Modification of the existing MRLs for cypermethrin in various crops 1

EFSA Journal 2011;9(6):2280 REASONED OPINION Modification of the existing MRLs for cypermethrin in various crops 1 European Food Safety Authority 2 European Food Safety Authority (EFSA), Parma, Italy SUMMARY According to Article 6 of the Regulation (EC) No 396/2005, France, herewith referred to as the Evaluating Member State (EMS), received an application from the company AGRIPHAR SA to modify the existing MRLs for cypermethrin in table olives, olives for oil production, lettuce and other salad plants, spinach, purslane, beet leaves (chard) and herbs. In order to accommodate for the intended use of cypermethrin on these crops in Southern Europe, it is proposed to raise the existing MRLs. The EMS France drafted an evaluation report according to Article 8 of Regulation (EC) No 396/2005 which was submitted to the European Commission and forwarded to EFSA on 20 December 2010. EFSA derives the following conclusions based on the submitted evaluation report prepared by the EMS, the Draft Assessment Report (DAR) prepared by the rapporteur Member State (RMS) Belgium under Directive 91/414/EEC as well as the JMPR evaluations of cypermethrin. The toxicological profile of cypermethrin was assessed in the framework of the peer review under Directive 91/414/EEC and the data were sufficient to derive an ADI of 0.05 mg/kg bw/day and an ARfD of 0.2 mg/kg bw. It is noted that cypermethrin is a mixture of isomers and one of its isomer pairs - cis-2-isomer - is used also as an active substance alpha-cypermethrin and has higher toxicity than cypermethrin (ADI of 0.015 mg/kg bw/d; ARfD of 0.04 mg/kg bw). The metabolism of cypermethrin in primary crops was investigated in fruit and fruiting vegetables, leafy vegetables and pulses and oilseeds. From these studies the peer review established the residue definition for risk assessment and enforcement as cypermethrin (sum of isomers). The same residue definition is established in Regulation (EC) No 396/2005. For the uses on the crops under consideration, EFSA concludes that the metabolism of cypermethrin is sufficiently addressed and the residue definitions as agreed in the peer review are applicable. EFSA considers that the data are sufficient to derive the following MRL proposals: 0.4 mg/kg in table olives and olives for oil production, 3 mg/kg in lettuce and 4 mg/kg in spinach, beet leaves (chard), rocket, mustard, parsley, sage, rosemary, thyme, basil, laurel and tarragon. The proposed extrapolation of residue data from lettuce to the whole group of salad plants is not acceptable. The proposed extrapolation of residue data from spinach to the whole group of herbs is not fully supported. Adequate analytical enforcement methods are available to monitor cypermethrin residues (sum of isomers) in the crops under consideration. 1 On request from the European Commission, Question No EFSA-Q-2010-01498, issued on 17 June 2011. 2 Correspondence: pesticides.mrl@efsa.europa.eu Suggested citation: European Food Safety Authority; Modification of the existing MRLs for cypermethrin in various crops. EFSA Journal 2011;9(6):2280. [30 pp.] doi:10.2903/j.efsa.2011.2280. Available online: www.efsa.europa.eu/efsajournal European Food Safety Authority, 2011

The effects of processing on the nature of cypermethrin residues have not been investigated in the peer review. According to the evaluation of the JMPR, during sterilisation and pasteurization processes no degradation of cypermethrin occurs and therefore for processed commodities the same residue definition as for raw agricultural commodities is applicable. No specific studies investigating the effects of processing on the magnitude of cypermethrin residues have been submitted in the framework of the current application. The JMPR has assessed the processing studies with olives. The study results indicate a concentration of residues in refined and crude olive oil. For other crops under consideration the need for processing studies is less relevant. The following processing factors derived by the JMPR are recommended for enforcement purposes: Olives, crude olive oil: 7.5 Olives, refined olive oil: 8.2 The possible occurrence of cypermethrin residues in rotational and/or succeeding crops was also investigated. It was concluded by the peer review that the nature of residues in rotational crops and primary crops is similar. The need for a plant-back restriction should be considered at national level before granting an authorization of cypermethrin. Residues of cypermethrin in commodities of animal origin were not assessed in the framework of this application, since the crops under consideration are normally not fed to livestock. The consumer risk assessment was performed with revision 2 of the EFSA PRIMo. This exposure assessment model contains the relevant European food consumption data for different sub-groups of the EU population. Since the existing EU MRLs are set for the sum of isomers, it is not known whether residues in food commodities result from the use of cypermethrin or from other individual cypermethrin isomers. As alpha-cypermethrin is known to be more toxic than cypermethrin and other isomers, EFSA calculated two scenarios of the chronic exposure. In scenario 1 EFSA assumed that the existing EU MRLs are based on the use of cypermethrin only. The median residue values as derived from the residue trials on olives, lettuce and spinach were used as input values and were also extrapolated to the crops for which MRL proposals were derived. For other food commodities of animal and plant origin, the existing MRLs as established in Annexes II and IIIB of Regulation (EC) No 396/2005 were used as input values. The acute exposure calculation was performed to assess the consumer exposure to cypermethrin residues resulting from the intake of the commodities under consideration assuming the consumption of a large portion of the food items as reported in the national food surveys containing residues at the highest level as observed in supervised field trials. The estimated exposure was compared with the toxicological reference value derived for cypermethrin. No long-term consumer intake concerns were identified for any of the European diets incorporated in the EFSA PRIMo. The total calculated intake values ranged from 9.4-82.7% of the ADI (UK toddler diet). The individual contribution of residues in the crops under consideration to the total consumer exposure in the percentage of the ADI accounted for less that 2% of the ADI. EFSA is aware that the calculated chronic consumer exposure might be underestimated as not all MRLs result from the use of cypermethrin. No acute consumer risk was identified in relation to the MRL proposals for the crops under consideration. The calculated maximum exposure in the percentage of the ARfD was 27% for lettuce, 23.7% for spinach, 18.4 % for beet leaves (chard) and below 10% for other crops under consideration. In a more conservative scenario 2 EFSA assumed that the existing EU MRLs result from the use of alpha-cypermethrin only. The EU MRLs as established in Annexes II and IIIB of Regulation (EC) No EFSA Journal 2011;9(6):2280 2

396/2005 were used as input values. The estimated exposure was compared with the toxicological reference value derived for alpha-cypermethrin. In scenario 2 long term consumer intake concerns could not be excluded for 16 diets included in the EFSA PRIMo. The total calculated intake values accounted for a maximum of 275.8% of the ADI (UK Toddler). EFSA is aware that this exposure calculation might be overestimated as not all MRLs result from the use of alpha-cypermethrin; however, further refinements could not be performed due to the lack of information on the source of the MRL. EFSA concludes that currently the risk assessment regarding the actual consumer exposure to cypermethrin residues cannot be finalised. Considering that chronic consumer intake concerns have been identified in relation to the existing EU MRLs for cypermethrin, EFSA is of the opinion that additional uses of cypermethrin contributing to the toxicological burden currently cannot be supported. To perform more accurate consumer exposure assessments, full information on all authorised uses of various cypermethrin isomers is required. In addition, EFSA proposes to set separate residue definitions for those cypermethrin isomers which have different toxicological reference values. It is noted that the review of the existing EU MRLs for cypermethrin (alpha-, zeta-cypermethrin and cypermethrin) is ongoing according to Article 12 of Regulation (EC) No 306/2005. It is also noted that the existing EU MRLs for products of animal origin established in Regulation (EC) No 396/2005 do not correspond with the MRL values set for cypermethrin under Regulation (EC) No 37/2010 for its use as a veterinary drug. In order to avoid legal uncertainties, EFSA would strongly recommend revising the contradictious MRLs for meat, fat, liver and kidney of ruminants (bovine, sheep, goat) and milk. KEY WORDS Cypermethrin, alpha-cypermethrin, olives, lettuce, spinach and similar leaves, MRL application, Regulation (EC) No 396/2005, consumer risk assessment, sum of isomers, pyrethroid insecticide/acaricide EFSA Journal 2011;9(6):2280 3

TABLE OF CONTENTS Summary... 1 Table of contents... 4 Background... 5 Terms of reference... 5 The active substance and its use pattern... 6 Assessment... 8 1. Methods of analysis... 8 1.1. Methods for enforcement of residues in food of plant origin... 8 1.2. Methods for enforcement of residues in food of animal origin... 8 2. Mammalian toxicology... 9 3. Residues... 9 3.1. Nature and magnitude of residues in plant... 9 3.1.1. Primary crops... 9 3.1.2. Rotational crops... 14 3.2. Nature and magnitude of residues in livestock... 15 4. Consumer risk assessment... 15 Conclusions and recommendations... 18 References... 18 Appendix A. Good Agricultural Practices (GAPs)... 22 Appendix B. Pesticide Residues Intake Model (PRIMo)... 23 Appendix C. Existing EU maximum residue limits (MRLs)... 26 Abbreviations... 29 EFSA Journal 2011;9(6):2280 4

BACKGROUND Commission Regulation (EC) No 396/2005 3 establishes the rules governing the setting of pesticide MRLs at Community level. Article 6 of that regulation lays down that a party requesting an authorisation for the use of a plant protection product in accordance with Council Directive 91/414/EEC 4, shall submit to a Member State, when appropriate, an application to set or modify an MRL in accordance with the provisions of Article 7 of that regulation. France, hereafter referred to as the evaluating Member State (EMS), received an application from the company AGRIPHAR SA 5 to modify the existing MRLs for the active substance cypermethrin in table olives, olives for oil production, lettuce and other salad plants, spinach and similar leaves, herbs. This application was notified to the European Commission and EFSA and subsequently evaluated by the EMS in accordance with Article 8 of the Regulation. After completion, the evaluation report of the EMS was submitted to the European Commission who forwarded the application, the evaluation report and the supporting dossier to EFSA on 20 December 2010. The application was included in the EFSA Register of Questions with the reference number EFSA-Q-2010-01498 and the following subject: Cypermethrin - Application to modify the existing MRLs in various crops. The EMS proposed the following MRLs: 0.5 mg/kg in table olives and olives for oil production, 3 mg/kg in lettuce and other salad plants, spinach and similar (leaves) and in herbs. EFSA then proceeded with the assessment of the application as required by Article 10 of the Regulation. TERMS OF REFERENCE In accordance with Article 10 of Regulation (EC) No 396/2005, EFSA shall, based on the evaluation report provided by the evaluating Member State, provide a reasoned opinion on the risks to the consumer associated with the application. In accordance with Article 11 of that Regulation, the reasoned opinion shall be provided as soon as possible and at the latest within three months (which may be extended to six months where more detailed evaluations need to be carried out) from the date of receipt of the application. Where EFSA requests supplementary information, the time limit laid down shall be suspended until that information has been provided. In this particular case the calculated deadline for providing the reasoned opinion is 20 March 2011. 3 Regulation (EC) No 396/2005 of the European Parliament and of the Council of 23 February 2005. OJ L 70, 16.3.2005, p. 1-16. 4 Council Directive 91/414/EEC of 15 July 1991, OJ L 230, 19.8.1991, p. 1-32. 5 AGRIPHAR SA, Rue de Renory 26/1, 4102, Ougree, Belgium EFSA Journal 2011;9(6):2280 5

THE ACTIVE SUBSTANCE AND ITS USE PATTERN Cypermethrin is the ISO common name for (RS)-α-cyano-3-phenoxybenzyl (1RS,3RS;1RS,3SR)-3- (2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate (IUPAC). Cypermethrin contains two chiral centres and one double bond with cis/trans isomers giving a racemic mixture of 8 optical isomers comprising 4 diastereoisomeric pairs. Some subsets of cypermethrin isomers have their own ISO common names: alpha-cypermethrin, beta-cypermethrin, theta-cypermethrin and zeta-cypermethrin. The chemical structure of cypermethrin 6 is herewith reported: CH3 CH3 CL 1 CO - O C CH H C CL CN 1R 6 αs 6 H O An overview of the eight isomers of cypermethrin is given in the table below: C.A. denomination of the isomers 1 [1R-(1α(S*),3α)] cis-2 (**) 2 [1S-(1α(R*),3α)] insecticide activity +++ 3 [1R-(1α(R*),3α)] cis-1-4 [1S-(1α(S*),3α)] 5 [1R-(1α(S*),3β)] trans-4-6 [1S-(1α(R*),3β)] 7 [1R-(1α(R*),3β)] trans-3-8 [1S-(1α(S*),3β)] (**) Isomers cis-2 are the main components of alpha-cypermethrin. According to FAO specifications, the minimum purity of cypermethrin shall be not less than 900 g/kg with the cis-isomer content between 40% minimum and 60% maximum of the cypermethrin content (FAO, 1995). Cypermethrin is a synthetic non-systemic acaricide/insecticide belonging to the chemical class of pyrethroids. Cypermethrin acts on the nervous system of the insect and disturbs the 6 1R,S describes the configuration at the carboxyl-bearing carbon atom (C-1) of the cyclopropane ring; cis and trans describes the relationship to this carboxyl of the dichlorovinyl group at C-3; α R,S describes the configuration of the CN-bearing carbon atom (α). EFSA Journal 2011;9(6):2280 6

function of neurons by interaction with the sodium channel. It controls a wide range of insects (Lepidoptera, Coleoptera, Diptera, Hemiptera). It is also used as animal ectoparasiticide. Cypermethrin is fat soluble. Cypermethrin was evaluated according to Directive 91/414/EEC with Belgium designated as the rapporteur Member State (RMS). It was included in Annex I of this Directive by Directive 05/53/EC 7 for uses as insecticide only. EFSA was not involved in the peer review and therefore no EFSA conclusion is available. The representative uses evaluated in the peer review were foliar applications on wheat, barley and oilseed rape. The EU MRLs for cypermethrin (sum of isomers) are established in Annexes II and IIIB of Regulation (EC) No 396/2005 (see Appendix C). The existing EU MRLs for cypermethrin are set at the LOQ of 0.05 mg/kg in table olives and olives for oil production, at 2 mg/kg in lettuce and other salads plants and herbs and at 0.7 mg/kg in spinach and similar leaves. Codex Alimentarius has established CXLs for a wide range of commodities. The CXL for lettuce and other salad plants and spinach and similar leaves is set at 0.7 mg/kg and in olives at the LOQ of 0.05 mg/kg. Since cypermethrin is used also as a veterinary drug, maximum residue limits are set for cypermethrin (sum of isomers) in commodities of animal origin in Regulation (EC) No 37/2010 8 (0.02 mg/kg in ruminant meat, 0.2 mg/kg in ruminant fat, 0.02 mg/kg in ruminant liver, kidney and milk; 0.05 mg/kg in the skin and muscle of fish belonging to Salmonidae family). It is noted that the MRLs for products of animal origin established in Regulation (EC) No 396/2005 do not correspond with the MRL values established under Regulation (EC) No 37/2010. In other words, contradictious MRLs are in place for meat, fat, liver and kidney of ruminants (bovine, sheep, goat) and milk. In order to avoid legal uncertainties, EFSA would strongly recommend to revise these contradictious MRLs. The details of the intended GAPs for the use of cypermethrin in Southern Europe are given in Appendix A. 7 Commission Directive 2005/53/EC of 16 September 2005, OJ L 241, p. 51-56 8 Commission Regulation (EU) No 37/2010 of 22 December 2009, OJ L 15, 20.01.2010,p.1-72 EFSA Journal 2011;9(6):2280 7

ASSESSMENT EFSA bases its assessment on the evaluation report submitted by the EMS (France, 2010), the Draft Assessment Report (DAR) and its Addendum prepared under Council Directive 91/414/EEC (Belgium, 1999, 2004), the Commission Review Report on cypermethrin (EC, 2005) as well as the JMPR Evaluation reports (FAO, 2009). The assessment is performed in accordance with the legal provisions of the Uniform Principles for the Evaluation of the Authorization of Plant Protection Products set out in Annex VI to Council Directive 91/414/EEC and the currently applicable guidance documents relevant for the consumer risk assessment of pesticide residues (EC, 1996, 1997a, 1997b, 1997c, 1997d, 1997e, 1997f, 1997g, 2000, 2004, 2010, 2011; OECD, 2011). 1. Methods of analysis 1.1. Methods for enforcement of residues in food of plant origin Analytical methods for the determination of cypermethrin residues in plant commodities were assessed in the DAR and in the Addendum to the DAR under Directive 91/414/EEC (Belgium, 1999; 2004). A DFG S23 multi-residue method using capillary GC-ECD principle is sufficiently validated for the determination of cypermethrin residues (sum of isomers) at the validated LOQ of 0.05 mg/kg in high oil content matrices (rape seeds and oil) and at the LOQ of 0.025 mg/kg in dry matrices (wheat grain and straw). Each diastereoisomer of cypermethrin is measured individually and the total cypermethrin residue is calculated by summing up the 4 individual diastereoisomers. Also the QuEChERS method using gas chromatography is applicable to analyse for the sum of cypermethrin isomers at the LOQ of 0.01 mg/kg in high water and high acid content matrices and at the LOQ of 0.05 mg/kg in dry matrices (www.crl-pesticides.eu). In the framework of the current application the applicant submitted validation data for the method proposed for the enforcement of cypermethrin residues in lettuce, spinach and olives. The residues of cypermethrin are extracted with acetonitrile. An aliquot of the extract is dried with anhydrous sodium sulphate and the solvent evaporated. The extract is cleaned by solid phase extraction on an activated carbon column and finally on an amino phase column. For olives an additional liquid/liquid extraction of the dried acetonitrile extract with hexane is made. Residues of cypermethrin are analysed by GC- MSD. The ILV of the method for the determination of residues in lettuce was also provided. The submitted validation data indicate that the method is applicable for the determination of cypermethrin residues (sum of isomers) at the LOQ of 0.01 mg/kg in matrices with high water and high oil content. EFSA concludes that sufficiently validated analytical methods are available to monitor the sum of cypermethrin isomers in the crops under consideration. 1.2. Methods for enforcement of residues in food of animal origin Analytical methods for the determination of cypermethrin residues in food of animal origin are not assessed in the current application since the crops under consideration are normally not fed to livestock. EFSA Journal 2011;9(6):2280 8

2. Mammalian toxicology The toxicological profile of the active substance cypermethrin was assessed in the framework of the peer review under Directive 91/414/EEC. Studies were performed with cypermethrin and were partly based on the bridging studies with alpha-cypermethrin (cis-isomer present in cypermethrin). The isomer composition has an impact on the toxicological profile of the active substance and therefore for alpha-cypermethrin which contains the most toxic cis-isomer, lower toxicological reference values have been derived. The toxicological reference values are compiled in Table 2-1. Table 2-1: Overview of the toxicological reference values Cypermethrin Source Year Value Study relied upon Safety factor ADI COM 2005 0.05 mg/kg bw/d 2 yr rat 100 ARfD COM 2005 0.2 mg/kg bw Acute neurotoxicity rat 100 Alpha-cypermethrin ADI COM 2004 0.015 mg/kg bw/d 1 yr dog 100 ARfD COM 2004 0.04 mg/kg bw Acute neurotoxicity rat 100 3. Residues 3.1. Nature and magnitude of residues in plant 3.1.1. Primary crops 3.1.1.1. Nature of residues The metabolism of cypermethrin in primary crops was evaluated in the framework of the peer review under Directive 91/414/EEC (Belgium, 1999). Studies were conducted with separate cis- and transisomers of cypermethrin and also with the isomeric mixture (1:1 cis/trans). The overview of the metabolism study designs is presented in the table below. Table 3-1: Summary of available metabolism studies in plants Group Crop Label position Fruits and fruiting vegetable Leafy vegetables Apples Lettuce 14 C-benzyl** 14 C-cyclopropyl ciscypermethrin 14 C-cyclopropyl and 14 C-benzyl Method, F, G or P (a) Rate Application details No/ Interval F n.r. 3/25-37 d G F 10-20 g a.s./ leaf 0.3 kg a.s./ha Sampling (DAT) 26 (leaves); 22 (apples) Remarks 3 apple trees (80-90 leaves/tree; 90-100 apples/tree) 1 18 ** Study I 2 18, 21 Spray Study II EFSA Journal 2011;9(6):2280 9

Pulses and oilseeds Group Crop Label position Cotton 14 C-cyclopropyl and 14 C-benzyl Method, F, G or P (a) G Rate 10-20 g a.s./ leaf Application details No/ Interval Sampling (DAT) Remarks 1 42 ** Study I 14 C-benzyl G 15 g/plant 14 C-cyclopropyl and 14 C-benzyl F 0.3 kg a.s./ha 1-2 35 Study II 3 >100 ** Study III Soybean 14 C-aryl and 14 C-benzyl G 0.54 2 >40 (a): Outdoor/field use (F) or glasshouse/ /indoor application (G) or protected (P) **: Cis- and trans-cypermethrin labelled separately n.r. - not reported in the DAR Lettuce In lettuce (study I) the parent was the major component of the TRR: 46-55% after application of ciscypermethrin and 27-46% after application of trans-cypermethrin. A similar metabolism of two isomers was observed. 3-phenoxybenzoic acid (SD36750) was present in lettuce treated with benzyl labelled cis- and trans-cypermethrin, accounting for 10-15% of the TRR. Amide analogue of cypermethrin (WL47133) was also identified, being present in both studies with both isomers (8.2-15.2% TRR). An isomeric conversion from cis- to trans-cypermethrin occurred (50%), the reverse reaction was less important. In lettuce (study II) the parent cypermethrin was the main component (32.5-49.5% TRR) together with the conjugate of cyclopropane carboxylic acid with sugars (33.6-42.16% TRR). Cotton In cotton (study I) the parent compound was the major component of the radioactive residues (28.5-37.9% TRR). 3-phenoxybenzoic acid (SD36750) accounted for 11.5% of the TRR. Amide analogue of cypermethrin was also identified in both studies with both isomers (5.2-15.6% TRR). The results of study III indicated that most of the radioactivity was localized in cotton leaves (6.8-11.4 mg eq./kg) with lower radioactivity levels in boll cases (0.65-1.65 mg eq./kg) and seed kernels (0.06-0.23 mg eq./kg). The characterisation of the TRR in seeds was not undertaken. Unchanged parent cypermethrin was found to be the major compound of the TRR in cotton bolls (0.12-0.19 mg eq./kg) and leaves (2.47-5.95 mg eq./kg). In leaves 3-phenoxybenzoic acid (SD36750) was present in benzyl labelled cis- and trans-cypermethrin studies, accounting for 1.38-1.66 mg/kg. No conversion of transto cis-isomer was observed. Apples In apples (peel extract and leaves) the parent compound (both isomers) was the major component of the radioactivity. Conversion from cis- to trans-isomer was observed (30% in leaves and 15% in peel). The identified free metabolites were at very low levels. The polar conjugated material accounted for 22-40% of the radioactivity in the leaves and for 7-10% of the radioactivity in the peel. A similar metabolic pathway was observed in leaves and peel. EFSA Journal 2011;9(6):2280 10

Soybean The total radioactive residues in soybean accounted for 28.26 mg/kg in beans, 0.29 mg/kg in pods and 0.1 mg/kg in beans. The characterisation of the TRR was undertaken in soybean foliage only. Parent cypermethrin was the main component of the TRR (61%) with free metabolites below 10% of the TRR. The main radioactivity consisted of polar components of cypermethrin metabolites. The metabolism of cypermethrin in plants involves an initial hydrolysis of the ester linkage of the cypermethrin molecule to yield 3-phenoxybenzaldehyde as the first hydrolysis product. This metabolite then undergoes the reduction to the phenoxybenzylalcohol and oxidation to form the 3- phenoxybenzoic acid. These metabolites occurred as conjugates with sugars and also in their free form. The parent compound could also be converted into its amide analogue by hydrolysis of the cyano group (but without any further transformation) or to its cis- and trans- hydroxylated derivatives. These components did not appear in their conjugated form. The metabolic pattern was similar in all three crop groups investigated and therefore the peer review concluded that the risk assessment and enforcement residue definition should be set as parent cypermethrin, including all isomers. The same residue definition is set in the Regulation (EC) No 396/2005 and is also in line with the residue definitions set by the Codex Alimentarius Commission. For the uses on the crops under consideration, EFSA concludes that the metabolism of cypermethrin is sufficiently addressed and the residue definitions agreed in the peer review are applicable. It should be noted that based on the results of the metabolism it is expected that the isomer ratio does not shift to the more toxic cis-isomer. 3.1.1.2. Magnitude of residues a. Olives In support of the intended GAP the applicant submitted 8 GAP compliant residue trials on olives. The trials have been performed in Spain, Italy and Greece in 2006 and 2007. Based on the submitted data the applicant proposes to derive the MRLs for table olives and olives for oil production. According to the revision 8 of the EU guidance document (EC, 2008), an extrapolation of residue data from table olives to olives for oil production is not supported as 8 GAP compliant trials are required on table olives and 4 GAP compliant trials are required on olives for oil production. According to revision 9 of the EU guidance document, an extrapolation of residue data from table olives to olives for oil production (and vice versa) is acceptable (EC, 2011). From the submitted residue data set no distinction can be made on which olives the residue trials have been performed. EFSA concludes that the proposed extrapolation by the EMS is acceptable. b. Lettuce In support of the intended GAP the applicant submitted 8 GAP compliant residue trials on head lettuce and 3 residue trials on an open leaf lettuce. The trials have been performed in various SEU countries in 2005 and 2006. The applicant proposes to extrapolate the residue data from lettuce to the whole group of salad plants (lamb`s lettuce, scarole, cress, land cress, rocket, red mustard, leaves and sprouts of Brassica spp.). According to the revision 8 of the EU guidance document (EC, 2008), the proposed extrapolation cannot be accepted as the supporting trials on lamb`s lettuce/cress are not available. Also according to the revision 9 of the EU guidance document (EC, 2011) at least 8 residue trials on an open-leaf lettuce variety would be required to support the group extrapolation. Consequently the submitted residue data support the MRL proposal on lettuce only. EFSA Journal 2011;9(6):2280 11

However, the extrapolation of residue data from spinach to few minor crops in the salad plant group, e.g. rocket and red mustard, would be possible according to EU guidance documents (EC, 2008). See point c). c. Spinach In support of the intended GAP on spinach, beet leaves (chard) and herbs (parsley, sage, rosemary, thyme, basil, laurel, tarragon), the applicant submitted 4 GAP compliant residue trails on spinach. Trials were performed in 2006 and 2007 in Southern European countries. The applicant proposes to extrapolate the residue data from spinach to the whole group of spinach and similar (leaves) and herbs. According to the EU guidance documents (EC, 2008, 2011), 4 residue trials on spinach would be sufficient to extrapolate residue data to any other single minor crop within a group; however, if the extrapolation is intended from spinach to the whole group of minor crops (in this case herbs group and/or spinach and similar (leaves) group), at least 8 trials on spinach would be required. EFSA therefore is of the opinion that the residue data extrapolation from spinach to the whole group of herbs is not fully supported, but the extrapolation of residues to the crops listed in the intended use -parsley, sage, rosemary, thyme, basil, laurel, tarragon (Appendix A) is in line with the EC guidance document. As for the spinach group the extrapolation of residue data from spinach to beet leaves (chard) is acceptable. In addition, the applicant proposed to extrapolate residue data from lettuce to the whole group of salad plants. This was not acceptable (see section b), but the extrapolation from spinach to rocket and red mustard is acceptable according to the EU guidance documents (EC, 2008, 2011). The results of the residue trials, the related risk assessment input values (highest residue, median residue) and the MRL proposals are summarized in Table 3-2. The storage stability of cypermethrin in primary crops was investigated in the Addendum to the DAR (Belgium, 2004). Residues of cypermethrin were found to be stable at -18 C for up to 12 months in matrices with high oil content as well as in dry matrices. The JMPR has evaluated the storage stability of cypermethrin also in high water content matrices (FAO, 2009). The studies demonstrate that in high water content matrices the residues of cypermethrin are stable for up to 12 months when stored deep frozen. As the supervised residue trial samples were stored under conditions for which the integrity of the samples was demonstrated, it is concluded that the residue data are valid with regard to the storage stability. According to the EMS, the analytical method used to analyse supervised residue trial samples was already evaluated for the enforcement and thus is sufficiently validated and fit for purpose (France, 2010). The isomer ratio was not reported separately. EFSA considers that the data are sufficient to derive the following MRL proposals: 0.4 mg/kg in table olives and olives for oil production, 3 mg/kg in lettuce and 4 mg/kg in spinach, beet leaves (chard), rocket, mustard, parsley, sage, rosemary, thyme, basil, laurel and tarragon. The proposed extrapolation of residue data from lettuce to the whole group of salad plants is not acceptable. The proposed extrapolation of residue data from spinach to the whole group of herbs is not fully supported. EFSA Journal 2011;9(6):2280 12

Table 3-2: Overview of the available residues trials data Commodity Region (a) Outdoor /Indoor Individual trial results (mg/kg) Enforcement (Cypermethrin (sum of isomers)) Olives SEU Outdoor 0.04; 3 x 0.08; 0.09; 0.12; 0.13; 0.33 Lettuce SEU Outdoor 0.27; 0.43; 0.49; 0.61; 0.65; 0.74; 0.75 e ; 1.10; 1.30 e ; 1.7; 2.01 e Spinach beet leaves (chard) Spinach rocket, mustard for leave consumption SEU Outdoor 1.0; 1.17; 1.4; 2.10 Risk assessment (Cypermethrin (sum of isomers)) 0.04; 3 x 0.08; 0.09; 0.12; 0.13; 0.33 0.27; 0.43; 0.49; 0.61; 0.65; 0.74; 0.75 e ; 1.10; 1.30 e ; 1.7; 2.01 e 1.0; 1.17; 1.4; 2.10 Median residue (mg/kg) (b) Highest residue (mg/kg) (c) MRL proposal (mg/kg) Media n CF (d) 0.09 0.33 0.4 1.0 R ber =0.26 R max =0.40 Comments OECD MRL f = 0.5 mg/kg 0.74 2.01 3.0 1.0 R ber =2.6 R max =2.47 OECD MRL f = 4.0 mg/kg The proposed extrapolation to the whole group of salad plants is not acceptable. 1.29 2.10 4.0 1.0 R ber =3.85 R max =3.91 OECD MRL f = 5.0 mg/kg Spinach parsley, sage, rosemary, thyme, basil, laurel, tarragon (a): NEU, SEU, EU or Import (country code). In the case of indoor uses there is no necessity to differentiate between NEU and SEU. (b): Median value of the individual trial results according to the enforcement residue definition. (c): Highest value of the individual trial results according to the enforcement residue definition. (d): The median conversion factor for enforcement to risk assessment is obtained by calculating the median of the individual conversion factors for each residues trial. (*): Indicates that the MRL is set at the limit of analytical quantification. (e): Trials with an open-leaf lettuce (f): OECD MRL is calculated with the OECD calculator (OECD, 2011). EFSA Journal 2011;9(6):2280 13

3.1.1.3. Effect of industrial processing and/or household preparation The effects of processing on the nature of cypermethrin residues have been evaluated by the JMPR in the studies performed at two test conditions representing pasteurization and sterilization processes (20 minutes at 90 C, ph 4; 20 minutes at 120 C, ph 5) (FAO, 2009). Cypermethrin was stable to hydrolysis under the investigated conditions. In processed commodities therefore the same residues as in raw commodities are expected. No specific studies investigating the effects of processing on the magnitude of cypermethrin residues have been submitted in the framework of the current application. In 2008 the JMPR assessed the effect of processing on the magnitude of alpha-cypermethrin residues in processed olive products. The JMPR derived a processing factor of 7.5 for crude olive oil and a processing factor of 8.2 for refined olive oil (FAO, 2009). The study results confirm the lipophilic nature of cypermethrin and indicate a concentration of residues in oil. For other crops under consideration the need for processing studies is less relevant. The derived processing factors for crude and refined olive oil are recommended for the inclusion in Annex VI of Regulation (EC) No 396/2005. 3.1.2. Rotational crops 3.1.2.1. Preliminary considerations The crops under consideration, except olives, can all be grown in rotation with other plants and therefore the possible occurrence of residues in succeeding crops resulting from the use on primary crops has to be assessed. The soil degradation studies evaluated in the framework of the peer review demonstrate that the degradation rate of cypermethrin in soil is moderate with the maximum DT 90 of 375 days which is above the trigger value of 100 days (EC, 2005). Thus, further studies investigating the nature and magnitude of the compound uptake in rotational crops are required. The identified soil metabolites of cypermethrin were 3-phenoxybenzoic acid and DCVA (3-(2,2-dichlorovinyl)2,2- dimethylcyclopropanecarboxylic acid). 3.1.2.2. Nature of residues The metabolism of cypermethrin in rotational crops was assessed in the DAR prepared under Directive 91/414/EEC (Belgium, 1999). The studies were performed with 14 C-cypermethrin labelled in the benzyl and cyclopropyl rings. Lettuce was grown as primary crop and was treated with cypermethrin twice at an application rate of 0.3 kg a.s./ha (6N). After the harvest of lettuce (PHI varied from 18 and 21 days), the 0-10 cm top layer of soil was thoroughly mixed and potatoes were planted as rotational crops. Soil samples were analysed after the harvest of lettuce. The results indicate that cypermethrin residues strongly adhered to soil accounting for 0.18 mg eq./kg and 0.10 mg eq./kg for benzyl and cyclopropyl labelled cypermethrin, respectively. The presence of 3-phenoxybenzoic acid and DCVA was confirmed but no further information on the amounts of these substances is available. According to the DAR, mature potatoes contained very low levels of residues in tubers and haulms and in most of the samples no residues were detected. The JMPR refers to a confined rotational crop study performed with wheat, cotton, lettuce and sugar beet (FAO, 2009). Soil was treated with 14 C-benzyl cypermethrin at the application rate of 1 kg a.s./ha EFSA Journal 2011;9(6):2280 14

and the crops were sown 30, 60, 90 and 120 days later. Study indicated that low levels of radioactive residues are present in the crops with concentrations decreasing as the time interval increased. The levels were too low for component identification. A parallel experiment with 14 C-cyclopropyl had been available producing similar results (FAO, 2009). From the available studies it can be concluded that cypermethrin is the relevant residue in rotational and/or succeeding crops. 3.1.2.3. Magnitude of residues The rotational crop field study was assessed in the DAR (Belgium, 1999). In the study bare soil was treated at an application rate of 0.5 kg a.s./ha and in the next year field beans, sugar beet and wheat were sown. Intervals between treatments and the harvest were 71 weeks for beans, 99 weeks for sugar beet and 108 weeks for wheat. The samples of beans (seed and foliage) and sugar beet foliage were analysed for cypermethrin whereas sugar beet roots and wheat straw was analysed also for 3- phenoxybenzoic acid and DCVA. Samples of wheat grain were not analysed for residues. In the sugar beet root and beans parent cypermethrin was below the LOQ of 0.01 mg/kg. Metabolites in the analysed samples were below 0.05 mg/kg. The study was considered as incomplete (no data at all have been given about residues in wheat grain and the residues of metabolites were not determined in beans and sugar beet foliage). During the peer review the experts concluded that, considering the application rate in the study, no residues are expected in rotational crops and additional studies are not required. Considering that the total seasonal application rate on the crops under consideration is lower than in the investigated studies (0.2N), it is unlikely that significant cypermethrin residues will occur in rotational and/or succeeding crops. However, considering the deficiencies in the rotational crop field study, the need for a plant-back restriction should be considered at national level before granting an authorization of cypermethrin. 3.2. Nature and magnitude of residues in livestock Since the crops under consideration and/or their by-products are not normally fed to livestock, the nature and magnitude of cypermethrin residues in livestock was not assessed in the framework of this application. 4. Consumer risk assessment The consumer risk assessment was 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 sub-groups of the EU population 9 (EFSA, 2007). Since the existing EU MRLs are set for the sum of isomers, it is not known whether residues in food commodities result from the use of cypermethrin only or from any other cypermethrin isomer which is also used as an active substance. As alpha-cypermethrin is known to be more toxic than other cypermethrin isomers, EFSA calculated two scenarios of the chronic exposure. 9 The calculation of the long-term exposure (chronic exposure) is based on the mean consumption data representative for 22 national diets collected from MS surveys plus 1 regional and 4 cluster diets from the WHO GEMS Food database; for the acute exposure assessment the most critical large portion consumption data from 19 national diets collected from MS surveys is used. The complete list of diets incorporated in EFSA PRIMo is given in its reference section (EFSA, 2007). EFSA Journal 2011;9(6):2280 15

Scenario 1 In scenario 1 EFSA assumed that the existing EU MRLs result from the use of cypermethrin only. For the calculation of the chronic exposure, EFSA used the median residue values as derived from the residue trials on olives, lettuce and spinach (see Table 3-2) which were also extrapolated to the crops for which MRL proposals were derived. For the remaining commodities of plant and animal origin the existing MRLs as established in Annexes II and IIIB of Regulation (EC) No 396/2005 were used as input values. The model assumptions for the long-term exposure assessment are considered to be rather conservative, assuming that all food items consumed have been treated with the active substance under consideration. In reality, it is not likely that all food consumed will contain residues at the MRL or at levels of the median residue values identified in supervised field trials. On the other hand, assuming that all residues refer to the less toxic cypermethrin may lead to an underestimation of the toxicological burden for consumers. The acute exposure assessment was performed only with regard to the commodities under consideration assuming the consumption of a large portion of the food items as reported in the national food surveys containing residues at the highest level as observed in supervised field trials. The input values used for the dietary exposure calculation are summarized in Table 4-1. Table 4-1: Input values for the consumer dietary exposure assessment Commodity Chronic exposure assessment Acute exposure assessment Input value (mg/kg) Comment Risk assessment residue definition: Cypermethrin (sum of isomers) Table olives, olives for oil production Input value (mg/kg) Comment 0.09 Median residue 0.33 Highest residue Lettuce 0.74 Median residue 2.01 Highest residue Spinach, beet leaves (chard), rocket, mustard, parsley, sage, rosemary, thyme, basil, laurel, tarragon Meat of swine, bovine, sheep, goat, horses 1.29 Median residue (spinach) Meat of poultry 0.02 MRL*0.2 a Other commodities of food and animal origin 2.10 Highest residue (spinach) 0.4 MRL*0.2 a Acute risk assessment was undertaken only with regard to the crops under consideration. MRL See Appendix C a existing MRLs for cypermethrin in meat are expressed on a fat basis (20% of fat in the meat) The estimated exposure was compared with the toxicological reference values derived for cypermethrin. The results of the intake calculations are presented in Appendix B (scenario 1) to this reasoned opinion. In scenario 1 no long-term consumer intake concerns were identified for any of the European diets incorporated in the EFSA PRIMo. The total calculated intake values ranged from 9.4-82.7% of the ADI (UK toddler diet). The contribution of residues in the crops under consideration to the total consumer exposure in the percentage of the ADI accounted for a maximum of 1.18% for spinach (FR EFSA Journal 2011;9(6):2280 16

toddler diet), 0.79% for lettuce (ES adult diet), 0.35% for olives for oil production (WHO Cluster diet B), 0.21% for beet leaves (chard) (ES adult and ES child diets), below 0.13% for herbs under consideration, 0.014% for table olives (WHO Cluster diet B) and 0.016% for rocket (DE child diet). EFSA is aware that the calculated consumer exposure might be underestimated as not all MRLs result from the use of cypermethrin. No acute consumer risk was identified in relation to the MRL proposals for the crops under consideration. The calculated maximum exposure in percentage of the ARfD was 27% for lettuce, 23.7% for spinach, 18.4 % for beet leaves (chard) and below 10% for other crops under consideration. Scenario 2 In a more conservative scenario 2 EFSA assumed that the existing EU MRLs result from the use of alpha-cypermethrin only. The existing EU MRLs as established for cypermethrin in Annexes II and IIIB of Regulation (EC) No 396/2005 were used as input values. As MRLs for meat have been set on a fat basis, residues were recalculated assuming that meat contains 20% of fat. The model assumptions for the long-term exposure assessment are considered to be rather conservative, assuming that all food items consumed have been treated with the active substance under consideration. In reality, it is not likely that all food consumed will contain residues at the MRL or at levels of the median residue values identified in supervised field trials. However, if this first tier exposure assessment, does not exceed the toxicological reference value for long-term exposure (i.e. the ADI), a consumer health risk can be excluded with a high probability. The estimated exposure was compared with the toxicological reference value derived for alphacypermethrin. The results of the intake calculations are presented in Appendix B (scenario 2) to this reasoned opinion. In scenario 2 long term consumer intake concerns could not be excluded for 16 diets included in the EFSA PRIMo. The total calculated intake values accounted for a maximum of 275.8% of the ADI (UK Toddler). EFSA is aware that this exposure calculation might be overestimated as not all MRLs result from the use of alpha-cypermethrin; however, further refinements could not be performed due to the lack of information on the source of the MRL. EFSA concludes that currently the risk assessment regarding the actual consumer exposure to cypermethrin residues cannot be finalised. Considering that chronic consumer intake concerns have been identified in relation to the existing EU MRLs for cypermethrin, EFSA is of the opinion that additional uses of cypermethrin contributing to the toxicological burden currently cannot be supported. To perform more accurate consumer exposure assessments, full information on all authorised uses of various cypermethrin isomers is required. In addition, EFSA proposes to set separate residue definitions for those cypermethrin isomers which have different toxicological reference values. It is noted that the review of the existing EU MRLs for cypermethrin (alpha-, zeta-cypermethrin and cypermethrin) is ongoing according to Article 12 of Regulation (EC) No 306/2005. EFSA Journal 2011;9(6):2280 17

CONCLUSIONS AND RECOMMENDATIONS CONCLUSIONS The toxicological profile of cypermethrin was assessed in the framework of the peer review under Directive 91/414/EEC and the data were sufficient to derive an ADI of 0.05 mg/kg bw/day and an ARfD of 0.2 mg/kg bw. It is noted that cypermethrin is a mixture of isomers and one of its isomer pairs - cis-2-isomer - is used also as an active substance alpha-cypermethrin and has higher toxicity than cypermethrin (ADI of 0.015 mg/kg bw/d; ARfD of 0.04 mg/kg bw). The metabolism of cypermethrin in primary crops was investigated in fruit and fruiting vegetables, leafy vegetables and pulses and oilseeds. From these studies the peer review established the residue definition for risk assessment and enforcement as cypermethrin (sum of isomers). The same residue definition is established in Regulation (EC) No 396/2005. For the uses on the crops under consideration, EFSA concludes that the metabolism of cypermethrin is sufficiently addressed and the residue definitions as agreed in the peer review are applicable. EFSA considers that the data are sufficient to derive the following MRL proposals: 0.4 mg/kg in table olives and olives for oil production, 3 mg/kg in lettuce and 4 mg/kg in spinach, beet leaves (chard), rocket, mustard, parsley, sage, rosemary, thyme, basil, laurel and tarragon. The proposed extrapolation of residue data from lettuce to the whole group of salad plants is not acceptable. The proposed extrapolation of residue data from spinach to the whole group of herbs is not fully supported. Adequate analytical enforcement methods are available to monitor cypermethrin residues (sum of isomers) in the crops under consideration. The effects of processing on the nature of cypermethrin residues have not been investigated in the peer review. According to the evaluation of the JMPR, during sterilisation and pasteurization processes no degradation of cypermethrin occurs and therefore for processed commodities the same residue definition as for raw agricultural commodities is applicable. No specific studies investigating the effects of processing on the magnitude of cypermethrin residues have been submitted in the framework of the current application. The JMPR has assessed the processing studies with olives. The study results indicate a concentration of residues in refined and crude olive oil. For other crops under consideration the need for processing studies is less relevant. The following processing factors derived by the JMPR are recommended for enforcement purposes: Olives, crude olive oil: 7.5 Olives, refined olive oil: 8.2 The possible occurrence of cypermethrin residues in rotational and/or succeeding crops was also investigated. It was concluded by the peer review that the nature of residues in rotational crops and primary crops is similar. The need for a plant-back restriction should be considered at national level before granting an authorization of cypermethrin. Residues of cypermethrin in commodities of animal origin were not assessed in the framework of this application, since the crops under consideration are normally not fed to livestock. The consumer risk assessment was performed with revision 2 of the EFSA PRIMo. This exposure assessment model contains the relevant European food consumption data for different sub-groups of the EU population. Since the existing EU MRLs are set for the sum of isomers, it is not known whether residues in food commodities result from the use of cypermethrin or from other individual cypermethrin isomer. As alpha-cypermethrin is known to be more toxic than cypermethrin and other isomers, EFSA calculated two scenarios of the chronic exposure. EFSA Journal 2011;9(6):2280 18

In scenario 1 EFSA assumed that the existing EU MRLs are based on the use of cypermethrin only. The median residue values as derived from the residue trials on olives, lettuce and spinach were used as input values and were also extrapolated to the crops for which MRL proposals were derived. For other food commodities of animal and plant origin, the existing MRLs as established in Annexes II and IIIB of Regulation (EC) No 396/2005 were used as input values. The acute exposure calculation was performed to assess the consumer exposure to cypermethrin residues resulting from the intake of the commodities under consideration assuming the consumption of a large portion of the food items as reported in the national food surveys containing residues at the highest level as observed in supervised field trials. The estimated exposure was compared with the toxicological reference value derived for cypermethrin. No long-term consumer intake concerns were identified for any of the European diets incorporated in the EFSA PRIMo. The total calculated intake values ranged from 9.4-82.7% of the ADI (UK toddler diet). The individual contribution of residues in the crops under consideration to the total consumer exposure in the percentage of the ADI accounted for less that 2% of the ADI. EFSA is aware that the calculated chronic consumer exposure might be underestimated as not all MRLs result from the use of cypermethrin. No acute consumer risk was identified in relation to the MRL proposals for the crops under consideration. The calculated maximum exposure in the percentage of the ARfD was 27% for lettuce, 23.7% for spinach, 18.4 % for beet leaves (chard) and below 10% for other crops under consideration. In a more conservative scenario 2 EFSA assumed that the existing EU MRLs result from the use of alpha-cypermethrin only. The EU MRLs as established in Annexes II and IIIB of Regulation (EC) No 396/2005 were used as input values. The estimated exposure was compared with the toxicological reference value derived for alpha-cypermethrin. In scenario 2 long term consumer intake concerns could not be excluded for 16 diets included in the EFSA PRIMo. The total calculated intake values accounted for a maximum of 275.8% of the ADI (UK Toddler). EFSA is aware that this exposure calculation might be overestimated as not all MRLs result from the use of alpha-cypermethrin; however, further refinements could not be performed due to the lack of information on the source of the MRL. EFSA concludes that currently the risk assessment regarding the actual consumer exposure to cypermethrin residues cannot be finalised. Considering that chronic consumer intake concerns have been identified in relation to the existing EU MRLs for cypermethrin, EFSA is of the opinion that additional uses of cypermethrin contributing to the toxicological burden currently cannot be supported. To perform more accurate consumer exposure assessments, full information on all authorised uses of various cypermethrin isomers is required. In addition, EFSA proposes to set separate residue definitions for those cypermethrin isomers which have different toxicological reference values. It is noted that the review of the existing EU MRLs for cypermethrin (alpha-, zeta-cypermethrin and cypermethrin) is ongoing according to Article 12 of Regulation (EC) No 306/2005. It is also noted that the existing EU MRLs for products of animal origin established in Regulation (EC) No 396/2005 do not correspond with the MRL values set for cypermethrin under Regulation (EC) No 37/2010 for its use as a veterinary drug. In order to avoid legal uncertainties, EFSA would strongly recommend revising the contradictious MRLs for meat, fat, liver and kidney of ruminants (bovine, sheep, goat) and milk. EFSA Journal 2011;9(6):2280 19