Modification of the existing MRLs for cyflufenamid in various crops 1

Transcription

1 ESA Journal 2011;9(5):2161 REASONED OPINION Modification of the existing MRLs for cyflufenamid in various crops 1 European ood Safety Authority 2 European ood Safety Authority (ESA), Parma, Italy SUMMARY In accordance with Article 6 of Regulation (EC) No 396/2005, The United Kingdom, herewith referred as the evaluating Member State (EMS), received an application from Nisso Chemical Europe GmbH to modify the existing MRLs for the active substance cyflufenamid in apples, pears, table and wine grapes, courgette, cucumber and melon. In order to accommodate for the intended uses of cyflufenamid, it is suggested to raise the existing MRLs from 0.02* mg/kg for these crops to the proposed MRL of 0.05 mg/kg for apples, pears and courgettes, to the MRL of 0.04 mg/kg for cucumber and melon and to the MRL of 0.15 mg/kg for table and wine grapes. The United Kingdom as the Evaluating Member State (EMS) drafted an evaluation report according to Article 8 of Regulation (EC) No 396/2005, which was submitted to the European Commission and forwarded to ESA on 13 September During the assessment some data requirements were identifed which prevented ESA to conclude on the consumer risk assessment. The EMS, in collaboration with the applicant, fulfilled the data requirements and provided an updated evaluation report received on 29 March ESA bases its assessment on the updated Evaluation Report, the Draft Assessment Report prepared by the United Kingdom, the ESA conclusion issued in the framework of the peer review and the ESA reasoned opinion on the modification of the existing MRL for cyflufenamid in oats. The toxicological profile of cyflufenamid was assessed in the framework of the peer review under Directive 91/414/EEC and the data were sufficient to propose an ADI of 0.04 mg/kg bw/day and an ARfD of 0.05 mg/kg bw. The metabolism of cyflufenamid in primary crops was investigated in cereals (winter and spring wheat), fruit crops (apples) and fruiting vegetables (cucumber). rom the metabolism studies on wheat, the peer review concluded on the residue definition for risk assessment and enforcement as the sum of cyflufenamid (Z-isomer) plus its E-isomer. or the use on apples, pears, table and wine grapes, cucumber, courgette and melon, ESA concluded that the metabolism of cyflufenamid in primary crops is sufficiently elucidated and that the derived residue definitions for cereals are also appropriate for fruit crops and fruiting vegetables. The supervised residue trials are sufficient and adequate to derive MRL proposals respectively for the intended uses on apples, pears, table and wine grapes, cucumber, courgette and melon. The studies confirmed that a MRL of 0.05 mg/kg would be appropriate for the intended uses of cyflufenamid on 1 On request from the European Commission, Question No ESA-Q , issued on 11 May Correspondence: pesticides@efsa.europa.eu Suggested citation: European ood Safety Authority; Modification of the existing MRLs for cyflufenamid in various crops. ESA Journal 2011;9(5):2161. [35 pp.] doi: /j.efsa Available online: European ood Safety Authority, 20

2 apples, pears and courgette, a MRL of 0.04 mg/kg would be sufficient for cucumbers and melon whilst a MRL of 0.15 mg/kg is considered as suitable for table and wine grapes. ESA notes that storage stability was demonstrated for the crops under consideration except grapes. Studies on stored grapes are currently ongoing to confirm the validity of the submitted residue trials. However, since the storage stability was demonstrated for similar matrices, this data are considered as confirmatory data only. Analytical methods are available to enforce the proposed MRLs on the commodities under consideration. No additional processing studies are necessary taking into account the low levels of cyflufenamid residues in the crops under consideration and the low dietary exposure of the consumers. Moreover, based on the metabolic pathways depicted in relevant metabolism studies, it is not expected that toxicological relevant degradation products may occur under the representative processing conditions. Specific studies investigating the magnitude of cyflufenamid residues in processed commodities are not required, as the residues expected in primary crops are low and/or the total theoretical maximum daily intake (TMDI) is below the trigger value of 10 % of the ADI. The occurrence of cyflufenamid residues in rotational crops was investigated in the Draft Assessment Report in the framework of the peer review. Based on the available information on the nature and magnitude of residues in succeeding crops, it was concluded that significant residue levels (>0.01 mg/kg) are unlikely to occur in rotational crops provided that cyflufenamid is applied according to the GAP assessed under this application. Since apple pomace is used as a feed product, a potential carry-over into food of animal origin was assessed. The calculated livestock dietary burden exceeded the trigger value of 0.1 mg/kg (dry matter) for meat ruminants but was mainly driven by the existing MRLs of feed products. The impact of cyflufenamid residues in apple pomace to the total livestock exposure was shown to be insignificant and therefore the modification of the MRLs for commodities of animal origin is not required in the framework of the current application. The consumer dietary risk assessment for cyflufenamid was performed with revision 2 of the ESA PRIMo. or the calculation of the chronic exposure, ESA used the median residue value as derived from the residue trials on apples, pears, table and wine grapes, cucumber, courgette and melon. The median residue values for cereals grains were derived from the previous ESA reasoned opinion and the ESA conclusion. or the remaining commodities of plant and animal origin, the existing MRLs as established in Annex III of Regulation (EC) No 396/2005 were used as input values. The acute dietary intake risk assessment was carried out only with regard to the products for which a MRL is requested applying the respective highest residue values as derived from the supervised residue trials on the crops under consideration. No chronic intake concerns were identified for any of the European diets and the total intake values accounted for a maximum of 4.6% of the ADI. The contribution of the different crops under consideration to the total dietary intake was low (0.33% ADI NL child). No acute intake concerns were identified in relation to the MRL proposals for the crops under consideration (15.7% of the ARfD Table grapes). ESA concludes that the intended use of cyflufenamid on apples, pears, table- and wine grapes, cucumbers, courgettes and melons will not result in a dietary exposure posing a consumer health risk. Thus, ESA proposes to amend the current MRLs as summarised in the table below: ESA Journal 2011;9(5):2161 2

3 Code number (a) Commodity Existing EU MRL Proposed EU MRL Enforcement residue definition: sum of cyflufenamid (Z-isomer) and its E-isomer Justification for the proposal Apples 0.02* 0.05 The MRL proposals are sufficiently Pears 0.02* 0.05 supported by data and no risk for consumers was identified for the intended Table grapes 0.02* 0.15 uses Wine grapes 0.02* Cucumbers 0.02* Courgettes 0.02* Melon 0.02* 0.04 (a): According to Annex I of Regulation (EC) No 396/2005. (*): Indicates that the MRL is set at the limit of analytical quantification. KEY WORDS Cyflufenamid, apples, pears, grapes, cucumbers, courgettes, melons, MRL application, Regulation (EC) No 396/2005, consumer risk assessment, amide fungicide ESA Journal 2011;9(5):2161 3

4 TABLE O CONTENTS Summary... 1 Table of contents... 4 Background... 5 Terms of reference... 5 The active substance and its use pattern... 6 Assessment Methods of analysis Methods for enforcement of residues in food of plant origin Methods for enforcement of residues in food of animal origin Mammalian toxicology Residues Nature and magnitude of residues in plant Primary crops Rotational crops Nature and magnitude of residues in livestock Dietary burden of livestock Consumer risk assessment Conclusions and recommendations References Appendix A. Good Agricultural Practices (GAPs) Appendix B. Pesticide Residues Intake Model (PRIMo) Appendix C. Existing EU maximum residue limits (MRLs) Appendix D. List of metabolites and related structural formula Abbreviations ESA Journal 2011;9(5):2161 4

5 BACKGROUND Regulation (EC) No 396/ 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 a MRL in accordance with the provisions of Article 7 of that Regulation. The United Kingdom, hereafter referred to as the evaluating Member State (EMS), received an application from the company Nisso Chemical Europe GmbH 5 to modify the existing MRLs for the active substance cyflufenamid in apples, pears, table and wine grapes, cucumber, courgette and melon. This application was notified to the European Commission and ESA 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 ESA on 13 September The application was included in the ESA Register of Questions with the reference number ESA-Q and the following subject: Cyflufenamid Application to modify the existing MRLs in various crops The United Kingdom proposed to modify the existing MRL of 0.02* mg/kg of cyflufenamid for all the crops and to propose a MRL of 0.05 mg/kg for apples, pears and courgettes, a MRL of 0.04 mg/kg for cucumbers and melons and a MRL of 0.15 mg/kg for table and wine grapes. ESA then proceeded with the assessment of the application as required by Article 10 of the Regulation. On 21 December 2010 some data requirements were identified, which prevented ESA to conclude on the consumer risk assessment. An updated evaluation report, addressing those data requirements, was submitted by the EMS on 29 March 2011 and was taken into consideration by ESA to issue this reasoned opinion. TERMS O REERENCE In accordance with Article 10 of Regulation (EC) No 396/2005, ESA 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 ESA 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 29 March Regulation (EC) No 396/2005 of the Parliament and of the Council of 23 ebruary OJ L 70, , p Council Directive 91/414/EEC of 15 July OJ L 230, , p Nisso Chemical Europe GmbH, Stein Straβe 27, 40210, Düsseldorf, Germany ESA Journal 2011;9(5):2161 5

6 THE ACTIVE SUBSTANCE AND ITS USE PATTERN Cyflufenamid is the ISO common name for (Z)-N-[ -(cyclopropylmethoxyimino)-2,3-difluoro-6- (trifluoromethyl)benzyl]-2-phenylacetamide (IUPAC). The chemical structure of the compound is herewith reported. N O O C 3 N H Molecular weight: g/mole Cyflufenamid belongs to the class of amide fungicides. It is fungitoxic to powdery/downy mildew on crops through translaminar and vapour activity, although the mode of action has not been established. It is considered as fat soluble since it has a log P ow of 4.7. Cyflufenamid is considered as a new active substance in the scope of Directive 91/414/EEC. The United Kingdom was the designated Rapporteur Member State. It was included in Annex I of this Directive by Directive 2009/154/EC 6 which entered into force on 1 April 2010 for use as fungicide only. The peer review of cyflufenamid was completed and an ESA conclusion was issued on 8 April The representative uses evaluated and covering northern and southern Member States comprise foliar spraying with conventional tractor-mounted devices against powdery mildew in winter and spring wheat, triticale, rye and barley, from growth stage of BBCH 30 up to growth stage of BBCH 59 with a maximum of two applications, at a maximum individual application rate per spray of 25 g a.s./ha with an interval of 28 days between applications. In the European Union temporary MRLs were established for cyflufenamid in the Annex IIIA of Regulation (EC) No 396/2005 by Regulation (EC) No 839/ The existing MRLs are summarized in Appendix C. These temporary MRLs have been derived from MRLs that have been set at national level before Regulation (EC) No 396/2005 entered into force. MRLs above the LOQ have been amended by Commission Regulation (EC) No 1050/ for barley (0.1 mg/kg), oat (0.1 mg/kg), wheat and rye (0.05 mg/kg) and a MRL of 0.03* mg/kg has been set for animal commodities based on the ESA reasoned opinion (ESA, 2009b). No Codex MRLs were set for cyflufenamid. The residue definition for cyflufenamid in the Regulation (EC) No 396/2005 currently is set as parent cyflufenamid. The intended GAPs for which a modification of the existing MRLs is requested in northern (Germany, The United Kingdom, Poland, Czech Republic, Slovakia, Hungary, Romania, Austria, The Netherlands) and southern (Greece, Italy, Spain, Potugal) Europe refer to outdoor uses of cyflufenamid on apples, pears, table and wine grapes, courgettes and melons and also indoor uses on melons and cucumbers using tractor mounted/trailed air blast/boom sprayer or hand-held sprayer. The details of the GAPs are given in Appendix A. 6 Commission Directive (EC) No 154/2009 of 30 November 2009, OJ L 314 of , p Commission Regulation (EC) No 839/2008 of 31 July 2008, OJ L 234 of , p Commission Regulation (EC) No 1050/2009 of 28 October 2009, OJ L 290 of , p ESA Journal 2011;9(5):2161 6

7 ASSESSMENT ESA bases its assessment on the updated evaluation report submitted by the EMS (The United Kingdom, 2011), the Draft Assessment Report (DAR) (The United Kingdom, 2006) prepared under Council Directive 91/414/EEC, the final addendum to the DAR (The United Kingdom, 2009), the ESA conclusion (ESA, 2009a) as well as the previously issued ESA reasoned opinion on the modification of the existing MRL for cyflufenamid in oats (ESA, 2009b). 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, 2007, 2010, 2011, OECD 2011a and 2011b). 1. Methods of analysis 1.1. Methods for enforcement of residues in food of plant origin Analytical methods for the determination of cyflufenamid residues in plant commodities were assessed in the DAR and in the conclusion on the peer review under Directive 91/414/EEC (ESA, 2009a). A GC-MS method is available and considered as sufficiently validated to monitor cyflufenamid residues in cereal grains with a LOQ of 0.01 mg/kg. In the ESA conclusion a data requirement was set to clarify whether the method was able to separate the E- and Z- isomers or not. In the frame of the MRL application on oats (ESA, 2009b), the RMS confirmed that the method used in the residue studies cannot separate the two isomers. However, this analytical method was considered as appropriate for enforcement of residue definition proposed as the sum of cyflufenamid (Z-isomer) plus its E-isomer for cereal crops only. (ESA, 2009a). Two analytical methods were used to determine the cyflufenamid residues in grapes and apples (GC- MSD) and in cucumbers, courgettes, melons (peel/pulp) (HPLC/MS-MS). The validation data were included in the updated Evaluation Report (UK, 2011). An ILV for the determination of cyflufenamid residues in apples and grapes was also considered as acceptable. These methods were sufficiently validated in high acid and high water content matrices in accordance with the current guidance document SANCO/825/00 rev.8.1 at the Limit of Quantification of 0.01 mg/kg and were also recommended as enforcement methods. Although it was not reported whether these two analytical methods used in the supervised residue trials analysed only the cyflufenamid (Z-isomer) or cover both the Z- and E-isomers in compliance with the new proposed residue definition for monitoring, they can be considered as appropriate for enforcement purposes. Since the commodities under consideration belong to the group of high water and high acid content commodities, ESA concludes that sufficiently validated analytical methods for enforcing the proposed MRLs for cyflufenamid on apples, pears, grapes, cucumbers, courgettes and melons are acceptable Methods for enforcement of residues in food of animal origin In the peer review a residue definition for risk assessment and enforcement for the commodities of animal origin was set as the sum of cyflufenamid, the E-isomer 9 and metabolite , expressed as (E)-B:(E)-N-[α-(cyclopropylmethocyimino)-2,3-difluoro-6-(trifluoromethyl)benzyl]-2-phenylacetamide:see Appendix D ESA Journal 2011;9(5):2161 7

8 cyflufenamid (ESA, 2009a). A LC/MS/MS analytical method was provided in the framework of the modification of the existing MRL for cyflufenamid in oats (ESA, 2009b) and was considered as sufficiently validated at the LOQ of 0.03 mg/kg (parent cyflufenamid 0.01 mg/kg, E-isomer 0.01 mg/kg and mg/kg) for the determination of cyflufenamid residues in the commodities of animal origin (ESA, 2009b). 2. Mammalian toxicology The toxicological reference values for cyflufenamid were derived during the peer review and are compiled in the Table 2-1 (ESA, 2009a). Table 2-1. Cyflufenamid Overview of the toxicological reference values Source Year Value (mg/kg bw/d) Study relied upon ADI ESA yr rat 1 yr dog ARfD ESA Rabbit developmental toxicity Safety factor During the peer review, the meeting of experts requested that the toxicological potential of the stereoisomer of cyflufenamid, 149-(E)-B, should be addressed for the consumer risk assessment. According to the information presented in the DAR (The United Kingdom, 2006), the stereoisomer of cyflufenamid, 149-(E)-B is not expected to be of higher toxicity than the parent compound given the site of the stereoisomerism. Moreover, the aglycone metabolites that were identified in the apple and cucumber metabolism studies (see section ) were also recovered in the rat excreta and were therefore considered as covered by the available toxicological studies on the parent cyflufenamid. Some glucosides conjugated metabolites, i.e B-Glu 11 (apples) and OH-B-Glu 12 (apples, cucumbers) were not detected in the rat metabolism but these are not expected to contribute significantly to the toxicological burden since they occurred at a very low level (<1% TRR) : 2,3-difluoro-6-(trifluoromethyl)benzamidine: see Appendix D 149-4B-Glu:N-{(Z)- [2,3-difluoro-6-trifluoromethyl -( -glucopyranosylimino)benzyl]}-2-phenylacetamide: see Appendix D OH-B-Glu:Glycosides conjugate of OH-B ESA Journal 2011;9(5):2161 8

9 3. Residues 3.1. Nature and magnitude of residues in plant Primary crops Nature of residues The metabolism of cyflufenamid in cereals (winter wheat) was investigated by the RMS (The United Kingdom, 2006) and reviewed by ESA (ESA, 2009a) in the framework of the peer review under Directive 91/414/EEC. Metabolism studies were also submitted on apples (fruit crops) and cucumbers (fruiting vegetables) in order to support the intended uses in the framework of this application. The design of the studies is summarised in Table 3-1. Table 3-1. Summary of available metabolism studies in plants Group Crop Label position Cereals Winter wheat (Study A) Winter wheat (Study B) Winter wheat (Study C) fluorinated phenyl-u- 14 C fluorinated phenyl-u- 14 C cyclopropyl- 2,3-14 C ruit crops Apple fluorinated phenyl-u- 14 C ruiting vegetables Cucumber fluorinated phenyl-u- 14 C Method, or G (a) oliar spray application oliar spray application oliar spray application Spray application Application details Rate (g a.s./ha) No/ Interval (5.4N) Not specified 50 (1.6N) (a): Outdoor/field use () or glasshouse/protected crops/indoor application (G) DAT: Days after treatment. 200 (6.6N) GS 32 and GS 32 and GS 32 and 59 Sampling -orage and roots (2 hours after each application) -Mature grain, husk, straw, root: 266 days after sowing -orage and roots (2 hours after each application), 7 weeks before harvest -Mature grain, husk, straw, root: normal harvest. -orage and roots (2 hours after each application), 3-4 weeks before harvest -Mature grain, husk, straw, root: normal harvest. 1 Leaves: 2 hrs after application Apples/leaves: 3, 6, 13 weeks after application and 31 DAT 7-35 DAT. ESA Journal 2011;9(5):2161 9

10 a. Cereals Modification of the existing MRL for cyflufenamid in various crops The major component of the total radioactive residues in all cereal plant parts was cyflufenamid at levels of up to 99% TRR in forage, 37% TRR in straw and 7% TRR in grain. The E-isomer of cyflufenamid was quantified in forage and parts of mature crops at levels up to 4% TRR (approximately 10% of the level of cyflufenamid), which was significantly higher than the content of the E-isomer in the technical material of cyflufenamid. This indicated a shift of isomer ratio of the Z- isomer to the E-isomer. In samples from mature plants also low concentrations (all < 5%) of the following metabolites were identified: OH-B 13, OH-B 14, 149--α-OH-B 15, and 149-4B-Glu. The residue definition for monitoring and risk assessment was set as the sum of cyflufenamid (Zisomer) plus its E-isomer which was restricted to cereal crops only as no other metabolism studies covering other categories of crops were submitted in the framework of the peer review under Directive 91/414/EEC. b. Apples At all sampling intervals, the major part of the total radioactive residues in apple fruit were recovered in the surface wash fraction, i.e. 52.3% TRR (13 weeks after treatment) and 88.1% TRR (3 weeks after application) while the total residues recovered in peel and flesh extracts accounted for up to respectively 17.6% and 11.5% TRR at harvest (13 weeks after application). In apple fruit at harvest, the parent compound was found to be the predominant compound of the total residues (66.2% TRR mg/kg) while the following minor metabolites were also detected: E-isomer of cyflufenamid (1.33% TRR), 149-4B-Glu (<0.5% TRR) and OH-B-Glu (<0.5% TRR). ESA noted that the fate of cyflufenamid was not investigated with regard to the cyclopropyl ring moiety. c. Cucumbers On the day of application, a non negligible part of the total radioactivity remained in the surface wash fraction (52.7% TRR) and the extracted radioactivity from the fruit accounted for up to 47.2% TRR. The parent cyflufenamid was recovered at a level of 96.3% TRR in cucumber fruit. No other metabolite was detected on day 0, 7 to 14 days after the treatment, cyflufenamid constituted the major compound of the total residues (55% TRR) while other minor metabolites were also detected as the E- isomer (1% TRR), OH-B (8.5% TRR) and 149--α-OH-B (7% TRR). Both in the apple and cucumber metabolism studies, no significant isomeric conversion from the Z- isomer to E-isomer occurred. The main transformation pathway of cyflufenamid in fruit crops and fruiting vegetables consisted of the hydroxylation on the phenyl ring with subsequent glucose conjugation. Another route of degradation observed specifically in apples was the hydrolytic cleavage of the cyclopropylmethyloxyl moiety with further glucose conjugation. or the intended uses on fruit crops and fruiting vegetables, ESA concludes that the metabolism of cyflufenamid is sufficiently addressed and that the residue definition for monitoring and risk assessment for cereals agreed in the peer review is also applicable to fruit crops and fruiting vegetables OH-B:N-{(Z)-[(cyclopropylmethoxy)imino][2,3-difluoro-6-(trifluoromethyl)phenyl]methyl}-2-(3- hydroxyphenyl)acetamide: see Appendix D OH-B:N-{(Z)-[(cyclopropylmethoxy)imino][2,3-difluoro-6-(trifluoromethyl)phenyl]methyl}-2-(4- hydroxyphenyl)acetamide: see Appendix D α-OH-B:N-{(Z)-[(cyclopropylmethoxy)imino][2,3-difluoro-6-(trifluoromethyl)phenyl]methyl}-2-hydroxy-2- phenylacetamide: see Appendix D :N'-(cyclopropylmethoxy)-2,3-difluoro-6-(trifluoromethyl)benzenecarboximidamide: see Appendix D ESA Journal 2011;9(5):

11 The current residue definition in Regulation (EC) No 396/2005 is not identical to the residue definitions established during the peer review (ESA, 2009a) which only comprises the Z-isomer of cyflufenamid. As already mentioned in the previous ESA reasoned opinion (ESA, 2009b), ESA proposes to change the enforcement residue definition to be in line with the residue definition established on cereals during the Peer Review (ESA, 2009a). Based on the metabolism data presented hereabove, there is clear evidence that this modification will not have an impact on the level of the EU MRLs already established Magnitude of residues a. Apples and pears In total 16 supervised field trials (8 trials covering northern Europe and 8 trials covering southern Europe) were submitted which comply with the intended GAP. The residue data on apples and pears were pooled to derive the MRL proposals for these crops. Such an extrapolation is in compliance with the EU guidance document (EC, 2011). The trials demonstrated that a modification of the existing MRLof 0.02* mg/kg into 0.05 mg/kg would be appropriate. b. Table and wine grapes In total, 9 residue trials covering respectively northern and southern Europe were carried out in accordance with the intended GAP and considered as appropriate to derive a MRL proposal of 0.15 mg/kg. c. Courgettes In total, 4 residue trials performed in accordance with the intended GAP were submitted to cover northern and southern Europe, respectively. These trials were considered as appropriate to propose a MRL of 0.05 mg/kg. d. Cucumbers 8 residue trials performed under indoor conditions were performed in accordance with the intended GAP to derive a MRL proposal of 0.04 mg/kg. e. Melons In total 16 residue trials (8 trials for NEU and 8 trials for SEU) (outdoor conditions) and 8 residue trials covering the indoor conditions were performed in accordance with the intended GAP. The residue database was considered as acceptable in order to derive a MRL proposal of 0.04 mg/kg. 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. reezer storage stability data were reported in the DAR under Directive 91/414/EEC (The United Kingdom, 2006) and were evaluated during the peer review (ESA, 2009a). The data showed that residues of cyflufenamid were stable at -18 C in barley straw and shoots for at least 25 months and in barley grain for at least 22 months. Storage stability data on apples, grapes and cucumbers were submitted in the framework of this application. The residues of the parent compound were demonstrated to be stable in matrices with high water content for up to 283 days and in matrices with high acid content for 126 days when samples are stored at -18 C. The samples of the supervised field trials for apples/pears and cucurbits (melons, courgettes and cucumbers) were stored for a maximum ESA Journal 2011;9(5):

12 of 185 and 203 days, respectively and were covered by the available storage stability data. The grapes samples were stored for 30 to 183 days and some of the samples were therefore not sufficiently covered by the available storage stability data. Since apples and grapes are a comparable matrix in terms of ph, it is assumed that the storage period of the samples from the residue trials on grapes are covered by the available storage stability data on apple. ESA notes that additional storage stability studies are currently being conducted on stored grapes samples in order to confirm this assumption. The analytical method used in the supervised residue trials on apples, pears, grapes, courgettes, cucumbers and melons was assessed in section 1.1. and was shown to be sufficiently validated for enforcement purposes (EC, 2004) in compliance with the residue definition for monitoring. ESA Journal 2011;9(5):

13 Table 3-2. Overview of the available residues trials data Commodity Region (a) Outdoor/Indoor Individual trial results Median Enforcement Risk assessment residue (b) Highest residue (c) MRL proposal Median C (d) Comments Enforcement and risk assessment residue definition: Sum of cyflufenamid (Z-isomer) plus its E-isomer Apples NEU Outdoor <0.01; <0.01; 3x0.01; 0.02 Pears Outdoor 0.02; ; Apples SEU Outdoor <0.01; 2x0.01; 0.023; 0.026; Pears Outdoor 0.015; ; Table and wine grapes NEU Outdoor 0.015; 0.016; 0.02; 0.027; 0.027; 0.03; 0.037; 0.04; 0.07 SEU Outdoor 6x<0.01; 0.024; 0.03; 0.12 Courgettes NEU Outdoor <0.01; <0.01; 0.014; 0.02 <0.01; <0.01; 3x0.01; 0.02 <0.01; 2x0.01; 0.023; 0.026; ; 0.016; 0.02; 0.027; 0.027; 0.03; 0.037; 0.04; x<0.01; 0.024; 0.03; R max =0.044 R ber =0.040 OECD MRL=0.06 mg/kg R max =0.042 R ber =0.048 OECD MRL=0.06 mg/kg R max =0.082 R ber =0.074 OECD MRL=0.1 mg/kg R max =0.135 R ber =0.048 OECD MRL=0.2 mg/kg <0.01; <0.01; 0.014; R max =0.038 R ber =0.031 OECD MRL=0.04 (e) SEU Outdoor 3x0.02; x0.02; R max =0.076 R ber =0.050 OECD MRL=0.08 (e) mg/kg mg/kg ESA Journal 2011;9(5):

14 Commodity Region (a) Outdoor/Indoor Individual trial results Median Enforcement Risk assessment residue (b) Highest residue (c) MRL proposal Median C (d) Comments Cucumbers NEU/S EU Indoor 3x<0.01; 2x0.01; 0.016; 2x0.02 Melons NEU Outdoor 2x<0.01; 0.011; 0.013; ; ; ; SEU Outdoor 5x<0.01; ; ; N/S EU Indoor 4x<0.01; 2x0.0147; ; x<0.01; 2x0.01; 0.016; 2x0.02 2x<0.01; 0.011; 0.013; ; ; ; x<0.01; ; ; x<0.01; 2x0.0147; ; R max =0.028 R ber =0.034 OECD MRL=0.04 mg/kg R max =0.025 R ber =0.032 OECD MRL=0.05 mg/kg R max =0.037 R ber =0.031 OECD MRL=0.05 mg/kg R max =0.023 R ber =0.030 OECD MRL=0.04 mg/kg (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. (e): High uncertainty due to the small dataset. (*): Indicates that the MRL is set at the limit of analytical quantification. ESA Journal 2011;9(5):

15 Effect of industrial processing and/or household preparation Under the peer review it was concluded that the effect of processing on the nature and magnitude of cyflufenamid residues was not required with regard to the notified intended uses on cereals (ESA, 2009a). As far as the current application is concerned, ESA acknowledges that according to the current guidance document (ESA, 1997d) no additional processing studies are necessary taking into account the low levels of cyflufenamid residues in the crops under consideration and the low dietary exposure of the consumers. Data on the magnitude of the residues of cyflufenamid in processed commodities are not triggered as no significant residue levels (<0.1 mg/kg) occurred in apples, pears and cucurbits (cucumbers, courgettes, melons). Also, for grapes, since a low dietary exposure for the consumers is expected (TMDI <10% ADI), no additional processing studies are required (EC, 1997d). However, ESA is of the opinion that it would be desirable to further investigate the effect of processing on the nature and magnitude of residues (standard hydrolysis studies simulating pasteurisation, boiling and sterilisation, processing of the products under consideration, in particular for grapes and apples (production of juice and wine)) Rotational crops Preliminary considerations ruiting vegetables (cucumbers, courgettes, melons) are crops grown in rotation. According to the soil degradation studies performed in the framework of the peer review, the DT 90 values were derived for cyflufenamid and its relevant soil metabolites. Under aerobic soil conditions cyflufenamid exhibits low to high persistence and forms its relevant soil metabolites: , , and (The United Kingdom, 2006). The DT 90 values for cyflufenamid and its metabolites and 149-6, exceed 100 days, therefore rotational crop studies are necessary Nature of residues Confined rotational crop studies were performed in the framework of the peer review of Directive 91/414/EEC by applying 14 C-cyflufenamid to bare soil at an application rate of 0.05 kg a.s./ha (1.6N) (The United Kingdom, 2006). Spring wheat was sown 30, 120 and 270 DAT, carrots 30 and 120 DAT, and lettuce 30 DAT. Translocation of radioactive residues was low. TRR found in crop parts intended for human consumption was maximum mg/kg. Highest levels of TRR were found in wheat straw (maximum 0.09 mg/kg). Cyflufenamid is extensively metabolised in soil to , 149-, and These metabolites were not identified in rotational crops apart from a single compound in carrot foliage identified as During the peer review it was concluded that field studies on rotational crops are not necessary, as based on the results of the submitted confined metabolism study, residues of cyflufenamid in parts of rotational crops intended for human consumption are expected below the LOQ : N'-(cyclopropylmethoxy)-2,3-difluoro-6-(trifluoromethyl)benzenecarboximidamide: see Appendix D : (Z)-N-[α-(cyclopropylmethoxyimino)-2,3-difluoro-6-(trifluoromethyl)benzyl]malonamic acid: see Appendix D : 2,3-difluoro-6-(trifluoromethyl)benazamide: see Appendix D ESA Journal 2011;9(5):

16 Magnitude of residues Modification of the existing MRL for cyflufenamid in various crops With regard to the current application ESA concludes that significant residue levels (exceeding 0.01 mg/kg) in rotational crops will not occur provided that cyflufenamid is applied according to the proposed GAP Nature and magnitude of residues in livestock Dietary burden of livestock The median and maximum dietary burden for livestock was calculated using the agreed European methodology (EC, 1996). The input values for the dietary burden calculation were selected according to the latest AO recommendations (AO, 2009) considering the livestock intake from apple byproduct (pomace) and from all other feed products on which the existing EU MRLs are set above the LOQ (oat, barley, rye and wheat). To refine the calculations, ESA used the risk assessment values reported in the previously issued ESA reasoned opinion on oat grain and straw (ESA, 2009b) and the default processing factor of 2.5 was applied to the STMR value for apple pomace. The input values for the dietary burden calculation are summarized in Table 3-3. Table 3-3. Input values for the dietary burden calculation Commodity Median dietary burden Maximum dietary burden Input value Comment Input value Risk assessment residue definition: sum of cyflufenamid (Z-isomer) and its E-isomer Comment Apple pomace 0.04 STMR*P (2.5) 0.04 STMR*P (2.5) Oat grain 0.02 STMR (ESA, 2009b) Oat straw 0.11 STMR (ESA, 2009b) Barley grain 0.02 STMR (ESA, 2009a) Barley straw 0.2 STMR (ESA, 2009a) Wheat grain 0.02 STMR (ESA, 2009a) Wheat straw 0.2 STMR (ESA, 2009a) 0.02 STMR (ESA, 2009b) 0.24 HR (ESA, 2009b) 0.02 STMR (ESA, 2009a) 0.54 HR (ESA, 2009a) 0.02 STMR (ESA, 2009a) 0.56 HR (ESA, 2009a) Wheat bran 0.16 STMR*P (8) 0.16 STMR*P (8) In order to estimate the contribution of cyflufenamid residues in apple pomace to the total livestock dietary exposure, ESA performed two dietary burden calculations: in scenario 1 apple pomace was included in the calculation while in scenario 2 apple pomace was excluded from the dietary burden calculation and only the feed items for which MRLs are set above the LOQ were taken into consideration. ESA Journal 2011;9(5):

17 The results of the dietary burden calculation according to the scenarios 1 and 2 are summarized in the tables 3-4 and 3-5. Table 3-4. Results of the dietary burden calculation scenario 1 Maximum dietary burden (mg/kg bw/d) Median dietary burden (mg/kg bw/d) Highest contributing commodity Max dietary burden (mg/kg DM) (a) Risk assessment residue definition: sum of cyflufenamid (Z-isomer) and its E-isomer Trigger exceeded(y/n) Dairy ruminants Wheat straw Yes Meat ruminants Wheat straw Yes Poultry Wheat bran No Pigs Wheat bran No (a): Dry matter feed Table 3-5. Results of the dietary burden calculation scenario 2 Maximum dietary burden (mg/kg bw/d) Median dietary burden (mg/kg bw/d) Highest contributing commodity Max dietary burden (mg/kg DM) (a) Risk assessment residue definition: sum of cyflufenamid (Z-isomer) and its E-isomer Trigger exceeded(y/n) Dairy ruminants Wheat straw Yes Meat ruminants Wheat straw Yes Poultry Wheat bran No Pigs Wheat bran No (a): Dry matter feed rom the comparison of the two scenarios it is evident that the dietary burden exceeds the trigger of 0.1 mg/kg DM for ruminants and that it is mainly driven by the existing uses on feed items; the contribution of apple pomace to the total livestock exposure is insignificant. Therefore it is concluded that the established EU MRLs for livestock are sufficient to cover the intended uses. 4. Consumer risk assessment The consumer risk assessment was performed with revision 2 of the ESA Pesticide Residues Intake Model (PRIMo). This exposure assessment model contains the relevant European food consumption data for different sub-groups of the EU population 20 (ESA, 2007). or the calculation of the chronic exposure, ESA used the median residue values as derived from the residue trials on apples and pears, table and wine grapes, cucumbers, courgettes and melons (see Table 3-2), and in the previously issued ESA reasoned opinion (ESA, 2009b). or the remaining commodities of plant and animal origin, the existing MRLs as established in Annexes IIIA 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 20 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 ood 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 ESA PRIMo is given in its reference section (ESA, 2007). ESA Journal 2011;9(5):

18 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 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. In addition, when required, a variability factor accounting for the inhomogeneous distribution on the individual items consumed was included in the calculation. 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 Comment Input value Comment Risk assessment residue definition for commodities of plant origin: sum of cyflufenamid (Z-isomer) and its E- isomer Risk assessment definition for commodities of animal origin: sum of cyflufenamid, the E-isomer and metabolite 149-1, expressed as cyflufenamid Apples and pears STMR Highest residue Table and wine grapes STMR 0.12 Highest residue Cucumbers 0.01 STMR 0.02 Highest residue Courgettes 0.02 STMR 0.04 Highest residue Melons STMR Highest residue Oat 0.02 STMR (barley) (ESA, 2009b) Barley 0.02 STMR (ESA, 2009a) Rye 0.02 STMR (wheat) (ESA, 2009a) Wheat 0.02 STMR (ESA, 2009a) Other commodities of plant and animal origin EU MRL See Appendix C Acute risk assessment was undertaken only with regard to the products for which a MRL proposal is requested. The estimated exposure was then compared with the toxicological reference values derived for cyflufenamid (see Table 2-1). The results of the intake calculation are presented in Appendix B to this reasoned opinion. No long-term consumer intake concerns were identified for any of the European diets incorporated in the ESA PRIMo model. The total calculated intake values ranged from 0.5 to 4.6 % of the ADI. The contribution of residues in apples and pears, table and wine grapes, cucumbers, courgettes and melons to the total consumer exposure accounted for 0.33 % of the ADI (NL child). ESA Journal 2011;9(5):

19 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 15.7 % for table grapes, 7.8% for melons, 6.9% for apples, 6.4% for pears, 5.7% for wine grapes and 3.7% for courgettes. ESA Journal 2011;9(5):

20 CONCLUSIONS AND RECOMMENDATIONS CONCLUSIONS The toxicological profile of cyflufenamid was assessed in the framework of the peer review under Directive 91/414/EEC and the data were sufficient to propose an ADI of 0.04 mg/kg bw/day and an ARfD of 0.05 mg/kg bw. The metabolism of cyflufenamid in primary crops was investigated in cereals (winter and spring wheat), fruit crops (apples) and fruiting vegetables (cucumber). rom the metabolism studies on wheat, the peer review concluded on the residue definition for risk assessment and enforcement as the sum of cyflufenamid (Z-isomer) plus its E-isomer. or the use on apples, pears, table and wine grapes, cucumber, courgette and melon, ESA concluded that the metabolism of cyflufenamid in primary crops is sufficiently elucidated and that the derived residue definitions for cereals are also appropriate for fruit crops and fruiting vegetables. The supervised residue trials are sufficient and adequate to derive MRL proposals respectively for the intended uses on apples, pears, table and wine grapes, cucumber, courgette and melon. The studies confirmed that a MRL of 0.05 mg/kg would be appropriate for the intended uses of cyflufenamid on apples, pears and courgette, a MRL of 0.04 mg/kg would be sufficient for cucumbers and melon whilst a MRL of 0.15 mg/kg is considered as suitable for table and wine grapes. ESA notes that storage stability was demonstrated for the crops under consideration except grapes. Studies on stored grapes are currently ongoing to confirm the validity of the submitted residue trials. However, since the storage stability was demonstrated for similar matrices, these data are considered as confirmatory data only. Analytical methods are available to enforce the proposed MRLs on the commodities under consideration. No additional processing studies are necessary taking into account the low levels of cyflufenamid residues in the crops under consideration and the low dietary exposure of the consumers. Moreover, based on the metabolic pathways depicted in relevant metabolism studies, it is not expected that toxicological relevant degradation products may occur under the representative processing conditions. Specific studies investigating the magnitude of cyflufenamid residues in processed commodities are not required, as the residues expected in primary crops are low and/or the total theoretical maximum daily intake (TMDI) is below the trigger value of 10 % of the ADI. The occurrence of cyflufenamid residues in rotational crops was investigated in the Draft Assessment Report in the framework of the peer review. Based on the available information on the nature and magnitude of residues in succeeding crops, it was concluded that significant residue levels (>0.01 mg/kg) are unlikely to occur in rotational crops provided that cyflufenamid is applied according to the GAP assessed under this application. Since apple pomace is used as a feed product, a potential carry-over into food of animal origin was assessed. The calculated livestock dietary burden exceeded the trigger value of 0.1 mg/kg (dry matter) for meat ruminants but was mainly driven by the existing MRLs of feed products. The impact of cyflufenamid residues in apple pomace to the total livestock exposure was shown to be insignificant and therefore the modification of the MRLs for commodities of animal origin is not required in the framework of the current application. The consumer dietary risk assessment for cyflufenamid was performed with revision 2 of the ESA PRIMo. or the calculation of the chronic exposure, ESA used the median residue value as derived from the residue trials on apples, pears, table and wine grapes, cucumber, courgette and melon. The median residue values for cereals grains were derived from the previous ESA reasoned opinion and ESA Journal 2011;9(5):

21 the ESA conclusion. or the remaining commodities of plant and animal origin, the existing MRLs as established in Annex III of Regulation (EC) No 396/2005 were used as input values. The acute dietary intake risk assessment was carried out only with regard to the products for which a MRL is requested applying the respective highest residue values as derived from the supervised residue trials on the crops under consideration. No chronic intake concerns were identified for any of the European diets and the total intake values accounted for a maximum of 4.6% of the ADI. The contribution of the different crops under consideration to the total dietary intake was low (0.33% ADI NL child). No acute intake concerns were identified in relation to the MRL proposals for the crops under consideration (15.7% of the ARfD Table grapes). ESA concludes that the intended use of cyflufenamid on apples,, pears, table- and wine grapes, cucumbers, courgettes and melons will not result in a dietary exposure posing a consumer health risk. RECOMMENDATIONS ESA proposes to amend the current MRLs as summarised in the table below: Code number (a) Commodity Existing EU MRL Proposed EU MRL Enforcement residue definition: sum of cyflufenamid (Z-isomer) and its E-isomer Justification for the proposal Apples 0.02* 0.05 The MRL proposals are sufficiently Pears 0.02* 0.05 supported by data and no risk for consumers was identified for the intended Table grapes 0.02* 0.15 uses Wine grapes 0.02* Cucumbers 0.02* Courgettes 0.02* Melon 0.02* 0.04 (a): According to Annex I of Regulation (EC) No 396/2005. (*): Indicates that the MRL is set at the limit of analytical quantification. ESA Journal 2011;9(5):

22 REERENCES EC (European Commission), Appendix G. Livestock eeding Studies. 7031/VI/95 rev.4. Available from: EC (European Commission), 1997a. Appendix A. Metabolism and distribution in plants. 7028/IV/95- rev.3. Available from: EC (European Commission), 1997b. Appendix B. General recommendations for the design, preparation and realization of residue trials. Annex 2. Classification of (minor) crops not listed in the Appendix of Council Directive 90/642/EEC. 7029/VI/95-rev.6. Available from: EC (European Commission), 1997c. Appendix C. Testing of plant protection products in rotational crops. 7524/VI/95-rev.2. Available from: EC (European Commission), 1997d. Appendix E. Processing studies. 7035/VI/95-rev.5. Available from: EC (European Commission), 1997e. Appendix. Metabolism and distribution in domestic animals. 7030/VI/95-rev. 3. Available from: EC (European Commission), 1997f. Appendix H. Storage stability of residue samples. 7032/VI/95- rev.5. Available from: EC (European Commission), 1997g. Appendix I. Calculation of maximum residue level and safety intervals. 7039/VI/95. As amended by the document: classes to be used for the setting of EU pesticide maximum residue levels (MRLs). SANCO 10634/2010. Available from: EC (European Commission), Residue analytical methods. or pre-registration data requirement for Annex II (part A, section 4) and Annex III (part A, section 5 of Directive 91/414. SANCO/3029/99-rev.4. Available from: EC (European Commission), Residue analytical methods. or post-registration control. SANCO/825/00-rev.7. Available from: EC (European Commission), Classes to be used for the setting of EU pesticide Maximum Residue Levels (MRLs). SANCO 10634/2010 Rev. 0, finalized in the Standing Committee on the ood Chain and Animal Health at its meeting of March EC (European Commission), Appendix D. Guidelines on comparability, extrapolation, group tolerances and data requirements for setting MRLs. 7525/VI/95-rev.9. Available from: ESA (European ood Safety Authority), Pesticide Residues Intake Model for assessment of acute and chronic consumer exposure to pesticide residues-rev.2. Available from ESA (European ood Safety Authority), 2009a. Conclusion on the peer review of the pesticide risk assessment of the active substance [cyflufenamid]. ESA Scientific Report (2009) 259, ESA (European ood Safety Authority), 2009b. Reasoned opinion on the modification of the existing MRL for [cyflufenamid] in oats prepared by ESA Pesticide Risk Assessment Peer Review (PRAPeR) Unit. ESA Scientific Report (2009) 291, ESA Journal 2011;9(5):