directive 98/8/ec concerning the placing biocidal … · 2010-09-07 · directive 98/8/ec...

Lonza GmbH

RMS: Italy

Didecylmethylpoly(oxyethyl)

ammonium Propionate CAS 94667-33-1

January 2010

Doc I_ Evaluation Report

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Directive 98/8/EC concerning the placing biocidal products on the market

Inclusion of active substances in Annex I or IA to Directive 98/8/EC

Document I

Evaluation Report

Didecylmethylpoly(oxyethyl)ammonium Propionate

Product-Type 2 Private area and public health area disinfectants

(PT2.01 medical equipment; PT2.04 chemical toilets)

Rapporteur Member State: Italy

Draft January 2010

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RMS: Italy Didecylmethylpoly(oxyethyl)ammonium

Propionate January 2010


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CONTENTS

1. PURPOSE FOR WHICH THE COMPETENT AUTHORITY REPORT WAS PREPARED ............................................................................................................... 4

1.1 Introduction ...................................................................................................... 4

1.2 Applicant of the active substance..................................................................... 4

1.3 Manufacturer of the active substance and product (s) ................................... 4

1.4 Acceptance of the dossier and evaluation work .............................................. 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 ............................................................... 8

2.1.3. Classification and Labelling ............................................................ 10

2.2 Summary of the Risk Assessment ................................................................ 12

2.2.1 Human Health Risk Assessment...................................................... 12

2.2.2 Local exposure assessment .............................................................. 16

2.2.3 Systemic exposure assesment .......................................................... 20 2.2.4 Risk characterisation for local effects 25

2.2.5. Risk characterisation for systemic effects 32

2.2.6 Environmental Risk Assessment 40

2.2.7. List of endpoints ............................................................................. 49

3. PROPOSAL FOR THE DECISION ..................................................................... 51

3.1. Background to the Decision.......................................................................... 51

3.2. Proposed Decision regarding Inclusion in Annex I.................................... 52

3.3.. Elements to be taken into account by Member States when authorising products.......................................................................................................... 53

3.4. Requirement for further information ......................................................... 53

3.5 Updating this Evaluation Report ................................................................. 53

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APPENDIX I: LIST OF ENDPOINTS 54 CHAPTER 1: Identity, Physical and Chemical Properties 54

CHAPTER 2: METHODS OF ANALYSIS............................................................ 57

CHAPTER 3: IMPACT ON HUMAN HEALTH 58

CHAPTER 4: FATE AND BEHAVIOUR IN THE ENVIRONMENT................... 63

CHAPTER 5: EFFECT ON NON TARGET SPECIES........................................... 65

CHAPTER 6: OTHER END POINTS ..................................................................... 67

APPENDIX II: LIST OF INTENDED USES ............................................................... 67

APPENDIX III: LIST OF STUDIES............................................................................. 69

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PURPOSE FOR WHICH THE COMPETENT AUTHORITY REPORT WAS PREPARED

1.1 Introduction

The Competent Authority (CA) Report was prepared on a dossier for the existing biocidal active substance, Didecylmethylpoly(oxyethyl)ammonium Propionate (Bardap 26), according to the procedures of Biocidal Products Directive 98/8/EC, as a part of the review programme referred to in Article 16(2) of the Directive. This Document I and the supporting Documents IIA, IIB, IIC, IIIA, IIIB and the Confidential Annex have been prepared by the Istituto Superiore di Sanità in support of the decision to include Didecylmethylpoly(oxyethyl)ammonium Propionate, as product type 2: “private area and public health area disinfectant” (PT2.01 medical equipment; PT2.04 chemical toilets), in Annex I of the Directive. This draft report is still to be peer-reviewed by the other Member States and the Commission. 1.2 Applicant of the active substance

Lonza GmbH Morianstrasse 32 DE-42041 Wuppertal Germany

Phone: 0049 202 245380 Fax: 0049 202 2453830

1.3 Manufacturer of the active substance and product (s)

Lonza GmbH Nattermannallee 1 DE-50829 Koeln Germany

Phone: 0049 221 99199250 Fax: 0049 221 99199111 [email protected]

1.4 Acceptance of the dossier and evaluation work

On 31st July 2007, the Italian Competent Authority received a dossier from the Applicant. The Rapporteur Member State accepted the dossier as complete for the purpose of the evaluation on 31st October 2007. During the evaluation period communication between the RMS and the applicant has resulted in revised documents at all document levels.

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2 OVERALL SUMMARY AND CONCLUSIONS

2.1 Presentation of the Active Substance

The Applicant claimed for the possibility to read across data from Didecyldimethylammonium chloride (DDAC) to Didecylmethylpoly(oxyethyl)ammonium Propionate (Bardap 26) with regard to several studies of toxicology, environmental fate and behaviour and ecotoxicology. The proposal for read across has been accepted and the rationale behind the acceptance is reported in Doc IIIA in the respective sections.

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

Identification of the active substance

CAS-No. 94667-33-1

EINECS-No. None assigned

Other No. (CIPAC, ELINCS) None assigned

IUPAC Name alpha.-[2-(Didecylmethylammonio)ethyl]-.omega.-hydroxy-poly(oxy-1,2-ethanediyl) propionate

Chemical Name (CAS Index name) Poly(oxy-1,2-ethanediyl), .alpha.-[2-(didecylmethylammonio)ethyl]-.omega.-hydroxy-, propanoate

Common name, synonyms Didecylmethylpoly(oxyethyl)ammonium Propionate; N,N-Didecyl-N-methyl-poly(oxyethyl)ammonium Propionate, Bardap 26, Bardap 26 AS, DMPAP (internal abbreviation for the active substance), Dodigen 3519 (synonym of toll manufacturer for Bardap 26), Dodigen 3519 AS (active substance name of toll manufacturer), HOE S3519 (internal company code of toll manufacturer), P4140 (old internal company code of applicant), LZ1524.1 (new internal company code of applicant)

Molecular formula C26H55NO3(C2H4O)n where n = 0 – 3

Structural formula

n = 0 – 3

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Molecular weight (g/mol) 437.777 (average value on the basis of the distribution presented in the table below)

No. of oxyethyl

moieties (1)

Individual MW(*)

Relative distribution

Individual contribution

to average MW Monomer (1) 429.726 0.84 360.970

Dimer (2) 473.779 0.15 71.067Trimer (3) 517.832 <0.01 5.178

Tetramer (4) 561.885 <0.001 0.562

MW TOTAL: 437.777

(*) AWs used: C=12.011; H=1.00794; N=14.0067; O=15.999

Purity 90 – 99 % (solvent-free active substance) Clarification required by RMS

Impurities The full details are confidential and can be found in the Annex of Confidential Data

Since differing information have been provided in Doc. IIIA Section 2 with regard to the active substance purity and the content of the impurities, clarification is required.

Identification of the representative product

Trade name BP-15

Manufacturer's development code number(s) None assigned

Active substances Didecylmethylpoly(oxyethyl)ammonium propionate

Content of the active substances 150 g/kg of Didecylmethylpoly(oxyethyl)- ammonium propionate (clarification required by RMS)

Function Disinfectant

Physical state of preparation Liquid

Nature of preparation Solution

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Physico-Chemical Properties

Didecylmethylpoly(oxyethyl)ammonium propionate (CAS 94667-33-1) is a quaternary ammonium compound. According to the Applicant, the solvent-free active substance is typically 90–99 % pure with several impurities (see Annex of Confidential Data). Physico-chemical properties (with the exception of Doc IIIA 3.4, 3.8, and 3.17) were studied for Bardap 26 AS/Dodigen 3519, which is Didecylmethylpoly(oxyethyl)ammonium propionate 93.5% w/w pure, prepared by removal of process solvents (diol/water) from a typical production process.

Didecylmethylpoly(oxyethyl)ammonium propionate is a yellow liquid with a weakly aromatic odour. Its relative density D4

20 is 0.942. No freezing point is observed down to -50°C, whereas boiling ranges from 180 to 195 ºC. Its vapour pressure, extrapolated from the experimental vapour pressure curve Log Pvap vs. 1/T, is 1.8E-06 Pa, 4.0E-06 Pa, and 1.4E-04 Pa at 20 °C, 25 °C, and 50 °C, respectively. The Henry’s law constant (1.03E-011 and 4.72E-13 Pa m3/mol for the monomer and the dimer, respectively) has been estimated by QSAR using HENRYWIN v 3.10 model. The structure of the active substance is confirmed by absorption spectra (UV/Vis, IR, NMR) and mass spectrum. Didecylmethylpoly(oxyethyl)ammonium propionate is completely miscible in water in the pH range 5-9 at room temperature, as well as in ethanol and octanol (solubility > 250 g/l at ca. 20°C in either case). Since the active substance is irreversibly ionised, no dissociation constant can be determined. Partition coefficient is not determinable, either. EC method A.8 is not applicable for surface-active substances such as Didecylmethylpoly(oxyethyl)ammonium propionate. Also assessment by KOWWIN is considered inaccurate, being the software database very limited for surfactants. On the other hand, log Pow can be roughly obtained from solubility in pure n-octanol and water (log Pow ≈ 0). However, this calculation is of no use with regard to environmental fate & behaviour and secondary poisoning risk (experimental BCF available). Since neither decomposition nor chemical transformation is observed below 150°C, Didecylmethylpoly(oxyethyl)ammonium propionate can be considered stable. Didecylmethylpoly(oxyethyl)ammonium propionate has proved to have an auto-ignition temperature of 264 °C, with a flash point of 134 °C. On the basis of experience in use and/or structural formula (absence of reactive groups), it does not show explosive properties or oxidizing properties. Didecylmethylpoly(oxyethyl)ammonium propionate has also proved to be a surfactant (surface tension: 30.5 mN/m at 20 °C for an 1 g/l aqueous solution) and a non-newtonian fluid (dynamic viscosity: 3000 mPa⋅s and 400 mPa⋅s at 20 and 40 °C, respectively). Polyethylene (Type Hostalen GM 6255, 7745 and 7746) has proved to be resistant against the test material [Bardap26 (70 % active substance in 18% polyethylene glycol, 10% polyethylene glycol and water)]. Experience in use showed that 316 l stainless steel is satisfactory at optimum handling temperatures [for higher temperatures: stainless steel containing 6% or more molybdenum (Rolled alloys AL-6XN, Avesta 254-SMO, INCO 25-6MO)]. PVC, polyolefin, Teflon, Kynar, Kalrez and vinyl ester are satisfactory to temperatures recommended by manufacturer. Natural rubber, neoprene and Buna-N should be avoided. There is no risk to be expected due to physical-chemical properties of the formulated product BP-15, either.

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Analytical Methods

The RMS is waiting for the submission of a study report in progress specific for the active substance. The HPLC-ELSD and GC-FID analytical methods submitted for substances different from Didecylmethylpoly(oxyethyl)ammonium propionate have been neither considered nor commented by RMS, since they are not pertinent to the active substance. Didecylmethylpoly(oxyethyl)ammonium propionate was also screened by ion chromatography, but the method cannot be considered acceptable by the RMS. No validation work has been carried out for the a.s. nor for the impurities detected. In particular, no qualitative/quantitative analysis has been performed; no data on linearity have been provided, either. As far as chromatograms are concerned, no peak-assignment has been accomplished. In conclusion, a specific analytical method for the identification/quantification of Didecylmethylpoly(oxyethyl)ammonium propionate and impurities >1g/kg in the active substance as manufactured is deemed necessary. Full validation in compliance with TNsG (chapter 2, 4.1) is required. A fully-validated analytical method for the identification/quantification of Didecylmethylpoly(oxyethyl)ammonium propionate in BP-15 should be also submitted.

LC-MS methods have been used for the determination of residues of the active substance in soil and water down to a level of 0.01 mg/kg and 0.1 µg/l, respectively. Both methods are sufficiently specific, linear, accurate and precise and, therefore, are regarded as acceptable.

As for the determination of residues in air, the justification for non-submission of data provided by the Applicant is not acceptable, since the application techniques of the product include space fumigation for PT 2. A new justification for the non-submission of data or a fully-validated analytical method for residues in air specific for Didecylmethylpoly(oxyethyl)ammonium propionate is deemed necessary, as required by TNsG.

No analytical method is necessary for the determination of residues in body fluids and tissues, being the active substance neither toxic nor highly toxic.

The determination of residues in food/feed of plant/animal origin is not required for PT 2.

2.1.2. Intended Uses and Efficacy

Bardap 26 (active substance N,N-Didecyl-N-methyl-poly(oxyethyl)ammonium Propionate, DMPAP) is used for preventive protection of private area and public health area, medical equipment (PT2.01), chemical toilets (PT2.04) with preventive efficacy against bacteria and fungi. The use concentration depends on the type of application technique, use class required and on additional formulation components.

DMPAP is effective against Gram+ bacteria and enveloped viruses but has limited efficacy against non-enveloped viruses and bacterial spores. Reduced efficacy is shown against Gram- bacteria compared to Gram+ bacteria. Against fungi, there exists a selective activity spectrum.

Since it is surface active, Bardap- 26t has fair wetting properties and reacts strongly with cell walls of micro-organisms. Its mode of action, therefore, is to destroy the cell walls by sticking on the exterior structures and by entering and disintegrating the inner phospholipid-bilayer-based

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membrane structures. Due to its interaction with phospholipid-bilayer structures, it severely alters the cell wall permeability, disturbs membrane-bound ion-translocation mechanisms, and may facilitate the uptake of other biocides.

The product is used at different concentrations (from 0.8 g/L -7.00 g/L) for different PT use. The efficacy of the substance in aqueous solution has been adequately demonstrated through laboratory tests following specific ENs. Its use is for professional and general use.

In addition, in order to facilitate the work of Member States in granting or reviewing authorisations, and to apply adequately the provisions of Article 5(1) of Directive 98/8/EC and the common principles laid down in Annex VI of that Directive, the intended uses of the substance, as identified during the evaluation process, are listed in Appendix II.

Product type 2.01

PT 2.01 These data are confidential These data are confidential


Product type 2.04


2.1.3. Classification and Labelling

Justification for the proposal: Didecylmethylpoly(oxyethyl)ammonium Propionate is currently not classified according to Annex I of Council Directive 67/548/EC. Based on the results from studies presented in the dossier, classification of Didecylmethylpoly(oxyethyl)ammonium Propionate was proposed according to the criteria set out in Directive 67/548/EEC( with amendments), 99/45/EC (with successive adaptations) and 2006/8/EC Proposal for the classification and labelling of the active substance

On the basis of review of the submitted data, specific concentration limits have been proposed for the environmental classification of active substance, and the substance is not biodegradable. Class of danger C; N

Risk phrases R 22 Harmful if swallowed

R 34 Causes burns

R 50-53 Very toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment.

Safety phrases S 26 In case of contact with eyes, rinse immediately with plenty of water and seek medical advice

S 28 After contact with skin, wash immediately with plenty of soap and water

S 29 Do not empty into drains.

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S 36/37/39 Wear suitable protective clothing, gloves and eye/face protection

S 45 In case of accident or if you feel unwell, seek medical advice immediately (show the label where possible)

S 60 This material and its container must be disposed of as hazardous waste

S 61 Avoid release to the environment. Refer to special instructions/ safety data sheets

Specific limits Specific concentration limits for the environmental classification

Cn ≥ 2.5%: N; R50-53

Proposal for the classification and labelling of the product: BP-15

Class of danger C ; N

Risk phrases R 34 Causes burns

R 50-53 Very toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment.

Safety phrases S 26 In case of contact with eyes, rinse immediately with plenty of water and seek medical advice

S 28 After contact with skin, wash immediately with plenty of soap and water

S 29 Do not empty into drains

S 36/37/39 Wear suitable protective clothing, gloves and eye/face protection

S 45 In case of accident or if you feel unwell, seek medical advice immediately (show the label where possible);

S 60; This material and its container must be disposed of as hazardous waste.

S 61; Avoid release to the environment. Refer to special instructions/safety data sheets

Justification for the proposal: PB-15 (a.i. concentration 15%) does not contain any co-formulants which are substances of concern. The classification is by calculation according to the conventional method.

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2.2. Summary of the Risk Assessment

2.2.1 Human Health Risk Assessment

Acute effects

Didecylmethylpoly(oxyethyl)ammonium Propionate (Bardap26) is highly ionic and, therefore, it is expected not to be readily absorbed from the gastrointestinal tract or skin. No specific studies on Bardap26 toxicokinetics and metabolism are available, however, the read across from data on a structurally related compound, namely Didecyldimethylammonium Chloride (DDAC), has been accepted. The rationale for the read across acceptance is explained in details at the beginning of Doc.IIIA- Section 6. Less than 3% of an oral dose of DDAC was eliminated via urine following a single oral dose, whereas more than 90% is excreted in the faeces. Although it was not possible to discriminate between unabsorbed/absorbed material, based on the chemical nature of the test substance it can be anticipated that about 90% is present in faeces as unabsorbed material. On the basis of these data on DDAC, it is expected that Bardap26 oral absorption is limited to ≈10%. The majority of DDAC metabolism is expected to be carried out by intestinal flora giving rise to hydroxylation products in the alkyl chain. About 0.1% of a DDAC dose delivered as aqueous solution fully penetrated human skin in vitro in 24 h; mean total DDAC absorbed was 9.41%,(rounded to 10% for risk characterization purposes), including the radioactivity present in the dermis and epidermis at the dose site. The lowest determined oral LD50 value for Didecylmethylpoly(oxyethyl)ammonium Propionate is 662 mg/kg. There was a dose-related increase in mortality. Clinical signs included hypoactivity, irregular/shallow breathing, ano-genital staining and diarrhoea. Gross necropsy findings in decedents included discoloured liver, red lungs and fluid-filled stomach. The active substance is classified as ‘Harmful if swallowed’ on the basis of this study and is assigned the symbol Xn and risk phrase R22. A acute dermal toxicity study was not available on Bardap 26, and data on DDAC were considered fully valid. The rabbit acute dermal LD50 of Didecyldimethylammonium Chloride is 3342 mg/kg. DDAC caused skin irritation at the dose site in all animals. Didecyldimethylammonium Chloride is corrosive to dermal tissue and only moderately toxic systemically by the dermal route. Didecylmethylpoly(oxyethyl)ammonium Propionate is not volatile as the vapour pressure is 1.8x 10-6 Pa2. Thus, inhalation of N,N-Didecyl-N-methyl-poly(oxyethyl)ammonium Propionate is not considered a potential route of exposure. Didecylmethylpoly(oxyethyl)ammonium Propionate induced severe erythema, desquamation and corrosive eschar in the rabbit skin, and it is therefore classified as corrosive to skin, requiring R34 as risk phrase. Didecylmethylpoly(oxyethyl)ammonium Propionate is also irritant to eye N,N-Didecyl-N-methyl-poly(oxyethyl)ammonium Propionate is not a skin sensitiser. From a two-week skin irritation study in rats carried out with DDAC, by applying the read across principle, it can be derived a NOAEL/NOAEC of 0.6% DDAC in water at 2.0 ml/kg body

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weight per day after a 5 day application and a NOAEL/NOAEC of 0.3% DDAC in water at 2.0 ml/kg body weight per day after 2-week application. Anyway, the NOEL for Bardap26 has been derived from the NOEL of DDAC considering the different Molecular Weights (MW) of Bardap26 (437.777) and of DDAC (362.1).

The following formula has been applied:

NOEL Bardap26 = (NOELDDAC/ MWDDAC) x MW Bardap26 = (6mg/kg bw/day /362.1) x 437.777 = 7.3 mg/kg bw/day

The NOEL Bardap26 of 7.3 mg/kg bw/day corresponds to NOEL Bardap26 of 0.365% Bardap26. Repeated dose effects

Didecylmethylpoly(oxyethyl)ammonium Propionate intake in the diet over 90-days did not result in death in rodents. No clinically observable signs of toxicity were detected. However at high dietary administration dose level, evident toxicity is noted in rat; reduction in body weight gain, food consumption, clinical chemistry changes, small spleen in females, reduced absolute liver weight and body weight relative liver weight. The NOEL was equivalent to 90 mg a.s./kg/day and the LOEL was 275 mg a.s./kg/day Subchronic oral toxicity studies on a non rodent species, dermal toxicity studies in rodents and chronic toxicity/carcinogenicity study have not been conducted on Didecylmethylpoly(oxyethyl)ammonium Propionate, however they have been conducted using the structurally related compound Didecyldimethylammonium Chloride (DDAC). The read across from data on DDAC has been accepted. The rationale for the read across acceptance is explained in details at the beginning of Doc.IIIA- Section 6. In a 1-year feeding study in dogs with Didecyldimethylammonium Chloride, the two highest doses (10 and 20 mg/kg/day) resulted in g.i.-related complications including emesis and abnormal faeces, resulting in death of 2 out of 4 animal at 20 mg/kg/day. The clinical signs observed in all the animals treated at 10 mg/kg/d (emesis, salivation, soft/loose faeces) persisted for the entire study duration; taking into account that the treatment dosage is reached with 2 different administrations within the day (lowering the entity of the bolus dose achievable with a single administration-possibly giving rise to more severe effects) this dosage cannot be considered as the NOAEL derived from the study. The NO(A)EL should be fixed equal to 3 mg/kg/d, related to local effects on gut mucosa. The clinical signs reported at 10 mg/kg/d, on which the NOAEL derivation is based, are consistent with the irritation/corrosive properties of the test item: only a small amount of DDAC becomes systemically available, without giving rise to any significant systemic effects. The systemic effects (10-15% decrease in body weight), were seen at 20/30 mg/kg/d, although secondary to effects in the gut. Therefore it is not appropriate to use 3 mg/kg/d to derive a systemic AEL and consequently for AEL calculation it is proposed to use the immediately higher value (systemic NOAEL=10 mg/kg/d).

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The NOAELs for non neoplastic effects after chronic dietary DDAC administration were 32-41 mg/kg/day for rats and 76 – 93 mg/kg/day for mice. NOAELs values derivation was mainly based on unspecific effects, such as decreased body weights, considered to be secondary to local effects on gut mucosa and intestinal microflora. No organ specific toxicity was evidenced. In line with the fact that the main outcome directly derives from the irritation/corrosion properties of the active substance, the subchronic and chronic NOAELs are similar in rodents, and little difference is expected between the 2 exposure scenario. Adequate studies evaluating teratogenicity and adequate two-generation study have been conducted on the chemical and structural analogue, Didecyldimethylammonium Chloride. Didecyldimethylammonium Chloride does not affect reproduction or development at doses that are not toxic to the mother.In view of the chemical and structural similarities, the available data was considered appropriate for Didecylmethylpoly(oxyethyl)ammonium Propionate, taking into account both the chemical and structural similarities and the need for reducing unnecessary animal experiments. The NOAEL from maternal toxicity in the reproductive toxicity study was 1 mg/kg/d. It is not considered appropriate to use that NOAEL for systemic AEL derivation, since the administration was by gavage, and considering the local effects on the gut mucosa, it is obvious that a bolus dose is more irritant than the same amount taken slowly and mixed with the other dietary components, as it was in the 1-year dog study from which the relevant NOAEL is taken for risk characterization. Didecylmethylpoly(oxyethyl)ammonium Propionate produced no mutagenic activity in any screening studies including in vitro (bacterial or mammalian cell mutation, mammalian cell chromosomal aberration) and in vivo (bone marrow chromosomal aberration) studies. A carcinogenicity study using the chemical and structural analogue, Didecyldimethylammonium Chloride showed that the NOAELs for non neoplastic end-points were 32-41 mg/kg/day (750 ppm) for rats and 76-93 mg/kg/day (500 ppm) for mice. Didecyldimethylammonium Chloride did not result in an increase in tumors and was not considered oncogenic in either study. Thus, it is considered that Didecylmethylpoly(oxyethyl)ammonium Propionate will not be oncogenic. The lack of any structural similarity to known neurotoxins or of any alert for neurotoxic effects, shown by quaternary ammonium chemicals in general, supports the conclusion that DDAC has no neurotoxic potential. Medical data

No medical reports on the manufacturing personnel have been submitted.

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Exposure assessment

As for the PT2.01: The biocidal product containing the active substance is used as a disinfectant in the general sanitary sector for disinfection of objects or floors, walls and ceilings. The product is diluted in water and the end use concentration is of 5 g/L. The Bardap26-based products are also used at a concentration of 150g/L as a disinfectant/pre-wash for instruments such as hospital equipment and utensils. This product is diluted in water, the highest identified end use concentration of 0.8 g/L.

As for the PT2.04: The biocidal product containing the active substance is used at a concentration of 150g/L as a biocide in the chemical toilets. The end use concentration is 7000 ppm (equivalent to 7 g/L).

All the procedures are conducted by trained professional and non-professionals.

According to the intended uses, the human exposure assessment has been carried out both for primary exposed users (professionals and non-professional) and secondary exposed population (consumers and/or bystanders). Furthermore, the assessments have been conducted in accordance with the Technical Notes for Guidance (TNsG) on Human Exposure to Biocidal Products, ConsExpo Model and RISKOFDERM database.

The use of the active substance in products used for Product type 2 (Private area and public health area disinfectants and other biocidal products), together with EU assumptions are summarised in the Doc.IIB.

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2.2.2 Local exposure assessment

Bardap-26 exhibits irritant/corrosive properties which mainly affect the exposure. The resulting local effects have been considered for the primary exposure applying the same exposure scenarios used for the evaluation of the systemic effects . These scenarios are deemed to be relevant for fully addressing the toxicological effects arising from the use of Bardap26-based products. For the local effects assessing, the inhalation uptake can be considered negligible due to the low vapor pressure of Bardap26. Therefore, the only considered exposure route is the dermal one.

Professional users (Primary Exposure)

For assessing the local exposure, the dermal route is deemed to be the only relevant route eithr for professionals using Bardap26-based products as Product Type 2. The dermal local exposure for professional users directly exposed to Bardap26-based products are reported as follows: Scenario Total local exposure

(mg a.s./cm2)

PT 2.01 – Hard surface and instrument disinfectant.

Hard surface and instrument disinfectant (i.e. PT 2.01a and PT 2.01b):1) Mixing and loading (concentrate) (no inhalation exposure).

Body:1.55x10-4mg/cm2

Hard surface and instrument disinfectant (i.e. PT 2.01a):2) Spray

Body:3.5x10-4 mg/cm2

Hands:3.82x10-3mg/cm2

Hard surface and instrument disinfectant (i.e. PT 2.01a):3) Wipe


Hands: 3.7x10-3mg/cm2

Hard surface and instrument disinfectant (i.e. PT 2.01a):4) Mop (no inhalation exposure)


Hard surface and instrument disinfectant (i.e. PT 2.01a):5) Dipping and soaking



PT 2.04 – Chemical toilet disinfectant

Chemical toilet disinfectant (i.e. PT 2.04):1) Mixing and loading (concentrate), automated.

1.78 x 10-5 mg/cm2

Chemical toilet disinfectant (i.e. PT 2.04):2) Mixing and loading (concentrate), manual.

3.86 x 10-4 mg/cm2

Chemical toilet disinfectant (i.e. PT 2.04):3) Connect disposal pipe work.

2.1 x 10-7 mg/cm2

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Non-professional users (Primary Exposure)

The dermal local exposure for non professional users directly exposed to Bardap26-based products are reported as follows: Scenario Total local exposure

(mg a.s./cm2)

PT2.01 – Hard surface and instrument disinfectant

Hard surface and instrument disinfectant (i.e. PT 2.01a and PT 2.01b):1) Mixing and loading (concentrate)

Arms+Forearms: 1.4 x 10-3mg/cm2

Hard surface and instrument disinfectant (i.e. PT 2.01a):2) Spray (trigger)

2.12 x 10-4mg/cm2

Hard surface and instrument disinfectant (i.e. PT 2.01a):3) Spray (aerosol)

6.82 x 10-4mg/cm2

Hard surface and instrument disinfectant (i.e. PT 2.01b):4) Wipe

4.65 x 10-4 mg/cm2


Chemical toilet disinfectant (i.e. PT 2.04):1) Mixing and loading (concentrate), manual

9.35 x 10-4mg/cm2

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Indirect exposure as a result of use of the active substance in biocidal product (Secondary Exposure)

The only relevant scenario for dermal exposure considered in the assessment of the local effects has been derived from the ConsExpo Model of “Rubbing off”. It describes a situation in which a surface (table top, floor) is treated with a product and dermal exposure arises from contact with the treated surface.

The identified Scenario for PT 2.01 and 2.04 applied as disinfectant on hard surface and instrument and chemical toilet: Secondary exposure Exposure route: Dermal ConsExpo 4.1, Direct dermal contact with

product “rubbing off” (according to HEEG opinion agreed at TMI09). Exposure assessment for adult and children (acute skin contact)

The external dose (quantity of substance deposited on skin) is calculated as follow:

D = Sarea x Fdislod x Wf

With Sarea = Rtrans x t

Sarea: total area rubbed during exposure, calculated as the product of the transfer coefficient Rtrans and exposure duration, limited by Smax, the total treated surface (m2)

Fdislod: dislodgeable amount (amount of product applied on a surface area that may potentially be wiped off per unit of surface area) (kg/m2)

Wf: weight fraction of a.s. in product.

Rtrans: transfer coefficient (surface area treated with product that is in contact with the skin per unit of time) (m2/s).

T: contact time (s)

Fdislod = 30% (default value)

Wf = 0.007 (i.e., 0.7%)

Rtrans= 6000 cm2/h

T = 180 sec (i.e., 0.05 h default value)

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Considering an application rate (AR) of 0.01 mg/cm2 (layer of 0.01 cm with a product density of 1 g/cm3), it is obtained the following result:

D = 6000 cm2/h x 0.05 h x 0.01 mg/cm2 x 0.3 x 0.007 = 0.0063mg

Estimating the body surface, for an adult (i.e., man) it can be considered that legs, arms and forearms could be directly exposed to a biocidal treated surface. Therefore, the resulting value is 8480 cm2(arms 2280 + forearms 1140 + legs 5060 cm2, from TGD). On the other hand, as worst case for a child it can be considered that crawling on hard treated surface the whole body is exposed. Therefore, the exposed area is 4900 cm2 (from ConsExpo Model, General Fact sheet).

CHILD Local dose = 0.0063 mg / 4900 cm2 = 1.28 x 10-6 mg/ cm2

ADULT Local dose = 0.0063 mg / 8480 cm2 = 7.42 x 10-7 mg/ cm2

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2.2.3 Systemic exposure assessment

Due to the irritant/corrosive properties of Bardap26, the main toxicological effects are showed as local effects. Therefore, the systemic effects can be considered as secondary and rather negligible respect to the local ones. Anyway for completeness reasons, also a full exposure assessment for systemic effects has been carried out and included in the Competent Authority Report on Bardap26.

2.2.3.1 Professional users (Primary Exposure)

The assessment of primary exposure to professional users is based on EU default values. These exposure scenarios are used as a representation of realistic worst-case situations.

The following points have been taken into consideration:

1. Penetration factor of 100% in is applied TIER1 where no PPEs are considered to be worn. In TIER2, use of PPEs has been considered. Consequently, for body exposure, when cotton coveralls are worn and a protection factor of 75% is applied.

2. It is assumed that 100% of inhalation exposure is absorbed.

3. A dermal absorption value of 9.41% (rounded to10%) is used for the active substance reading-across from structural analogue, Didecyldimethylammonium Chloride (see Document IIA ).

4. Operator body weight (average for professional male and female users) is assumed to be 60 kg.

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Results of assessment

Total systemic exposure to the active substance of professional users using hard surface and instrument disinfectants (i.e. PT 2.01 and PT 2.04) is shown in the table below.

Scenario Total systemic exposure

(mg a.s./kg bw/day)

TIER1

Total systemic exposure

(mg a.s./kg bw/day)

TIER2



0.005 0.0005

Hard surface and instrument disinfectant (i.e. PT 2.01a): 2) Spray

0.062 0.027

Hard surface and instrument disinfectant (i.e. PT 2.01a): 3) Wipe

0.052 0.018

Hard surface and instrument disinfectant (i.e. PT 2.01a): 4) Mop (no inhalation exposure)

0.0023 0.00025

Hard surface and instrument disinfectant (i.e. PT 2.01a): 5) Dipping and soaking

0.0163 0.00563

PT 2.04 – Chemical toilet disinfectant.


0.0023 0.000575


0.125 0.0125


0.0000027 6.7 x 10-6

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Non-professional users (Primary Exposure)

The assessment to non-professional users is based on EU default values. These exposure scenarios are used as a representation of realistic worst-case situations.

The following points have been taken into consideration:

1. It is assumed that 100% of inhalation exposure is absorbed.

2. A dermal absorption value of 10% is used for the active substance.

3. Operator body weight (average for non-professional male and female users) is assumed to be 60 kg.


Total systemic exposure to the active substance of non-professional users using hard surface and instrument disinfectants (i.e. PT 2.01 and PT 2.04) is shown in the table below.

Scenario Total systemic exposure

(mg a.s./kg bw/day)

PT2.01 – Hard surface and instrument disinfectant.

Hard surface and instrument disinfectant (i.e. PT 2.01a and PT 2.01b): 1) Mixing and loading (concentrate).

0.008


0.0042


0.0089


3.62 x 10-6

PT 2.04 – Chemical toilet disinfectant.


0.0008

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Indirect exposure as a result of use of the active substance in biocidal product (Secondary Exposure)

Any indirect exposure to non-users is assumed to be negligible, however, to demonstrate this, the worst-case secondary exposure scenarios identified are considered below for each product type:

For the scenario concerning disinfection of hard surface and instrument the TNsG on Human Exposure to Biocides (Part 2, p47) suggests to take into account the following exposed populations for different exposure routes:

• Adults in healthcare and residential environments: inhalation of volatilised residues (acute), and

• Children and infants: inhalation and skin contact with wet residues (acute).

On the other hand, no chronic secondary exposure is foreseeable. The risk of child ingestion of domestic products is minimised through the use of child-resistant package closures.

As regards the Chemical toilet disinfection, the scenario identified in the TNsG on Human Exposure to Biocides (Part 2, p54) regards “Adults and children using toilets - skin contact (acute)”. In this case, the secondary exposure scenario for products in relation with surface disinfection/surface treatment (opinion by HEEG agreed in TMI09) has been applied.

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Total systemic exposure to secondary exposure to the active substance for use on hard surface (i.e., PT 2.01 and PT 2.04) is shown in the table below.

Scenario Total systemic exposure (mg a.s./kg bw/day)

PT2.01 – Hard surface

CHILD

Spray application – Dermal route 0.106

Air Space Spray– Dermal route 0.0076

INFANT 0.00765

Infant inhaling airborne disinfectant residues – Inhalation route

PT2.04 – Chemical toilet disinfectant

CHILD 4.2 x 10-4

ADULT 1.05 x 10-4

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2.2.4 Risk characterisation for local effects

Considering the repeated dose studies, the main critical effects associated with Bardap26 are due to its corrosive prosperities. In this context, the systemic effects such as the reduction of body weight and food consumption can be considered secondary compared to the corrosive properties of Bardap26. It can be concluded that Bardap26 actually does not cause ‘true’ systemic effects and the derivation of a systemic AEL is not considered as relevant.

As to the operators dermal exposure, a dermal AEL could possibly be considered. In the 2-week skin irritation study with rats, no systemic effects were observed and the NOAEL for local effects has been set at 6 mg/kg bw/day (reading across with 2-week skin irritation study with rats performed on DDAC, 0.3% DDAC).

Local NOEC derivation

The NOEL derived for the DDAC is of 0.3% of active substance in water (i.e., 3 g/l or 3000 mg/l or 3mg/ml). The total volume applied is of 2 ml/kg bw per day. Therefore, the resulted NOEL is of 6 mg/kg bw/day (=3mg/ml x 2ml/kg bw per day).

For Bardap26 a read across from the skin irritation study carried out on the analogous structurally compound DDAC has been accepted. Therefore, the NOEL for Bardap26 has been derived from the NOEL of DDAC considering the different Molecular Weights (MW) of Bardap26 (437.777) and of DDAC (362.1).

The following formula has been applied:

NOEL Bardap26 = (NOELDDAC/ MWDDAC) x MW Bardap26 = (6mg/kg bw/day /362.1) x 437.777 = 7.3 mg/kg bw/day

The NOEL Bardap26 of 7.3 mg/kg bw/day corresponds to NOEL Bardap26 of 0.365% Bardap26.

In the skin irritation study the treated body surface has not been well defined and therefore, the assumption of 10% coverage of the animal body could be made based on the guideline recommendations. According to the TGD, the total surface body of rat (male and female) is 400 cm2 and the mean body weight is 300g. Assuming that 10% of the body surface has been exposed to the test substance, the resulting exposed area is of 40cm2. For the characterization of the risk due to the local dermal effects a NO(A)EC (expressed in mg/cm2) has to be derived following the formula below:

2

2

)/()(²

/

cminsurfaceTreatedbwkgmgindosekginweightanimalaverage

cminsurfaceTreatedmginapplieddoseTotalcmmginNOAEC

×=

=

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NOEC = (0.3kg x 7.3 mg/kg bw/day) / 40cm2 = 0.055 mg/cm2

The NOEC value of 0.055 mg/cm2 is equivalent to a NOEC of 0.365%.

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Selection of AF Dermal AF: 3.2

1x, interspecies; 3.2x, human variability

Given that local toxicity based on the chemical reactivity of QUATs is the basis for the risk characterization, a reduced inter-species AFs when extrapolating data obtained in rats to humans could be used. In fact, for the local effects the QUATs show its effects at port of entry and therefore, it is justified to assume that both the components (toxicokinetic and -dynamic) do not contribute to interspecies differences.

Regarding intra-species differences it could be acceptable to lower the default factor disregarding the TK contribution (again 3.16 ≈ 3.2), given that chemical reactivity is the principle concern. Therefore, for the intraspecies AF only the Toxicodynamic component (3.16 ≈ 3.2) could be taken into consideration.

AEC derivation Based on the NOEC and the AF derived, the calculated AEC for dermal route is 0.017 mg/cm2 (non-irritating dose = 0.055 mg/cm2 / 3.2) or 0.12% (non-irritating concentration = 0.365% / 3.2).

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Risk Characterisation for local effects For dermal local effects the risk ratios for professional users directly exposed to Bardap26-based products have been derived considering an Acceptable Exposure Concentration (AEC) of 0.017mg/cm2. Scenario Local exposure

(mg a.s./cm2) AEC% = (Total local exposure x 100)/AEC

AEC = 0.017mg/cm2



Body:1.55x10-4mg/cm2 0.9

Hard surface and instrument disinfectant (i.e. PT 2.01a): 2) Spray



Body:2.1

Hands:22.5

Hard surface and instrument disinfectant (i.e. PT 2.01a): 3) Wipe


Hands: 3.7x10-3mg/cm2

Body:2.0

Hands:21.8

Hard surface and instrument disinfectant (i.e. PT 2.01a): 4) Mop (no inhalation exposure)


0.1

Hard surface and instrument disinfectant (i.e. PT 2.01a): 5) Dipping and soaking



Body:0.6

Hands:8.6



1.78 x 10-5 mg/cm2 0.1


3.86 x 10-4 mg/cm2 2.3


2.1 x 10-7 mg/cm2 0.0012

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For dermal local effects the risk ratios for non professional users directly exposed to Bardap26-based products have been derived considering an Acceptable Exposure Concentration (AEC) of 0.017mg/cm2. Scenario Total local exposure

(mg a.s./cm2) AEC% = (Total local exposure x 100)/AEC

AEC = 0.017mg/cm2

PT2.01 – Hard surface and instrument disinfectant

Hard surface and instrument disinfectant (i.e. PT 2.01a and PT 2.01b):1) Mixing and loading (concentrate)

Arms+Forearms: 1.4 x 10-3mg/cm2

8.2


2.12 x 10-4mg/cm2 1.2


6.82 x 10-4mg/cm2 4.0


4.65 x 10-4 mg/cm2 2.7


Chemical toilet disinfectant (i.e. PT 2.04):1) Mixing and loading (concentrate), manual

9.35 x 10-4mg/cm2 5.5

Conclusions: As regards the direct application of a biocidal product containing Bardap26, no risk can occur either for professional and non professional users.

Anyway, since the concentrated formulation contains 15% Bardap26, and in practice solution of 0.5% Bardap26 is used, at a concentration of 0.12% Bardap26 (0.12% (non-irritating concentration) clear local effects are observed in the study, personal protective equipments (PPEs) should be used to protect operators against the local effects of Bardap26. The only safe concentration is used by professionals in “Dipping and Soaking” scenario during the instrument disinfection. Therefore, the conclusion from the risk assessment due to the corrosive properties of Bardap26 is that PPE are per definition required when applying Bardap26.

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As concerns the risks arising from the secondary exposure, the only scenario considered as relevant is children and adults in direct contact with a treated surface. The resulting local dose is 7.42 x 10-7 mg/ cm2 and 1.28 x 10-6 mg/ cm2 for adult and child, respectively. The derived MOE ratios are above the MOEref (3.2) and therefore, it can be concluded that no risk occurs due to the secondary exposure. The resulting MOE ratios have been calculated as follow:

Exposure scenarios Local exposure value

(mg/cm2)

MOE = NOEC/ Local exposure value

NOEC = 0.055 mg/cm2

ConsExpo Model of “Rubbing off” - Adult

7.42 x 10-7 7410

ConsExpo Model of “Rubbing off” - Child

1.28 x 10-6 4300

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The PPEs which have to be used for protection from corrosiveness of Bardap26 are following

described.

Hygiene measures

Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after

handling the product.

Respiratory protection

In the case of vapour formation, use a respirator with an approved filter. Respirator with a

vapour filter of the following type should be used: EN 141.

Hand protection for long-term exposure

Suitable material for gloves: Nitrile rubber

Break through time / glove: > 480 min

Minimal thickness / glove: 0.7 mm

Take note of the information given by the producer concerning permeability and break through

times, and of special workplace conditions (mechanical strain, duration of contact).

Hand protection for short-term exposure (e.g. accidental aerosols from splashing etc.)

Suitable material for gloves: Nitrile rubber

Break through time / glove: > 30 min

Minimal thickness / glove: 0.4 mm

Take note of the information given by the producer concerning permeability and break through

times, and of special workplace conditions (mechanical strain, duration of contact).

Eye protection

Tightly fitting safety goggles; Face-shield.

Skin and body protection

Choose body protection according to the amount and concentration of the dangerous substance at

the work place, Rubber or plastic apron, Rubber or plastic boots.

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2.2.5 Risk characterisation for systemic effects

Due to the irritant/corrosive properties of Bardap26, the main toxicological effects are showed as local effects. Therefore, the systemic effects can be considered as secondary and rather negligible respect to the local ones. Anyway for completeness reasons, also a full risk assessment for systemic effects has been carried out and included in the Competent Authority Report on Bardap26.

AEL (Acceptable exposure level)

The systemic AEL derived from data on DDAC (see read across justification in IIIA Appendix 3) is 0.1 mg a.s./kg bw/day.

The AEL is calculated as follows: the lowest systemic toxicity NOAEL in a repeated dose study is 10 mg/kg b.w/day derived from the 52 weeks study on dogs. An assessment factor of 10 is used for interspecies variability and an assessment factor of 10 for taking into account intraspecies variability. Therefore, the AEL (based on systemic toxicity) is determined to be 0.1 mg/kg/day.

Exposure and risk from direct use of the product

Professional users

AEL approach for professional users

The risk assessment for professional users primarily exposed to Bardap26-based products has been carried out both using the AEL and the MOE approaches. Due to the irritant/corrosive properties of Bardap26, the use of the PPEs has to be considered as mandatory for professionals users. Following to that, Tier2 (including that PPEs are worn) has been regarded as the most realistic worst-case and therefore, the exposure values derived in Tier2 are the only taken into account in the following risk assessment. The AEL and MOE values are reported in Doc.IIC.

The AEL approach turns out to AEL-percentage values ranged from 0.0067 to 12.5%. Therefore, all the percentages are lower than the trigger value of 100%. Consequently, no risk could be foreseeable for professionals using Bardap26-based products.

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Risk characterisation is expressed as percentage of AEL (AEL/Exposure x100) Scenario AEL

mg/kg/day Systemic dose

mg/kg/day

TIER2

AEL% = (Exposure x 100)/

AEL



0.1 0.0005 0.5

2) Spray 0.1 0.027 27

3) Wipe 0.1 0.018 18

4) Mop 0.1 0.00025 0.25

5) Dipping and soaking 0.1 0.00563 5.63

PT2.04 – Chemical toilet disinfectant.

Chemical toilet disinfectant (i.e. PT 2.04): 1) Mixing and loading (concentrate), automated.

0.1 0.000575 0.575

2) Mixing and loading (concentrate), manual.

0.1 0.0125 12.5

3) Connect disposal pipe work. 0.1 6.7 x 10-6 0.0067

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Margin of Exposure (MOE) approach for professionals

The NOAEL for dermal sub-chronic effects (12 mg a.i./kg/day – highest possible dose that could be applied but no systemic toxicity observed) is used to determine the Margin of Exposure for dermal exposure. The NOAELdermal has to be calculated considering the dermal absorption determined in an in vitro study using human skin is 9.41%, rounded to 10%. The NOAEL results to be 1.2 mg a.i./kg/day. A safety factor of 100 (10 for interspecies difference x 10 for intraspecies difference) is used, although there is no evidence of systemic toxicity from dermal application of Bardap26. Therefore, the MOE (NOAEL/exposure) should be equal to or greater than 100 in order to determine no risk to human health.

The NOAEL for oral sub-chronic effects (10 mg a.i./kg/day) is used to determine the Margins of Exposure for inhalation exposure in the absence of sub-chronic inhalation toxicity data. A safety factor of 100 (10 for interspecies difference x 10 for intraspecies difference) is applied. Therefore, MOE (NOAEL/exposure) should be equal to or greater than 100 in order to determine no risk to human health.

The MOEs calculated for the dermal route give values from 723 to 1791045.

The MOEs derived for inhalation route range from 909 to 588235. According to that, no risk can occurs for professionals both through the dermal and inhalation routes.

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Calculations of MOE are as follows: Scenario Dermal

Systemic dose

mg/kg/day

TIER2

MOE = NOAEL (1.2 mg/kg bw/d) /

Systemic Dose

Inhalation systemic dose

mg/kg/day

MOE = NOAEL (10mg/kg bw/d)/

Systemic Exposure



0.0005 2400 - -

2) Spray 0.017 70.6 0.011 909

3) Wipe 0.0166 72.3 0.002 5000

4) Mop 0.00025 4800 - -

5) Dipping and soaking 0.0056 214 1.7 x 10-5 588235


Chemical toilet disinfectant (i.e. PT 2.04): 1) Mixing and loading (concentrate), automated.

0.000575 2087 - -

2) Mixing and loading (concentrate), manual.

0.0125 96 - -

3) Connect disposal pipe work.

6.7 x 10-6 179104 - -

Conclusions: As regards hard surface and instrument disinfection by professional users, an unacceptable risk could occur only during the spraying and wiping applications. On the other hand for chemical toilet disinfection, a risk results from the manual mixing and loading stage.

For all the other exposure scenarios no risk occurs through the dermal route for the direct application of the biocidal product.

Anyway, due to the irritant/corrosive properties of the active substance, the use of Personal Protective Equipments has to be prescribe as mandatory so as to avoid any risk.

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Non-Professional users

AEL approach for non-professional users

The risk assessment for non-professional users primarily exposed to Bardap26-based products has been carried out both using the AEL and the MOE approaches.

The AEL approach turns out to AEL-percentage values ranged from 0.00362 to 8.9%. Therefore, all the percentages are lower than the trigger value of 100%. Consequently, no risk could be foreseeable for professionals using Bardap26-based products.

For non-professional users, the following outcomes have been calculated.

Scenario AEL mg/kg/day

Systemic dose

mg/kg/day

AEL% = (Exposure x

100)/ AEL



0.1 0.008 8

2) Spray (trigger) 0.1 0.0042 4.2

3) Spray (aerosol) 0.1 0.0089 8.9

4) Wipe 0.1 3.62 x 10-6

0.00362


Chemical toilet disinfectant (i.e. PT 2.04): 1) Mixing and loading (concentrate), manual.

0.1 0.0008 0.8

Conclusions: According to the data reported above, no risk can occurs due to the direct use of the biocidal products by non-professionals.

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Margin of Exposure (MOE) approach for non-professional users

The NOAEL for dermal sub-chronic effects (12 mg a.i./kg/day – highest possible dose that could be applied but no systemic toxicity observed) is used to determine the Margin of Exposure for dermal exposure. The NOAELdermal has to be calculated considering the dermal absorption determined in an in vitro study using human skin is 9.41%, rounded to 10%. The NOAEL results to be 1.2 mg a.i./kg/day. A safety factor of 100 (10 for interspecies difference x 10 for intraspecies difference) is used, although there is no evidence of systemic toxicity from dermal application of Bardap26. Therefore, the MOE (NOAEL/exposure) should be equal to or greater than 100 in order to determine no risk to human health.

The NOAEL for oral sub-chronic effects (10 mg a.i./kg/day) is used to determine the Margins of Exposure for inhalation exposure in the absence of sub-chronic inhalation toxicity data. A safety factor of 100 (10 for interspecies difference x 10 for intraspecies difference) is applied. Therefore, MOE (NOAEL/exposure) should be equal to or greater than 100 in order to determine no risk to human health.

Scenario Dermal Systemic

dose mg/kg/day

MOE = NOAEL (1.2mg/kg/day) /

Systemic Dose

(MOEref = 100)

Inhalation Systemic dose

mg/kg/day

MOE = NOAEL (10

mg/kg/day) / Systemic Dose (MOEref = 100)



0.0008 1500 - -

2) Spray (trigger) 0.004 300 0.0002 50000

3) Spray (aerosol) 0.0083 144.6 0.0006 16667

4) Wipe 3.6 x 10-6 333333 - -


Chemical toilet disinfectant (i.e. PT 2.04): 1) Mixing and loading (concentrate), manual.

0.0008 1500 - -

Conclusion: No risk for non-professional users occurs for the direct application of the biocidal

product.

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Indirect exposure as a result of use

For the secondary exposure due to the use of hard surface cleaners, the following critical endpoints have been applied in the MOE approach:

Acute exposure

• Inhalation acute = use oral NOEL = 10 mg/kg bw/d

• Dermal acute NOEL = 6 mg/kg/day

The above NOELdermal was derived from a 2-week skin irritation study on rat carried out using DDAC as testing material.

Scenario NOAEL mg/kg/da

y

Systemic exposure

mg /kg bw/day

MOE (MOEref =

100)

PT2.01 – Hard surface

CHILD – Spray - Dermal 6 0.106 56

CHILD - Air Space Spray - Dermal 6 0.0076 790

INFANT - Infant inhaling airborne disinfectant residues / vapours

10 0.00765 1307

PT2.04 – Chemical toilet disinfectant

CHILD - Dermal 6 4.2 x 10-4 14285

ADULT- Dermal 6 1.05 x 10-4 57142

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Combined exposure

The risk of exposure to professional and non-professional users is considered to be small even based on worst-case EU default assumptions.

Users, professional and non professional, are potentially at risk from exposure from several sources of the biocidal product, either during or after use of treated articles. Some exposure estimates are based on daily work rates and therefore can not be combined. Some exposure estimates could justifiable be combined however, on the basis of the exposure estimates calculated it is unlikely that the AEL would be exceeded and it is unlikely that these combinations would be repeated daily.

The risk to all non-users is considered negligible.

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2.2.6 Environmental Risk Assessment

Fate and Distribution in the Environment Biodegradation DMPAP is inherent biodegradable. The primary biodegradation was 95%. In a Zahn-Wellens study (OECD 302 B) with DMPAP elimination was 53% after 3 hours was observed. The resulting partitioning to the aqueous phase is 47%, partitioning to sludge is 53% and total loss 95%. A study to determine aerobic biodegradation in a sewage treatment plant was conducted for the structural analog DDAC, which was found to completely biodegrade in aerobic conditions. At test termination (28 days) 93.3% of the radioactivity was evolved as 14CO2 , 1.32% was recovered in the extracts and 3.28% remained in the solid. One major metabolite was identified. In the abiotic sample 92.22% of the radioactivity was recovered in the extracts and 1.5% remained in the solid. This results confirm, that despite of a high adsorption to sludge particles a complete mineralisation of quaternary compounds does occur. An estimation of the phototransformation in air of the structural analog DDAC indicates that DMPAP would be very stable in air.

Didecylmethylpoly(oxyethyl)ammonium propionate was found to be not readily biodegradable. To simulate sewage treatment plant conditions more realistically a die away study with high sludge density and low, more realistic test substance conecentrations was performed using radiolabelled Didecylmethylpoly(oxyethyl)ammonium Propionate. The study was not conducted to any specified guideline. The TSS was adjusted to approximately 2500 mg/L. The biotic sludge was mixed overnight on a shaker table with the flask open to ambient air. The sludge used to prepare the abiotic control was amended with a 2.5% mercuric chloride buffer solution and autoclaved for 90 minutes. After the sludge was cooled to room temperature, the pH of the abiotic sludge was adjusted with 1.5 N KOH to match the pH of the biotic sludge (7.6). Two 1 gallon jugs, with gas trapping systems, containing 2 or 1 litres of either biotic or abiotic activated sludge, respectively, were dosed with 50 µg/l radiolabelled test substance.

The study was conduct to evaluate the rate and extent of primary degradation and mineralization of the test substance in the activate sludge. The test system was activated sludge previously exposed to nonlabelled Didecylmethylpoly(oxyethyl)ammonium Propionate at a nominal concentration of 150 µg/l in a porous pot. The abiotic control was identical to the biologically active treatment with the exception that it was amended at a nominal concentration of 1 g/l with mwercuric chloride and autoclaved prior to test initiation.

At test termination (28 days) 86% of the radioactivity was evolved as 14CO2 , 0.0% was recovered in the extracts and 5.79% remained in the solid. 6.34% of a polar metabolite was detected after 28 days. In the abiotic sample 101.88% of the radioactivity was recovered in the extracts and 3.01% remained in the solid.The study has been considered as supplemental information

Didecylmethylpoly(oxyethyl)ammonium Propionate biodegrades in a waste water treatment plant die-away silmulation test under aerobic conditions with a removal half life DT50 of 4.7 hours and a high conversion rate to CO2.

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A biodegradation study in two water/sediment systems has been performed with the chemical and structural analog, Didecyldimethylammonium Chloride and shoed that the substance easily migrates from the aqueous phase to the sediment phase and is also easily adsorbed to sediments (high Koc). The degradation in the sediment phase did not increase very much after the first month and the DT50 of the total system was not reached within the 120 days test duration. Abiotic Degradation DMPAP was hydrolytically stable during the 30-day hydrolysis study at pH 5, 7 or 9 at 25°C. An adequate study evaluating phototransformation in water has been conducted on the chemical and structural analog, DDAC. DDAC was found to be photolytically stable in the absence of a photosensitiser. In the presence of the energy from a xenon arc lamp and the photosensitising agent, acetone, it appears that DDAC breaks down to form a single degradate. The half-life of the test compound was determined to be 227 days (light, exposed) and 427 days (dark, exposed) with 7% degradation after 30 days. Distribution A study to determine adsorption and desorption in soil has been conducted on the chemical and structural analog, DDAC. In view of the chemical and structural similarities, it is considered that the available data is adequate for DMPAP. DDAC was cosidered as immobile in four soil/sediment types. The Koc values considered in the exposure assessment is 1103802ml/g.

Due to the fact that Alkyldimethylbenzylammonium Chloride was inherent biodegradable, field studies on accumulation in the sediment, aerobic degradation studies in soil, field soil dissipation and accumulation studies were not needed.

Mobility

The results of the adsorption in soil study indicate little or no potential for mobility in soil and should not pose an environmental risk for contamination of ground water. Thus, it is considered that a short or a long-term Mobility- Lysimeter study for DMPAP is not justified.

Bioaccumulation

Based on a measured BCF fish (81, read-across from DDAC data, see IIIA Section 7 introduction, IIA Appendix I) it is considered that DMPAP has a low potential for bioaccumulation.

No data are available on the BCFearthworm; calculation according to TGD (eq. 82d) is not applicable. Nevertheless, bioaccumulation in the terrestrial food chain would pose birds and mammals at risk of secondary poisoning in case of BCFearthworm in excess of 1.4 E+05 and 2.6 E+05, respectively (see IIA, 4.1.3; IIB, 3.3.5; IIIA, 7.5.5.1). In conclusion, terrestrial bioaccumulation cannot be estimated with the data available; however the risk of secondary poisoning via the terrestrial food chain is deemed unlikely.

Effects on Environmental Organisms

Aquatic Compartment

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The results of acute toxicity studies indicate that DMPAP is very toxic to fish, daphnia and algae. The most sensitive group is invertebrates (Daphnia 48-hour EC50 of 0.07 mg/l under semi-static conditions) whilst the less sensitive group is fish (common carp 96-hour LC50 of 0.62 mg/l under semi-static conditions). DMPAP is harmful to microbial activity in STP, being this inhibited at concentration higher than any other aquatic group (3h respiration inhibition test EC50 of 16.8 mg/l). The results of long term toxicity studies come from a read-across with DDAC data (see IIIA Section 7 introduction, IIA Appendix I) which indicate that DMPAP is expected to be very toxic to fish and daphnia.

Daphnia magna was more sensitive than fish, with a 21d NOEC (survival) of 0.010 mg/l recorded under flow-through conditions.

The PNECwater is derived from the lowest of the three NOECs (0.01 mg/l daphnia), leading to: PNECwater 0.001 mg/l.

Sediment

The hazard of DMPAP to sediment dwelling organisms is based on DDAC data (read-across, see IIIA Section 7 introduction, IIA Appendix I). In a 28 days test with Chironomus tentans, the NOEC (survival) was 530 mg/kg dw, corresponding to 356.16 mg/kg wwt.

The PNECsediment is calculated from the long term NOEC available as: PNECsediment 3.56 mg/kg wwt.

Terrestrial Compartment

The effect of DMPAP on earthworms was assessed in an acute toxicity test with E. foetida. The 14-day LC50 was 4390 mg/kg dry soil, the NOEC was 2000 mg/kg dry soil.

Based on DDAC data (read-across, see IIIA Section 7 introduction, IIA Appendix I) no effect of DMPAP on nitrite, nitrate, ammonium and carbon dioxide formation is expected at a concentration of 1000 mg/kg dry soil.

Based on DDAC data (read-across, see IIIA Section 7 introduction, IIA Appendix I) the EC50 for terrestrial plants is expected at 283 mg/kg dw (20 days growth test with mustard, mung bean and wheat), corresponding to an EC50 of 268.66 mg/kg wwt, corrected for the organic matter content.

The acute DMPAP LD50 for birds is observed at 226 mg/kg bw (northern bobwhite quail). Based on DDAC data (read-across, see IIIA Section 7 introduction), the short term dietary LC50 for birds is expected at > 5620 mg/kg (northern bobwhite quail and mallard).

DMPAP is toxic to mammals with a NOEC value of 100 mg/kg in mice in a 18 months body weight gain test (read-across from DDAC data, see IIIA Section 6, IIA Section 3).

The PNECsoil is derived from the EC50 plants as: PNECsoil 0.177 mg/kg wwt.

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The PNECbirds is derived from dietary toxicity studies as: PNECbirds 1.87 mg/kg food.

The PNECmammals is derived from an oral (18 months) repeated doses study on mouse, leading to: PNECmammals 3.33 mg/kg food.

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PBT Assessment

The active substance Bardap26 does not meet the PBT criteria. P criterion: Half life > >120 d in freshwater sediment.

From data of hydrolysis:

Bardap26 is hydrolytically stable over an environmentally relevant pH range of 5-9.

From data of photolysis in water:

Bardap26 was found to be photolytically stable in the absence of a photosensitiser

Studies of the distribution in the water sediment system suggest that Bardap26 easily migrates from the aqueous phase to the sediment phase and is also easily adsorbed to sediments (high Koc). The degradation in the sediment phase did not increase very much after the first month and the DT50 of the total system was not reached within the 120 days test duration.

Didecyldimethylpoly(oxyethyl)ammonium Propionate is not readily nor inherently biodegradable therefore it should be regarded as potentially persistent.

B criterion: BCF > 2000 For Bardap26 the calculated bioconcentration factor in fish is 81 (read acroos with other structurally related QUATs such as DDAC and ADBAC). Therefore, the B criterion is not fulfilled. T criterion: Chronic NOEC < 0.01 mg/L or CMR or endocrine disrupting effects, other evidence The substance is proposed to be classified as C; R22; R34 N;R50/53 The most sensitive specie is Daphnia Magna for which a NOEC of 0.01 mg/l has been derived from a 21 d reproduction study (read across from DDAC data). The whole evidence of the available information indicates that the T criterion is fulfilled.

Environmental Exposure Assessment

Aquatic Compartment Exposure assessment

The environmental loading resulting from all the other emission scenarios and the corresponding PEC values are summarised in the following table:

Estimated PECs Usage scenario Local emission

(kg/d) Influent to STP (mg/L)

Effluent from STP

(mg/L)

Surface water

(mg/L)

Sediment (mg/kg)

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Estimated PECs Usage scenario Local emission

(kg/d) Influent to STP (mg/L)

Effluent from STP

(mg/L)

Surface water

(mg/L)

Sediment (mg/kg)

Product type 2.01

PT 2.01a (i)

Worst-casea

0.0022 0.0011 9.5 x 10-4 3.6 x 10-5 0.85

PT2.01a (ii) Worst-casea

3.75 1.88 0.16 6.08 x 10-3 145.5

PT2.01a (ii) Refined

0.0375 0.0188 0.0016 6.08 x 10-5 1.46

PT2.01a (iii) Worst-casea

2.02 1.01 0.0868 3.28 x 10-3 78.4

PT2.01a (iii) Refined

0.0202 0.0101 8.69 x 10-4 3.28 x 10-5 0.78

PT2.01a (iv) Worst-casea

0.1875 0.0375 8.81 x 10-4 3.67 x 10-5 1.277

PT2.01a (iv) Refined

0.0750 0.0375 3.23 x 10-3 1.22 x 10-4 2.91

PT2.01b (i) Worst-casea

2.4 x 10-6 < 0.0001 < 0.0001 < 0.0001 < 0.0001

PT2.01b (i) Refined

2.4 x 10-7 < 0.0001 < 0.0001 < 0.0001 < 0.0001

Product type 2.04

PT2.04 (i)

Worst-casea

0.0938 0.0469 4.0 x 10-3 1.5 x 10-4 3.6

PT2.04 (i)

Refined

0.0500 0.0250 2.2 x 10-3 8.1 x 10-5 1.9

a Only default values has been used in the PEC calculation

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Terrestrial Compartment Exposure assessment

The environmental loading resulting from all the other emission scenarios and the corresponding PEC values are summarised in the following table:

Estimated PECs Usage scenario Local emission (kg/d) Sewage sludge,

Csludge (mg/kg) Soil, Csludgesoil (mg/kg)

Soil, Csludgesoil after 10 years (mg/kg)

Product type 2.01

PT2.01a (i) 0.0022 2.12 3.12 x 10-3 0.0312

PT2.01a (ii) Worst-casea

3.75 362 0.53 5.3

PT2.01a (ii) 0.0375 3.62 5.32 x 10-3 0.0532

PT2.01a (iii) Worst-casea

2.02 195 0.29 2.9

PT2.01a (iii) 0.0202 1.95 2.87 x 10-3 0.0287

PT2.01a (iv) Worst-casea

0.1875 18.1 0.03 0.3

PT2.01a (iv) 0.0750 7.24 0.011 0.11

PT2.01b (i)

Worst-casea

2.4 x 10-6 2.32 x 10-4 3.41 x 10-7 3.41 x 10-6

PT2.01b (i) 2.4 x 10-7 2.32 x 10-5 3.41 x 10-8 3.41 x 10-7

Product type 2.04

PT2.04 (i) Worst-casea

0.094 9.06 0.013 0.13

PT2.04 (i) 0.0500 4.83 7.1 x 10-3 0.071 a Only default values has been used

Atmospheric Compartment Exposure assessment The vapour pressure of DMPAP at ambient temperature as determined by OECD Guideline 104 is 1.8E-06 Pa and Henry's law constant is 3.03E-11 Pa. m3/mol. Therefore DMPAP is not considered volatile and is not expected to volatilize to air in significant quantities. Furthermore, the photochemical oxidative degradation half-life of DMPAP [Mean atmospheric half life = 0.23 days (2.8 hours)] in air was estimated using the Atmospheric Oxidation Program v1.90 (AOPWIN) on the structurally related DDAC, which is based on the structural activity relationship (QSAR's) methods developed by Atkinson, R (1985 to 1996). The estimated half-

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life of DMPAP in air via hydroxyl reactions is not expected to exceed 0.23 days at most (again read-across to DDAC). Therefore, even if present, DMAPA not expected to persist in air. Consequently, DMPAPis not expected to volatilise or persist in air in significant quantities.

Risk characterisation for the environmental

Assessment of risk for the aquatic compartment

The assessment of risk is based on a comparison of the PNEC values with the relevant compartment PECs values. A PEC/PNEC ratio of less than one indicates that the risks associated with the use(s) of the product are acceptable.

PEC/PNEC ratios for aquatic organisms exposed to DDAC used as private or public health area disinfectants and other biocidal products (PT02)

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Surface water Scenario PECsw (mg/L) PNEC (mg/L) PEC/limit value

PT 2.01a (i) 0.036 x 10-3 0.036

PT 2.01a (ii) 6.08 x 10-3 6.08

PT 2.01a (iii) 3.26 x 10-3 3.26

PT 2.01a (iv) 0.07 x 10-3 0.07

PT 2.01b < 0.001 x 10-3 < 0.001

PT 2.04 (i) 0.15 x 10-3

1 x 10-3

0.15

Sediment Scenario PECsed (mg/kg) PNEC (mg/kg) PEC/PNEC ratio

PT 2.01a (i) 0.85 0.24

PT 2.01a (ii) 146 41

PT 2.01a (iii) 78.4 22

PT 2.01a (iv) 7.3 2.05

PT 2.01b < 0.001 <0.0002

PT 2.04 (i) 3.6

3.56

1

STPs Scenario Influent from

STP (mg/L) PNEC (mg/L) PEC/PNEC ratio

PT 2.01a (i) 0.0011 0.007

PT 2.01a (ii) 1.88 11.2

PT 2.01a (iii) 1.01 6.0

PT 2.01a (iv) 0.09 0.5

PT 2.01b < 0.0001 0.0006

PT 2.04 (i) 0.045

0.168

0.27

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Groundwater

Usage scenario PEClocalsoil.

porew

Limit value (mg/l)

PEC/limit value

Product type 2

PT2.01a (i) 3.2 10-8 3.2 10-4

PT2.01a (ii) 5.5 10-6 5.5 10-2

PT2.01a (iii) 2.9 10-6 2.9 10-2

PT2.01a (iv) 3.1 10-7 3.1 10-3

PT 2.01b (i) 3.5 10-12 3.5 10-8

PT 2.04 (i) 1.3 10-7

1x10-4

1.3 10-3

Thus, as all PEC/Limit value ratios are < 1 for all use patterns, there is no concern with regard to the groundwater compartment.

Assessment of risk for the terrestrial compartment The assessment of risk is based on a comparison of the PNEC values with the relevant compartment PECs values. A PEC/PNEC ratio of less than one indicates that the risks associated with the use(s) of the product are acceptable.

PEC/PNEC ratios for aquatic organisms exposed to Bardap 26 used as private or public health area disinfectants and other biocidal products (PT02)

Usage scenario PEC soil (mg/kg)

PNECsoil (mg/kg)

PEC/PNEC

PT2.01a (i) 0.003 0.02

PT2.01a (ii) 0.53 2.99

PT2.01a (iii) 0.29 1.64

PT2.01a (iv) 0.03 0.17

PT 2.01b (i) 3.4 10-7 1.9 10-6

PT 2.04 (i) 0.013

0.177

0.07

2.2.7 List of endpoints

In order to facilitate the work of Member States in granting or reviewing authorisations, and to apply adequately the provisions of Article 5(1) of Directive 98/8/EC and the common principles

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laid down in Annex VI of that Directive, the most important endpoints, as identified during the evaluation process, are listed in Appendix I.

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3. PROPOSAL FOR THE DECISION

3.1. Background to the Decision

On the basis of the proposed and supported uses and the evaluation conducted as summarised in chapter 2 of this document, it can be concluded that under the conditions listed in chapter 3.2 Didecylmethylpoly(oxyethyl)ammonium Propionate (Bardap26) fulfils the requirements laid down in Article 5(1) (b), (c), and (d) of Directive 98/8/EC, apart from requirements in TNsG Chapter 2 Sections 4.1 and 4.2(b). Didecylmethylpoly(oxyethyl)ammonium Propionate is proposed to be included in Annex I of the Directive, provided that fully-validated analytical methods for the determination of the active substance in the active substance as manufactured and in the biocidal product as well as a fully-validated analytical method for residues in air (or a new justification for the non-submission of data) are supplied by the Applicant. For the Human Health, both a risk characterization for local effects and for systemic effects has been carried out. The local effects, caused by the irritant/corrosive properties of the active substance, are considered the main toxicological effects whereas the systemic effects are secondary and mainly negligible than the local ones. Nevertheless, a full risk assessment has been also performed for the systemic effects and for transparency reasons this assessment has been included in the Competent Authority Report. As regards the local effects, no risk has been identified both for professional and non professional users following to the direct use of Bardap26-based products. Moreover, no risk arises from the indirect exposure due to the dermal contact with a treated hard surface for children and adults. On the other hand, for the systemic effects no risk is expected both from direct exposure (for professional and non professional users) and indirect exposure for consumers. Anyway, due to the irritant/corrosive properties of Bardap26, the use of Personal Protective Equipment (PPE) has to be prescribed as mandatory for professional users. As regards the environmental risk assessment, for some usage scenarios a risk can be identified for the aquatic and the terrestrial compartments. Anyway, the PEC values have been derived for a worst case scenario only considering default values. Therefore, the PEC/PNEC ratios can be regarded as an overestimate and a more realistic worst case could be obtained by applying refinement values.

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3.2. Proposed Decision regarding Inclusion in Annex I

The Italian CA recommends that Didecylmethylpoly(oxyethyl)ammonium Propionate is included in Annex I to Directive 98/8/EC as an active substance for use as “private area and public health area disinfectant” (Product-type 2), subject to the following specific provisions and risk reduction measures:

Common name: Didecylmethylpoly(oxyethyl)ammonium Propionate

IUPAC name: Not applicable

CAS No.: 94667-33-1

EC No.: None assigned

Minimum degree of purity of the active substance:

The active substance as manufactured shall have a minimum purity of 90 – 99 % w/w

Identity and maximum content of impurities:

The identity and maximum content of impurities must not differ in such a way as to invalidate the assessment for the inclusion of the active substance on to Annex I.

Specific provisions and risk reduction measures:

Member States shall ensure that authorisations are subject to the following condition:

As regards occupational safety measures, it is suggested that suitable PPE should be worn.

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3.3 Elements to be taken into account by Member States when authorising products

• Products containing Didecylmethylpoly(oxyethyl)ammonium Propionate, may be used in hard surface and instrument disinfection and chemical toilet disinfection by professional and non professional users.

• Human health and environmental risk assessment has been performed on the knowledge that the employed solutions have a concentration of 0.5%, 0.08% and 0.07% for hard surface disinfectant, instrument disinfectant and chemical toilet disinfectant, respectively. The concentrated solution (15% a.s.) is only handled by professionals during the mixing and loading phase under controlled working conditions.

• The need of use Didecylmethylpoly(oxyethyl)ammonium Propionate in combination with other products to prevent resistance should be taken into account at products authorisation.

• When authorising the product use Member States Authorities should ensure that the following specific provisions and risk reduction measures described in Sections 3.2 and 3.5 are applied.

3.4. Requirement for further information

A specific analytical method for the identification / quantification of Didecylmethylpoly(oxyethyl)ammonium propionate and its impurities > 1g/kg in the active substance as manufactured is deemed necessary. Full validation in compliance with TNsG (chapter 2, 4.1) is required. A fully-validated analytical method for the identification/quantification of Didecylmethylpoly(oxyethyl)ammonium propionate in BP-15 should be also submitted. As for the determination of residues in air, a new justification for the non-submission of data or a fully-validated analytical method specific for Didecylmethylpoly(oxyethyl)ammonium propionate is deemed necessary, as required by TNsG. The Applicant is also required to fulfil RMS’s requests for clarification formulated under Sections 2 of Doc. IIIA and Doc. IIIB.

RMS believes that the nature of this request for additional data/information is such not to affect the inclusion of Didecyldimethylammonium chloride in Annex I.

3.5 Updating this Evaluation Report

This assessment report may need to be updated periodically in order to take account of scientific developments and results from the examination of any of the information referred to in Articles 7, 10.4 and 14 of Directive 98/8/EC. Such adaptations will be examined and finalised in connection with any amendment of the conditions for the inclusion of Didecylmethylpoly(oxyethyl)ammonium Propionate in Annex I to the Directive.

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APPENDIX I: List of endpoints

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

Labelling

Active substance (ISO Common Name) Not available.

No EINECS/ELINCS name is available for Didecylmethylpoly(oxyethyl)ammonium propionate, either

Function (e.g. fungicide) Disinfectant

Identity (Annex IIA, point II.)

Chemical name (IUPAC) alpha.-[2-(Didecylmethylammonio)ethyl]-.omega.-hydroxy-poly(oxy-1,2-ethanediyl) propionate

Chemical name (CA) Poly(oxy-1,2-ethanediyl), .alpha.-[2-(didecylmethylammonio)ethyl]-.omega.-hydroxy-, propanoate

CAS No 94667-33-1

EC No None assigned

Other substance No. These data are confidential

Minimum purity of the active substance as manufactured (g/kg or g/l)

900 – 990 g/kg

Identity of relevant impurities and additives (substances of concern) in the active substance as manufactured (g/kg)

None

Molecular formula C26H55NO3(C2H4O)n where n = 0−3

Molecular mass 437.777 g/mol (average value on the basis of the distribution presented in the table below) MWs used: C=12.011; H=1.00794; N=14.0067; O=15.999

No. of oxyethyl

moieties (1) MW Relative %

distribution MW individual

Monomer (1) 429.726 0.84 360.970Dimer (2) 473.779 0.15 71.067

Trimer (3) 517.832 <0.01 5.178

Tetramer (4) 561.885 <0.001 0.562

MW TOTAL: 437.777

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Structural formula

n = 0-3

Physical and chemical properties (Annex IIA, point III., unless otherwise indicated)

Freezing point (state purity) No freezing point down to −50 °C (93.5% w/w)

Boiling point (state purity) 180 – 195 °C (93.5% w/w)

Temperature of decomposition None detected

Appearance (state purity) Yellow weakly aromatic liquid (93.5% w/w)

Relative density (state purity) D420 = 0.942 (93.5% w/w)

Surface tension 30.5 mN/m (1 g/L aqueous solution)

Vapour pressure (in Pa, state temperature) 1.8E−06 Pa at 20°C 4.0E−06 Pa at 25°C

Henry’s law constant (Pa m3 mol -1) 3.03E−11 Pa m3 mol-1 (monomer component) 4.72E−13 Pa m3 mol-1 (dimer component)

Solubility in water (g/l or mg/l, state temperature) Completely miscible in the pH-range from 5 to 9 at room temperature

Ethanediol: > 250 g/l at ca. 20 °C Solubility in organic solvents (in g/l or mg/l, state temperature) (Annex IIIA, point III.1)

Octanol: > 250g/l at ca. 20 °C

Stability in organic solvents used in biocidal products including relevant breakdown products (IIIA, point III.2)

Not required, since didecylmethylpoly(oxyethyl)ammonium propionate is not formulated in organic solvents other than the process solvents for biocidal products. The a.s. proved to be stable in process solvents for at least 2 years (based on storage stability of Bardap 26 and experience in use)

Partition coefficient (log POW) (state temperature) Not determined. EC methods A.8 are not applicable for surface-active substances. Assessment by KOWWIN is inaccurate (software database very limited for surfactants). log POW could be roughly obtained from solubility in pure n-octanol and water (log POW ≈ 0). However, this calculation is of no use with regard to environmental fate & behaviour and secondary poisoning risk (experimental BCF available).

Dissociation constant (not stated in Annex IIA or IIIA; additional data requirement from TNsG)

Not applicable. The a.s. is fully dissociated in water

UV/VIS absorption (max.) (if absorption > 290 nm state ε at wavelength)

No significant absorption

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Quantum yield of direct phototransformation in water at λ > 290 nm (point VII.7.6.2.2)

Negligible

Flammability Not flammable

Explosive properties Not explosive

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

with regard to physical/chemical data No classification with regard to toxicological data C- Corrosive

R 22; R 34; S1/2; S 26, S 28; S 36/37/39; S 45 with regard to fate and behaviour data No classification with regard to ecotoxicological data N- Dangerous for the environment

R 50-53; S 29; S 60; S 61 Specific concentration limits for the environmental classification

Cn ≥ 2.5 %: N; R50-53

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Chapter 2: Methods of Analysis

Analytical methods for the active substance

Technical active substance (principle of method) (Annex IIA, point 4.1)

Not available. RMS is waiting for the submission of a study report in progress specific for the active substance

Impurities in technical active substance (principle of method) (Annex IIA, point 4.1)

Not available

Analytical methods for residues

Soil (principle of method and LOQ) (Annex IIA, point 4.2)

Extraction with methanol:water (90:10, v/v) containing 0.01 M ammonium formate and 0.1% formic acid. LC-MS (m/z = 356.2 for the monomer). LOQ (total didecylmethylpoly(oxyethyl)ammonium propionate) = 0.01 mg/kg

Air (principle of method and LOQ) (Annex IIA, point 4.2)

Not available

Water (principle of method and LOQ) (Annex IIA, point 4.2)

Extraction by liquid-liquid partition with 0.01 M heptanesulfonic acid and dichloromethane. Concentration by rotary evaporation and reconstitution in 0.1 % formic acid in methanol. LC-MS (m/z = 356.2 for the monomer). LOQ (total didecylmethylpoly(oxyethyl)ammonium propionate) = 0.1 µg/l

Body fluids and tissues (principle of method and LOQ) (Annex IIA, point 4.2)

Not required. The a.s. is neither toxic nor highly toxic

Food/feed of plant origin (principle of method and LOQ for methods for monitoring purposes) (Annex IIIA, point IV.1)

Not required for PT2

Food/feed of animal origin (principle of method and LOQ for methods for monitoring purposes) (Annex IIIA, point IV.1)

Not required for PT2

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Chapter 3: Impact on Human Health

For some of the endpoints addressed in Impact on Human Health Section, tests have been conducted on the chemical and structural analog, Didecyldimethylammonium Chloride (DDAC). The justification for read across of Didecylmethylpoly(oxyethyl)ammonium Propionate with data of DDAC has been accepted.

Absorption, distribution, metabolism and excretion in mammals (Annex IIA, point 6.2)

Rate and extent of oral absorption: Based on data on DDAC, and on the highly ionic nature of the a.s., it is expected that its oral absorption is limited (around 10%) and that the majority (90%) of orally administered a.s. is excreted unabsorbed via the faeces.

Rate and extent of dermal absorption: Less than 0.1% of the applied chemical and structural analog 14C-14C-DDAC dose dissolved in water fully penetrated human skin in 24h. The total dermal absorption is evaluated around 10% when the substance is diluted in water.

Distribution: Following DDAC oral administration, tissue residues were less than 1%.

Potential for accumulation: None Metabolism Four major metabolites of DDAC were

identified, as the product of alkyl chain hydroxylation.

Rate and extent of excretion: Following DDAC oral administration in rats: 89 – 99% excreted in faeces, 2.5% excreted in urine.

Toxicologically significant metabolite None

Acute toxicity (Annex IIA, point 6.1)

Rat LD50 oral 662 mg/kg bw Rabbit LD50 dermal 3342 mg/kg bw (data on

Didecyldimethylammonium Chloride) Rat LC50 inhalation Study not conducted-not required Skin irritation Corrosive

NOAEC for 5 day-application =0.6% DDAC in 2 ml ;

NOAEC for 2week-application =0.3% DDAC

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in 2 ml Eye irritation Corrosive Skin sensitization (test method used and result) Buehler test – not sensitizing

Repeated dose toxicity (Annex IIA, point 6.3)

Species/ target / critical effect Any species/ g.i. mucosa/ irritation of g.i. mucosa/reduced body weight.

Lowest relevant oral NOAEL / LOAEL On BARDAP26: NOEL = 90 mg/kg/day (rat –90 days feeding study).

Based on data on DDAC for longer studies (1 year dog):

NOELfor local effects = 3 mg/kg bw/day

NOELfor systemic effects = 10 mg/kg bw/day Lowest relevant dermal NOAEL / LOAEL (Data on Didecyldimethylammonium Chloride)

Systemic NOAEL = 12 mg/kg bw

Local NOAEL=2 mg/kg bw/day (Rat 90 days) Lowest relevant inhalation NOAEL / LOAEL Study not conducted – not required

Genotoxicity (Annex IIA, point 6.6)

In-vitro:

In vitro gene mutation study in bacteria Ames test – negative (with and without metabolic activation)

Chromosomal aberration test – negative (with and without metabolic activation)

Mouse lymphona assay – negative(with and without metabolic activation)

In-vivo:

Cytogenetic assay - negative

Carcinogenicity (Annex IIA, point 6.4)

Species/type of tumour Rat/none, Mouse/none (Didecyldimethylammonium Chloride).

lowest dose with tumours Negative

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Reproductive toxicity (Annex IIA, point 6.8)

Species/ Reproduction target / critical effect Rat/ NOAEL/ none (Didecyldimethylammonium Chloride)

Lowest relevant reproductive NOAEL / LOAEL NOAEL parental = 750 ppm

NOAEL F1 offspring = 750 ppm

NOAEL F2 offspring = 750 ppm

Species/Developmental target / critical effect Rat/ NOAEL/ none (Didecyldimethylammonium Chloride)

Lowest relevant developmental NOAEL / LOAEL NOAEL maternal = 10 mg/kg bw

NOAEL teratogen > 20 mg/kg bw

Species/Developmental target / critical effect Rabbit/ NOAEL/ none (Didecyldimethylammonium Chloride)

Lowest relevant developmental NOAEL / LOAEL NOAEL maternal = 1mg/kg bw

NOAEL teratogen = > 10 mg/kg bw

Neurotoxicity / Delayed neurotoxicity (Annex IIIA, point VI.1)

Species/ target/critical effect Study not conducted- not required

Lowest relevant developmental NOAEL / LOAEL.

Other toxicological studies (Annex IIIA, VI/XI)

None required

Medical data (Annex IIA, point 6.9)

No specific effects have been noted.

Summary for local effects

Value Study Safety factor

ADI (if residues in food or feed)

Not applicable

Professional/ Non-Professional users

AEC (Acceptable Exposure Concentration)

0.017 mg/cm2 (read across from DDAC)

52 week oral study in dogs 3.2

Reference value for dermal absorption

Not applicable

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Drinking water limit Not applicable

ARfD (acute reference dose)

Not applicable

Acceptable exposure scenarios for local effects (including method of calculation)

Professional users AEC% = 0.0012- 22.5

Production of active substance: Not applicable

Formulation of biocidal product Not applicable

Secondary exposure Not applicable

Non-professional users AEC% = 1.2-8.2

Indirect exposure as a result of use MOE = 4300-7410

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Summary for systemic effects

Value Study Safety factor

ADI (if residues in food or feed)

Not applicable

Professional/ Non-Professional users

AEL (Acceptable Exposure Level)

0.1 mg/kg/day (read across from DDAC)

52 week oral study in dogs 100

Reference value for dermal absorption

9.41 % (rounded to 10%) In vitro on human skin

Drinking water limit 0.1 µg/L As set by EU drinking water Directive 98/83/EC

ARfD (acute reference dose)

Not applicable

Acceptable exposure scenarios for systemic effects (including method of calculation)

Professional users AEL% = 0.0067 - 27 (total)

MOE% =70.6 - 179104 (dermal)

MOE% = 909- 588235 (inhalation)

Production of active substance: Not applicable

Formulation of biocidal product Not applicable

Secondary exposure Not applicable

Non-professional users AEL% = 0.00362 - 8.9 (total)

MOE = 144 – 3.3 x 105 (dermal)

MOE = 16667 - 50000 (inhalation)

Indirect exposure as a result of use MOE dermal = 56- 57142

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

Hydrolysis of active substance and relevant metabolites (DT50) (state pH and temperature)

pH 4: >1 year at 25°C



Photolytic / photo-oxidative degradation of active substance and resulting relevant metabolites

c.a. 0% after 30 days (DDAC)

Readily biodegradable (yes/no) No (inherently biodegradable)

Biodegradation in seawater Study waived

Non-extractable residues No data available

Distribution in water / sediment systems (active substance)

No data available

Distribution in water / sediment systems (metabolites)

No data available

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

Mineralization (aerobic) No data available

Laboratory studies (range or median, with number of measurements, with regression coefficient)

No data available

Field studies (state location, range or median with number of measurements)

No data available

Anaerobic degradation No data available

Soil photolysis No data available

Non-extractable residues No data available

Relevant metabolites - name and/or code, % of applied a.s. (range and maximum)

No data available

Soil accumulation and plateau concentration No data available

Adsorption/desorption (Annex IIA, point XII.7.7; Annex IIIA, point XII.1.2)

Ka , Kd

Kaoc , Kdoc

pH dependence (yes / no) (if yes type of

dependence)

Kd (Koc) values for four soil types: (read across with DDAC) Sand: 1’095 (437’805) Sandy loam: 8’179 (908’757) Silty clay loam: 32’791 (1’599’564) Silt loam: 30’851 (1’469’081) Koc mean is 1103802

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Fate and behaviour in air (Annex IIIA, point VII.3, VII.5)

Direct photolysis in air Study waived

Quantum yield of direct photolysis

Photo-oxidative degradation in air Latitude: ............. Season: ................. DT50 ..............

Volatilization

Monitoring data, if available (Annex VI, para. 44)

Soil (indicate location and type of study) No data available

Surface water (indicate location and type of study) No data available

Ground water (indicate location and type of study) No data available

Air (indicate location and type of study) No data available

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Chapter 5: Effects on Non-target Species

Toxicity data for aquatic species (most sensitive species of each group) (Annex IIA, point 8.2, Annex IIIA, point 10.2) Species Time-scale Endpoint Toxicity

Fish Bluegill (Lepomis macrochirus)

96 h Mortality LC50 0.52 mg/l

Zebra fish (Brachydanio rerio) 34 d Growth NOEC 0.0322 mg/l (read across from DDAC data)

Invertebrates Daphnia magna 48 h Immobilisation EC50 0.07 mg/l Daphnia magna 21 d Reproduction NOEC 0.010 mg/l

(read across from DDAC data)

Chironomus tentans 28d Mortality and growth NOEC 530 mg/kg (read across from DDAC data)

Algae Scenedesmus subspicatus 72hours Biomass production

and growth rate ErC50 0.34 mg/l

Scenedesmus subspicatus 72hours Biomass production and growth rate

NOErC 0.044 mg/l

Microorganisms Activated sewage sludge 3 hr Respiration inhibition EC50 16.8 mg/l

Effects on earthworms or other soil non-target organisms

Acute toxicity to Eisenia foetida(Annex IIIA, point XIII.3.2)

LC50 4390 mg/kg dw, in artificial soil NOEC 2000 mg/kg dw, in artificial soil

Reproductive toxicity to …………………………(Annex IIIA, point XIII.3.2)

No data available.

Acute toxicity to plants (Annex Point IIA 7.5.1.3)

EC50 mustard 283 mg/kg dw (read across from DDAC data)

Effects on soil micro-organisms (Annex IIA, point 7.4)

Nitrogen mineralization EC50 > 1000 mg/kg dw (read across from DDAC data)

Carbon mineralization EC50 > 1000 mg/kg dw (read across from DDAC data)

Effects on terrestrial vertebrates

Dose-related reduction in body weight gain - NOEC 100 mg/kg food

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mammals (Annex Point IIA6.8.2) Acute toxicity to birds(Annex IIIA, point XIII.1.1)

Northern bobwhite quail LD50 = 226 mg a.s./kg bw

Dietary toxicity to birds(Annex IIIA, point XIII.1.2)

Northern bobwhite quail and mallard LC50 = >5620 mg/kg a.s. food (read across from DDAC data)

Reproductive toxicity to birds(Annex IIIA, point XIII.1.3)

Not available

Effects on honeybees (Annex IIIA, point XIII.3.1)

Acute oral toxicity Not required Acute contact toxicity Not required

Effects on other beneficial arthropods (Annex IIIA, point XIII.3.1)

Acute oral toxicity Not required Acute contact toxicity Not required Acute toxicity to …………………………………..

Not required

Bioconcentration (Annex IIA, point 7.5) Bioconcentration factor (BCF) Measured BCFfish whole body = 81 (read across from DDAC

data) BCFearthworm not available

Depuration time (DT50) (DT90)

7-14d for the whole body

Level of metabolites (%) in organisms accounting for > 10 % of residues

No data available

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Chapter 6: Other End Points

APPENDIX II: List of Intended Uses

Product type : PT2, disinfectants for preventive protection of private area and public health area medical equipment and food and feed area surfaces and equipment with preventive efficacy against bacteria and fungi for industrial and professional use only.

Claim of the participant : The field of application of DMPAP is disinfectants for preventive protection of private area and public health area medical equipment and food and feed area surfaces and equipment with preventive efficacy against bacteria and fungi for industrial and professional use only.

DMPAP is effective against Gram+ bacteria and enveloped viruses but has limited efficacy against non-enveloped viruses and bacterial spores. Reduced efficacy is shown against Gram- bacteria compared to Gram+ bacteria. Against fungi, there exists a selective activity spectrum.

The product is used at different concentrations for different PT use.

Target organisms:

Organisms to be controlled are bacteria and fungi in private area and public health area where BARDAP acts as a disinfectant for medical equipment with general preventive efficacy against bacteria and fungi.

The effect on target organisms is :killing

Concentrations:

The following concentrations have to be confirmed after that new , correct tests of efficacy have been provided

PT2.01: These data are confidential

PT2.04: These data are confidential

Such procedures are assumed to be conducted by trained professional only .

Categories of users: The active substance is used in private and public areas as a disinfectant . It is supposed to be used for medical equipment disinfection. Its use is

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Professional

General public

Type of application:

PT2: Typical use of the product involves the disinfection of objects or floors, walls and ceilings i.e. hard surfaces, soaking the equipment (already washed.),and the disinfection of chemical toilets by scrubbing, mopping, wiping and spraying .

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APPENDIX III: List of studies Data protection is claimed by the applicant in accordance with Article 12.1(c) (i) and (ii) of Council Directive 98/8/EC for all study reports marked “Y” in the “Data Protection Claimed” column of the table below. For studies marked Yes(i) data protection is claimed under Article 12.1(c) (i), for studies marked Yes(ii) data protection is claimed under Article 12.1(c) (ii). These claims are based on information from the applicant. It is assumed that the relevant studies are not already protected in any other Member State of the European Union under existing national rules relating to biocidal products. It was however not possible to confirm the accuracy of this information.

List of studies for Active Substance (Doc. IIIA)

4.1(1) Anonymus (1990): International Standard ISO 2871-2:1990 (E). Surface active agents – Detergents – Determination of cationic-active matter content – Part 2: Cationic-active matter of low molecular mass (between 200 and 500).

6.1.5 (1) Allen, D.J (1994). P4140: Buehler delayed contact hypersensitivity study in the guinea pig. SPL project no. 102/188. Safepharm Laboratories Limited, Derby, UK (unpublished).

7.1.1.2.1 (1) Barnes, S (2004) Report No. LZA/246. Huntingdon Life Sciences, Woolley Road, Alconbury, Huntingdon. (Unpublished)

3.11 (1) Bird, L. (2004). Didecylmethylpoly(oxymethyl)ammonium Propionate Bardap 26 AS Auto ignition temperature (liquids and gases) . Report No.: LZA266/042169 Huntingdon Life Sciences, Huntingdon. (unpublished)

3.4.1 (2) Boese, and Schoenberger,B. (2001)Investigation of Dodigen 3519 with 13C-NMR spectroscopy, Project number 01/7/23-2639, Clariant Gmbh, Werk Gendorf, Germany. (unpublished)

4.2c (1) Brewin, S. (2003). Didecylmethylpoly(oxymethyl)ammonium Propionate Validation of methodology for the determination of residues in drinking, ground and surface water. Report No.: LZA245/033612 Huntingdon Life Sciences, Huntingdon.(unpublished)

4.2a (1) Brewin, S. (2003). Didecylmethylpoly(oxymethyl)ammonium Propionate Validation of methodology for the determination of residues in soil. Report No.: LZA244/033605 Huntingdon Life Sciences, Huntingdon. (unpublished)

7.1.2.1.1 (1) Bücking, H.W. and Ziemer, M. (1989) Evaluation of biodegradability of Bardap 26 (Disinfectant QAV) in the OECD-Confirmatory-Test Project No. 417/89 (B). Hoechst AG, Frankfurt (Unpublished).

7.1.1.2.1 (2) Clarke, N. (2001) Bardap 26 (LZ1524.1): Assessment of ready biodegradability; CO2 evolution test. SPL Project No. 102/381. Safepharm Laboratories Ltd, Derby, U.K. (unpublished)

7.4.1.4 (1) Clarke, N. (2001) Bardap 26(LZ1524.1): Assessment of the inhibitory effect on the respiration of activated sewage sludge SPL Project No. 102/382 SafePharm Laboratories, Derby, U.K. (unpublished)

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7.1.1.1.1 (1) Cuthbert, J. and Mullee, D. (2001) Determination of abiotic degradation, hydrolysis as a function of pH. SPL Project No. 102/383. Safepharm Laboratories Limited, Derby, UK (unpublished)

7.2.3.1 (1) Daly, D. (1989) Soil/Sediment Adsorption-Desorption of 14C-Didecyldimethylammonium Chloride (DDAC). Report No. 37009. ABC Laboratories, Inc., Columbia, MO, USA (Unpublished).

7.4.1.1 (2) Drottar K.R., Van Hoven R.L., Krueger H.O. (2001). A 96 hour flow-through acute toxicity test with the bluegill (Lepomis macrochirus). Wildlife International Ltd. Report No. 289A-154 (unpublished).

6.6.4 (1) Durward, R. (1994). P4140: Chromosome aberration teset in rat bone marrow in vivo. SPL project no. 102/187. Safepharm Laboratories Ltd., Derby, UK. (unpublished)

7.1.1.1.2 (2) Dykes, J. and M. Fennessey. (1989) Determination of the Photolysis Rate of Didecyldimethylammonium Chloride (DDAC) in pH 7 Buffered Solution at 25 °C. Report No. 37005. ABC Laboratories Inc., Columbia, MO, USA (Unpublished).

7.4.3.5.1 (1) England, D.C. and T. Leak (1995). Chronic Toxicity of Sediment-Incorporated Didecyldimethylammonium Chloride (DDAC)to Chironomus tentans. Final report No. 41005. ABC Laboratories, Columbia, MO, USA (unpublished).

7.4.3.3.1 (1) Fackler, P.H. (1990) Bioconcentration and Elimination of 14C-residues by Bluegill (Lepomis machrochirus) Exposed to Didecyldimethylammonium Chloride (DDAC). Report no. 89-7-3043. Springborn Laboratories, Inc., Wareham MA, USA (unpublished).

3.2 (1) Franke, J. (2002) Vapour Pressure Dodigen 3519 AS (Bardap 26 AS) Report No. 20010180.01. Sicherheitstechnik, Siemens Axiva, Frankfurt, Germany. (unpublished)

7.5.3.1.1 (1) Gallagher, S. and Grimes, J. and Beaver, J. (2001) Bardap 26: An acute oral toxicity study with thr northern bobwhite. Project No. 289-115 Wildlife International, Maryland, USA (unpublished)

6.4.2 Gill, M.W. and Van Miller. J.P. (1988). Ninety-day subchronic dermal toxicity study with Didecyldimethylammonium Chloride in rats. Project No: 51-554. Union Carbide, Bushy Run Research Center, R.D. 4, Mellon Road, Export, PA 15632 USA. (Unpublished)

6.5 (2) 6.7 (2)

Gill, M.W., J.S. Chun, and C.L. Wagner. (1991). Chronic dietary toxicity/oncogenicity study with Didecyldimethylammonium Chloride in rats. Report No. 53-566. Union Carbide, Bushy Run Research Center, Export, PA, U.S.A. (Unpublished)

6.7 (1) Gill, M.W., S.J. Hermansky, and C.L. Wagner. (1991). Chronic dietary oncogenicity study with Didecyldimethylammonium Chloride in mice. Report No: 53-528. Union Carbide, Bushy Run Research Center, Export, PA, U.S.A. (Unpublished)

7.5.1.3 (1) Gray, J. (2004) N,N-Didecyl-N,N-Dimethylammonium Chloride (DDAC) - Acute Toxicity to Terrestrial Plants. Huntingdon Life Sciences Report No. DKG/014 (unpublished).

7.5.1.1 (1) H.Q.M., DeVette, R. Hanstveit and J.A. Schoonmade. (2001) The assessment of the ecological effects of Didecyldimethylammonium Chloride (Guidelines OPPTS 850.5100 Soil Microbial Community Test, OECD 216 and OECD 217 and CTB section H.4.1). Study No.: IMW-99-9048-05. TNO Chemistry, Delft, The Netherlands (unpublished).

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6.1.4 (3) Hofmann, T. and Hollander, H. (1985). Hoe S 3519: Prüfung aug Augenreizung am Kaninchen. Report no. 85.1000. Hoechst Pharma Forschung Toxikologie, Frankfurt am Main, Germany (unpublished).

6.1.4 (2) Hofmann, Th. and Weigand, T. (1985). Hoe S 3519: Prűfung auf Hautreizung am Kaninchen. Report no. 85.1001. Hoechst Pharma Forschung Toxikologie, Frankfurt am Main, Germany. (unpublished).

7.4.3.4 (1) Hooftman, R.N. and H.Q.M. de Vette. (2001) Intermittent Flow Through Reproduction Test with Didecyldimethylammonium Chloride and Daphnia magna. TNO Report V99.1171. TNO Nutrition and Food Research, Department of Environmental Toxicology, The Netherlands (unpublished).

7.4.3.2 (1) Hooftman, R.N., H.Q.M. de Vette and B.Borst (2001). Early Life Stage Test under intermittent flow-thorugh conditions with Didecyldimethylammonium Chloride and the fish species, Brachydanio rerio (OECD Guideline No. 210). Report No. 99-9048-03. TNO Chemistry, Delft, The Netherlands (unpublished).

4.1 (2) Howes, D. (2004) N,N-Didecyl-N-methyl-poly(oxyethyl)ammonium Propionate – Screening by Ion Chromatography. Report No.: LZA/243. Huntingdon Life Sciences Ltd. (Unpublished)

5.3.1 Hueck, H.J.; Adema, D.M.M.; Wiegmann, J.R. (1966). Bacteriostatic, Fungistatic and Algistatic Activity of Fatty Nitrogen Compounds. Appl. Microbiol., 14(3), 308 -319 [Ref. No. A104a]

6.6.1 (1) Jung, R. and Weigand, W. (1986) Hoe S3519 Study of the mutagentic potential in strains of Salmonella typimurium (Ames test) and E.coli. Hoechst, Pharma Research Toxicology (unpublished)

3.8 Lichtenberg, F. (2000): Stability of Bardap 26 at 20°C, Lot No.1063366850. Lonza AG, Basel, Switzerland. Lonza Report No. 4027 (unpublished)

5.3.1 Linfield, W.M. (1970). Straight-Chain Alkylammonium Compounds. In "Cationic Surfactants" ed. J. Jungermann. Surfactants Science Series, Chapter 2, Marcel Dekker Inc., New York, pp. 9 – 70.

7.5.3.1.2 (1) Long, R.D., K.A. Hoxter, and G.J. Smith. (1991) Didecyldimethylammonium Chloride: A Dietary LC50 Study with the Northern Bobwhite. Report (No. 289-101). Wildlife International Ltd., Easton, MD, USA (unpublished). Lonza report No. 1785

7.5.3.1.2(2) Long, R.D., K.A. Hoxter, and G.J. Smith. (1991) Didecyldimethylammonium Chloride: A Dietary LC50 Study with the Mallard. Report (No. 289-102). Wildlife International Ltd., Easton, MD, USA (unpublished). Lonza Report No. 1783

5.7.1 McBain, A.J. (2004). Effects of quaternary-ammonium-based formulations on bacterial community dynamics and antimicrobial susceptibility. Appl. Eviron. Microbiol, 70(6), 3449-3456.

7.4.1.3 (1) Mead, C.and Mullee, D.M. (2001) Bardap 26: Algal Inhibition test. SPL Project No. 102/380 SafePharm Laboratories, Derby, U.K. (unpublished)

6.1.1 (1) Merkel, D. (2001) Acute oral toxicity test with Bardap 26. Lab Project identification number 10502. Product Safety Labs, Dayton, USA. (unpublished)

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6.1.4 (1) Merkel, D.J. (2001). Primary skin irritation test with Bardap 26. PSL project no: 10503. Product Safety Labs., New Jersey, USA (unpublished).

6.8.2 (1) Neeper-Bradley, T. L. (1991). Two-generation reproduction study in Sprague-Dawley (CD) rats with Didecyldimethylammonium Chloride administered in the diet. Report No. 52-648. Union Carbide, Bushy Run Research Center, Export, PA, U.S.A. (Unpublished)

6.8.1 (1) Neeper-Bradley, T.L. (1991). Developmental toxicity evaluation of Didecyldimethylammonium Chloride administered by gavage to CDÒ (Sprague-Dawley) rats. Project No: 53-534. Union Carbide, Bushy Run Research Center, Mellon Road, Export, PA 15632, USA. (Unpublished)

6.4.1 (2) Osheroff, M.R. (1990). Subchronic oral toxicity study of Didecyldimethylammonium Chloride in dogs. Study No. 2545-100. Hazelton Laboratories America, Inc., 9200 Leesburg Turnpike, Vienna, VA 22182, USA. (Unpublished)

3.2.1 Poncipe, C. (2006): Bardap 26. QSAR Estimation of Henry’s Law Constant. Safepharm Laboratories Ltd., Shardlow, England. Lonza Report No. 4013 (unpublished)

7.5.1.2 (1) Rodgers, M. (2003). Didecylmethylpoly(oxymethyl)ammonium Propionate (Bardap 26) Acute Toxicity (LC50) to the Earthworm. Report No.: LZA251/033986 Huntingdon Life Sciences, Huntingdon. (unpublished)

7.5.1.2 (2) Rodgers, M. 2003. Didecylmethylpoly(oxymethyl)ammonium Propionate (Bardap 26) Acute Toxicity (LC50) to the Earthworm. Report No.: LZA247/033913 Huntingdon Life Sciences, Huntingdon. (unpublished)

6.2 (1) Roper, C. S. (2001). The In Vitro Percutaneous Absorption of [14C]-Didecyldimethylammonium Chloride (DDAC) Through Human Skin. Report No. 19128. Inveresk Research. (Unpublished)

7.1.2.1.1 (2) Schaefer, E.C. (2001) Didecyldimethylammonium Chloride (DDAC): Dieaway in Activated Sludge. Project No. 289E-112. Wildlife International, Inc., Easton, MA, USA (Unpublished).

3.1.2 (1) Schneider,S.(2002) Determination of the Boiling Temperature of Bardap 26 AS/Dodigen 3519 AS. Report No. B 011/2002. AllessaChemie GmbH, Frankfurt. (unpublished)

3.1.1 (1) Schneider,S.(2002) Determination of the Freezing Temperature of Bardap 26 AS/Dodigen 3519 AS. Report No. B 010/2002. AllessaChemie GmbH, Frankfurt. (unpublished)

3.1.3 (1) Schneider,S.(2002) Determination of the Relative Density of Bardap 26 AS/Dodigen 3519 AS. Report No. B 012/2002. AllessaChemie GmbH, Frankfurt. (unpublished)

3.5 (1) Schneider,S.(2002) Determination of the Water Solubility of Bardap 26 AS/Dodigen 3519 AS. Report No. B 013/2002. AllessaChemie GmbH, Frankfurt. (unpublished)

6.5 (1) Schulze, G.E. (1991). Chronic oral toxicity study of Didecyldimethylammonium Chloride in dogs. Study No. 2545-102. Hazelton Washington, Inc., 9200 Leesburg Turnpike, Vienna, VA 22182, USA. HWA. (Unpublished)

6.2 (2) Selim, S. (1989). Absorption, Distribution, Metabolism and Excretion Studies of Didecyldimethylammonium Chloride (DDAC) in the Rat. Study No. P01421. Biological Test Center, Irvine, CA, USA. (Unpublished)

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6.1.2 (1) Siglin, J.C. (1987). Acute Dermal Toxicity Study in Rabbits LD50 Test (EPA), Test article DMD10AC. Study No. 3165.1.2C, Springborn Institute for Bioresearch, Inc., Spencerville, OH, USA. (Unpublished)

3.4.1 (1) Sloan, R. (2001) Bardap 26-Spectral data for biocidal products directive.Project No. HPT-038. Lonza Group (unpublished)

3.13(1) 3.14(2)

Sydney, P. (2006): Bardap 26 AS. Physicochemical Properties. Report No. LZA0269/062503. Huntingdon Life Sciences Ltd., Huntingdon, England. Lonza Report No. 4018 (unpublished)

6.4.1 (1) Thomas, O.N., Mullee, D.M. and Brooks, P.N. (1999). SPL project no. 102/274. Safepharm Laboratories Ltd., Derby, UK. (unpublished).

6.8.1 (2) Tyl, R.W. (1989). Developmental toxicity study of Didecyldimethylammonium Chloride administered by gavage to New Zealand white rabbits. Project No: 51-590. Union Carbide, Bushy Run Research Center, Mellon Road, Export, PA 15632, USA. (Unpublished)

7.1.1.2.2 (1) 7.4.1.4 (2)

Voelskov. (1996). Untersuchung auf Bakterienschädlichkeit Sauerstoff - Zehrungs - Hemmtest. Hoechst. Report No. V89-0273-unpublished).

7.4.1.1 (1) Wetton P.M., Mullee D.M. (2001). Acute toxicity to common carp Cyprinus carpio. SafePharm Laboratories. Report No. 102/370 (unpublished).

7.4.1.2 (1) Wetton, P.M., Mullee, D.M. (2001) Bardap 26: Acute toxicity to Daphnia Magna. SPL Project No. 102/371 SafePharm Laboratories, Derby, U.K. (unpublished)

6.6.3 (2) Wright, N.P. (2001). Bardap 26 (LZ1524.1): L5178Y TK+/- mouse lymphoma assay. SPL project no. 102/392. Safepharm Laboratories Ltd., Derby, UK. (unpublished)

6.6.2 (1) Wright, N.P. (2002). Bardap 26 (LZ1524.1): Chromosome aberration test in human lymphocytes in vitro. SPl project no. 102/391. Safepharm Laboratories Ltd., Derby, UK. (unpublished)

3.12 (1) Young, S. (2003). Didecylmethylpoly(oxyethyl)ammonium Propionate (Bardap 26 AS) Flash Point. Report No.: LZA249/033839. Huntingdon Life Sciences, Huntingdon (unpublished)

3.7 (1) Young, S. (2003). Didecylmethylpoly(oxyethyl)ammonium propionate (Bardap 26 AS) Solubility in Ethanediol and Octanol. Report No.: LZA248/033929 Huntingdon Life Sciences Ltd. Huntingdon, (unpublished)

3.14 (1) Young, S. (2004). Didecylmethylpoly(oxyethyl)ammonium Propionate (Bardap 26 AS) Viscosity. Report No.: LZA250/033939 Huntingdon Life Sciences, Huntingdon.(unpublished)

List of studies for Biocidal Product (Doc. IIIB)

Section No Reference

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3.2 (1) Warncke, U. (2004) Explosive properties of SPU-01840-F-0-SL. Document No.: Wa-030204-01840. Spiess-Urania Chemicals GmbH, Versuchsstation, Christinenthal, Germany, (unpublished). Lonza Report No. 3853

3.4 (1) 3.5 (1) 3.6 (1) 3.7 (1) 3.10.1 (1) 3.10.2 (2)

Warncke, U. (2004) Determinations of physical-chemical properties of the test item SPU-01840-F-0-SL. Study code U04PCF01. Spiess-Urania Chemicals GmbH, Versuchsstation, Christinenthal, Germany, (unpublished). Lonza Report No. 3858

3.8(2) 3.10.2(1)

Warncke,U. (2005) Determination of the viscosity and the persistent foaming of the test item Korasit KS. Spiess-Urania Chemicals GmbH, Versuchsstation Christinenthal, Germany (unpublished). Lonza Report No. 3968

5.10.2 Dell’Era, S. (2009) Fungicidal efficacy of Bardap 26 in formulations according to EN 1650 Lonza AG, Application Technology Laboratory, Basel, Switzerland .Report No. PN 09-36/6. [LON 4418] 9

Dell’Era, S. (2009) Bactericidal efficacy of Bardap 26 in formulations according to EN 1276. Lonza AG, Application Technology Laboratory, Basel, Switzerland. Report No. PN 09-36/5. [LON 4417]

Grinda, M.; Rudolph, D. 1994 : Efficacy test report according EN 113. BAM 81-6324 Ba. Lonza Report No. 3903

Grinda, M.; Heidrich, G. 2003 : Efficacy test report on fungus cellar testing. BAM IV.1/6771 A2. Lonza Report No. 3830

Hueck, H.J.; Adema, D.M.M.; Wiegmann, J.R. (1966). Bacteriostatic, Fungistatic and Algistatic Activity of Fatty Nitrogen Compounds. Appl. Microbiol., 14(3), 308 -319 [Ref. No. A104a]

Linfield, W.M. (1970). Straight-Chain Alkylammonium Compounds. In "Cationic Surfactants" ed. J. Jungermann. Surfactants Science Series, Chapter 2, Marcel Dekker Inc., New York, pp. 9 – 70.

Schumacher, P.; Fennert, E.M. 1995 : Efficacy test report according ENV 807. MPA 3.2/691/2. Lonza Report No. 3831

Schumacher, P.; Fennert, E.M. 1996 : Efficacy test report according EN 113. MPA 3.2/691/1. Lonza Report No. 3827

Schumacher, P.; Fennert, E.M. 1997 : Efficacy test report according EN 47. MPA 3.2/7107. Lonza Report No. 3832

5.11.2 McBain, A.J. (2004). Effects of quaternary-ammonium-based formulations on bacterial community dynamics and antimicrobial susceptibility. Appl. Eviron. Microbiol, 70(6), 3449-3456.

6.1.1 (1) Kuszewski, B. (1996). Acute Oral Toxicity Test of Korasit KS in Rats. medcon Kontraktlabor GmbH, Walsrode. Project No.: 10-04-0136/00-96. (unpublished). Lonza Report No. 3740

6.1.2 (1) Kuszewski, B. (1996) Acute Dermal Toxicity Test of Korasit KS in Rats. medcon Kontraktlabor GmbH, Walsrode. Project No.: 10-04-0135/00-96. (unpublished). Lonza Report No. 3739

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6.2 (1) Leuschner, P. J. (2003). Acute Skin Irritation Test (Patch Test) of SPU-01840-F-O-SL in Rabbits. Laboratory of Pharmacology and Toxicology KG, Hamburg. LPT Report No.: 16754/03 (unpublished). Lonza Report No. 3738

6.2 (2) Leuschner, J. (2003). Acute Eye Irritation Study of SPU-01840-F-O-SL by instillation into the conjunctival sac of Rabbits. Laboratory of Pharmacology and Toxicology KG, Hamburg. LPT Report No.: 16755/03 (unpublished). Lonza Report No. 3737

6.3 (1) Chevalier, F. (2003). Examination of SPU-01840-F-O-SL in the Skin Sensitisation Test in Guinea Pigs according to Magnusson and Kligman (Maximisation Test). Laboratory of Pharmacology and Toxicology KG, Hamburg. LPT Report No.: 16756/03 (unpublished). Lonza Report No. 3736

7.4 (1) Scheerbaum, D. (2004) Acute Toxicity of SPU-01840-F-0-SL to Fish. Dr. U. Noack- Laboratorium für Angewandte Biologie. Project No. 030505SU (unpublished). Lonza Report No. 3861

7.4 (2) Noack, U. (2004) Acute Toxicity of SPU-01840-F-0-SL to Daphnia magna. Dr. U. Noack- Laboratorium für Angewandte Biologie. Project No. 030505SU (unpublished). Lonza Report No. 3862

7.4 (3) Scheerbaum, D. (2004) Acute Toxicity of SPU-01840-F-0-SL to Algae. Dr. U. Noack- Laboratorium für Angewandte Biologie. Project No. 030505SU (unpublished). Lonza Report No. 3863