Alkyl (C ) dimethylbenzyl ammonium chloride Product-type 8 (Wood preservative)

Transcription

1 CA-Sept12-Doc.3.7a-rev1 Directive 98/8/EC concerning the placing biocidal products on the market Inclusion of active substances in Annex I to Directive 98/8/EC Assessment Report Alkyl (C ) dimethylbenzyl ammonium chloride Product-type 8 (Wood preservative) September 2012 Annex I Italy

2 Alkyl (C ) dimethylbenzyl (PT 8) Finalised in the Standing Committee on Biocidal Products at its meeting on 21 September 2012 in view of its inclusion in Annex I to Directive 98/8/EC CONTENTS 1. STATEMENT OF SUBJECT MATTER AND PURPOSE Procedure followed Purpose of the assessment report Overall conclusion in the context of Directive 98/8/EC OVERALL SUMMARY AND CONCLUSIONS Presentation of the Active Substance Identity, Physico-Chemical Properties & Methods of Analysis Intended Uses and Efficacy Classification and Labelling Summary of the Risk Assessment Human Health Risk Assessment Hazard identification Effects assessment Exposure assessment Risk characterization for local effects Environmental Risk Assessment Fate and distribution in the environment Effects assessment PBT assessment Exposure assessment Risk characterisation DECISION Background to the Proposed Decision Proposed Decision regarding Inclusion in Annex I Elements to be taken into account by Member States when authorising products

3 3.4. Requirement for further information Updating this Assessment Report APPENDIX I: LIST OF END POINTS Chapter 1: Identity, Physical and Chemical Properties, Details of Uses, Further Information, and Proposed Classification and Labelling Chapter 2: Methods of Analysis Chapter 3: Impact on Human Health Chapter 4: Fate and Behaviour in the Environment Chapter 5: Effects on Non-target Species Chapter 6: Other End Points APPENDIX II: LIST OF USES SUPPORTED BY AVAILABLE DATA APPENDIX III: LIST OF STUDIES

4 1. STATEMENT OF SUBJECT MATTER AND PURPOSE 1.1. Procedure followed This assessment report has been established as a result of the evaluation of Alkyl (C12-16) dimethylbenzyl as product-type 8 (wood preservative), carried out in the context of the work programme for the review of existing active substances provided for in Article 16(2) of Directive 98/8/EC concerning the placing of biocidal products on the market 1, with a view to the possible inclusion of this substance into Annex I or IA to the Directive. Alkyl (C12-16) dimethylbenzyl (CAS no ) was notified as an existing active substance, by Lonza Cologne GmbH, Stepan Europe, Mason Europe Limited, hereafter referred to as the applicant, in product-type 8. Commission Regulation (EC) No 2032/2003 of 4 November lays down the detailed rules for the evaluation of dossiers and for the decision-making process in order to include or not an existing active substance into Annex I or IA to the Directive. In accordance with the provisions of Article 5(2) of that Regulation, Italy was designated as Rapporteur Member State to carry out the assessment on the basis of the dossier submitted by the applicant. The deadline for submission of a complete dossier for Alkyl (C12-16) dimethylbenzyl as an active substance in Product Type 8 was 28 th March 2004, in accordance with Annex V of Regulation (EC) No 2032/2003. On 28 th March 2004, 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 28 th September On 27 th June 2005 the time period was suspended and the evaluation taken up again on 27 th March 2006 after the applicant has submitted the necessary data. After that, the evaluation phase was suspended again on the 17 th July 2006 and taken up on 18 th July On 31 st July 2007, the Rapporteur Member State submitted, in accordance with the provisions of Article 10(5) and (7) of Regulation (EC) No 2032/2003, to the Commission and the applicant a copy of the evaluation report, hereafter referred to as the competent authority report. The Commission made the report available to all Member States by electronic means on 19 th 1 Directive 98/8/EC of the European Parliament and of the Council of 16 February 1998 concerning the placing biocidal products on the market. OJ L 123, , p.1 2 Commission Regulation (EC) No 2032/2003 of 4 November 2003 on the second phase of the 10-year work programme referred to in Article 16(2) of Directive 98/8/EC of the European Parliament and of the Council concerning the placing of biocidal products on the market and amending Regulation (EC) No 1896/2000. OJ L 307, , p. 1 4

5 September The competent authority report included a recommendation for the inclusion of Alkyl (C12-16) dimethylbenzyl in Annex I to the Directive for PT 8. In accordance with Article 12 of Regulation (EC) No 2032/2003, the Commission made the competent authority report publicly available by electronic means on 10 th October This report did not include such information that was to be treated as confidential in accordance with Article 19 of Directive 98/8/EC. In order to review the competent authority report and the comments received on it, consultations of technical experts from all Member States (peer review) were organised by the Commission. Revisions agreed upon were presented at technical and competent authority meetings and the competent authority report was amended accordingly. On the basis of the final competent authority report, the Commission proposed the inclusion of Alkyl (C12-16) dimethylbenzyl in Annex I to Directive 98/8/EC and consulted the Standing Committee on Biocidal Product on 21 September In accordance with Article 11(4) of Regulation (EC) No 2032/2003, the present assessment report contains the conclusions of the Standing Committee on Biocidal Products, as finalised during its meeting held on 21 September Purpose of the assessment report This assessment report has been developed and finalised in support of the decision to include Alkyl (C12-16) dimethylbenzyl in Annex I to Directive 98/8/EC for producttype 8. The aim of the assessment report is to facilitate the authorisation in Member States of individual biocidal products in product-type 8 that contain Alkyl (C12-16) dimethylbenzyl. In their evaluation, Member States shall apply the provisions of Directive 98/8/EC, in particular the provisions of Article 5 as well as the common principles laid down in Annex VI. For the implementation of the common principles of Annex VI, the content and conclusions of this assessment report, which is available at the Commission website 3, shall be taken into account. However, where conclusions of this assessment report are based on data protected under the provisions of Directive 98/8/EC, such conclusions may not be used to the benefit of another applicant, unless access to these data has been granted Overall conclusion in the context of Directive 98/8/EC 3 5

6 The overall conclusion from the evaluation is that it may be expected that there are products containing Alkyl (C12-16) dimethylbenzyl for the product-type 8, which will fulfil the requirements laid down in Article 10(1) and (2) of Directive 98/8/EC. This conclusion is however subject to: i. compliance with the particular requirements in the following sections of this assessment report, ii. the implementation of the provisions of Article 5(1) of Directive 98/8/EC, and iii. the common principles laid down in Annex VI to Directive 98/8/EC. Furthermore, these conclusions were reached within the framework of the uses that were proposed and supported by the applicant (see Appendix II). Extension of the scenario beyond those described will require an evaluation at product authorisation level in order to establish whether the proposed extensions of use will satisfy the requirements of Article 5(1) and of the common principles laid down in Annex VI to Directive 98/8/EC. 6

7 2. OVERALL SUMMARY AND CONCLUSIONS 2.1. Presentation of the Active Substance Identity, Physico-Chemical Properties & Methods of Analysis Identification of the active substance CAS No EINECS No Other substance No.: None assigned IUPAC Name Not applicable Common name, synonyms Quaternary ammonium compounds, benzyl-c12-16-alkyldimethyl, chlorides; ADBAC Alkylbenzyldimethylammonium Chloride Alkyl(C12-16)dimethylbenzyls Ammonium, alkyl(c12-c16)dimethylbenzyl-, chlorides Benzyl-C12-C16-alkyldimethyl s Chemical name (CA) Quaternary ammonium compounds, benzyl-c12-16-alkyldimethyl, chlorides Molecular formula C 9 H 13 N Cl R where R = C 12 H 25, C 14 H 29 or C 16 H 33 Structural formula R N + Cl - Alkyl chain lengths distribution R = C 12 H 25 C 14 H 29 C 16 H 33 Chain Length Specification for ( ) Typical Analysis of a Commercial Product C % 41.82% C % 48.43% C16 < 12% 9.51% Molecular weight (g/mol) g/mol (Avg. = g/mol) Purity 94 99% w/w dry weight (*) Impurities See Confidential Data The active substance Alkyl (C12-16) dimethylbenzyl (C ADBAC) does not contain additives or impurities that would be of toxicological/environmental concern. ( ) In May 2011 the RMS agreed with the amendment proposed by the joint Notifiers as regards the alkyl chain lengths distribution of the active substance. This amendment, reflecting the complexity of the raw materials and processes used in their manufacture, can be considered as a negligible change, which does not affect the overall assessment of the active substance for both human and environmental health that has been conducted so far. 7

8 (*) The active substance is not manufactured solvent-free but always exists in process solvents. Identification of the representative product Trade name BQ-25 Manufacturers development code number Not assigned Active substance Quaternary ammonium compounds, benzyl-c12-16-alkyldimethyl, chlorides Content of the active substance 25% (a.s %) Function Fungistatic, insecticide Physical state of preparation Liquid Nature of preparation Solution The product does not contain substances of concern. Physico-chemical properties The active substance Alkyl (C12-16) dimethylbenzyl (C ADBAC) is a light beige solid which decomposes above 150 C before melting. Its relative density was determined to be 0.96 at 20 C. Its vapour pressure was calculated to be 6.03E-04 Pa at 20 C, 8.5E-04 at 25 C and 4.22E-03 at 50 C, with a Henry s Law constant of 5.03E-07 Pa m 3 mol 1 at 20 C. C ADBAC is highly soluble in water (water solubility at 20 C is 409 g/l at ph 5.5; 431 g/l at ph 6.5; 379 g/l at ph 8.2). Furthermore, it is readily soluble in Ethanol (>250 g/l at 20 C), Isopropanol (>250 g/l at 20 C) and Octanol (>250 m/l at 20 C). The partition coefficient n-octanol/water is not determinable since the active substance is a surfactant in the octanol/water system, thus preventing the use of the shake-flask method. The HPLC Method is not applicable either, due to the absence of suitable calibration compounds and to the fact that ionic compounds interact with the HPLC column by forces other than partitioning. Also the log Pow assessment by KOWWIN is deemed inaccurate, being the software database very limited for surface active substances. On the other hand, log Pow could be roughly obtained from solubility in n-octanol and water (Pow 1, log Pow 0). However, this result is of no use with regard to environmental fate and behaviour and secondary poisoning risk assessment, since there is an experimental BCF available. C ADBAC does not exhibit hazardous physico-chemical properties. The substance is thermally stable, is not classified as highly flammable and does not show explosive or oxidising properties. C ADBAC has a low vapour pressure and is highly soluble in water. There is no risk to be expected due to the physico-chemical properties of the product BQ-25, either. 8

9 Analytical methods Analysis of the active substance as manufactured The Applicant proposed a method in which the quaternary ammonium content was determined using a biphasic competitive titration between reagent water and chloroform with bromophenol blue indicator. The titrant, sodium tetraphenylborate (STPB), was standardized before being used to titrate triplicate 1:1:1 solutions of 5 mg/ml aqueous ADBAC Quat 80%, ph 10 phosphate buffer and chloroform containing indicator. Gas chromatography with flame ionization detection (GC-FID) was used to determine the distribution of the alkyl chain lengths of Alkyl Dimethyl Benzyl Ammonium Chloride. The test substance was diluted in isopropanol to yield solutions of 126 and 123 mg/ml which were injected (1μl) onto the GC. Following peak assignment relative to reference chromatograms, the alkyl chain lengths distribution was calculated assuming relative response coefficients of unity for duplicate analyses. The requirements stated in TNsG Chapter 2 Section 4.1 were not accomplished. No data concerning recovery rates, linearity, limit of determination, specificity and intra-laboratory repeatability were available. A suitable method was requested. An additional analytical method ( Kurz M. and Ranft V. (2007) Determination of quaternary ammonium compounds and related quaternary impurities by HPLC-ELSD, Section 4.1(2) Doc. IIIA) was submitted at the mid-july The method was not deemed acceptable, due to the deficiencies/mistakes affecting both the validation work and the original study report. Hence, the RMS required the full validation of the developed method for both C ADBAC and impurities > 0.1% w/w, in compliance with SANCO/3030/99 rev.4 11/07/00. Anyway, at the TMIV08 it was concluded that the HPLC-ELSD method could be considered acceptable for C ADBAC. It was also agreed that the Applicant should have provided further information on the analytical method and considered the possibility to use of an internal standard for quantitative analysis as suggested by AT. In 2011, a new study (Zehr, P.S. (2010), Methods Validation for the Preliminary Characterization Analyses of Alkyldimethyl[ethyl]benzyl Ammonium Biocides ) for the determination of the active substance C ADBAC, impurities and process solvents in commercially available technical concentrate Maquat MC % (nominal active substance content: 50% w/w) was submitted, superseding Doc. IIIA Sections 4.1(1) and (2). Results are now summarized in Section 4.1(3)(a) in Doc. IIIA and Section 4.1(3)(b)-(c) in the Confidential Data. Except for one impurity, valid analytical methods are available for impurities and process solvents in 50% w/w C ADBAC-based technical concentrate; additional information/clarification must be provided in any case (please refer to the RMS comments/requests in the evaluation box of the relevant study summaries). Following the submission of Zehr, P.S. (2010), in April 2011 an additional study addressing batch-analysis (Dung Truong, M.S. (2011), Batch analysis of Alkyl(C )dimethylbenzyl Ammonium Chlorides ) was presented. Only two batches per Notifier have been investigated, whereas the TNsG for on the assessment of technical equivalence of substances regulated under 98/8/EC require the analytical profile of at least five different representative batches of each source for the purpose of Tier I assessment. In conclusion, a new five-batch analysis for each 9

10 source of the active substance must be submitted to allow the assessment of the technical equivalence of the three joint Notifiers supporting C ADBAC and also to confirm the active substance specification under Sec. 2 Doc. IIIA. Data should be submitted to the RMS prior to product authorization phase at national level. Residues As regards the analysis of C ADBAC residues, LC-MS methods have been used in soil and water (drinking-, ground- and surface water) with a LOQ of 0.01 mg/kg and 0.1 μg/l as total C ADBAC, respectively. Only one mass fragment related to C 12 -ADBAC was used for the purpose of validation. During the evaluation of the Dossier in 2006, these methods were considered sufficiently specific, linear, accurate and precise by the RMS and were therefore accepted. At that time, the Addendum to TNsG on Data Requirements Analytical Methods (based on SANCO/825/00) had not been endorsed yet and the conclusion on the specificity of the methods had been drawn by the RMS on the following grounds: - no further fragmentation was likely to occur under the LC-MS experimental conditions adopted; - the chromatograms of untreated matrices showed no interferences; - the m/z of the ion monitored ([C 12 -ADBA] +, m/z = 304.3) was sufficiently high that in the RMS opinion LC-MS could be reasonably considered specific enough. On the contrary, the Addendum (adopted in May 2009) states that a confirmatory method is not necessary in case of a highly specific technique, which means the use of three fragment ions (possibly with m/z ratio >100) when MS detection is carried out. So, according to the Addendum, the available data (given for one LC-MS ion only) are not actually sufficient to prove the specificity of the submitted methods, which are necessary for post-authorization control and monitoring purposes. Furthermore, a bilateral discussion with DE occurred in 2010 on analogous LC-MS analytical methods for residues in soil and water for structurally-related quaternary ammonium compounds, with only one mass fragment (instead of three) validated. It was agreed that highly specific confirmatory methods for residues in soil and water were necessary and were to be submitted for the product authorization phase at national level. The same position (i.e. the request for additional validation data) has been recently agreed with DE-CA in the commenting step for the very same substance (CAS ) notified by another Applicant. In that case, LC/MS-MS analytical methods for residues in soil and water (both drinking- and surfacewater) were available, with only one mass transition (instead of two) validated. In conclusion, in line with the Addendum to TNsG on Data Requirements Analytical Methods and also for the sake of consistency with the approach adopted for structurally-related quaternary ammonium compounds and for the same active substance notified by another Applicant, additional highly-specific confirmatory methods for C ADBAC residues in soil and water (both drinking- and surface-water) are to be submitted at the product authorization phase at national level. No analytical method is required for the determination of residues in air, since the a.s. is nonvolatile and will not be used in spray application. 10

11 No analytical method is deemed necessary for the determination of residues in body fluids and tissues, being the a.s. neither toxic nor highly toxic. Wood treated with C ADBAC-containing biocidal product is not intended for and contains label restrictions against use in areas where food for human consumption is prepared, consumed or stored, or where the feedingstuff for livestock is prepared, consumed or stored. Therefore, no analytical method for the determination of residues in food/feed of plant/animal origin is required, either. 11

12 Intended Uses and Efficacy The active substance Alkyl (C12-16) dimethylbenzyl (C ADBAC) in Type 8 products acts as a fungistatic and an insecticide. It is used for preventive protection of wood and constructional timbers in Hazard Classes 1 to 4A according to ISO draft standard. Effectiveness C ADBAC is a cationic surfactant type active substance. Since it is surface active, it 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 membrane structures. Due to its interaction with phospholipid-bilayer-based structures, it severely alters the cell wall permeability, disturbs membrane-bound ion-translocation mechanisms and may facilitate the uptake of other biocides. The field of application of Alkyldimethylbenzylammonium Chloride includes wood preservatives for the preventive treatment against wood destroying organisms and against wood discolouring moulds and fungi. The use concentration depends on the type of application technique, use class required, and on additional formulation components. Quaternary amine (quat) biocides in the wood preservation market are always used in formulations in combination with other active substances. Efficacy studies with quats alone require considerably higher concentrations than those actually used in these formulations. Therefore, the use of quat only efficacy data for risk assessment may provide an exaggerated environmental exposure level. Against fungi, a selective activity spectrum exists. The biocidal product (BQ-25) contains 25% Quaternary ammonium compounds, benzyl-c12-16-alkyldimethyl, chlorides in water. It is used in drenching/dipping and vacuum pressure process applications. In practice it is always used in formulations in combination with other active substances. The biocidal product concentrate is diluted to a suitable working strength with water. The degree of dilution will vary depending on the wood species, type of wood product and anticipated use. The requirements for the final concentration of C ADBAC vary between 0.4% and 2.0%. The application rate of C ADBAC in wood is 2.0 kg/m 3. Number and timing of applications depends on application technique, wood species, moisture and hazard class. An uptake of approximately 2.0 kg/m 3 should be achieved by these application methods in order to ensure the protection level for the different use classes required. BQ-25 is used for preventive protection of wood and constructional timbers in areas with moderate or subtropical climate in Hazard Classes 1 to 4A according to ISO draft standard Since after approx. 40 years of use worldwide no reports of selective acquisition of C ADBA-resistance in the field of wood protection exists, the risk of development of resistance 12

13 to is considered negligible. On the other hand, C ADBAC as a wood preservative works by preventing growth of organisms, not by killing organisms that are present thus reducing the potential for resistant organisms to develop. In addition, for hard surface sanitization/disinfection (where antimicrobial activity is based on direct killing of organisms present on surfaces), investigations on exposure of domestic microbial communities to quaternary ammonium biocidal substances showed no increased antimicrobial resistance (McBain A.J. et al. 2004). Therefore, we can agree that development of resistance can be considered negligible. 13

14 Classification and Labelling The proposed Classification and labelling of active substance based on Directive 67/548/EEC Class of danger Xn R22 C R34 N R50 R phrases R22 Harmful if swallowed R34 Causes burns R50 Very toxic to aquatic organisms S phrases S26 In case of contact with eyes, rinse immediately with plenty of water and seek medical advise. S28 After contact with skin, wash immediately with plenty of. S36/37/39 Wear suitable protective clothing, gloves and eye/face protection S45 In case of accident or if you feel unwell, seek medical advice immediately (show label where possible) S60 This material and its container must be disposed of as hazardous waste S61 Avoid release to the environment. Refer to special instructions/safety data sets Specific Cn 0.25 %: N; R50 concentration limits for the environmental classification Justification for the proposal The substance is currently not classified according to Annex I of Council Directive 67/548/EC (with amendments and adaptations). On the basis of the results from studies presented in the dossier, classification of C ADBAC was proposed according to principles detailed in Annex VI of Council Directive 67/548/EEC (with amendments and adaptations). Related to N; R 50, LC50 is below 1 mg/l with proposal for specific concentration limits and the substance is readily biodegradable. 14

15 Proposed Classification and labelling of the active substance based on Regulation EC 1272/2008: Classification: Hazard Class and Category Hazard Codes Statement Labelling: GHS Pictogram Signal Word Hazard Statement Specific concentration limits for the aquatic hazard classification Acute toxicity (oral), Hazard Category 4 Skin Corrosion Hazard Category 1B_ Aquatic Acute 1_ H302 H314 H400 GHS05, GHS07, GHS09 Danger H302: Harmful if swallowed. H314: Causes severe skin burns and eye damage H400: Very toxic to aquatic life. M factor=100 As precautionary statements are not included in Annex VI of Regulation EC 1272/2008, no proposal is made. 15

16 2.2. Summary of the Risk Assessment Human Health Risk Assessment Hazard identification C ADBAC is not expected to be readily absorbed from the gastrointestinal tract or skin being a highly ionic compound. The oral absorption can be considered approximately 10% based on the 5-8% of the C ADBAC administered dose eliminated via urine and tissue residues (less than 1% of the administered dose seven days after single and repeated oral dosing). More than 90% is excreted in the faeces and the pattern did not change after repeated doses. 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. The C ADBAC dermal absorption determined in an in vitro study using human skin at two different concentrations (0.03% and 0.3%) of the active substance is 8.3%. The majority of C ADBAC metabolism is expected to be carried out by intestinal flora; the metabolites, which account for less than 60% of the administered dose, include hydroxyl and hydroxyketo derivatives of the dodecyl, tetradecyl and hexadecyl chains. There was no metabolite that accounted for more than 10% of the total dose administered. The oral LD 50 for Alkyl (C12-16) dimethylbenzyl is 344 mg/kg. No clinical signs or mortality were observed until a dosage or a concentration is attained that causes irritation of the gut mucosa or affects the gastrointestinal flora. Indeed, irritation and corrosivity are the major outcomes of toxicity related to C ADBAC. The rabbit acute dermal LD 50 of C ADBAC is 2848 mg/kg bw (at the application site clear signs of irritation and topic toxic effects were evident). Inhalation of C ADBAC is not considered a potential route of exposure based on scenarios and vapour pressure (< 1x10-3 Pa at 50ºC). C ADBAC is a severe skin and eye irritant, classified as Corrosive (R34, may cause burns) and on the basis of the available data is not a skin sensitizer. From a two-week skin irritation study in rats, it can be derived a NOAEL/NOAEC for short term skin irritation equal to 0.3% C ADBAC in water at 2.0 ml/kg body weight per day. 16

17 Effects assessment Similarly to acute effects, repeated C ADBAC intake in the diet results in effects up to death in rodents at concentrations affecting the gastrointestinal mucosa and resulting in dehydration and wasting or affects the gastrointestinal flora. Indeed, again irritation and corrosivity are the major outcomes of toxicity related to C ADBAC and no specific organ toxicity was evidenced. The subchronic oral toxicity NO(A)ELs were 85 mg/kg/day in mice, 31 mg/kg/day in rats and 13.1 mg/kg/day in dogs, mainly based on decrease in body weights, reduced food consumption and appearance of clinical signs related to the irritation and damages to the gut mucosa.. The changes in haematology and clinical biochemistry reported at high doses of treatment appear to be secondary to a reduced food intake and dehydration very likely leading to a reduced renal blood flow. The NOELs related to non neoplastic effects in chronic oral toxicity studies were 44 mg/kg/day for rats and 73 mg/kg/day for mice. It appears that subchronic and chronic NOAEL are in the same order of magnitude, in line with the fact that the main outcome directly derives from the irritative/corrosive properties of the substance. In a 90-day subchronic dermal study in rats, no systemic effects were seen at the highest dose that could be applied without excessive skin irritation (20 mg/kg/day). No systemic effects are anticipated after higher dermal or inhalation exposure. Indeed, due to its corrosive characteristics, C ADBAC will react locally and only a scant amount will become systemically available. C ADBAC displayed no genotoxic activity in the three mutagenicity tests required for the authorisation of Biocidal Products: Salmonella mutagenicity assay, chromosomal aberration assay in human lymphocytes in vitro and mutagenicity test in CHO/HPRT forward mutation assay. Moreover, no clastogenic activity in vivo was observed in a mouse micronucleus study. C ADBAC is not carcinogenic and does not affect reproduction or development at doses that are not toxic to the mother. No evidence of neurotoxicity was observed in any of the acute, subchronic or chronic studies, in line with the absence of any structural alert for neurotoxicity or similarity with any known neurotoxic agent. Medical data No medical reports on the manufacturing personnel have been submitted 17

18 Exposure assessment The biocidal product containing the active substance is used in two wood preservative treatment applications: dipping and vacuum pressure processes. For both processes, the preservative is delivered to the processing plant by tanker in the form of a concentrate. The concentrate contains 25% of the active substance Alkyl (C12-16) dimethylbenzyl ammonium chloride. It is diluted down to a suitable working strength with water. The degree of dilution varies depending on the wood species, type of wood product and anticipated use. Alkyldimethylbenzylammonium Chloride concentrations in both processes vary between 0.4% and 2%. Furthermore, the use classes 1 to 4A are envisaged for the Alkyl (C12-16) dimethylbenzyl containing wood preservative product. Due to the irritant/corrosive properties of C ADBAC, the systemic effects can be considered as secondary in comparison to the local ones. Nevertheless, a small amount of active substance becomes systematically available and gives rise to some non-significant systemic effects, such as decreasing of body weight. Therefore, both a systemic and a local exposure assessment have been connsidered so as to provide a comprehensive overview of the effects resulting from the use of C ADBAC. 18

19 LOCAL EXPOSURE ASSESSMENT C ADBAC exhibits irritant/corrosive properties which mainly affect the human exposure. In order to quantify the local exposure, the scenarios adopted have been selected from TNsG on Human Exposure and RISKOFDERM Model. In this context, it has not been taken into consideration any reduction factors from wearing clothes and/or Personal Protective Equipments; no dermal penetration has been considered, either. C ADBAC is a non-volatile active substance and therefore the inhalation uptake can be considered as negligible in assessing the exposure due to the local effects. Industrial/Professional users (primary exposure) In the local exposure assessment the dermal route is deemed to be the most relevant one for industrial/professional users handling both concentrated (Mixing and loading process) and diluted C ADBAC-based solutions (dipping and vacuum-pressure applications). The resulted exposure values are reported below. Information on assumptions and input values used in the relevant scenarios are provided in Doc. IIB. Table Summary of the exposure local dose for industrial/professional users EXPOSURE MODEL Hands exposure Body exposure Feet exposure mg/cm 2 mg/cm 2 mg/cm 2 MIXING&LOADING Riskofderm Connecting lines APPLICATION PHASE (Dipping treatment): Handling Model1 APPLICATION PHASE (Vacuum Pressure treatment): Handling Model

20 Secondary exposure: Child playing on weathered structure and mouthing ingestion (Local Exposure due to irritant effect) The local irritant effect of the C ADBAC deems to be more relevant in the case of the secondary exposure than the systemic effect. In particular, this is the case of the scenario in which has taking into account the exposure for child chewing wood. Therefore it has been drafted an exposure scenario considering that the maximum absorption of product is 2 mg/cm 3 (see above). The volume of the timber chips is 16 cm 3 (4 cm x 4 cm x 1 cm) as reported in the TNsG, Part 3, p. 50 and User Guidance, p. 52. The fraction extracted by chewing is 10% as reported in User Guidance, p. 52. The amount of saliva produced is 1.5 ml/min median value reported for stimulated saliva production ( A maximum absorption a.s mg/cm3 2 B size of chewed timber cut-off (chip) cm2 16 C depth of chewed timber cut-off (chip) cm 1 D = B x C volume of chip cm3 16 E a.s. extracted by chewing fraction 0.1 F = A x D x E a.s. in the mouth mg 3.2 G Amount of saliva produced ml/min 1.5 H Event duration min 1 The event duration has been conservatively assumed to be of 1 min. Any increase in duration time is associated with an higher production of saliva and consequently with an higher dilution. Anyhow this has to be considered a very worst case scenario, as the release of the 10% of the active substance in a very short time (i.e. 1 min) has to be considered unrealistic. The estimate of the concentration in the mouth has been derived with the above reported parameters revealing the following exposure calculation: Amount of active substance in the mouth: F = A x D x E = 3.2 mg Concentration in the mouth = F/(G x H) = 2.2 mg/ml = 2200 mg/kg Local dose expressed as percentage of active substance = 0.22 % 20

21 SYSTEMIC EXPOSURE ASSESSMENT Industrial/Professional exposure (Primary Exposure) There are four main strata of workers that may potentially be exposed to the wood preservative in the process plant: workers that handle wet treated lumber, workers that handle treated wood after drying, maintenance workers of equipment, forklift operators. Industrial/professional exposure from the use processes has been estimated using the scenarios reported in the Technical Notes for Guidance on Human Exposure to Biocidal Products. In a TIER 1 evaluation, representing a worst-case estimate, only the default values have been taken into account. As general assumptions, it was agreed that in the Tier 1 the estimate of the primary exposure has been carried without considering the use of the personal protective equipment (PPE) or a 100% clothing penetration with old gloves. A correction is applied for the maximum dermal absorption of 8%. As concerns the inhalation exposure, an agreed default value for inhalation uptake of 100% has been taken into account. Furthermore, the value of 1.25 m 3 /hour for the inhalation rate, due to moderate physical activity, has been used. Furthermore, as a worst case scenario, all calculations are based on the wood treatment solution employed containing 2% a.s. The neat concentrate of the substance (containing 25% a.s.) is only handled under closed conditions during the Mixing and loading process. The scenarios in TIER 1 predict potential exposure assuming that no PPE is employed. In reality due to the irritant/corrosive properties of the active substance, PPE will be worn, hence the estimates reported below have to be considered as overestimates. In TIER 2, refined values have been considered and the assessment has been conducted assuming use of personal protective equipment including protective clothing, gloves and footwear. The exposure calculations were performed according to the recommendations of the TNsG (Human Exposure to Biocidal Products, as revised by User Guidance version 1 (EC, 2002a). Model calculations have been undertaken using measured data given in the TNsG as revised in the user guidance and are considered to represent a reasonable scenario for risk assessment purposes. For vacuum/pressure treatment, dermal exposure has been assessed assuming clothing penetration of 10% (User Guidance version 1, p42), except for certain exposure scenarios (dipping and cleaning out dipping tank) where it is assumed that impermeable coveralls will be worn (penetration = 4%; TNsG - Part 3, p60). Also, to reduce exposure via the hands, operators would be required to wear new protective gloves at the start of each daily dipping session. New gloves reduce hand-in-glove exposure by a factor of 0.6 (TNsG, Part 2, p.192). The dermal penetration of C ADBAC used for this assessment is 8%, as discussed in Section 4.1 of document IIB. The duration of the tasks has been reviewed on the basis of more realistic values only for the dipping process and therefore, it has been considered an exposure period of 20 minutes for dermal exposure. 21

22 In TIER 2, for the Mixing and Loading process has been considered also the exposure scenario of RISKOFDERM Toolkit (Connecting lines). For automated transfer/pumping the Human Exposure Expert Group (HEEG) has concluded that in case of evaluated available data and models for the assessment of the exposure to operators during the loading of products into vessels or systems in industrial scale the exposure could be considered as negligible, with a very low or accidental exposure during connecting lines. Alternatively, the RISKOFDERM Connecting lines could be used. (Opinion presented and accepted at the March meeting (2008) in the Technical Meeting in the Biocides Group). Indicative dermal exposure values for RISKOFDERM Toolkit Connecting lines referred in the HEEG document are mg/cm 2 /h (0.92 mg/min) for hands. The model is a semi-quantitative model and assumes that small contaminations and no body exposure take place during the task. Being the Mixing and Loading an automated task, only the exposure assessment carried out by using RISKOFDERM should be taken into consideration for the purpose of Annex I inclusion. For both the Tiers, the default value for body weight of an exposed adult is assumed to be 60 kg in order to include women (50th Percentile = 60.3 kg according to ECETOC, 2001). 22

23 In the following tables the estimates calculated on the basis of the TNsG scenarios for Total Exposure to Alkyl (C12-16) dimethylbenzyl (C ADBAC) in Wood Preservation are reported. Table Exposure to Alkyl (C12-16) dimethylbenzyl (C ADBAC) in Wood Preservation (Tiers 1-2) Exposure scenario Dipping Mixing and loading concentrate (25% solution)(model 7)* Dermal Exposure (mg) Inhalation Exposure (mg) Tier 1 Tier 2 Tier 1 Tier 2 Total Exposure (mg) Tier 1 Tier 2 Total Systemic dose (mg/kg/d) Tier 1 Tier Dipping Mixing and loading concentrate (25% solution)(riskofderm toolkit) Automated Dipping Application (2% solution) Vacuum/pressure treatment (2% solution)(including feet exposure assessment) *This Model refers to a manual task. Being the mixing and loading for C ADBAC an automated task, only the RISKOFDERM model should be taken into account. 23

24 Non-professional exposure (Consumers) (Primary Exposure) Consumers are not involved in the application (wood treatment) stage. Consumer exposure is restricted to handling of treated lumber in operations such as erecting fences. Consumers are not involved in the application stage. The level of exposure is considered to be comparable to (or less than) occupation exposure to workers that handle treated wood after it is dry. Indirect exposure as a result of use of the active substance in biocidal product The secondary human exposure estimates consider the potential for the exposure of professional adults, infants and children in a number of possible scenarios in which they may come into contact with C ADBAC treated timber. The scenarios used in this assessment are described in the TNsG on Human Exposure to Biocidal Products Part 3, p50-51 as revised by User Guidance version 1 p50-54 (EC, 2002a). For non-professional exposure (consumers) the following scenarios have been considered: Acute phase reference scenarios Adult (professionals): sanding treated wood from vacuum/pressure impregnated timber - inhalation and dermal route. Adult (non-professionals): sanding treated wood from vacuum/pressure impregnated timber - inhalation and dermal route. Infant: chewing wood off-cut oral route (wood from vacuum/pressure impregnated timber) Child not relevant. Chronic phase reference scenarios Adult inhalation route not relevant Child playing on playground structure outdoors - dermal route. Infant playing on weathered structure and mouthing - dermal and ingestion. 24

25 In the following table are reported the systemic exposure values of total uptake for humans. Table Summary of the total systemic uptake for the secondary exposure. Acute Adult sanding Infant mouthing Chronic Adult sanding Child playing Infant playing Oral Dermal Inhalation Combined Non-professionals mg/kg/day mg/kg bw mg/kg/day 0.32mg/kg/day Professionals mg/kg/day mg/kg bw mg/kg/day Non-professionals mg/kg bw/day mg/kg/day mg/kg/day mg/kg day 25

26 Risk characterization Risk Characterisation for local effects Considering the repeated dose studies, the main critical effects associated with C ADBAC 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 C ADBAC. It can be concluded that C ADBAC actually does not cause true systemic effects and the derivation of a systemic AEL is not considered as relevant. As regards 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 (0.3% C ADBAC). However, based on the new guideline for the Risk characterisation of local effects, it was agreed (TMIII09) to include also a quantitative assessment for the secondary exposure scenario (child mouthing treated wood). Therefore, the AEC for dermal route was derived as follows. Local NOEC derivation - Dermal route The NOEL derived for the C ADBAC 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). 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 cm 2 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 40cm 2. For the characterization of the risk due to the local dermal effects a NO(A)EC (expressed in mg/cm 2 ) has to be derived following the formula below: NOAEC in mg / cm 2 = = Total dose applied in mg Treated surface in cm² ( average animal weight in kg) ( dose in mg / kg bw) 2 Treated surface in cm NOEC = (0.3kg x 6 mg/kg bw/day) / 40cm 2 = 0.045mg/cm 2 The NOEC value of mg/cm 2 is equivalent to a NOEC of 0.3%. 26

27 Selection of Assessment Factor for the dermal route (AF) 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 ), given that chemical reactivity is the principle concern. Therefore, for the intraspecies AF only the Toxicodynamic component ( ) could be taken into consideration. Therefore, for the dermal route the overall AF turns out to be AF: 3.2 = 1x, interspecies; 3.2x, human variability. AEC derivation Based on the NOEC and the AF derived, the calculated AEC for dermal route is mg/cm 2 (0.045 mg/cm 2 / 3.2) or 0.094% (0. 3% / 3.2). Local AEC derivation Oral route For the oral AEC derivation no toxicological study is available. 27

28 Exposure and risk from use of the product For industrial/professional users, the risk resulting from the direct use of biocidal products containing C ADBAC has been assessed by applying the AEC approach. Therefore, the dermal loads have been compared to the calculated dermal AEC of mg/cm 2. EXPOSURE MODEL Hands exposure mg/cm 2 AEC hands % Body exposure AEC body % mg/cm 2 Feet exposure mg/cm 2 AEC feet % MIXING&LOADING Riskofderm Connecting lines APPLICATION PHASE (Dipping treatment): Handling Model1 APPLICATION PHASE (Vacuum Pressure treatment): Handling Model AEC% = (Exposure x 100)/AEC Conclusion: for local effects, no unacceptable risk can occurs for industrial/professional users handling concentrate biocidal product during the mixing and loading phase. As regards, the application stage, no risk has been highlighted for body. On the other hand, an unacceptable risk can be envisaged for both hands and feet during the application phase. However, feet contamination can be reduced by prescribing that suitable impermeable boots are worn. In addition to that, the risk for hands can be lowered by using appropriate and suitable gloves. Furthermore, the gloves should be frequently replaced. However, for the risk assessment this discussion is not really relevant, since the formulation BC-25 contains 25% C ADBAC, and in practice solutions of 2.0% and 0.4% C ADBAC are used. Therefore, at 0.3% C ADBAC (6 mg/kg bw/day) clear local effects are not observed in the study. For C ADBAC the primary effects are the local effects, hence for the risk assessment of C ADBAC it is more relevant to take into account the concentration of the active substance on the skin than the dose expressed in mg/kg bw/day (systemic effects). Being the concentrations of the C ADBAC solutions applied are equal or higher than the (marginal) NOEL from the 2-week skin irritation study, for all intended uses listed in the CAR, personal protective equipments (PPEs) should be used to protect operators against the local effects of C ADBAC. The conclusion from the qualitative risk assessment due to the corrosive properties of C ADBAC is that PPE are per definition required when applying C ADBAC. 28

29 Exposure and risk from indirect exposure to the product As concerns the risks arising from the secondary exposure, the only scenario considered as relevant is child mouthing treated wood. The resulting local dose is 0.22% C ADBAC. Text revised following a German comment raised during the 60-day commenting period: (ADDED) Being the skin less sensitive than the mucosa membrane of the digestive tract, RMS agrees with Germany that the dermal 2-week study in rats is not fully representative of the oral local effects and therefore a route-to-route extrapolation without correction with an additional AF (although discussed and accepted during the TM) can lead to an underestimation of the AEC oral. Therefore, RMS agrees with the German proposal to include an use restriction for ADBAC-treated wood possibly entering into contact with children. In conclusion, not being fully addressed the risk arising from child sucking and mouthing treated wood, the scenario has not been assessed. Therefore, the use of ADBAC treated wood has to be restricted to applications where biocidal treatment is unavoidable (e.g., construction) but definitely excludes applications to treated wood composites which would otherwise come into contact with children. In order to overruled the use restriction at product authorization level an AEC oral should be derived by either using an oral toxicity study for the local effects or considering an additional assessment factors when the dermal 2-week study in rats is used. In this regards, an oral toxicity study for a structurally similar compound (i.e., DDAC) could be also submitted. This on the basis of the scientific acceptability of the read-across already discussed and agreed during at the Technical Meetings. If this is the case, differences in the molecular weight between the tested material and the active substance (ADBAC) should be taken into account in the derivation of the oral AEC (agreed at TM). The scenario estimated for the secondary exposure was agreed during the Technical Meetings when no specific guidelines were available on the risk characterization for the local effects. The assessment should not be considered as comprehensive of the overall exposure pathways. Thus, additional exposure scenarios covering any relevant exposure scenarios should be estimated at Product Authorization stage when the guidelines on the risk characterization for the local effects are finalized, depending on the use patterns. Therefore, based on the above discussion, it is considered inappropriate to use an AEL approach for C ADBAC and similar quaternary amines, because there is no true systemic toxicity. C ADBAC, and other quaternary amine biocides, do not exhibit systemic toxicity as based on changes to organs or effects on reproduction, development, mutagenicity, carcinogenicity, neurobehavior or other key toxicological endpoints. Rather, effects observed in toxicity studies occur only at irritant doses and general effects, including body weight changes at lower doses and death at high doses, are secondary to these irritant responses. 29