Reasoned opinion on the modification of the existing MRLs for difenoconazole in peppers and aubergines 1

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1 EFSA Journal 2014;12(4):3676 ABSTRACT REASOED OPIIO Reasoned opinion on the modification of the existing MRLs for difenoconazole in peppers and aubergines 1 European Food Safety Authority 2 European Food Safety Authority (EFSA), Parma, Italy In accordance with Article 6 of Regulation (EC) o 396/2005, Greece, hereafter referred to as the evaluating Member State (EMS), received an application from SYGETA HELLAS ABEE to modify the existing MRLs for the active substance difenoconazole in peppers and aubergines. In order to accommodate the intended uses of difenoconazole Greece proposed to raise the existing MRLs from the values of 0.5 mg/kg to 0.7 mg/kg for peppers and from 0.4 mg/kg to 0.6 mg/kg for aubergines. Greece drafted an evaluation report in accordance with Article 8 of Regulation (EC) o 396/2005, which was submitted to the European Commission and forwarded to EFSA. According to EFSA the data are sufficient to derive MRL proposals of 0.8 mg/kg for the proposed use on peppers and 0.4 mg/kg for the use on aubergines reflecting the indoor use. An alternative MRL proposal of 0.6 mg/kg was derived for aubergines for further risk management considerations, based on SEU outdoor trials which were performed with a higher number of applications compared to the notified GAP. Based on the risk assessment results, EFSA concludes that the proposed use of difenoconazole on peppers and aubergines will not result in a consumer exposure exceeding the toxicological reference values and therefore is unlikely to pose a consumer health risk. The risk assessment for the triazole derivative metabolites is still pending. European Food Safety Authority, 2014 KEY WORDS difenoconazole, various crops, MRL application, Regulation (EC) o 396/2005, consumer risk assessment, triazole fungicides, triazole derivative metabolites (TDMs) 1 On request from European Commission, Question o EFSA-Q , approved on 16 April Correspondence: pesticides.mrl@efsa.europa.eu Suggested citation: EFSA (European Food Safety Authority), Reasoned opinion on the modification of the existing MRLs for difenoconazole in peppers and aubergines. EFSA Journal 2014;12(4):3676, 27 pp. doi: /j.efsa Available online: European Food Safety Authority, 2014

2 SUMMARY In accordance with Article 6 of Regulation (EC) o 396/2005, Greece, hereafter referred to as the evaluating Member State (EMS), received an application from SYGETA HELLAS ABEE 3 to modify the existing MRLs for the active substance difenoconazole in peppers and aubergines. In order to accommodate the intended uses of difenoconazole Greece proposed to raise the existing MRLs from the values of 0.5 mg/kg to 0.7 mg/kg for peppers and from 0.4 mg/kg to 0.6 mg/kg for aubergines. Greece drafted an evaluation report in accordance with Article 8 of Regulation (EC) o 396/2005, which was submitted to the European Commission and forwarded to EFSA on 30 August EFSA bases its assessment on the evaluation report submitted by the EMS, the Draft Assessment Report (DAR) prepared under Council Directive 91/414/EEC, the conclusion on the peer review of the pesticide risk assessment of the active substance difenoconazole, as well as the conclusions from previous EFSA opinions on difenoconazole. The toxicological profile of difenoconazole was assessed in the framework of the peer review under Directive 91/414/EEC and the data were sufficient to propose an ADI of 0.01 mg/kg bw per day and an ARfD of 0.16 mg/kg bw. EFSA defined toxicological reference values also for the triazole derivative metabolites (TDMs). The metabolism of difenoconazole in primary crops was investigated in tomatoes, grapes, oilseed rape, potatoes and wheat following foliar and seed treatment (cereals only) during the peer review. From these studies the peer review concluded to establish the residue definition for enforcement as difenoconazole. The current residue definition set in Regulation (EC) o 396/2005 is identical to that derived in the peer review assessment. For risk assessment, considering that TDMs are toxicologically relevant metabolites, two separate plant residue definitions were proposed: 1) difenoconazole and 2) provisionally, triazole derivative metabolites. TDMs are common metabolites of active substances belonging to the chemical class of triazoles. EFSA concludes that the results of the above mentioned metabolism studies can be extrapolated to the crops under consideration and no additional studies are required. EFSA concludes that the submitted supervised residue trials are sufficient to derive MRL proposals of 0.8 mg/kg for the proposed use on peppers and 0.4 mg/kg for the use on aubergines reflecting the indoor use. An alternative MRL proposal of 0.6 mg/kg was derived for aubergines for further risk management considerations, based on SEU outdoor trials which were performed with a higher number of applications compared to the notified GAP. The effects of processing on the magnitude of difenoconazole residues was evaluated during the peer review where it was concluded that the compound is hydrolytically stable and the same residue definition as for raw agricultural commodities (RAC) is applicable. o additional studies were submitted under this application. The occurrence of difenoconazole residues in rotational crops was investigated 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 are unlikely to occur in rotational crops provided that the compound is used on peppers and aubergines according to the proposed GAP (Good Agricultural Practice). However, there are still some open points regarding the possible occurrence of triazole derivative metabolites in rotational crops which will be addressed during the assessment of the confirmatory data. Residues of difenoconazole 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. 3 Syngenta Hella Aebe, Anthoussas Avenue, GR-15349, Athens, Greece EFSA Journal 2014;12(4):3676 2

3 The consumer risk assessment was performed with revision 2 of the EFSA Pesticide Residues Intake Model (PRIMo). For the calculation of chronic exposure, EFSA used the median residue values as derived from the residue trials on the crops under consideration. For the remaining commodities of plant and animal origin, the existing MRLs as established in Annex IIIA of Regulation (EC) o 396/2005 were used as input values. 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 estimated exposure was then compared with toxicological reference values derived for difenoconazole. o long-term consumer intake concerns were identified for the any diets incorporated in the EFSA PRIMo. The total calculated intake accounted for up to 98 % of the ADI (WHO cluster diet B). The contribution of difenoconazole residues of the assessed commodities to the total consumer exposure accounted 0.8% of the ADI for peppers and 0.4% for aubergines. o acute consumer risk was identified regarding the MRLs proposals for the crops under consideration. The highest maximum exposure in percentage of the ARfD was calculated for the residue in peppers 19% of the ARfD and 4% for aubergines. EFSA concludes that the proposed use of difenoconazole on peppers and aubergines will not result in a consumer exposure exceeding the toxicological reference values and therefore is unlikely to pose a consumer health risk. The consumer risk assessment related to TDMs was not undertaken in this application as the assessment of confirmatory data for triazole pesticides are still under assessment. Thus, EFSA proposes to amend the existing MRLs as reported in the summary table. Summary table number (a) Commodity Existing EU MRL Proposed EU MRL Enforcement residue definition: difenoconazole Justification for the proposal Peppers The MRL proposal is sufficiently supported by data and no consumer health risk was identified for the intended uses on this crop Aubergines or 0.6 (a): According to Annex I of Regulation (EC) o 396/2005. (*): Indicates that the MRL is set at the limit of analytical quantification. The MRL proposal of 0.4 mg/kg which reflects the intended indoor GAP is sufficiently supported by data; no consumer health risk was identified. The intended EU outdoor use is not supported by data. The alternative MRL proposal of 0.6 mg/kg was derived from SEU trials, performed with 3 or 4 applications instead of 2 applications as defined in the GAP. The MRL proposal might be slightly higher than the residues expected after treatment according to the GAP. o consumer health risk was identified for this proposal. Thus, a risk management decision should be taken on the most appropriate MRL for aubergines. EFSA Journal 2014;12(4):3676 3

4 TABLE OF COTETS Abstract... 1 Summary... 2 Table of contents... 4 Background... 5 Terms of reference... 5 The active substance and its use pattern... 6 Assessment Method 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 ature and magnitude of residues in plant Primary crops Rotational crops Consumer risk assessment Conclusions and recommendations References Appendices Appendix A. Good Agricultural Practice (GAPs) Appendix B. Pesticide Residue Intake Model (PRIMo) Appendix C. Existing EU maximum residue levels (MRLs) Appendix D. List of metabolites and related structural formula Abbreviations EFSA Journal 2014;12(4):3676 4

5 BACKGROUD Regulation (EC) o 396/ establishes the rules governing the setting of pesticide MRLs at European Union level. Article 6 of that Regulation lays down that any party having a legitimate interest or requesting an authorisation for the use of a plant protection product in accordance with Council Directive 91/414/EEC 5, repealed by Regulation (EC) o 1107/2009 6, shall submit to a Member State, when appropriate, an application to modify a MRL in accordance with the provisions of Article 7 of that Regulation. Greece, hereafter referred to as the evaluating Member State (EMS), received an application from the company SYGETA HELLAS ABEE 7 to modify the existing MRLs for the active substance difenoconazole in peppers and aubergines. This application was notified to the European Commission and EFSA, and was subsequently evaluated by the EMS in accordance with Article 8 of the Regulation. After completion, the evaluation report was submitted to the European Commission who forwarded the application, the evaluation report and the supporting dossier to EFSA on 30 August The application was included in the EFSA Register of Questions with the reference number EFSA-Q and the following subject: Application to modify the existing MRLs in peppers and aubergines (egg plants) Greece proposed to raise the existing MRLs of difenoconazole from the current MRL values of 0.5 mg/kg to 0.7 mg/kg in peppers and from 0.4 mg/kg to 0.6 mg/kg in aubergines. EFSA proceeded with the assessment of the application and the evaluation report as required by Article 10 of the Regulation. TERMS OF REFERECE In accordance with Article 10 of Regulation (EC) o 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 deadline for providing the reasoned opinion is 30 ovember Regulation (EC) o 396/2005 of the Parliament and of the Council of 23 February 2005 on maximum residue levels of pesticides in or on food and feed of plant and animal origin and amending Council Directive 91/414/EEC. OJ L 70, , p Council Directive 91/414/EEC of 15 July 1991 concerning the placing of plant products on the market. OJ L 230, , p Regulation (EC) o 1107/2009 of the European Parliament and of the Council of 21 October 2009 concerning the placing of plant protection products on the market and repealing Council Directives 79/117/EEC and 91/414/EEC. OJ L 309, , p Syngenta Hella Aebe, Anthoussas Avenue, GR-15349, Athens, Greece EFSA Journal 2014;12(4):3676 5

6 THE ACTIVE SUBSTACE AD ITS USE PATTER is the ISO common name for 1-[2-[2-chloro-4-(4-chloro-phenoxy)-phenyl]-4- methyl[1,3]dioxolan-2-ylmethyl]-1h-[1,2,4] triazole (IUPAC) and its chemical structure is as follows: O Cl Cl O O Molecular weight: g/mol is a systemic triazole fungicide that controls broad-spectrum of foliar, seed and soilborne diseases, caused by Ascomycetes, Basidiomycetes and Deuteromycetes, in cereals, soya, rice, grapes, pome fruit, stone fruit, potatoes, sugar beet and several vegetable and ornamental crops. It is applied by foliar spray or seed treatment. acts by interference with ergosterol biosynthesis in target fungi by inhibition of the C-14-demethylation of sterols, which leads to morphological and functional changes of the fungal cell membrane. was included in Annex I to Directive 91/414/EEC on 1 st January 2009 by Directive 2008/69/EC 8. The Draft Assessment Report (DAR) as drafted by the designated rapporteur Member State (RMS) Sweden, was peer reviewed by EFSA (EFSA, 2011a). The representative uses evaluated in the peer review were foliar applications on pome fruit, carrots and seed treatment of various cereals (wheat, barley, triticale, rye and oats). The confirmatory data regarding the residues of triazole derivative metabolites (TDMs) in primary crops, rotational crops, processed commodities and products of animal origin required in Regulation (EC) o1100/ were submitted by the manufacturer and are currently under assessment. The EU MRLs for difenoconazole are established in Annex IIIA of Regulation (EC) o 396/2005 (Appendix C). EFSA has issued a number of reasoned opinions since the entry into force of this Regulation, (EFSA, 2010a-b, 2011b, 2012, 2013). The MRL review for difenoconazole according to Article12 of Regulation (EC) o 396/2005 is at an early stage. For the crops under consideration there are not CXLs in place for difenoconazole. The details of the intended GAPs for difenoconazole are given in Appendix A. 8 Commission Directive 2008/69/EC of 1 July 2008 amending Council Directive 91/414/EEC to include clofentezine, dicamba, difenoconazole, diflubenzuron, imazaquin, lenacil, oxadiazon, picloram and pyriproxyfen as active substances. OJ L 172, , p Commission Implementing Regulation (EU) o 1100/2011 of 31 October 2011 amending Implementing Regulation (EU) o 540/2011 as regards the conditions of approval of the active substances dicamba, difenoconazole, and imazaquin. OJ L 285, , p EFSA Journal 2014;12(4):3676 6

7 ASSESSMET EFSA bases its assessment on the evaluation report submitted by the EMS (Greece, 2013), the Draft Assessment Report (DAR) prepared under Council Directive 91/414/EEC (Sweden, 2006), the conclusion on the peer review of the pesticide risk assessment of the active substance difenoconazole (EFSA, 2011a), as well as the conclusions from previous EFSA opinions on difenoconazole (EFSA, 2010a-b, 2011b, 2012, 2013). The assessment is performed in accordance with the legal provisions of the Uniform Principles for the Evaluation and the Authorisation of Plant Protection Products adopted by Commission Regulation (EU) o 546/ and the currently applicable guidance documents relevant for the consumer risk assessment of pesticide residues (EC, 1996, 1997a-g, 2000, 2010a-b, 2011; OECD, 2011). 1. Method of analysis 1.1. Methods for enforcement of residues in food of plant origin The analytical methods for the determination of difenoconazole residues in plant commodities were assessed in the DAR and in the conclusion of the peer review under Directive 91/414/EEC (Sweden, 2006; EFSA, 2011a). The multi-residues DFG S19 method using LC-MS/MS was sufficiently validated at the LOQ of 0.02 mg/kg for high water content commodities and at the LOQ of 0.05 mg/kg for dry and high fat content commodities (wheat grain and oil seed rape). The multi-residue QuEChERS method described in the European Standard E 15662:2008 is also applicable. The liquid chromatography coupled with tandem mass spectrum detection (LC-MS/MS) method analyses difenoconazole residues in high water, high acid content and dry commodities (cereals) at the LOQ of 0.01 mg/kg (CE, 2008). Additional analytical methods based on gas chromatography were submitted under the current application. These methods were used for the determination of difenoconazole residues in several plant commodities at the validated level of LOQ of 0.01mg/kg (Greece, 2013). Based on available data, EFSA concludes that there are sufficiently validated enforcement methods to control difenoconazole residues in peppers and aubergines Methods for enforcement of residues in food of animal origin Analytical methods for the determination of residues in food of animal origin are not assessed in the current application, since the crops under consideration are not used as feed for animal. 2. Mammalian toxicology The toxicological profile of the active substance difenoconazole was assessed in the framework of the peer review under Directive 91/414/EEC (EFSA, 2011a). The data were sufficient to derive toxicological reference values for difenoconazole which are compiled in Table 2-1. In plants, metabolism studies have shown the active substances belonging to the chemical class of triazoles to be degraded/metabolized to a certain group of metabolites known as triazole derivative metabolites (TDMs), the major ones being the metabolites 1,2,4-triazole 11, triazole alanine 12, triazole lactic acid 13 and triazole acetic acid 14. These TDMs were initially considered of no toxicological concern, but recent evaluations indicate that they are of toxicological relevance. EFSA defined 10 Commission Regulation (EU) o 546/2011 of 10 June 2011 implementing Regulation (EC) o 1107/2009 of the European Parliament and of the Council as regards uniform principles for evaluation and authorisation of plant protection products. OJ L 155, , p ,2,4-triazole, see Appendix D 12 Triazole alanine, see Appendix D 13 Triazole lactic acid, see Appendix D 14 Triazole acetic acid, see Appendix D EFSA Journal 2014;12(4):3676 7

8 toxicological reference values also for 1,2,4-triazole, triazole alanine, triazole acetic acid and triazole lactic acid (EFSA, 2011a). Table 2-1: Overview of the toxicological reference values Source Year Value Study relied upon Safety factor ADI EFSA mg/kg bw per day Rat 2 year study 100 ARfD EFSA mg/kg bw Rat developmental study 100 1,2,4-triazole, triazole acetic acid and triazole lactic acid ADI EFSA mg/kg bw per day Rat, multigeneration study 1000 ARfD EFSA mg/kg bw Rat, developmental study 500 Triazole alanine ADI EFSA mg/kg bw per day Rat, developmental study 1000 ARfD EFSA mg/kg bw Rat, developmental study Residues 3.1. ature and magnitude of residues in plant Primary crops ature of residues The metabolism of difenoconazole in primary crops following foliar and seed treatment was evaluated in the framework of the peer review under Directive 91/414/EEC (EFSA, 2011a). Metabolism studies were performed with fruit and fruiting vegetables (tomatoes, grapes), root and tuber vegetables (potatoes), pulses and oilseeds (oilseed rape) and cereals (wheat) using [phenyl- 14 C] and [triazole- 14 C] labelled difenoconazole following foliar applications with a total of 2 to 6 treatments. Detailed results are reported in previously issued reasoned opinions (EFSA, 2012, 2013). The residue definition set in Regulation (EC) o 396/2005 is identical to that derived during the peer review (i.e. parent difenoconazole). For risk assessment, considering that TDMs are toxicologically relevant metabolites, two separate plant residue definitions were proposed: 1) difenoconazole and 2) provisionally, triazole derivative metabolites. TDMs are common metabolites of active substances belonging to the chemical class of triazoles. o final definition can be proposed for TDMs at this stage, since a global and harmonized approach is needed for all compounds of the triazole chemical class (EFSA 2011a). For the uses on peppers and aubergines, EFSA concludes that the metabolism of difenoconazole is sufficiently addressed and the residue definitions for enforcement and risk assessment agreed in the peer review are applicable Magnitude of residues In support of the MRL application, the notifier provided residue trials on difenoconazole on peppers and tomatoes. o residue data on TDMs were submitted. EFSA Journal 2014;12(4):3676 8

9 a) Peppers Modification of the existing MRLs for difenoconazole in peppers and aubergines Some indoor and outdoor trials were not performed with a total of 2 applications as proposed in the GAPs, but with 3 or 4 applications. Since the residue levels observed in the trials conducted with a total of 2 to 4 applications were seen to be not significantly different (H-test, 5%), EFSA concludes that the contribution of the first application(s) to the final residue level can be considered negligible. All trials were therefore considered valid for deriving an MRL proposal, despite the different number of applications tested. EU & SEU GAP (indoor use): 2 x 125 g a.s./ha, PHI 3 days For the intended indoor use the applicant submitted in total 8 residue trials on peppers which have been performed over two seasons in 2005 and 2006 in the EU and the SEU under indoor conditions. Only one residue trial was performed in compliance with the cgap with a total of 2 applications, while the remaining seven trials were performed with 3 or 4 applications. All trials were considered valid for deriving the MRL proposal. EU GAP (outdoor): 2 x 125 g a.s./ha, PHI 3 days For the intended EU outdoor use, the applicant submitted in total 8 residue trials on peppers which have been performed over two seasons in 2011 and 2012 in the EU. The trials were performed according to the GAP with 2 applications of 125 g/ha and a PHI of 3 days. For one trial difenoconazole residues was higher at a longer PHI. SEU GAP (outdoor): 2 x 125 g a.s./ha, PHI 3 days For the intended SEU outdoor use, the applicant submitted in total 12 residue trials on peppers which have been performed over three seasons in 2005, 2011 and Eight trials were performed with 2 applications of 125 g/ha, thus they are fully compliant with the proposed GAP. Four trials were performed with 3 applications. In 2 trials difenoconazole residues were higher at a longer PHI. b) Aubergines EU & SEU GAP (indoor use): 2 x 125 g a.s./ha, PHI 3 days In total 13 residue trials on tomatoes, which have been performed over four seasons under indoor conditions, were submitted by the applicant. The applicant proposed to extrapolate from tomatoes to aubergines, as defined in the EU guidance document (EC, 2011). Only 4 trials were performed according to the GAP with 2 applications of 125 g/ha and a PHI of 3 days while eight trial were performed with 3 applications. As the residue concentrations measured in the trial with 3 applications were lower than those observed after 2 applications (U-test, 5%), the whole dataset was considered to derive an MRL proposal. One trial conducted with 4 applications was identified as an outlier; thus, it was disregarded from the MRL calculation. EU GAP (outdoor): 2 x 125 g a.s./ha, PHI 3 days For the EU outdoor use, no residue trials were submitted under this application. SEU GAP (outdoor): 2 x 125 g a.s./ha, PHI 3 days For the intended SEU outdoor 9 residue trials on tomatoes were submitted, which have been performed in three seasons 2003, 2006 and Six residue trials were performed with 3 applications while in three trials the tomatoes were treated with 4 applications. The fact that the residue levels observed in the outdoor trials conducted with a total of 3 and 4 applications are significantly higher than the levels observed under indoor conditions with a total of 2 and 3 applications (U-test, 5%), gives some indications that on tomatoes the number of applications may have an impact on the final EFSA Journal 2014;12(4):3676 9

10 residue levels. This finding is in contrast to the observations in peppers where the number of trials was found to have no significant impact. Also the comparison of the indoor residue trials on tomatoes performed with 2 and 3 applications provided some evidence that the number of trials is not significantly impacting the final residues on the crop. Thus, EFSA derived an alternative tentative MRL proposal of 0.6 mg/kg from the outdoor trials; this value is affected by some uncertainties and might be slightly higher than the residues expected after treatment according to the GAP. The results of the residue trials, the related risk assessment input values (highest residue, median residue) and the MRL proposals are summarised in Table 3-1. The storage stability of difenoconazole in primary crops was investigated in the DAR under Directive 91/414/EEC (Sweden, 2006). Residues of difenoconazole were found to be stable at -20 C for up to 2 years in various matrices with high water (tomatoes, potatoes) high oil content and dry matrices. In lettuce head, soybeans and bananas the storage stability of difenoconazole is demonstrated for at least 12 months under deep freeze conditions. As the crops under consideration belong to the high water content group and the trial samples were stored under proper conditions (-18 C/-20 C for up to 7 months), it is concluded that the residue data are valid regarding storage stability. According to the EMS, the analytical methods used to analyse the supervised residue trial samples have been sufficiently validated and were proven to be fit for the purpose (Greece, 2013). EFSA concludes that the data are sufficient to derive MRL proposals of 0.8 mg/kg for the proposed use on peppers in EU/SEU/EU and 0.4 mg/kg for the use on aubergines reflecting the indoor use. An alternative MRL proposal of 0.6 mg/kg was derived for further risk management considerations; it is based on SEU outdoor trials which were performed with a higher number of applications compared to the notified GAP. The intended EU outdoor use for aubergines is not supported by data. EFSA Journal 2014;12(4):

11 Table 3-1: Overview of the available residues trials data Commodity Residue region (a) Outdoor /Indoor Individual trial results Enforcement () Risk assessment () Median residue (b) Highest residue (c) MRL proposal Median CF (d) Comments (e) Peppers EU Outdoor application rate 2x 125 g/ha (GAP compliant): 0.03, 0.08, 0.12, 0.15, 0.18, 0.19, 0.25, 0.48 f SEU Outdoor application rate 2x, 125 g/ha (GAP compliant): 0.02, 0.03, 0.06, 0.09, 0.2, 0.2, 0.29 f ; 0.36 f application rate 3x 125 g/ha : 0.08, 0.11, 0.19 f, n.a. R ber = 0.47 R max = 0.62 MRL OECD = n.a. R ber = 0.54 R max = 0.56 MRLOECD = 0.7 Tomatoes aubergines EU Indoor GAP (2x 125 g/ha): 0.25 GAP (3x 125 g/ha): 0.06, 0.12 f, 0.13 f, 0.13, 0.15, 0.27 GAP (4x 125 g/ha): 0.40 SEU Outdoor application rate 3x 125 g/ha:, 0.13, 0.15, 0.16, 0.18 f, 0.23 f, 0.24 application rate 4x 125 g/ha: 0.09, 0.18 f, n.a. Rber= 0.54 Rmax= 0.53 MRLOECD = tentative n.a. R ber = 0.47 R max = 0.43 MRLOECD = 0.6 EU Outdoor o residue data submitted EU Indoor application rate 2x 125 g/ha (GAP compliant): 0.15, 0.10 f, 0.11, 0.24 f application rate 3x 125 g/ha: 0.04 f, 0.07, 0.08, 0.08, 0.10, 0.10, 0.10 f, n.a. R ber = 0.24 R max = 0.24 MRLOECD = 0.4 (a): EU (orthern and Central Europe), SEU (Southern Europe and Mediterranean), EU (i.e. indoor use) or Import (country code) (EC, 2011). (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 residue trial. (e): Statistical estimation of MRLs according to the EU methodology (R ber, R max ; EC, 1997g) and unrounded/rounded values according to the OECD methodology (OECD, 2011). (f): Higher residue concentration at a longer PHI than at the minimum PHI defined in the GAP. n.a. :not appropriate EFSA Journal 2014;12(4):

12 Effect of industrial processing and/or household preparation The effect of processing on the nature of difenoconazole was investigated in studies performed at three test conditions representing pasteurization, baking/brewing/boiling and sterilization (20 minutes at 90 C, ph 4; 60 minutes at 100 C ph 5; 20 minutes at 120 C, ph 6). The peer review concluded that the compound is hydrolytically stable under the representative processing conditions. Thus, for processed commodities the same residue definition as for raw agricultural commodities is applicable (EFSA, 2011a). Additional studies investigating the effects of processing on the magnitude of difenoconazole residues in the crops under consideration have not been submitted in the framework of this application. It is noted that processing studies for carrots and tomatoes (cooking, canning and juicing) were submitted in the framework of previously submitted MRL applications (EFSA 2010a, 2010b) Rotational crops Preliminary considerations Peppers and aubergines can be grown in rotation with other crops 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 demonstrated that the degradation rate of difenoconazole is slow. The maximum DT 90 observed in field studies was 879 days (EFSA, 2011a), which is above the trigger value of 100 days ature of residues The studies on the nature of difenoconazole in rotational crops were described in detail during the peer review and in the previously issued EFSA reasoned opinion (EFSA, 2012). The confined rotational crops studies were performed with leafy vegetables (lettuce, spinach), root vegetables (carrot, sugar beet, turnips), cereals (spring and winter wheat, maize) and oilseeds (mustard). was applied to bare soil at a rate of 750 g/ha one month prior to crop planting and samples were analysed for difenoconazole and triazole alanine. The samples were not analysed for the other TDM compounds. The residues in the samples analysed were below the LOQs. According to the peer review, further information on TDM residues in rotational crops is still required (EFSA, 2011a). Pending the outcome of the evaluation of confirmatory data (according to Regulation (EC) o 1100/2011) on the formation of TDMs in rotational crops, the same residue definitions as established in primary crops are currently applicable Magnitude of residues Considering that the maximum seasonal application rate on the crops under consideration in the framework of this application (max. 2 x kg a.s./ha) is lower than in the rotational crop field studies (750 g/ha), it is unlikely that significant levels of parent difenoconazole will be found in rotational crops. The possible occurrence of triazole derivative metabolites (TDMs) in rotational crops will be addressed in the assessment of the confirmatory data that were recently submitted by the notifier. As long as this assessment is not completed, EFSA recommends that Member States granting an authorization for plant protection products containing difenoconazole should take the necessary risk mitigation measures (e.g. definition of pre-plant intervals) to avoid TDM residues in rotational crops. EFSA Journal 2014;12(4):

13 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 15 (EFSA, 2007). For the calculation of chronic exposure, EFSA used the median residue values as derived from the residue trials on peppers and tomatoes (see Table 3-1), the median residue values reported in the framework of the setting of temporary MRLs of difenoconazole (Greece, 2013), and in previously issued EFSA reasoned opinions (EFSA, 2013). For the remaining commodities of plant and animal origin, the existing MRLs as established in Annex IIIA of Regulation (EC) o 396/2005 were used as input values. The model assumptions for the long-term exposure assessment are considered to be sufficiently conservative for a first tier exposure assessment, 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 acute exposure assessment was performed only with regard to the crops under consideration assuming the consumption of a large portion of the food items as reported in the national food surveys and that these items contained residues at the highest level as observed in supervised field trials. A variability factor accounting for the inhomogeneous distribution on the individual items consumed was included in the calculation, when required (EFSA, 2007). The input values used for the dietary exposure calculation are summarised in Table 4-1. Table 4-1: Input values for the consumer dietary exposure assessment Commodity Input Risk assessment residue definition: difenoconazole Chronic exposure assessment Comment Acute exposure assessment Input Comment Peppers 0.17 Median residue 0.48 Highest residue Aubergine 0.13 (0.18) Median residue (reflecting the tentative MRL proposal derived from SEU outdoor trials) 0.24 (0.36) Highest (reflecting tentative proposal) residue the MRL Quince 0.11 Median residue (EFSA, 2013) Acute risk assessment was performed only with regard to Papaya 0.01 Median residue (EFSA, 2013) crops under consideration. Carrot 0.1 Median residue (EFSA, 2013) Beetroot 0.1 Median residue (EFSA, 2013) Horseradish 0.1 Median residue (EFSA, 2013) Jerusalem artichoke 0.1 Median residue (EFSA, 2013) 15 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 2014;12(4):

14 Commodity Input Chronic exposure assessment Comment Parsnip 0.1 Median residue (EFSA, 2013) Parsley root 0.1 Median residue (EFSA, 2013) Salsify 0.1 Median residue (EFSA, 2013) Radish 0.1 Median residue (EFSA, 2013) Garlic 0.01 Median residue (EFSA, 2013) Onion (bulb) 0.01 Median residue (EFSA, 2013) Shallot 0.01 Median residue (EFSA, 2013) Spring onion 0.43 Median residue (EFSA, 2013) Melon 0.01 Median residue (EFSA, 2013) Pumpkins, watermelons 0.01 Median residue (EFSA, 2013) Witloof 0.01 Median residue (EFSA, 2013) Globe artichoke 0.36 Median residue (EFSA, 2013) Rice 0.88 Median residue (EFSA, 2013) Chicory roots 0.2 Median residue (EFSA, 2013) Raspberries 0.04 Median residue (EFSA, 2012) Blackberries 0.04 Median residue (EFSA, 2012) Cucumber, gherkin, courgette 0.01 Median residue (EFSA, 2012) Beet leaves 0.04 Median residue (EFSA, 2012) Broccoli 0.13 Median residue (EFSA, 2012) Cardoons 0.83 Median residue (EFSA, 2012) Strawberry 0.14 Median residue (EFSA, 2012) Swedes, Turnips 0.08 Median residue (EFSA, 2012) Fennel 1.66 Median residue (EFSA, 2012) Herbs (parsley, chervil ) 4.65 Median residue (EFSA, 2012) Apples, pears 0.11 Median residue (FAO, 2008) Olives (table and oil) 0.47 Median residue (FAO, 2008) Sugar beet 0.02 Median residue (FAO, 2008) Peaches 0.15 Median residue (FAO, 2008) Apricots 0.14 Median residue (EC, 2008c) Tomatoes 0.72 Median residue (EC, 2008c) Celery 0.94 Median residue (EC, 2008c) Meat of swine, bovine, sheep, goat, horses Fat of swine, bovine, sheep, goat, horses Edible offal of swine, bovine, sheep, goat, horses 0.01 Median residue (FAO, 2011) Median residue (FAO, 2011) 0.04 Median residue (FAO, 2011) Acute exposure assessment Input Comment EFSA Journal 2014;12(4):

15 Commodity Other commodities of food and animal origin Input MRLs Chronic exposure assessment Comment See Appendix C Acute exposure assessment Input Comment The estimated exposure was then compared with the toxicological reference values derived for difenoconazole (see Table 2-1). The results of the intake calculation are presented in Appendix B to this reasoned opinion. o long-term consumer intake concerns were identified for the any of the European diets incorporated in the EFSA PRIMo. The total calculated intake accounted for up to 98 % of the ADI (WHO cluster diet B). The contribution of residues to the total consumer exposure accounted 0.8% of the ADI for peppers and 0.4% for aubergines. The exposure calculation with the alternative value for aubergines reflecting the SEU outdoor trials which were performed with a higher number of applications compared to the GAP resulted in a slightly higher exposure of 0.5% of the ADI. o acute consumer risk was identified in relation to the MRL proposals for peppers and aubergines. The calculated maximum exposure in percentage of the ARfD was 19 % for peppers and 4 % for aubergines. The alternative calculation for aubergines with the highest residue derived for the tentative MRL proposal resulted in an exposure of 6% of the ARfD. EFSA concludes that the intended use of difenoconazole on peppers and tomatoes will not result in a consumer exposure exceeding the toxicological reference value and therefore is unlikely to pose a public health concern. For aubergines two MRL proposals were derived for further risk management considerations. COCLUSIOS AD RECOMMEDATIOS COCLUSIOS The toxicological profile of difenoconazole was assessed in the framework of the peer review under Directive 91/414/EEC and the data were sufficient to propose an ADI of 0.01 mg/kg bw per day and an ARfD of 0.16 mg/kg bw. EFSA defined toxicological reference values also for the triazole derivative metabolites (TDMs). The metabolism of difenoconazole in primary crops was investigated in tomatoes, grapes, oilseed rape, potatoes and wheat following foliar and seed treatment (cereals only) during the peer review. From these studies the peer review concluded to establish the residue definition for enforcement as difenoconazole. The current residue definition set in Regulation (EC) o 396/2005 is identical to that derived in the peer review assessment. For risk assessment, considering that TDMs are toxicologically relevant metabolites, two separate plant residue definitions were proposed: 1) difenoconazole and 2) provisionally, triazole derivative metabolites. TDMs are common metabolites of active substances belonging to the chemical class of triazoles. EFSA concludes that the results of the above mentioned metabolism studies can be extrapolated to the crops under consideration and no additional studies are required. EFSA concludes that the submitted supervised residue trials are sufficient to derive MRL proposals of 0.8 mg/kg for the proposed use on peppers and 0.4 mg/kg for the use on aubergines reflecting the indoor use. An alternative MRL proposal of 0.6 mg/kg was derived for aubergines for further risk management considerations, based on SEU outdoor trials which were performed with a higher number of applications compared to the notified GAP. EFSA Journal 2014;12(4):

16 The effects of processing on the magnitude of difenoconazole residues was evaluated during the peer review where it was concluded that the compound is hydrolytically stable and the same residue definition as for raw agricultural commodities (RAC) is applicable. o additional studies were submitted under this application. The occurrence of difenoconazole residues in rotational crops was investigated 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 are unlikely to occur in rotational crops provided that the compound is used on peppers and aubergines according to the proposed GAP (Good Agricultural Practice). However, there are still some open points regarding the possible occurrence of triazole derivative metabolites in rotational crops which will be addressed during the assessment of the confirmatory data. Residues of difenoconazole 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 Pesticide Residues Intake Model (PRIMo). For the calculation of chronic exposure, EFSA used the median residue values as derived from the residue trials on the crops under consideration. For the remaining commodities of plant and animal origin, the existing MRLs as established in Annex IIIA of Regulation (EC) o 396/2005 were used as input values. 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 estimated exposure was then compared with toxicological reference values derived for difenoconazole. o long-term consumer intake concerns were identified for the any diets incorporated in the EFSA PRIMo. The total calculated intake accounted for up to 98 % of the ADI (WHO cluster diet B). The contribution of difenoconazole residues of the assessed commodities to the total consumer exposure accounted 0.8% of the ADI for peppers and 0.4% for aubergines. o acute consumer risk was identified regarding the MRLs proposals for the crops under consideration. The highest maximum exposure in percentage of the ARfD was calculated for the residue in peppers 19% of the ARfD and 4% for aubergines. EFSA concludes that the proposed use of difenoconazole on peppers and aubergines will not result in a consumer exposure exceeding the toxicological reference values and therefore is unlikely to pose a consumer health risk. The consumer risk assessment related to TDMs was not undertaken in this application as the assessment of confirmatory data for triazole pesticides are still under assessment. RECOMMEDATIOS number (a) Commodity Existing EU MRL Enforcement residue definition: difenoconazole Proposed EU MRL Justification for the proposal Peppers The MRL proposal is sufficiently supported by data and no consumer health risk was identified for the intended uses on this crop Aubergines or 0.6 The MRL proposal of 0.4 mg/kg which reflects the intended indoor GAP is sufficiently supported by data; no EFSA Journal 2014;12(4):

17 number (a) Commodity Existing EU MRL Proposed EU MRL (a): According to Annex I of Regulation (EC) o 396/2005. (*): Indicates that the MRL is set at the limit of analytical quantification. Justification for the proposal consumer health risk was identified. The intended EU outdoor use is not supported by data. The alternative MRL proposal of 0.6 mg/kg was derived from SEU trials, performed with 3 or 4 applications instead of 2 applications as defined in the GAP. The MRL proposal might be slightly higher than the residues expected after treatment according to the GAP. o consumer health risk was identified for this proposal. Thus, a risk management decision should be taken on the most appropriate MRL for aubergines. REFERECES EC (European Commission), 1997a. Appendix A. Metabolism and distribution in plants. 7028/IV/95- rev.3. EC (European Commission), 1997b. Appendix B. General recommendations for the design, preparation and realisation 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. EC (European Commission), 1997c. Appendix C. Testing of plant protection products in rotational crops. 7524/VI/95-rev.2. EC (European Commission), 1997d. Appendix E. Processing studies. 7035/VI/95-rev.5. EC (European Commission), 1997e. Appendix F. Metabolism and distribution in domestic animals. 7030/VI/95-rev.3. EC (European Commission), 1997f. Appendix H. Storage stability of residue samples. 7032/VI/95- rev.5. EC (European Commission), 1997g. Appendix I. Calculation of maximum residue level and safety intervals. 7039/VI/95. EC (European Commission), Residue analytical methods. For pre-registration data requirement for Annex II (part A, section 4) and Annex III (part A, section 5 of Directive 91/414). SACO/3029/99-rev.4. EC (European Commission), 2010a. Classes to be used for the setting of EU pesticide Maximum Residue Levels (MRLs). SACO 10634/2010 Rev. 0, finalised in the Standing Committee on the Food Chain and Animal Health at its meeting of March EC (European Commission), 2010b. Residue analytical methods. For post-registration control. SACO/825/00-rev.8.1. EC (European Commission), Appendix D. Guidelines on comparability, extrapolation, group tolerances and data requirements for setting MRLs. 7525/VI/95-rev.9. EFSA (European Food Safety Authority), Reasoned opinion on the potential chronic and acute risk to consumers health arising from proposed temporary EU MRLs. Available online: EFSA Journal 2014;12(4):

18 EFSA (European Food Safety Authority), 2010a. Reasoned opinion on the modification of the existing MRLs for difenoconazole in swedes and turnips. EFSA Journal 2010;8(2):1510, 36 pp. doi: /j.efsa EFSA (European Food Safety Authority), 2010b. Reasoned opinion on the modification of the existing MRLs for difenoconazole in peppers and aubergines. EFSA Journal 2010;8(6):1651, 27 pp. doi: /j.efsa EFSA (European Food Safety Authority), 2011a. Conclusion on the peer review of the pesticide risk assessment of the active substance difenoconazole. EFSA Journal 2011;9(1):1967, 71 pp. doi: /j.efsa EFSA (European Food Safety Authority), 2011b. Reasoned opinion on the modification of the existing MRLs for difenoconazole in beet leaves (chard), globe artichokes, broccoli, cardoons and strawberries. EFSA Journal 2011;9(5):2153, 32 pp. doi: /j.efsa EFSA (European Food Safety Authority), Reasoned opinion on the modification of the existing MRLs for difenoconazole in raspberries, blackberries and cucurbits (edible peel) EFSA Journal 2012;10(8):2867, 30 pp. doi: /j.efsa EFSA (European Food Safety Authority), Reasoned opinion on the modification of the existing MRLs for difenoconazole in various crops. EFSA Journal 2013;11(3):3149, 37 pp. doi: /j.efsa E (European Committee for Standardisation), Foods of plant origin - Determination of pesticide residues using GC-MS and/or LC-MS/MS following acetonitrile extraction/partitioning and clean-up by dispersive SPE. QuEChERS-method. E ovember FAO (Food and Agriculture Organization of the United ations), Submission and evaluation of pesticide residues data for the estimation of Maximum Residue Levels in food and feed. Pesticide Residues. 2nd Ed. FAO Plant Production and Protection Paper 197, 264 pp. FAO (Food and Agriculture Organization of the United ations), In: Pesticide residues in food Evaluations. Part I. Residues. FAO Plant Production and Protection Paper 192, pp. FAO (Food and Agriculture Organization of the United ations), In: Pesticide residues in food Evaluations. Part I. Residues. FAO Plant Production and Protection Paper 206, pp. Greece, Evaluation report on the modification on the active substance difenoconazole in peppers and aubergines prepared by the evaluating Member State Greece under Article 8 of Regulation (EC) 396/2005, 24 July 2013, 96 pp. Meier U, Growth Stages of mono- and dicotyledonous plants. BBCH Monograph, 2nd Ed., Federal Biological Research Centre of Agriculture and Forest. Braunschweig, Germany. OECD (Organisation for Economic Co-operation and Development), OECD MRL Calculator: spreadsheet for single data set and spreadsheet for multiple data set, 2 March In: Pesticide Publications/Publications on Pesticide Residues. Sweden, Draft assessment report on the active substance difenoconazole prepared by the rapporteur Member State Sweden in the framework of Council Directive 91/414/EEC, December EFSA Journal 2014;12(4):