO n/a information Europe Council of Europe, 5th for Edition, Sodium Chloride, Ph Document Eur monograph 0193 IIIB3 Supporting Budavari 1999 The Merck Index, Merck & NO n/a information S. (Ed.) Co., Inc., Monograph for number 8742 Document IIIB3 Supporting Sweetma 2005 Martindale: The Complete NO n/a information n S. (Ed.) Drug Reference: Sodium, for London: Pharmaceutical

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Section Author(s Year Title Data Owner No / ) Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published Document Press, Sodium IIIB3 Supporting USPC 2007 USPC Official 5/1/07 - NO n/a information 7/31/07, USP Monographs, for Sodium Chloride Document IIIB3 Supporting Appel L.J. 1997 A clinical trial of the effects NO n/a information et al. of dietary patterns on blood for B6 pressure, New Eng. J. Med. 336 (16) 1117-1124.

Supporting Barbarino 2005 Effects of a 0.9% sodium NO n/a information S., et al. chloride ophthalmic solution for B6 on the ocular surface of symptomatic contact lens wearers, Can. J. Ophtalmol 40, 45-50

Supporting Contreras 1983 Prenatal and early postnatal NO n/a information R.J. and sodium chloride intake for B6 Kosten modifies the solution T.J. preferences of adult rats, Nutr., 113,1051-1062

Supporting Hunt 1993 Developmental sensitivity to NO n/a information R.AandTu high dietary sodium chloride for B6 cker D.C. in borderline hypersensitive rats, Hypertension 22, 542­ 550

Supporting Law M.R. 2000 Salt Blood Pressure and NO n/a information Cardiovascular Diseases, for B6 Journal of Cardiovascular Risk, 7, (1) 5-8

Supporting Lawler 1993 A chronic high-salt diet fails NO n/a information J.E., et to enhance blood pressure for B6 al. reactivity in SHR, BHR and WKY rats, Physiol. Behav., 54, 941-946

Supporting Meneely, 1952 Chronic Sodium Chloride NO n/a information G.R., et Toxicity in the Albino Rat: I. for B6 al. Growth on a Purified Diet Containing Various Levels of Sodium Chloride, J. Nutr.

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Section Author(s Year Title Data Owner No / ) Source (where different Protection Reference from company) Claimed No Company (Yes/No) Report No. GLP (where relevant) (Un)Published 48, 489

Supporting NIH - U.S. National Library NO n/a information of Medicine, Toxnet - for B6 Toxicology Data Network, HSDB - Hazardous Substances Data Bank with search Sodium chloride. Available at https://toxnet.nlm.nih.gov/

Supporting UK Expert 2002 Review of Sodium chloride, NO n/a information Group on EVM/01/08 revised version for B6 Vitamins March, 2002. Available at and http://www.food.gov.uk/mul Minerals timedia/pdfs/evm0108p.pdf;

Supporting 1998 Sodium chloride. RTECS - NO n/a information Registry of Toxic Effects of for B6 Chemical Substances Available at http://search.ccinfoweb.ccoh s.ca/ccohs/isp/search/search .isp?OueryText=sodium+chl oride&MaxDocs=500&Result Start=1&SortSpec=Score+d esc&hTab=4&h ideTabs=F&se archOnly=4&Coll = rte&Searc h.x=49&Search.y=6, June 2009

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Appendix IV: List of abbreviations

Stand. term / Explanation Abbreviation A ampere Ach acetylcholine AchE acetylcholinesterase ad hoc DBP WG ad hoc Working Group for disinfectant by-products ADI acceptable daily intake ADME administration distribution metabolism and excretion ADP adenosine diphosphate AE acid equivalent AF assessment factor AFID alkali flame-ionisation detector or detection A/G albumin/globulin ratio ai active ingredient ALD50 approximate median lethal dose, 50% ALT alanine aminotransferase (SGPT) Ann. Annex

AOEL acceptable operator exposure level AOX adsorbable organic halogens AMD automatic multiple development ANOVA analysis of variance AP alkaline phosphatase Approx/app approximate ARC anticipated residue contribution ArfD acute reference dose as active substance AST aspartate aminotransferase (SGOT) ASV air saturation value

ATP adenosine triphosphate BAF bioaccumulation factor av Cl available chlorine BCF bioconcentration factor bfa body fluid assay BOD biological oxygen demand

bp boiling point

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Stand. term / Explanation Abbreviation BPC Biocides Product Committee BPD Biocidal Products Directive BSAF biota-sediment accumulation factor BSE bovine spongiform encephalopathy BSP bromosulfophthalein Bt Bacillus thuringiensis Bti Bacillus thuringiensis israelensis Btk Bacillus thuringiensis kurstaki Btt Bacillus thuringiensis tenebrionis BUN blood urea nitrogen bw body weight c centi- (x 10-2) °C degrees Celsius (centigrade) CA controlled atmosphere CAC combined available chlorine CAD computer aided design

CADDY computer aided dossier and data supply (an electronic dossier interchange and archiving format) CCSP Centre for Chemical Substances and Preparations cd candela CDA controlled drop(let) application cDNA complementary DNA CEC cation exchange capacity cf confer, compare to CFU colony forming units ChE cholinesterase CI confidence interval CIP cleaning-in-place CL confidence limits cm centimetre CNS central nervous system COD chemical oxygen demand CPK creatinine phosphatase CPO chlorine-produced oxidants cv coefficient of variation Cv ceiling value

78 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Stand. term / Explanation Abbreviation d day(s) DBPs disinfection by-products DES diethylstilboestrol DIS draft international standard (ISO) DMSO dimethylsulfoxide DNA deoxyribonucleic acid dna designated national authority DO dissolved oxygen DOC dissolved organic carbon dpi days post inoculation DRP detailed review paper (OECD) DT50(lab) period required for 50 percent dissipation (under laboratory conditions) (define method of estimation) DT90(field) period required for 90 percent dissipation (under field conditions) (define method of estimation) dw dry weight DWLs Drinking Water Limits DWQG drinking water quality guidelines S decadic molar extinction coefficient U LU LD o median effective concentration ECD electron capture detector ED50 median effective dose EDI estimated daily intake EINECS European inventory of existing commercial substances ELINCS European list of notified chemical substances ELISA enzyme linked immunosorbent assay e-mail electronic mail EMDI estimated maximum daily intake EN European norm ENV environment EPMA electron probe micro-analysis ERL extraneous residue limit ESPE46/51 evaluation system for pesticides EUSES European Union system for the evaluation of substances F field FAC free available chlorine

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Stand. term / Explanation Abbreviation F0 parental generation F1 filial generation, first F2 filial generation, second FBS full base set FELS fish early-life stage FIA fluorescence immuno-assay FID flame ionisation detector Fmol fractional equivalent of the metabolite's molecular weight compared to the active substance FOB functional observation battery foc organic carbon factor (compartment dependent) fp availablezing point FPD flame photometric detector FPLC fast protein liquid chromatography g gram(s) GAP good agricultural practice GC gas chromatography GC-EC gas chromatography with electron capture detector GC-FID gas chromatography with flame ionisation detector GC-MS gas chromatography-mass spectrometry GC-MSD gas chromatography with mass-selective detection GEP good experimental practice GFP good field practice GGT gamma glutamyl transferase GI gastro-intestinal GIT gastro-intestinal tract GL guideline level GLC gas liquid chromatography GLP good laboratory practice GM geometric mean GMO genetically modified organism GMM genetically modified micro-organism GPC gel-permeation chromatography GPS global positioning system GSH glutathione GV granulosevirus

80 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Stand. term / Explanation Abbreviation

h hour(s) H Henry's Law constant (calculated as a unitless value) ha hectare(s) HAAs haloacetic acids Hb haemoglobin HC5 concentration which will be harmless to at least 95% of the species present with a given level of confidence (usually 95%) HCG human chorionic gonadotropin Hct haematocrit HDT highest dose tested hL hectolitre HEED high energy electron diffraction HH human health HID helium ionisation detector HPAEC high performance anion exchange chromatography HPLC high pressure liquid chromatography or high performance liquid chromatography HPLC-MS high pressure liquid chromatography - mass spectrometry HPPLC high pressure planar liquid chromatography HPTLC high performance thin layer chromatography HRGC high resolution gas chromatography HS Shannon-Weaver index Ht haematocrit HUSS human and use safety standard I indoor

I50 inhibitory dose, 50%

IC50 median immobilisation concentration or median inhibitory concentration 1 ICM integrated crop management ID ionisation detector IEDI international estimated daily intake IGR insect growth regulator im intramuscular inh inhalation INT 2-p-iodophenyl-3-p-nitrophenyl-5-phenyltetrazoliumchloride testing method ip intraperitoneal

81 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Stand. term / Explanation Abbreviation IPM integrated pest management IR infrared ISBN international standard book number ISSN international standard serial number IUCLID International Uniform Chemical Information Database iv intravenous IVF in vitro fertilisation

k (in combination) kilo k rate constant for biodegradation K Kelvin Ka acid dissociation constant Kb base dissociation constant Kads adsorption constant Kdes apparent desorption coefficient

kg kilogram KH Henry's Law constant (in atmosphere per cubic metre per mole) Koc organic carbon adsorption coefficient Kom organic matter adsorption coefficient Kow octanol-water partition coefficient

Kp solid-water partition coefficient kPa kilopascal(s) L litre LAN local area network LASER light amplification by stimulated emission of radiation LBC loosely bound capacity LC liquid chromatography LC-MS liquid chromatography- mass spectrometry

LC50 lethal concentration, median LCA life cycle analysis LC-MS-MS liquid chromatography with tandem mass spectrometry

LD50 lethal dose, median; dosis letalis media LDH lactate dehydrogenase In natural logarithm LOAEC lowest observable adverse effect concentration LOAEL lowest observable adverse effect level

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Stand. term / Explanation Abbreviation LOD limit of detection LOEC lowest observable effect concentration LOEL lowest observable effect level log logarithm to the base 10 LOQ limit of quantification (determination) LPLC low pressure liquid chromatography LSC liquid scintillation counting or counter LSD least squared denominator multiple range test LSS liquid scintillation spectrometry LT lethal threshold m metre M molar pm micrometre (micron) MAC maximum allowable concentration MAK maximum allowable concentration MC moisture content MCH mean corpuscular haemoglobin MCHC mean corpuscular haemoglobin concentration MCV mean corpuscular volume

MDL method detection limit MFO mixed function oxidase

pg microgram mg milligram MHC moisture holding capacity MIC minimum inhibitory concentration min minute(s) MKC minimum killing concentration mL millilitre MLT median lethal time MLD minimum lethal dose mm millimetre MMAD mass median aerodynamic diameter mo month(s) MOE margin of exposure mol mole(s)

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Stand. term / Explanation Abbreviation MOS margin of safety mp melting point MRE maximum residue expected MRL maximum residue level or limit mRNA messenger ribonucleic acid MS mass spectrometry MSDS material safety data sheet MTD maximum tolerated dose MT material test MW molecular weight n.a. not applicable n- normal (defining isomeric configuration) n number of observations NAEL no adverse effect level nd not detected NEDI national estimated daily intake NEL no effect level NERL no effect residue level

ng nanogram nm nanometre NMR nuclear magnetic resonance O c o' c number NOAEC no observed adverse effect concentration NOAEL no observed adverse effect level NOEC no observed effect concentration NOED no observed effect dose NOEL no observed effect level NOIS notice of intent to suspend NPD nitrogen-phosphorus detector or detection

NPV nuclear polyhedrosis virus NR not reported NTE neurotoxic target esterase OC organic carbon content OCR optical character recognition ODP ozone-depleting potential

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Stand. term / Explanation Abbreviation ODS ozone-depleting substances OEL occupational exposure limit OH hydroxide OJ Official Journal OM organic matter content

p precursor Pa pascal PAD pulsed amperometric detection 2-PAM 2-pralidoxime

pc paper chromatography PC personal computer PCV haematocrit (packed corpuscular volume) PEC predicted environmental concentration PECA predicted environmental concentration in air PECS predicted environmental concentration in soil PECSW predicted environmental concentration in surface water PECGW predicted environmental concentration in ground water PED plasma-emissions-detector

pH pH-value PHED pesticide handler's exposure data PIC prior informed consent pic phage inhibitory capacity PIXE proton induced X-ray emission pKa negative logarithm (to the base 10) of the acid dissociation constant pKb negative logarithm (to the base 10) of the base dissociation constant PNEC predicted no effect concentration (compartment to be added as subscript)

po by mouth POP persistent organic pollutants

ppb parts per billion (10-9) PPE personal protective equipment ppm parts per million (10-6) PPP plant protection product

ppq parts per quadrillion (10-15)

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Stand. term / Explanation Abbreviation

ppt parts per trillion (10-12) PSP phenolsulfophthalein PrT prothrombin time PRL practical residue limit PT product type PT(CEN) project team CEN PTDI provisional tolerable daily intake PTT partial thromboplastin time

QA quality assurance QAU quality assurance unit (Q)SAR quantitative structure-activity relationship r correlation coefficient r 2 coefficient of determination RA risk assessment RBC red blood cell REI restricted entry interval RENI Registry Nomenclature Information System Rf retardation factor

RfD reference dose RH relative humidity RL50 median residual lifetime RNA ribonucleic acid RP reversed phase rpm revolutions per minute rRNA ribosomal ribonucleic acid RRT relative retention time RSD relative standard deviation s second S solubility SAC strong adsorption capacity SAP serum alkaline phosphatase SAR structure/activity relationship SBLC shallow bed liquid chromatography sc subcutaneous sce sister chromatid exchange

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Stand. term / Explanation Abbreviation SCAS semi-continous Active sludge SCTER smallest chronic toxicity exposure ratio (TER) SD standard deviation se standard error SEM standard error of the mean SEP standard evaluation procedure SF safety factor SFC supercritical fluid chromatography SFE supercritical fluid extraction SIMS secondary ion mass spectroscopy S/L short term to long term ratio SMEs small and medium sized enterprises SOP standard operating procedures sp species (only after a generic name) SPE solid phase extraction SPF specific pathogen available spp subspecies SSD sulphur specific detector SSMS spark source mass spectrometry STEL short term exposure limit STER smallest toxicity exposure ratio (TER) STMR supervised trials median residue STP sewage treatment plant SWLs Swimming Water Limits t tonne(s) (metric ton) t1/2 half-life (define method of estimation) T3 tri-iodothyroxine T4 thyroxine T25 tumorigenic dose that causes tumours in 25% of the test animals TAC total available chlorine TADI temporary acceptable daily intake TBC tightly bound capacity TCD thermal conductivity detector TDI Tolerable daily intake TG technical guideline, technical group

87 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Stand. term / Explanation Abbreviation TGD Technical guidance document TID thermionic detector, alkali flame detector TDR time domain reflectometry TER toxicity exposure ratio TERI toxicity exposure ratio for initial exposure TERST toxicity exposure ratio following repeated exposure TERLT toxicity exposure ratio following chronic exposure tert tertiary (in a chemical name) TEP typical end-use product TGGE temperature gradient gel electrophoresis THMs trihalomethanes TIFF tag image file format TLC thin layer chromatography Tlm median tolerance limit TLV threshold limit value 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 TRC total residual chlorine TRO total residual oxidant tRNA transfer ribonucleic acid TSH thyroid stimulating hormone (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)

88 Active chlorine released from Product-type 1 July 2020 hypochlorous acid

Stand. term / Explanation Abbreviation vis visible WBC white blood cell WHO The World Health Organization wk week wt weight w/v weight per volume ww wet weight w/w weight per weight XRFA X-ray fluorescence analysis y year < less than < less than or equal to > greater than > greater than or equal to

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