APPROVED: 22 July 2016 AMENDED: 24 November 2016

Transcription

1 REASNED PININ APPRVED: 22 July 2016 AMENDED: 24 November 2016 doi: /j.efsa Setting of maximum residue levels for amitraz, coumaphos, flumequine, oxytetracycline, permethrin and streptomycin in certain products of animal origin Abstract European Food Safety Authority (EFSA) Amitraz, coumaphos, flumequine, oxytetracycline, permethrin and streptomycin are substances used in veterinary medicinal products; in the past they were also used in the EU as active ingredients in plant protection products. Legal limits for residues in food resulting from the different types of uses are established in the pesticide legislation (Regulation (EC) No 396/2005) and under the legislation related to veterinary medicinal products (Regulation (EU) No 37/2010). The European Commission planned to align the pesticide legislation on MRLs with the veterinary MRLs. EFSA was requested to provide an opinion on potential consumer health risks related to the planned MRL harmonisation. Based on the risk assessment performed, EFSA concluded that for amitraz, permethrin, flumequine and streptomycin the expected consumer exposure via residues in food of animal origin will not exceed the toxicological reference values and therefore the MRLs set under Regulation (EU) No 37/2010 are unlikely to pose an unacceptable risk to consumers. As regards coumaphos, risk managers should consider additional risk management measures to ensure that the existing MRLs are sufficiently protective for consumers. EFSA did not recommend MRL proposals for oxytetracycline since a consumer health concern could not be excluded based on the information available for this assessment European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority. Keywords: pesticide residues, veterinary medicinal products, maximum residue levels (MRLs), consumer risk assessment Requestor: European Commission Question numbers: EFSA-Q , EFSA-Q to EFSA-Q Correspondence: pesticides.mrl@efsa.europa.eu EFSA Journal 2016;14(8):4570

2 Amendment: An editorial correction was carried out that does not materially affect the contents or outcome of this scientific output. To avoid confusion, the older version has been removed from the EFSA Journal, but is available on request, as is a version showing all the changes made. In the summary table on p. 6, the proposed MRL for streptomycin in sheep muscle was wrongly indicated as 1 and has been corrected to 0.5. The MRL of 0.5 was correctly reported in the document and was used to conduct the consumer risk assessment. Therefore this editorial correction does not affect the outcome of the risk assessment. Suggested citation: EFSA (European Food Safety Authority), Reasoned opinion on the setting of maximum residue levels for amitraz, coumaphos, flumequine, oxytetracycline, permethrin and streptomycin in certain products of animal origin. EFSA Journal 2016;14(8):4570, 39 pp. doi: / j.efsa ISSN: European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority. This is an open access article under the terms of the Creative Commons Attribution-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited and no modifications or adaptations are made. The EFSA Journal is a publication of the European Food Safety Authority, an agency of the European Union. 2 EFSA Journal 2016;14(8):4570

3 Summary Amitraz, coumaphos, flumequine, oxytetracycline, permethrin and streptomycin are substances used in veterinary medicinal products; in the past they were also used in the EU as active ingredients in plant protection products. Legal limits for residues in food resulting from the different types of uses are established in the pesticide legislation (Regulation (EC) No 396/2005) and under the legislation related to veterinary medicinal products (Regulation (EU) No 37/2010). In order to harmonise the maximum residue levels (MRLs) for these so-called dual use substances, the European Commission planned to take over the veterinary MRLs in the pesticide MRL legislation. In accordance with Article 43 of Regulation (EC) No 396/2005, the European Commission requested EFSA to provide an opinion on potential consumer health risks related to the planned MRL harmonisation. The assessment of EFSA should take into account the information provided in the summary reports of the European Medicines Agency (EMA) Committee for Medicinal Products for Veterinary Use (CVMP). Since the information in the CVMP summary reports was not sufficient to address the questions of the European Commission, additional sources of information were used. Based on the risk assessment performed for the six substances EFSA derived MRL proposals as reported in the summary table below: Code (a) Commodity Existing veterinary MRL (b) Existing pesticide MRL (c) Proposed MRL Comment/justification Existing enforcement residue definition in Regulation (EC) No 396/2005: Amitraz (amitraz including the metabolites containing the 2,4-dimethylaniline moiety, expressed as amitraz) Proposed enforcement residue definition for food products listed below (d) : Amitraz (amitraz including the metabolites containing the 2,4-dimethylaniline (DMA) moiety, expressed as amitraz) Swine Fat tissue Liver Kidney Bovine Fat tissue Liver Kidney Sheep Fat tissue Liver Kidney Goat Fat tissue Liver Kidney Milk Cattle Milk Sheep Milk Goat Honey and other apiculture products (e) 0.4 The existing residue definition does not have to be modified EFSA recommends taking over the MRLs set under Regulation (EU) No 37/2010 in the EU pesticide MRL legislation EFSA proposes to apply the veterinary MRL set for porcine fat including skin in natural proportions to swine fat No consumer health risk was identified for the products containing residues at the proposed MRLs 3 EFSA Journal 2016;14(8):4570

4 Code (a) Commodity Existing veterinary MRL (b) Existing pesticide MRL (c) Proposed MRL Comment/justification Existing enforcement residue definition in Regulation (EC) No 396/2005: Permethrin (sum of isomers) Proposed enforcement residue definition for food products listed below (d) : Permethrin (sum of isomers) (F) Bovine Fat tissue * Liver * Kidney * Milk Cattle * * 0.05 The existing residue definition does not have to be modified. The suffix (F) should be added Existing enforcement residue definition in Regulation (EC) No 396/2005 (f) Proposed enforcement residue definition for honey (d) : Coumaphos Honey and other apiculture products (g) 0.1 (see comments) Existing enforcement residue definition in Regulation (EC) No 396/2005 (f) Proposed enforcement residue definition for food products listed below (d) : Flumequine Swine Fat tissue 0.3 (e) Liver Kidney Bovine Fat tissue Liver Kidney Sheep Fat tissue Liver Kidney Goat Fat tissue Liver Kidney to the residue definition, indicating that there is a potential to accumulate in fat EFSA recommends taking over the existing MRLs set under Regulation (EU) No 37/2010 in the EU pesticide MRL legislation. No consumer health risk was identified for the products containing residues at the proposed MRLs The marker substance established in Regulation (EU) No 37/2010 is an appropriate residue definition for honey. No short-term consumer health risk was identified for honey containing residues of 0.1 mg/kg Honey was a minor contributor in the chronic exposure assessment (max. 4% of ADI). However, the overall long-term exposure calculated on the basis of the existing EU MRLs set for pesticides (default MRL of 0.01 mg/kg) exceeded the ADI. The veterinary MRL for honey may be taken over in the EU pesticide legislation, if additional risk management measures are taken as regards the existing MRLs (e.g. setting MRLs for plant or animal products, except honey, at a lower level than the default value of 0.01 mg/kg) (g) 0.2 The marker substance established in Regulation (EU) No 37/2010 is an appropriate residue definition for the food products assessed EFSA recommends taking over the MRLs set under Regulation (EU) No 37/2010 in the EU pesticide MRL legislation. EFSA proposes to apply the veterinary MRL set for porcine and poultry fat including skin in natural proportions to swine and poultry fat, respectively No consumer health risk was identified for the products containing residues at the proposed MRLs 4 EFSA Journal 2016;14(8):4570

5 Code (a) Commodity Existing veterinary MRL (b) Existing pesticide MRL (c) Proposed MRL Equine Fat tissue Liver Kidney Poultry Fat tissue 0.25 (e) Liver Kidney ther farmed terrestrial animals Comment/justification Fat tissue Liver Kidney Milk Cattle Milk Sheep Milk Goat Existing enforcement residue definition in Regulation (EC) No 396/2005 (f) Proposed enforcement residue definition for food products listed below (d) : xytetracycline (sum of oxytetracycline and its 4-epimer) Swine Liver Kidney Bovine Liver Kidney Sheep Liver Kidney Goat Liver Kidney Equine Liver Kidney Poultry Liver Kidney (g) No MRL proposed The marker substance established in Regulation (EU) No 37/2010 is an appropriate residue definition for the food products assessed The calculated short-term exposure for bovine milk containing residues at the veterinary MRL exceeded the toxicological reference value. For the remaining veterinary MRLs, no short-term consumer health risk was identified A consumer health concern could not be excluded in the long-term risk assessment, based on the information available for this assessment. For a more detailed assessment further information on the toxicological properties of the active substance and/or on the residue levels expected in food products from treated animal would be required 5 EFSA Journal 2016;14(8):4570

6 Code (a) Commodity ther farmed terrestrial animals Existing veterinary MRL (b) 0.1 Existing pesticide MRL (c) Proposed MRL Comment/justification Liver Kidney Milk Cattle Sheep Goat Horse thers Birds eggs 0.2 Chicken Duck Geese Quail thers 0.2 Existing enforcement residue definition in Regulation (EC) No 396/2005 (f) Proposed enforcement residue definition for food products listed below (d) : Streptomycin Swine Fat tissue 0.5 (e) Liver Kidney Bovine Fat tissue Liver Kidney Sheep Fat tissue Liver Kidney Goat Fat tissue Liver Kidney ther farmed terrestrial animals Fat tissue Liver Kidney Milk Cattle Milk Sheep Milk Goat (g) 0.5 The marker substance established in Regulation (EU) No 37/2010 is an appropriate residue definition for the food products assessed EFSA recommends taking over the MRLs set under Regulation (EU) No 37/2010 in the EU pesticide MRL legislation EFSA proposes to apply the veterinary MRL set for porcine fat including skin in natural proportions to swine fat The veterinary MRL set for rabbit tissues should be taken over for the corresponding food product in Regulation (EC) No 396/2005, i.e. for other farmed terrestrial animals No consumer health risk was identified for the products containing residues at the proposed MRLs 6 EFSA Journal 2016;14(8):4570

7 *: Indicates that the MRL is set at the limit of analytical quantification (LQ). (a): Commodity code number according to Annex I of Regulation (EC) No 396/2005. (b): Existing MRLs in Regulation No (EU) No 37/2010. (c): Existing MRLs in Regulation (EC) No 396/2005. (d): EFSA did not derive proposals of enforcement residue definition for plant products or other animal products not listed in the table due to lack of information and because the mandate was restricted to the assessment of the MRLs set under Regulation (EU) No 37/2010. (e): MRL applies to skin and fat (Regulation (EU) No 37/2010). (f): Since the pesticide is not explicitly mentioned in Annex II, III or IV of Regulation (EC) No 396/2005, in accordance with Article 18(1)(b) of the Regulation, the default MRL applies and no specific residue definition has been established for the active substance. (g): Default MRL value according to Article 18(1)(b) of Regulation (EC) No 396/2005. (F): Fat-soluble. 7 EFSA Journal 2016;14(8):4570

8 Table of contents Abstract... 1 Summary Introduction Background Terms of Reference Interpretation of the Terms of Reference Assessment Amitraz Legislative background pesticide use of amitraz Legislative background veterinary use of amitraz Toxicological properties of amitraz Nature and magnitude of residues in food of animal origin Consumer risk assessment Permethrin Legislative background pesticide use of permethrin Legislative background veterinary use of permethrin Toxicological properties of permethrin Nature and magnitude of residues in food of animal origin Consumer risk assessment Coumaphos Legislative background pesticide use of coumaphos Legislative background veterinary use of coumaphos Toxicological reference values derived for coumaphos Nature and magnitude of residues in food of animal origin Consumer risk assessment Flumequine Legislative background pesticide use of flumequine Legislative background veterinary use of flumequine Toxicological properties of flumequine Nature and magnitude of residues in food of animal origin Consumer risk assessment xytetracycline Legislative background pesticide use of oxytetracycline Legislative background veterinary use of oxytetracycline Toxicological properties of oxytetracycline Nature and magnitude of residues in food of animal origin Consumer risk assessment Streptomycin Legislative background pesticide use of streptomycin Legislative background veterinary use of streptomycin Toxicological properties of streptomycin Nature and magnitude of residues in food of animal origin Consumer risk assessment Conclusions and recommendations References Abbreviations Appendix A Used compound codes Appendix B List of the existing MRLs set for animal products EFSA Journal 2016;14(8):4570

9 1. Introduction 1.1. Background Amitraz, permethrin, coumaphos, flumequine, oxytetracycline and streptomycin are pharmacologically active substances used in veterinary medicine. Commission Regulation (EU) No 37/ sets maximum residue limits (MRLs) for those substances in certain products of animal origin. Even though those active substances are not approved for use in plant protection products in the European Union (EU) and the exposure of consumers to pesticide residues is not expected, it would be appropriate to align the MRLs in Regulation (EC) No 396/ to the levels as provided for in Regulation (EU) No 37/2010. In accordance with Article 14(1)(a) of Regulation (EC) No 396/2005, the draft measure setting those MRLs should be based on an opinion of EFSA. n 17 May 2016, the European Commission therefore sent a mandate to EFSA requesting a consumer risk assessment in relation to the MRLs set in Regulation (EU) No 37/2010 for amitraz, coumaphos, flumequine, oxytetracycline, permethrin and streptomycin in products of animal origin. For reasons of transparency and traceability, EFSA has created separate questions for each of the six active substances covered by the mandate in the EFSA Register of Questions with the following reference numbers and subjects: Question number EFSA-Q EFSA-Q EFSA-Q EFSA-Q EFSA-Q EFSA-Q Subject Setting of MRL for amitraz in certain products of animal origin Setting of MRL for coumafos in certain products of animal origin Setting of MRL for flumequine in certain products of animal origin Setting of MRL for oxytetracycline in certain products of animal origin Setting of MRL for permethrin in certain products of animal origin Setting of MRL for streptomycin in certain products of animal origin 1.2. Terms of Reference The European Commission requested EFSA to deliver a reasoned opinion according to Article 43 of Regulation (EU) No 396/2005 on the above-mentioned substances in products of animal origin, in particular whether the levels established under Regulation (EU) No 37/2010 are appropriate from a consumer point of view. The consumer assessment in relation to the MRLs set in Regulation (EU) No 37/2010 should be based on the information as outlined in the relevant reports of the Committee for Veterinary Medicinal Products (CVMP), which are published on the website of the European Medicines Agency (EMA, formerly known as European Medicines Evaluation Agency, EMEA). The agreed deadline for providing the reasoned opinion is 31 July Interpretation of the Terms of Reference The European Commission requested EFSA to assess whether the MRLs set in Regulation (EU) No 37/2010 are appropriate from a consumer health point of view. In order to address the question, EFSA took the following approach: The assessment in this reasoned opinion focussed on the food products for which MRLs are established under Regulation (EU) No 37/2010 for the six substances under discussion. As the descriptions of the food products under Regulation (EC) No 396/2005 and Regulation (EU) No 37/2010 are not fully comparable, the existing veterinary medicine MRLs (MRL-V) were translated to the closest matching food item in the food classification of Regulation (EC) No 396/2005 (Annex I); where relevant, discrepancies in the food products to which the MRLs apply were highlighted. 1 Commission Regulation (EU) No 37/2010 of 22 December 2009 on pharmacologically active substances and their classification regarding maximum residue limits in foodstuffs of animal origin. J L 15, , p Regulation (EC) No 396/2005 of the Parliament and of the Council of 23 February 2005 on maximum residue levels of pesticides in or on food and feed of plant and animal origin and amending Council Directive 91/414/EEC. J L 70, , p EFSA Journal 2016;14(8):4570

10 EFSA considered the marker residue defined in Regulation (EU) No 37/2010 as the most appropriate residue definition for the enforcement of those MRLs. For risk assessment the same residue definition (i.e. the marker residue) should be used, unless the information provided in the CVMP reports gives evidence that using the marker residue would be likely to underestimate the consumer risk. In the latter case, conversion factors were used to cover relevant metabolites that are expected to contribute to the dietary burden. The risk assessment (chronic and acute) was based on the MRLs established for the food products of animal origin subject to the assessment. This approach is in contrast to the current risk assessment methodology used for pesticide residues in food of animal origin where the median residue (STMR) or highest residue (HR) would normally be used instead of the MRL value. Using the legal limit in the dietary risk assessment would lead to a more conservative estimate of the exposure. In the chronic risk assessment, the existing EU MRLs set under Regulation (EC) No 396/2005 were used to estimate the exposure for plant products and animal products not covered by the current request. The risk assessment was performed with the methodology and the consumption data used in the framework of the pesticide risk assessment (EFSA Pesticide Residues Intake Model). Considering that in the EFSA PRIMo the consumer exposure is calculated for meat, the MRLs for muscle and fat were recalculated to meat assuming a fat content of 10% for poultry meat and 20% for meat of other animal species (FA, 2009b). The most appropriate toxicological reference values derived in the pesticide evaluation under the peer review or the reference values derived by CVMP were applied. In the framework of the assessment of veterinary medicinal products usually no ARfD values are derived. In case no appropriate ARfD could be retrieved from the evaluation under the pesticide legislation, the ADI value was used as a conservative surrogate ARfD value. If the acute and chronic exposure assessment performed as described above does not exceed the toxicological reference considered by EFSA as the most appropriate value in this risk assessment context, EFSA would conclude that the existing MRLs set in Regulation (EU) No 37/2010 do not pose a consumer health concern and can therefore be recommended to be taken over in Regulation (EC) No 396/2005. In case the exposure accounted for more than 100% of the toxicological reference value, EFSA provided further information on the reasons for the exceedance and propose risk management options. It is EFSA s understanding that the mandate does not request to: re-evaluate the scientific basis of the existing MRLs set under Regulation (EU) No 37/2010; assess the appropriateness of the marker residue defined in Regulation (EU) No 37/2010; derive proposals for residue definitions for products not covered by Regulation (EU) No 37/2010; derive MRL proposals for products not covered by Regulation (EU) No 37/2010; re-evaluate the toxicological reference values set for the six substances concerned; assess the availability and appropriateness of analytical methods for enforcement purpose. 2. Assessment EFSA based its assessment on the CVMP summary reports for amitraz (CVMP, 1996a,b, 1997, 1998b, 1999b, 2004), permethrin (CVMP, 1998a, 2000b, 2002c), coumaphos (CVMP, 1999a, 2001), flumequine (CVMP, 1998c, 1999c,d, 2002b), oxytetracycline (CVMP 1995b) and streptomycin (CVMP 1995a, 2000a, 2002a, 2006). In addition, the draft assessment reports (DAR) prepared under Directive 91/414/EEC 3 for amitraz (Austria, 1998, 2002) and permethrin (Ireland, 1998) as well as the Commission review reports for the active substance amitraz and permethrin (European Commission, 2000, 2003) were used as source of information for this assessment. Furthermore, the Joint Meeting on Pesticide Residues (JMPR) reports and FA specifications for the pesticide permethrin (FA, 1999, 2002, 2009a, 2010, 2015), the JMPR monograph on coumaphos (FA, 1969) and the Joint FA/WH 3 Council Directive 91/414/EEC of 15 July 1991 concerning the placing of plant protection products on the market. J L 230, , p EFSA Journal 2016;14(8):4570

11 Expert Committee on Food Additives (JECFA) monograph and evaluations on oxytetracycline (WH, 1990, 1999; FA, 1991). The consumer risk assessments for the six active substances were performed with revision 2 of the EFSA Pesticide Residues Intake Model (PRIMo). This exposure assessment model contains the relevant European food consumption data for different subgroups of the EU population (EFSA, 2007). The result of the intake calculation using the EFSA PRIMo is a key supporting document and it is made publicly available as a background document to this reasoned opinion. Considering the different profiles and legislative history, each individual active substance was assessed separately Amitraz Amitraz is the IS common name for N,N 0 -[(methylimino)dimethylidyne]di-2,4-xylidine (IUPAC). utside the EU amitraz is used in plant protection products as a contact insecticide and acaricide. In veterinary medicinal products amitraz is used against ectoparasites. The chemical structures of the active substance and its main metabolites are reported in Appendix A Legislative background pesticide use of amitraz Amitraz was evaluated in the framework of Directive 91/414/EEC with Austria designated as the rapporteur Member State (RMS). The uses supported by the notifier were on pome fruit (apple and pear), tomato and aubergine, cotton and hops (Austria, 2002). EFSA was not involved in the process and therefore no EFSA conclusion is available. A decision of non-inclusion of amitraz in Annex I of Directive 91/414/EEC was taken by means of Decision 2004/141/EC. 4 Consequently, all the authorisations of plant protection products containing amitraz had to be withdrawn by 12 August 2004, with the exception of few uses, 5 with a period of grace until 12 August The non-inclusion decision was based on the finding that the information provided by the applicant was insufficient to satisfy the data requirements set out in Directive 91/414/EEC, in particular with regard to the acute exposure of consumers. Concerns were identified regarding the acceptability of acute exposure of consumers in view of possible neurological effects of the active substance (European Commission, 2003). In accordance with Regulation (EU) No 540/2011 6, amitraz is not approved under Regulation (EC) No 1107/2009 7, repealing Directive 91/414/EEC. MRLs for amitraz (residue definition: amitraz including the metabolites containing the 2,4- dimethylaniline moiety expressed as amitraz) are set in Annex II of Regulation (EC) No 396/2005. MRLs are at the limit of quantification (LQ). It is noted that no MRLs are formally set for animal products except for poultry (product code to ) and bird eggs (product code to ). A review of the enforcement residue definition and the existing MRLs under Article 12 is not foreseen because the decision on non-approval was taken before September Legislative background veterinary use of amitraz Amitraz was evaluated in accordance with the provisions laid down in Regulation (EEC) No 2377/90 8 (repealed and replaced by Regulation (EC) No 470/ ) for use in food-producing animal species. Based on the favourable opinion and assessment reports adopted by the CVMP (1996a,b, 1997, 1998b, 4 Commission Decision of 12 February 2004 concerning the non-inclusion of amitraz in Annex I to Council Directive 91/414/EEC and the withdrawal of authorisations for plant protection products containing this active substance (2004/141/EC). J L 46, , p Cotton in Greece, pear trees after harvest in the United Kingdom, the Netherlands and Portugal, tree nursery and strawberry in the Netherlands for which authorisations were to be withdrawn by 30 June 2007 with a period of grace up to 31 December 2007 latest. 6 Commission Implementing Regulation (EU) No 540/2011 of 25 May 2011 implementing Regulation (EC) No 1107/2009 of the European Parliament and of the Council as regards the list of approved active substances. J L 153, , p Regulation (EC) No 1107/2009 of the European Parliament and of the Council of 21 ctober 2009 concerning the placing of plant protection products on the market and repealing Council Directives 79/117/EEC and 91/414/EEC. J L 309, , p Council Regulation (EEC) No 2377/90 of 26 June 1990 laying down a Community procedure for the establishment of maximum residue limits of veterinary medicinal products in foodstuffs of animal origin. J L 224, , p Regulation (EC) No 470/2009 of the European Parliament and of the Council laying down Community procedures for the establishment of residue limits of pharmacologically active substances in foodstuffs of animal origin, repealing Council Regulation (EEC) No 2377/90 and amending Directive 2001/82/EC of the European Parliament and of the Council and Regulation (EC) No 726/2004 of the European Parliament and of the Council. J L 152, , p EFSA Journal 2016;14(8):4570

12 1999b, 2004), MRLs were established for amitraz on fat, liver, kidney of porcine, bovine, ovine and caprine, milk of ruminants and honey in Regulation (EEC) No 2377/90 through several amending regulations. Amitraz is nowadays listed in Table 1 of Regulation (EU) No 37/2010 (replacing Annex I to IV of Regulation (EEC) No 2377/90) Toxicological properties of amitraz The toxicological profile of the active substance amitraz was assessed by the RMS in the framework of the peer review under Directive 91/414/EEC (Austria, 1998, 2002). The toxicological properties of amitraz were also assessed by the CVMP (1996a,b, 1997, 1998b, 1999b, 2004). The toxicological reference values proposed by the RMS for the parent compound are compiled in Table 1. Table 1: Toxicological reference values derived for amitraz Pesticide evaluation Veterinary medicinal product evaluation ADI Value Details, source Value Details, source mg/kg bw per day Dog, 2-year and 90 day studies, SF 100, Austria (2002) ARfD 0.01 mg/kg bw Dog, 2-year oral study, SF 25 (a), Austria (2002) Conclusion mg/kg bw per day Nature and magnitude of residues in food of animal origin Dog, 2-year oral study, SF 100, CVMP (2004) No ARfD value derived by CVMP The same ADI value, based on the same study, was derived in the legislative framework of pesticides and veterinary medicinal products The setting of ARfD value is not part of the assessment of veterinary medicinal products. Thus, the most appropriate toxicological value for short-term dietary risk assessment is the ARfD derived for the use of amitraz as pesticide ADI: acceptable daily intake; ARfD: acute reference dose; bw: body weight; SF: safety factor. (a): Based on the NAEL of 0.25 mg/kg bw of the dog study with a SF of 25, supported by available information from human volunteers (Austria, 2002). Amitraz was evaluated under the veterinary MRL procedure for the topical use as spray, pour-on or dip on pigs, cattle, sheep, goats and for use as sustained-release strips to be suspended in beehives. In line with the EU MRLs established for amitraz on products of plant origin, the CVMP defined the marker residue as sum of amitraz and all metabolites containing the 2,4-DMA moiety, expressed as amitraz (CVMP, 1996a,b, 1998b, 2004). Although the metabolism of amitraz in bees was not investigated, the CVMP agreed to apply the same marker residue to honey because the same metabolic pathway was observed in a wide range of animals and in plants (CVMP, 1997, 1999b). Residue depletion studies on pigs, cows and sheep following topical applications of amitraz at the therapeutic dose rates were reviewed by the CVMP. Dermal absorption showed to be limited; the highest residue concentrations were found in the subcutaneous fat (fat + skin for pigs), particularly of the site of application, liver and kidney and lower concentrations in ornamental/renal fat, muscle and milk. Residue concentrations declined rapidly within the first days (CVMP, 2004). Several non-glp studies investigating residues in honey were reported. Depending on the formulation and dosage regime used, residues in honey were found to vary. In a GLP study carried out in 1998 at the recommended dose (500 g a.s./strip, two strips per hive suspended for 6 weeks), the highest residue of 0.23 mg/kg was observed 2 days after the end of treatment. Mean residues in honey declined from 0.1 to 0.08 mg/kg between 4 and 15 days after the end of treatment. Residues in wax were much higher and did not correlate with residues in honey, as they were about 4.7 mg/kg 10 days posttreatment but increased in 5 days to 73 mg/kg (CVMP, 1999b). The metabolism of amitraz was assessed by the RMS Austria in the framework of Directive 91/414/EEC. After oral administration of radiolabelled amitraz to lactating cows and laying hens, higher radioactivity levels were found in the excretion organs (kidney, liver). The nature of the residues in tissues, milk and eggs was considered as being well characterised, with amitraz, its hydrolysis products BTS and BTS and the compounds containing the 2,4-DMA moiety considered to be residues of concern. No metabolites were found which had not previously been identified in the rat. Based on the metabolism studies, Austria defined the residue definition for enforcement and for risk assessment as amitraz, including the metabolites containing the 2,4-dimethylaniline moiety, expressed as amitraz. The 12 EFSA Journal 2016;14(8):4570

13 residue definition was proposed for enforcement and risk assessment of residues in both plant and animal origin commodities (Austria, 1998, 2002). The current residue definition set in Regulation (EC) No 396/2005 corresponds to the residue definition/marker residue derived in the above-mentioned assessments. EFSA concludes that the marker residue derived by the CVMP is appropriate to be used as residue definition for enforcement and risk assessment for the animal commodities assessed in the framework of this reasoned opinion. In Appendix B, Table B.1, a list of the existing MRLs set for animal products under Regulation (EC) No 396/2005 and Regulation (EU) 37/2010 can be found. Amitraz residues were repeatedly found in honey analysed under the national pesticide monitoring programmes. In 2014, residues in honey were found up to 0.05 mg/kg Consumer risk assessment In order to address the question whether the MRLs established under Regulation (EU) No 37/2010 are sufficiently protective from a consumer health point of view, EFSA calculated the long-term exposure related to residues in food taking into account the existing EU MRLs set in Regulation (EC) No 396/2005 for plant products, poultry and eggs; in addition, the MRLs for animal products set in Regulation (EU) No 37/2010 were included as input values for the long-term exposure assessment. The short-term risk assessment was performed only for the animal products for which MRLs are established under the veterinary legislation. The input values for the long-term and short-term exposure assessment are summarised in Table 2. Table 2: Input values for dietary exposure assessment for amitraz Chronic exposure assessment Acute exposure assessment Commodity Input Comment Input Comment Residue definition for risk assessment: Amitraz (amitraz including the metabolites containing the 2, 4-dimethylaniline moiety expressed as amitraz) Swine, sheep fat 0.4 MRL-V 0.4 MRL-V Bovine, goat fat 0.2 MRL-V 0.2 MRL-V Swine, bovine liver 0.2 MRL-V 0.2 MRL-V Sheep, goat liver 0.1 MRL-V 0.1 MRL-V Swine, bovine, sheep, goat kidney 0.2 MRL-V 0.2 MRL-V Cattle, sheep, goat milk 0.01 MRL-V 0.01 MRL-V Honey 0.2 MRL-V 0.2 MRL-V Swine, sheep meat % of MRL-V set % of MRL-V set Bovine, goat meat 0.04 for fat (a) 0.04 for fat (a) ther plant and animal origin commodities MRLs MRLs in Reg. (EC) No 396/2005 Acute risk assessment undertaken only with regard to the MRLs under consideration MRL-V: Veterinary MRL, for an active substance used in veterinary medicinal products. (a): Consumption figures in the EFSA PRIMo are expressed as meat and were represented in the calculation by its 20% of fat content (FA, 2009b) since no MRL value is set for muscle tissue. The estimated long-term exposure, expressed as percentage of the ADI value of mg/kg bw per day, accounted for 75%; the MRLs in animal commodities under assessment contributed to the overall long-term exposure by a maximum of 17%, with milk and milk products being the main contributor (maximum 13% of the ADI). The estimated short-term exposure for the individual products of animal origin was below the ARfD (0.01 mg/kg bw), with the highest short-term exposure identified for bovine liver (16%), bovine milk (12%), sheep meat (8%) and < 8% for the remaining products. EFSA concludes that the estimated consumer exposure resulting from the MRLs set in Regulation (EU) No 37/2010 for amitraz is unlikely to pose a consumer health risk EFSA Journal 2016;14(8):4570

14 2.2. Permethrin Permethrin is the IS common name for 3-phenoxybenzyl (1RS,3RS;1RS,3SR)-3-(2,2-dichlorovinyl)- 2,2-dimethylcyclopropanecarboxylate or 3-phenoxybenzyl (1RS)-cis-trans-3-(2,2-dichlorovinyl)-2,2- dimethylcyclopropanecarboxylate (IUPAC). The active substance belongs to the group of pyrethroids and it is used as insecticide and acaricide in plant protection products and against ectoparasites in veterinary medicinal products. Permethrin is also approved for use in the EU as biocide (product-type 8, wood preservative; product-type 18, insecticide, acaricide and product to control other arthropods by means other than repulsion or attraction) by Regulation (EU) No 1090/ Permethrin is a mixture of two stereoisomeric pairs (cis-isomer and trans-isomer). Different cis/ trans ratios of permethrin are available on the market (25/75, 40/60 or 80/20). FA specifications for permethrin have been developed for technical material with a 25/75 and 40/60 cis/trans isomer ratios (FA, 2009a, 2010, 2015). The chemical structure of the active substance is reported in Appendix A Legislative background pesticide use of permethrin Permethrin was evaluated in the framework of Directive 91/414/EEC with Ireland designated as RMS. The active substance assessed in the DAR was a mixture of cis/trans isomers containing up to 40% of the cis-isomer (Ireland, 1998). Several uses (apple, stone and berry fruits, tomato, pepper, cucurbits, head cabbage, lettuce, fresh pea/bean, potato, cereals) were supported by the applicant in the peer review. EFSA was not involved in the peer review process and therefore no EFSA conclusion is available. A decision of non-inclusion in Annex I of the Directive was taken by means of Decision 2000/817/EC. 11 The reason for the non-inclusion was the lack of appropriate information on environmental fate and ecotoxicology; all applicants of the active substance formally withdrew their support to the application for inclusion (European Commission, 2000). Consequently, all the authorisations of plant protection products containing permethrin were revoked by 25 June 2001 (with the exception of forestry uses for which permethrin was allowed to be used until 25 July 2003). In accordance with Regulation (EU) No 540/2011, permethrin is not approved under Regulation (EC) No 1107/2009, repealing Directive 91/414/EEC. MRLs for permethrin (residue definition: sum of isomers) are set in Annex II of Regulation (EC) No 396/2005. All MRLs are at the LQ. It is noted that no MRLs are formally set for equine products (product code to ), for other terrestrial animal products (product code to ) and for bird eggs (product code to ), except chicken eggs (product code ). A review of the enforcement residue definition and the existing MRLs under Article 12 is not foreseen because the decision on non-approval was taken before September Legislative background veterinary use of permethrin Permethrin was evaluated in accordance with the provisions laid down in Regulation (EEC) No 2377/90 (repealed and replaced by Regulation (EC) No 470/2009) for use in food-producing animal species. Based on the favourable opinion and assessment reports adopted by the CVMP (1998a, 2000b, 2002c), MRLs were established through several amending regulations. Since sufficient data were provided to support its use on bovine species only, the provisional MRLs on porcine, caprine and poultry definitively expired on 1 January Permethrin is nowadays listed in Table 1 of Regulation (EU) No 37/2010 (replacing Annex I to IV of Regulation (EEC) No 2377/90). MRLs are established on muscle, fat, liver, kidney and milk of bovine Toxicological properties of permethrin The toxicological profile of the active substance permethrin (cis/trans ratio up to 40/60) was assessed by the RMS in the framework of the peer review under Directive 91/414/EEC (Ireland, 1998). Ireland proposed toxicological reference values (see Table 3), which were never formally adopted. The toxicity of permethrin was also assessed by the CVMP. The toxicity of permethrin was found to depend on the cis/trans isomer ratio, being the cis-isomer more toxic than the trans-isomer; the ADI value was 10 Commission Implementing Regulation (EU) No 1090/2014 of 16 ctober 2014 approving permethrin as an existing active substance for use in biocidal products for product-types 8 and 18. J L 299, , p Commission Decision of 27 December 2000 concerning the non-inclusion of permethrin in Annex I to Council Directive 91/414/ EEC and the withdrawal of authorisations for plant protection products containing this active substance (Decision 2000/817/ EC). J L 332, , p EFSA Journal 2016;14(8):4570

15 derived to cover also permethrin containing up to 80% of the more toxic cis-isomer (cis/trans ratio of 80/20) which can be used in veterinary medicinal products (CVMP, 1998a, 2000b, 2002c). The toxicological reference values are compiled in Table 3. Table 3: Toxicological reference values derived for permethrin ADI Pesticide evaluation Veterinary medicinal product evaluation Value Details, source Value Details, SF, source 0.05 mg/kg bw per day For 40/60 cis/trans isomer ratio Dog, 1 year study (a), SF 100, Ireland (1998) 0.01 mg/kg bw per day The toxicity of permethrin has been first evaluated by JMPR between 1987 and 1999 and the ADI of mg/kg bw per day was established for permethrin with cis/trans ratios of 25/75 to 40/60 (FA, 1999). In 2002, JMPR reassessed permethrin as regards its acute toxicity and concluded on an ARfD of 1.5 mg/kg bw (rat, acute neurotoxicity study, SF 100) to apply to the same mixture of isomers (FA, 2002). For the chronic consumer risk assessment, EFSA considered the ADI of 0.01 mg/kg bw per day as most appropriate to be used for food of animal origin that may result from the use of permethrin in veterinary medicinal products. Although permethrin residues in plant products are more likely to result from the use of the less toxic isomer mixture compliant with the FA specifications (FA, 2009a, 2010, 2015), in a conservative risk assessment screening the ADI derived for the 80/20 isomer ratio can be used. For the acute risk assessment the same ADI was used as a conservative surrogate for an ARfD Nature and magnitude of residues in food of animal origin For 80/20 cis/trans isomer ratio Rat, dog overall chronic studies (a), SF 500 (b), CVMP (2002) ARfD Not relevant Ireland (1998) No ARfD value is derived by CVMP Conclusion The ADI derived in the legislative framework of pesticides and veterinary medicinal products is based on the same study, but differs in the safety factor (SF) applied The setting of ARfD value is not part of the assessment of veterinary medicinal products and was considered as not relevant by the RMS ADI: acceptable daily intake; ARfD: acute reference dose; bw: body weight. (a): Study conducted with approximately 40/60 cis/trans isomer mixture. (b): SF of 500 to account for the higher toxicity of the cis-isomer and apply ADI to the mixture up to 80/20 cis/trans used in veterinary medicines. Permethrin was evaluated by the CVMP in 1998, 2000 and 2002 for topical use in livestock (spray, powder, solution, ear-tag) and finally authorised for use in bovine only. In studies carried out in cattle dosed orally (1.25 mg) or topically (40 mg) with radiolabelled permethrin, the highest residues were found in cattle fat (up to 0.53 mg eq/kg) and skin (up to 25 mg eq/kg) with significant residues remaining at the site of application. Residues in liver, kidney and muscle remote from the application site were very low (less than 0.01 mg/kg). Seven and 14 days after topical treatment, more than 80% of the radiolabelled material in fat and 98% of the radiolabelled material in skin were extractable and consisted of unmetabolised permethrin. Extractability in liver was lower (between 30% and 60% depending on the label position), with ca. 50% of the extractable residues being unmetabolised permethrin; the remainder consisted of the cleavage products 3-2(2,2-dichlorovinyl)-2,2- dimethylcyclopro-panecarboxylate and 3-phenoxybenzyl alcohol. Residues in milk ranged from to mg eq/kg in cow s milk three to five milkings after the treatment. The residues concentrated in the fat phase and consisted mainly of unmetabolised permethrin (CVMP, 2002c). In the framework of the pesticide legislation, the RMS Ireland assessed the metabolism of permethrin after oral administration of radiolabelled compound to lactating goats and laying hens and concluded that parent permethrin was a suitable residue definition for enforcement and risk assessment in animal tissues and milk. Most of the radioactivity (> 80% in goats and 92% in hens) was rapidly eliminated in the excreta and radioactivity in edible tissues was low (< 1% of the recovered radioactivity in milk, liver and kidney of goats and 0.3% in liver and eggs of hens). Permethrin represented the major component of the total radioactive residue (TRR) in fat (89%), milk (57 56%) and eggs (50% yolk and 52% white). In goat muscle, levels of radioactivity were low ( mg/kg) and contained radioactive components including polar material or had a similar retention time to permethrin. More extensive metabolism was observed in liver and kidney. cis- and trans-dcva 15 EFSA Journal 2016;14(8):4570

16 (3-(2,2-dichlorovinyl)-2,2-dimethylcyclo-propanecarboxylic acid) and 3-PBA (3-phenoxybenzoic acid) were the predominant residues (free and conjugated); amounts of parent permethrin in these organs were not reported (Ireland, 1998). Permethrin (sum of isomers) was identified as a suitable marker residue following topical application to bovine. The current residue definition set in Regulation (EC) No 396/2005 is identical with the residue definition/marker residue derived in the above-mentioned assessments. EFSA concluded that the parent compound would be a suitable residue definition for risk assessment. Considering its affinity to fat tissues and its log P ow (> 5.3; FA, 2015), permethrin should be classified as fat-soluble in Regulation (EC) No 396/2005. In Appendix B, Table B.2, a list of the existing MRLs set for animal products under Regulation (EC) No 396/2005 and Regulation (EU) 37/2010 can be found Consumer risk assessment In order to address the question whether the MRLs established for permethrin under Regulation (EU) No 37/2010 are sufficiently protective from a consumer health point of view, EFSA calculated the long-term exposure related to residues in food taking into account the existing EU MRLs set in Regulation (EU) No 37/2010. For plant products and for the remaining animal products, the MRLs set in Regulation (EC) No 396/2005 at LQ were used as input values for the long-term exposure assessment. The short-term risk assessment was performed only for the animal products for which MRLs are established under the veterinary legislation. The input values for the long-term and shortterm exposure assessment are summarised in Table 4. Table 4: Input values for dietary exposure assessment for permethrin Chronic exposure assessment Commodity Input Comment Residue definition for risk assessment: Permethrin (sum of isomers) The estimated long-term exposure, expressed as percentage of the ADI value of 0.01 mg/kg bw per day, accounted for 35%; the MRLs in animal commodities under assessment (bovine) contributed to the overall long-term exposure by 22%, with milk and milk products being the main contributor (maximum 20% of the ADI). The short-term exposure for the individual products of animal origin was below the ADI which was selected as surrogate ARfD (0.01 mg/kg bw), with the highest short-term exposure identified for bovine milk (62%). EFSA concludes that the estimated consumer exposure resulting from the MRLs set in Regulation (EU) No 37/2010 for permethrin is unlikely to pose a consumer health risk Coumaphos Acute exposure assessment Input Comment Bovine meat 0.14 MRL-V (F)(a) 0.14 MRL-V (F)(a) Bovine fat 0.5 MRL-V 0.5 MRL-V Bovine liver 0.05 MRL-V 0.05 MRL-V Bovine kidney 0.05 MRL-V 0.05 MRL-V Bovine milk 0.05 MRL-V 0.05 MRL-V ther plant and animal commodities MRLs MRLs in Reg. (EC) No 396/2005 Acute risk assessment undertaken only with regard to the MRLs under consideration MRL-V: Veterinary MRL, for an active substance used in veterinary medicinal products. (a): Consumption figures in the EFSA PRIMo are expressed as meat. The MRLs for muscle (0.05 mg/kg) and fat (0.5 mg/kg) were recalculated to meat, assuming a fat content of 20% (FA, 2009b). Residues in meat = (F): Fat soluble. Coumaphos 12 is the IS common name for -3-chloro-4-methyl-2-oxo-2H-chromen-7-yl,-diethyl phosphorothioate or 3-chloro-7-diethoxyphosphinothioyloxy-4-methylcoumarin (IUPAC), a contact and 12 The name coumafos is approved by the World Health rganisation (WH). However, in this assessment EFSA used the approved IS common name, i.e. coumaphos EFSA Journal 2016;14(8):4570