Modification of the existing maximum residue levels for cyproconazole in pulses, barley and oat

Transcription

1 REASOED OPIIO APPROVED: 14 June 2016 doi: /j.efsa Modification of the existing maximum residue levels for cyproconazole in pulses, barley and oat Abstract European Food Safety Authority (EFSA) In accordance with Article 6 of Regulation (EC) o 396/2005, the evaluating Member State (EMS), France, received an application from Syngenta Crop Protection AG to modify the existing maximum residue levels (MRLs) for the active substance cyproconazole in pulses, barley and oat. According to EFSA, the data are sufficient to derive MRL proposals of 0.08 mg/kg for pulses, and 0.2 mg/kg for barley and oat grain. Adequate analytical enforcement methods are available to control the residues of cyproconazole on the commodities under consideration. Based on the results of the risk assessment conducted for cyproconazole, EFSA concludes that the proposed uses on pulses, barley and oat will not result in a consumer exposure exceeding the toxicological reference values and therefore are unlikely to pose a consumer health risk European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority. Keywords: cyproconazole, triazole derivative metabolites, pulses, cereals, MRL application, consumer risk assessment Requestor: European Commission Question number: EFSA-Q Correspondence: pesticides.mrl@efsa.europa.eu EFSA Journal 2016;14(7):4526

2 Suggested citation: EFSA (European Food Safety Authority), Reasoned opinion on the modification of the existing maximum residue levels for cyproconazole in pulses, barley and oat. EFSA Journal 2016;14(7):4526, 18 pp. doi: /j.efsa ISS: European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority. This is an open access article under the terms of the Creative Commons Attribution-oDerivs License, which permits use and distribution in any medium, provided the original work is properly cited and no modifications or adaptations are made. The EFSA Journal is a publication of the European Food Safety Authority, an agency of the European Union. 2 EFSA Journal 2016;14(7):4526

3 Summary In accordance with Article 6 of Regulation (EC) o 396/2005, the evaluating Member State (EMS), France, received an application from Syngenta Crop Protection AG to modify the existing maximum residue levels (MRLs) for the active substance cyproconazole in pulses, barley and oat. To accommodate for the intended uses of cyproconazole, France proposed to raise the existing MRLs to 0.08 mg/kg in pulses, and 0.2 mg/kg in barley and oat grains. France 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 the European Food Safety Authority (EFSA) on 26 February EFSA bases its assessment on the evaluation report, the draft assessment report (DAR) and its addendum prepared under Directive 91/414/EEC, the Commission review report on cyproconazole, the conclusion on the peer review of the pesticide risk assessment of the active substance cyproconazole and on the confirmatory data, the Joint Meeting on Pesticide Residues (JMPR) evaluation reports as well as the conclusions from previous EFSA opinions and statements on cyproconazole. The toxicological profile of cyproconazole was assessed in the framework of the peer review and the data were sufficient to derive an acceptable daily intake (ADI) of 0.02 mg/kg bw per day and an acute reference dose (ARfD) of 0.02 mg/kg bw. The metabolism of cyproconazole in primary crops was investigated in the fruit, root, cereal and pulses/oilseeds crop groups following foliar applications and in coffee. Considering that the representative use evaluated was on wheat, the peer review concluded on a monitoring residue definition as cyproconazole (sum of isomers) for the cereal group only. For risk assessment, two separate residue definitions were proposed: (1) cyproconazole (sum of isomers) and (2) triazole derivative metabolites (TDM), pending a harmonised approach on how to consider TDMs in the risk assessment. Afterwards, EFSA proposed to provisionally apply the same residue definitions to the pulses/oilseeds group. EFSA concludes that the submitted residue trials are sufficient to derive MRL proposals of 0.08 mg/kg on pulses, and 0.2 mg/kg on barley and oat grains. Adequate analytical enforcement methods are available to monitor residues of cyproconazole on these commodities at the validated limit of quantification (LOQ) of 0.01 mg/kg. Specific studies investigating the magnitude of cyproconazole residues in processed commodities are not requested as significant residues are not expected in raw agricultural commodities (RAC). Until the possible occurrence of TDMs in rotational crops is addressed, EFSA reiterates the general recommendation that Member States when granting authorisations for the use of cyproconazole should take appropriate risk management measures to avoid the occurrence of cyproconazole-related residues in rotational crops and/or succeeding crops. Considering the new Organisation for Economic Co-operation and Development (OECD) feedstuff tables, the residue levels in pulses, barley and oat resulting from the intended uses do not request a modification of the existing MRLs for animal products. The consumer risk assessment was performed with revision 2 of the EFSA Pesticide Residues Intake Model (PRIMo). The chronic intake calculation was performed using the median residue levels (STMR) derived from the submitted residue trials, the STMRs derived in previous EFSA assessments and from Codex and the existing MRLs for the remaining commodities. The highest chronic intake calculated accounted for up to 23% of the ADI (British, toddler). An acute consumer risk was not identified in relation to the MRL proposals for the crops under consideration. The highest acute consumer exposure was calculated to be 1% of the ARfD for barley. EFSA concludes that the proposed uses of cyproconazole on pulses, barley and oat will not result in a consumer exposure exceeding the toxicological reference values and therefore are unlikely to pose a health risk to consumers. However, EFSA emphasises that the above assessment does not take into consideration TDMs. EFSA recommends that a separate risk assessment should be performed for TDMs as soon as the confirmatory data requested for triazole compounds in the framework of Regulation (EC) o 1107/2009 have been evaluated and a general methodology on the risk assessment of triazole compounds and their TDMs is available. 3 EFSA Journal 2016;14(7):4526

4 EFSA proposes to amend the existing MRLs as reported in the summary table below: Code (a) Commodity Existing EU MRL (mg/kg) Proposed EU MRL (mg/kg) Enforcement residue definition: Cyproconazole (b) Comment/justification Pulses 0.05 (c) 0.08 EU and SEU, based on SEU trials on beans Barley EU and SEU, based SEU trials on barley Oat Extrapolation to oat EU: European Union; MRL: maximum residue level; EU: northern Europe; SEU: southern Europe. (a): Commodity code number according to Annex I of Regulation (EC) o 396/2005. (b): Fat soluble. (c): Indicates that the MRL is set at the limit of analytical quantification (LOQ). 4 EFSA Journal 2016;14(7):4526

5 Table of contents Abstract... 1 Summary... 3 Background... 6 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 ature of residues Magnitude of residues Effect of industrial processing and/or household preparation Rotational crops ature and magnitude of residues in livestock Dietary burden of livestock Consumer risk assessment Conclusions and recommendations References Abbreviations Appendix A Good agricultural practice Appendix B Used compound codes EFSA Journal 2016;14(7):4526

6 Background Regulation (EC) o 396/ (hereinafter referred to as the Regulation ) establishes the rules governing the setting of pesticide maximum residue levels (MRLs) at European Union (EU) level. Article 6 of the 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 Directive 91/414/EEC, 2 repealed by Regulation (EC) o 1107/2009 3, shall submit to a Member State, when appropriate, an application to modify a MRL in accordance with the provisions of Article 7 of the Regulation. France, hereafter referred to as the evaluating Member State (EMS), received an application from the company Syngenta Crop Protection AG 4 to modify the existing MRLs for the active substance cyproconazole in pulses, barley and oat. This application was notified to the European Commission and the European Food Safety Authority (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 and to EFSA on 26 February The application was included in the EFSA Register of Questions with the reference number EFSA-Q and the following subject: Cyproconazole Modification of existing MRLs in barley, oats and pulses France proposed to raise the existing MRLs of cyproconazole from the limit of quantification (LOQ) of mg/kg in pulses, and from 0.1 to 0.2 mg/kg in barley and oat grains. EFSA proceeded with the assessment of the application and the evaluation report as required by Article 10 of the Regulation. In accordance with Article 10 of Regulation (EC) o 396/2005, EFSA shall, based on the evaluation report provided by the EMS, provide a reasoned opinion on the risks to the consumer associated with the application. The evaluation report submitted by the EMS (France, 2016) and the exposure calculations using the EFSA Pesticide Residues Intake Model (PRIMo) are considered as supporting documents to this reasoned opinion and, thus, are made publicly available. In accordance with Article 11 of the Regulation, the reasoned opinion shall be provided as soon as possible and at the latest within 3 months (which may be extended to 6 months if more detailed evaluations need to be carried out) from the date of receipt of the application. If EFSA requests supplementary information, the time limit laid down shall be suspended until that information has been provided. The active substance and its use pattern Cyproconazole is the ISO common name for (2RS,3RS;2RS,3SR)-2-(4-chlorophenyl)-3-cyclopropyl- 1-(1H-1,2,4-triazol-1-yl)butan-2-ol (IUPAC), which is a mixture of approximately 1:1 of the two diastereomers, each of which is exactly a 1:1 mixture of the enantiomers. The chemical structures of the active substance and its main metabolites are reported in Appendix B. Cyproconazole was evaluated in the framework of Directive 91/414/EEC with Ireland designated as rapporteur Member State (RMS). It was included in Annex I of Directive 91/414/EEC by Directive 2011/56/EU 5 which entered into force on 1 June 2011 for use as fungicide. In accordance with Regulation (EU) o 540/2011 6, cyproconazole is approved under Regulation (EC) o 1107/2009, repealing Directive 91/414/EEC. The representative uses evaluated in the peer review were foliar applications on wheat. The draft assessment report (DAR) has been peer reviewed by EFSA (EFSA, 2010). The confirmatory data regarding specific provisions for approval were submitted and have been assessed (EFSA, 2014b). The EU MRLs for cyproconazole are established in Annex IIIA of Regulation (EC) o 396/2005. Since the entry into force of this regulation, EFSA has issued a number of reasoned opinions and 1 Regulation (EC) o 396/2005 of the Parliament and 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 protection 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 Crop Protection AG, Schwarzwaldallee 215, CH-4058 Basel, Switzerland. 5 Commission Implementing Directive 2011/56/EU of 27 April 2011 amending Council Directive 91/414/EEC to include cyproconazole as active substance and amending Commission Decision 2008/934/EC, OJ L 108, , p Commission Implementing Regulation (EU) o 540/2011 of 23 May 2011 implementing Regulation (EC) o 1107/2009 of the European Parliament and of the Council as regards the list of approved active substances. OJ L 153, , p EFSA Journal 2016;14(7):4526

7 statements on MRLs for cyproconazole, which proposals have been considered in the preparation of EU legislation. The MRL changes that were reported in the EU legislation since the entry into force of the Regulation are summarised in Table 1. The MRL review of cyproconazole according to Article 12 of Regulation (EC) o 396/2005 (hereafter Article 12 MRL review) is not initiated yet. Codex Alimentarius has established maximum residue limits (CXLs) for a range of commodities. The CXLs are set at the LOQ of 0.02 mg/kg on beans and peas (dry), and at 0.08 mg/kg on barley and oat. Table 1: Overview of the MRL changes since the entry into force of Regulation (EC) o 396/2005 Procedure (a) Considered by Regulation Remarks Art. 10 (EFSA, 2011b) (EU) o 270/2012 Rape seeds Art. 43 (EFSA, 2011c) (EU) o 441/2012 Implementation of CXL (CAC 2011) Art. 10 (EFSA, 2012) (EU) o 34/2013 Poppy seeds Art. 10 (EFSA, 2013) (EU) o 1004/2013 Mustard and gold of pleasure seeds MRL: maximum residue level; EFSA: European Food Safety Authority; EU: European Union; CXL: Codex maximum residue limit. (a): Art. 10: Assessment of MRL application according to Article 6 10 of Regulation (EC) o 396/2005. Art. 43: EFSA scientific opinion according to Article 43 of Regulation (EC) o 396/2005. The details of the intended Good Agricultural Practices (GAPs) for cyproconazole are given in Appendix A. Assessment EFSA has based its assessment on the evaluation report submitted by the EMS (France, 2016), the DAR and its additional reports and addendum prepared under Directive 91/414/EEC (Ireland, 2006, 2010a,b, 2014), the Commission review report on cyproconazole (European Commission, 2013), the conclusion on the peer review of the pesticide risk assessment of the active substance cyproconazole (EFSA, 2010), the outcome on the pesticide risk assessment of the confirmatory data for cyproconazole (EFSA, 2014b), the Joint Meeting on Pesticide Residues (JMPR) Evaluation reports (FAO, 2010, 2013) as well as the conclusions from previous EFSA opinions on cyproconazole (EFSA, 2011b, 2012, 2013) and statements on the EU position in the 43rd and 46th Sessions of the Codex Committee on Pesticide Residues (EFSA, 2011c, 2014a). 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 guidance documents relevant for the consumer risk assessment (European Commission, 1996, 1997a g, 2000, 2010a, b, 2015; OECD, 2011). 1. Method of analysis 1.1. Methods for enforcement of residues in food of plant origin The peer review according to Directive 91/414/EEC concluded that the multiresidue DFG S19 method using liquid chromatography with tandem mass spectrometry (LC MS/MS) is applicable to quantify residues of cyproconazole as sum of its isomers (method not stereoselective) in dry/protein (cereal grain) and high water content commodities (apple, melon) with a LOQ of 0.01 mg/kg (EFSA, 2010). In addition, the multiresidue Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) method was concluded to be sufficiently validated at the LOQ of 0.01 mg/kg in high oil content commodities (EFSA, 2011b, 2012, 2013). As the commodities under consideration belong to the dry group (with either protein or starch content), EFSA concludes that sufficiently validated analytical methods are available to enforce the proposed MRLs for cyproconazole Methods for enforcement of residues in food of animal origin The peer review according to Directive 91/414/EEC concluded that the multiresidue DFG S19 analytical method using LC MS/MS is applicable to quantify residues of cyproconazole as sum of its isomers in muscle, fat, kidney, liver, milk and eggs with a LOQ of 0.01 mg/kg (EFSA, 2010). 7 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 EFSA Journal 2016;14(7):4526

8 EFSA concludes that sufficiently validated analytical methods are available to enforce the MRLs for cyproconazole in food of animal origin. 2. Mammalian toxicology The toxicological profile of the active substance cyproconazole was assessed in the framework of the peer review under Directive 91/414/EEC (Ireland, 2006; EFSA, 2010). The data were sufficient to derive toxicological reference values compiled in Table 2. Table 2: Overview of the toxicological reference values Source Year Value Study Safety factor Cyproconazole ADI European Commission mg/kg bw per day Rat, multigeneration; long-term rat and mouse ARfD mg/kg bw Rat multigeneration; rabbit, developmental ADI: acceptable daily intake; ARfD: acute reference dose; bw: body weight. The reference values of the parent compound are applicable to the metabolites M36(Z2), M9/M14 (pair of diastereomers) and M38/Z1, which are included in the residue definition for risk assessment in commodities of ruminant origin (EFSA, 2010). Toxicological reference values were proposed also for the triazole derivative metabolites (TDMs) (EFSA, 2011a) in order to perform a separate risk assessment covering these metabolites. 3. Residues 3.1. ature and magnitude of residues in plant Primary crops ature of residues The metabolism of cyproconazole in primary crops was investigated in the framework of the peer review under Directive 91/414/EEC (Ireland, 2006; EFSA, 2010) and in a previous EFSA reasoned opinion (EFSA, 2011b) in the fruit, root, cereals and pulses/oilseeds crop groups following foliar applications or seed treatment (wheat grain) and in coffee. The peer review concluded on the following residue definitions, covering the cereal group only, as this was the representative use supported for the Annex I inclusion to Directive 91/414/EEC (EFSA, 2010): enforcement: cyproconazole (sum of isomers) risk assessment: cyproconazole (sum of isomers) and, TDMs (provisionally, pending the finalisation of a global and harmonised approach for all active substances of the triazole chemical group regarding the assessment of consumer exposure to TDMs). The details of the metabolism studies are presented in Table 3. Table 3: Summary of available metabolism studies in plants Crop groups Crops Applications (a) Sampling Comments Fruit Apple Foliar, A, g/ha 28 DALA Pre-GLP Grape Foliar, A, g/ha 29 DALA Pre-GLP Root Sugar beet Foliar, tri, or 120 g/ha 28 DALA Cereals Wheat Foliar, A, g/ha 34 DAT Pre-GLP Foliar, phy, or 200 g/ha 11 DAT 1 ; 41 DALA Foliar, tri, or 160 g/ha 11 DAT 1, 42 DALA Seed, tri, 1 g/100 g seed BBCH 51, maturity res < LOQ 8 EFSA Journal 2016;14(7):4526

9 Crop groups Crops Applications (a) Sampling Comments Pulses/oilseeds Peanuts Foliar, A, or 1,000 g/ha 0, 6-week prior and at maturity Foliar, A, 4 9 1,000 g/ha 21 DALA Miscellaneous Coffee Foliar, tri, or 200 g/ha 30 DALA GLP: Good Laboratory Practice; res: residues; BBCH: growth stages of mono- and dicotyledonous plants; LOQ: limit of quantification. (a): A: 14 C-a-carbon labelled; phy: 14 C-phenyl ring labelled; tri: 14 C-triazole ring labelled; DAT: days after treatment; DAT 1 : days after first treatment; DALA: days after last application. Afterwards, as the available metabolism studies showed that cyproconazole is a valid marker of the residues, EFSA proposed to provisionally apply to oilseeds the residue definitions proposed for cereals during the peer review (EFSA, 2011b, 2012, 2013) and pending the submission of additional information on TDMs. By analogy, those residue definitions can provisionally be applied to pulses. For the uses on pulses, barley and oat, EFSA concludes that the residue definitions for enforcement and risk assessment as agreed during the peer review are applicable. The residue definitions will be reconsidered under the Article 12 MRL review and in the light of the outcome of the assessment of the confirmatory data for TDMs. The current residue definition set in Regulation (EC) o 396/2005 refers to the active substance cyproconazole without specifying that all isomers are included Magnitude of residues In support of the MRL application, field residue trials conducted in beans, peas and barley were submitted. All samples were analysed for cyproconazole. In addition, samples of barley were analysed for 1,2,4-triazole (T), triazole alanine (TA), triazole acetic acid (TAA) and triazole lactic acid (TLA). Pulses (northern Europe (EU)/southern Europe (SEU) GAP: g/ha, preharvest interval (PHI) 35 days) EU. Eight GAP-compliant residue trials conducted on peas were submitted. Residues of cyproconazole at harvest were below the LOQ (< 0.01 mg/kg). SEU. Eight GAP-compliant residue trials conducted on beans were submitted. Residues of cyproconazole at harvest ranged from < 0.01 to 0.05 mg/kg. The use in the SEU resulted in a more critical residue situation and, based on this data set, EFSA derived a MRL of 0.08 mg/kg extrapolated to pulses as suggested by the guidance document SACO/7525/VI/95 (European Commission, 2015). Barley, oat (EU/SEU GAP: g/ha, BBCH 31 69, PHI (/A, not applicable)) EU. Eight GAP-compliant residue trials conducted on barley were selected. 8 The second and last application occurred at growth stage BBCH At harvest, residues of cyproconazole were at or close to 0.01 mg/kg in grain and ranged from 0.08 to 0.52 mg/kg in straw. SEU. Eight GAP-compliant residue trials conducted on barley were submitted. The second and last application occurred at the intended growth stage BBCH 69. At harvest, residues of cyproconazole ranged from < 0.01 to 0.10 mg/kg in grain and from 0.05 to 1.9 mg/kg in straw. The use in the SEU resulted in a more critical residue situation and based on this dataset, EFSA derived a MRL of 0.2 mg/kg for grain. According to the guidance document SACO/7525/VI/95 (European Commission, 2015), results from trials on barley can be extrapolated to oat. For TDMs, only TA and TAA were measured at levels above the LOQ (0.01 mg/kg) up to mg/kg in grain. The most abundant triazole metabolites in straw were TAA and TLA, up to 0.15 mg/kg. However, the validity of TDM results is pending the submission of analytical method validation data and of storage stability data. The results of the residue trials, the highest (HR) and the median (STMR) residue levels used as input values for the risk assessment and the dietary burden calculation of cyproconazole as well as the 8 EFSA disregarded two studies conducted in 1992 in two locations with three different formulations (soluble concentrate (SL), emulsifiable concentrate (EC) and water-dispersible granule (WG)), which were taken into account by the EMS (France, 2016). Although conducted at the GAP rate, the interval between the two applications of only 2 days is not compliant with the 3 4 weeks of the intended GAP. 9 EFSA Journal 2016;14(7):4526

10 MRL proposals are summarised in Table 4. The MRL derived from the more critical residue situation is highlighted in bold. The storage stability of cyproconazole in primary crops was investigated during the peer review and residues were found to be stable under frozen conditions for up to 39 months in dry/protein matrices and between 12 and 42 months in high water and oil content matrices. o data were provided for straw and for TDMs (EFSA, 2010). Since the trial samples were properly stored for a maximum of 12 (barley) and 7 (beans and peas) months prior to be analysed for cyproconazole, results are valid with regard to storage stability of parent compound. Samples were stored for up to 23 months prior to be analysed for TDMs (France, 2016). According to the EMS, the analytical methods used to analyse the residue trial samples have been sufficiently validated for cyproconazole and were proven to be fit for purpose. The validation of the analytical method (GRM053.01A) and the storage stability for TDMs have not been provided in this MRL application and are not requested pending the assessment of the confirmatory data on these metabolites. EFSA concludes that the data are sufficient to derive the following MRL proposals: 0.08 mg/kg: pulses, in EU and SEU (based on SEU trials on beans). 0.2 mg/kg: barley, oat grain, in EU and SEU (based on SEU trials on barley). Table 4: Overview of the available residues trials data Crop (GAPs) Peas (dry) ( g/ha, PHI 35 days) Beans (dry) ( g/ha, PHI 35 days) Barley ( g/ha, BBCH 31-69, PHI /A) Barley straw ( g/ha, BBCH 31-69, PHI /A) Region/ Indoor (a) Residue levels observed in the supervised residue trials (b) (mg/kg) EU 8 9 < 0.01 TDMs: not analysed for SEU 2 9 < 0.01; ; 0.02; 0.05 TDMs: not analysed for EU ; T & TLA: 8 9 < 0.01 TA: 0.06; ; 0.21; 0.22; 0.27; 0.28 TAA: 0.03; 0.06; 0.08; 0.09; 0.11; 0.12; 0.13; 0.40 SEU 3 9 < 0.01; 0.02; 0.06; 0.08; 0.09; 0.10 T & TLA: 8 9 < 0.01 TA: 0.06; ; , 0.16; 0.17; 0.30 TAA: 0.05; 0.09; 0.11; 0.12; 0.15; 0.19; 0.21; 0.22 EU 0.08; 0.12; 0.15; 0.16; 0.17; 0.22; 0.35; 0.52 T: 8 9 < 0.01 TA 4 9 < 0.01; 0.01; ; 0.03 TAA: < 0.01; 2 x 0.02; 3 x 0.03; 0.04, 0.08 TLA: 0.01; 0.03; 0.04; 3 x 0.05; 0.06 SEU 0.05; 0.47; 0.66; 0.74; 0.94; 0.98; 1.25; 1.91 T: 8 9 < 0.01 TA: 5 9 < 0.01; ; 0.06 TAA: 3 x 0.03; 2 x 0.04; 0.06; 0.08; 0.15 TLA: 0.02; 0.03; 0.05; 3 x 0.06; 0.07; 0.15 Recommendations/ comments (c) MRL, STMR and HR derived from the more critical SEU use. MRL OECD : 0.07/0.08 (SEU) Extrapolation to pulses Sample collected (EU) and (SEU) DALA MRL, STMR and HR derived from the more critical SEU use MRL OECD : 0.04/0.05 (EU) MRL OECD : 0.2/0.2 (SEU) Extrapolation to oat grain STMR and HR derived from the more critical SEU use Validity of TDM results to be confirmed by storage stability and analytical method validation data Extrapolation to oat straw MRL proposal (mg/kg) HR (d) (mg/ kg) STMR (e) (mg/kg) 0.01 (f) DALA: days after last application; GAPs: Good Agricultural Practices; MRL: maximum residue level; TDM: triazole derivative metabolites; OECD: Organisation for Economic Co-operation and Development; PHI: preharvest interval. (a): EU: Outdoor trials conducted in northern Europe, SEU: Outdoor trials conducted in southern Europe, Indoor: indoor EU trials or Country code: if non-eu trials. (b): Individual residue levels are reported in ascending order. (c): OECD MRL calculation (unrounded/rounded values). T: 1,2,4-triazole; TLA: triazole lactic acid; TA: triazole alanine; TAA: triazole acetic acid. (d): HR: Highest residue level according to the residue definition for risk assessment as cyproconazole (sum of isomers). (e): STMR: Median residue level according to residue definition for risk assessment as cyproconazole (sum of isomers). (f): Indicates that the MRL is proposed at the limit of analytical quantification (LOQ) EFSA Journal 2016;14(7):4526

11 Effect of industrial processing and/or household preparation Standard hydrolysis studies simulating the effect on the nature of cyproconazole residues under processing conditions representative of pasteurisation, boiling and sterilisation were assessed during the peer review. As cyproconazole showed to be hydrolytically stable, the same residue definition as for raw agricultural commodities (RAC) is applicable to processed commodities (EFSA, 2010). Specific studies to assess the magnitude of cyproconazole residues during the processing of pulses, barley and oat are not requested as residue levels in RAC did not exceed the trigger value of 0.1 mg/kg (European Commission, 1997d). The effect of processing on the nature and magnitude of TDMs has not been provided and is not requested pending the assessment of the confirmatory data on these metabolites Rotational crops Pulses, barley and oat can be grown in rotation with other plants and the possible occurrence of residues in succeeding crops resulting from the use on primary crops has to be assessed. The soil degradation rate of cyproconazole is slow with a maximum period required for 90% dissipation (DT 90f ) exceeding 1,000 days (EFSA, 2010). Studies on the nature and magnitude of cyproconazole residues in rotational crops were assessed in the framework of the peer review. Rotational crop metabolism was similar to primary crop metabolism for the a-carbon position labelling and rotational crop field trials indicated that significant residues were only found at maturity in leafy crops. However, due to deficiencies in the studies (no studies available with the 14 C labelling on the triazole ring, plant-back interval (PBI) less than 430 days not investigated), the peer review required further rotational crop data (EFSA, 2010). In the framework of this MRL application, the EMS summarised the results of two new field rotational crop studies conducted on barley (cereals), carrots (root) and lettuces (leafy) with 30/36, 60/61 and 322/375 PBIs after a single application on bare soil at a rate of 200 g/ha. Samples were analysed for cyproconazole and TDMs, but residue levels were reported only for the parent compound (France, 2016). In rotated crops, cyproconazole resulted in amounts up to 0.03 mg/kg (depending on the PBI) in barley straw and lettuces. EFSA would recommend reconsidering these findings together with the results of TDMs. As long as the assessment of these data is not completed in the framework of the confirmatory data for TDMs, EFSA reiterates the general recommendation that Member States when granting authorisations for the use of cyproconazole should take appropriate risk management measures to avoid the occurrence of cyproconazole related residues in rotational crops and/or succeeding crops ature and magnitude of residues in livestock As the use of cyproconazole resulted in significant residue levels in barley straw which might be fed to livestock, the nature and magnitude of residues in livestock was assessed in the framework of this application (European Commission, 1996). The metabolism of cyproconazole was investigated in lactating goats and hens with cyproconazole labelled in the a-carbon or phenyl ring position. Based on the ruminant metabolism studies, the peer review concluded on a residue definition as cyproconazole (sum of isomers) for enforcement. For risk assessment, two separate definitions were proposed: 1) cyproconazole (sum of isomers) and the metabolites M36(Z2), M38(Z1) and M9/M14 (pair of diastereomers), expressed as cyproconazole; 2) TDMs, provisionally, pending further data on TDMs in ruminant matrices. As the feeding study in cattle was not analysing the metabolites included in the residue definition for risk assessment, a conversion factor of 3 was derived for liver from the metabolism data. The residue was classified as fat soluble (EFSA, 2010). As metabolic pathways were generally found to be similar between rodents and ruminants, the results of the goat metabolism study can be extrapolated to pigs. The setting of a residue definition for poultry products was not triggered by the representative use (EFSA, 2010) EFSA Journal 2016;14(7):4526

12 Dietary burden of livestock In the framework of the current MRL application, EFSA has updated the dietary burdens for livestock using the animal OECD feedstuff table (OECD, 2009), the animal model calculator developed by EFSA and the highest and median residue levels resulting from the intended uses of cyproconazole. To conduct the calculations, EFSA used the median (STMR) and highest (HR) residue levels reported in Table 4 for pulses, barley and oat. For apple pomace and the other cereals, the values reported in a previous EFSA reasoned opinion (EFSA, 2011b) were considered. For rape seed and soyabean the values reported by JMPR (FAO, 2010) and related to the CXLs that were implemented in the EU legislation by Regulation (EU) o 441/ were used as input values. In order to account for the concentration of residues in apple pomace and lupin seed meal, default processing factors (PF) of 2.5 and 1.1 were applied, respectively. o information could be retrieved at this stage for sugar beet tops, stover, silage and milled products from cereals, for which existing EU MRL are above the LOQ. The input values for the dietary burden calculation are summarised in Table 5. Table 5: Input values for the dietary burden calculation Feed commodity Median dietary burden Maximum dietary burden Input (mg/kg) Comment (a) Input (mg/kg) Comment Bean, pea, lupin (dry) 0.01 STMR (see Table 4) 0.01 STMR (see Table 4) Lupin seed, meal 0.01 STMR-p (see Table 4) 0.01 STMR-p (see Table 4) Barley, oat grain 0.04 STMR (see Table 4) 0.04 STMR (see Table 4) Barley, oat straw 0.84 STMR (see Table 4) 1.91 HR (see Table 4) Wheat, rye, maize grain 0.02 STMR (EFSA, 2011b) 0.02 STMR (EFSA, 2011b) Wheat, rye straw 0.39 STMR (EFSA, 2011b) 2.00 HR (EFSA, 2011b) Apple pomace 0.25 MRL-p (EFSA, 2011b) 0.25 MRL-p (EFSA, 2011b) Rape, canola seed meal 0.02 STMR-p (FAO, 2010) 0.02 STMR-p (FAO, 2010) Soyabean seed 0.02 STMR (FAO, 2010) 0.02 STMR (FAO, 2010) Soyabean meal 0.01 STMR-p (FAO, 2010) 0.01 STMR-p (FAO, 2010) FAO: Food and Agriculture Organization of the United ations; HR: highest residue; MRL: maximum residue level; STMR: supervised trials median residue; STMR-p: supervised trials median residue for a processed commodity. (a): Lupin meal, STMR 9 PF = 0.01 mg/kg 9 1.1; Apple pomace, MRL 9 PF = 0.1 mg/kg as no STMR value is available; Rape seed meal, STMR 9 PF = mg/kg ; Soya bean meal, STMR 9 PF = 0.02 mg/kg (FAO, 2010). The estimated animal dietary intakes taking into account the OECD approach and the feedstuffs reported in Table 5 related to the uses of cyproconazole within EU are summarised in Table 6. Animal intakes considered at Codex level to derive the CXL values for animal products that were transposed in the EU legislation by Regulation (EU) o 441/2012 are reported in the column Previous assessment. These intakes were derived taking into account the OECD approach and the OECD feedstuff tables (FAO, 2009, 2010). As the animal dietary burdens estimated with the feedstuffs reported in Table 5 are far below the animal intakes considered at Codex level to derive the CXL values that were transposed in the EU legislation, EFSA concludes that a modification of the existing MRLs for commodities of animal origin is not required in the framework of the current MRL application. EFSA emphasises that livestock dietary burdens were calculated only for parent compound while livestock is also expected to be exposed to TDMs and that metabolites M36(Z2), M38(Z1) and M9/M14 were not analysed in cattle matrices of the feeding study. The nature and magnitude of residues and the potential carry-over of cyproconazole residues into commodities of animal origin will be further investigated in the framework of the Article 12 MRL review. 9 Commission Regulation (EU) o 441/2012 of 24 May 2012 amending Annexes II and III to Regulation (EC) o 396/2005 of the European Parliament and of the Council as regards maximum residue levels for bifenazate, bifenthrin, boscalid, cadusafos, chlorantraniliprole, chlorothalonil, clothianidin, cyproconazole, deltamethrin, dicamba, difenoconazole, dinocap, etoxazole, fenpyroximate, flubendiamide, fludioxonil, glyphosate, metalaxyl-m, meptyldinocap, novaluron, thiamethoxam and triazophos in or on certain products. OJ L 135, , p EFSA Journal 2016;14(7):4526

13 Table 6: Results of the dietary burden calculation Median Maximum Maximum Highest burden burden burden > 0.1 mg/kg Codex assessment Animal contributing (mg/kg (mg/kg (mg/kg DM (Y/) commodity (a) (mg/kg DM) bw) bw) DM) Beef cattle Y Barley straw 6.33 (FAO, 2010) (b) Dairy cattle Y Barley straw 5.05 (FAO, 2010) (b) Ram/Ewe Y Barley straw Bovine intakes taken into Lamb Y Barley straw Pig (breeding) Barley grain 4. Consumer risk assessment account at Codex level to derived MRLs in mammalian products Pig (finishing) Barley grain Poultry broiler Barley grain 1.40 (FAO, 2010) (c) Poultry layer Y Wheat straw Turkey Barley grain bw: body weight; DM: dry matter; FAO: Food and Agriculture Organization of the United ations; MRLs: maximum residue levels. (a): Considering the maximum dietary animal burden. (b): Intakes based on the Australian animal diets and considered to derive the CXL for mammalian offal and milk. (c): Intakes based on the EU animal diets and considered to derive the CXL (at LOQ) for poultry. The consumer risk assessment was performed with revision 2 of the EFSA PRIMo. This exposure assessment model contains the relevant European food consumption data for different subgroups of the EU population 10 (EFSA, 2007). To calculate the chronic exposure, EFSA used the STMR derived from the residue trials conducted for the crops under consideration in this MRL application and reported in Table 4, to update the most recent chronic assessment carried out in a previous EFSA reasoned opinion (EFSA, 2013). In addition, the STMR for kidney and the conversion factor (CF) for enforcement to risk assessment of 6 11 defined by Codex were used for kidney, liver and offal (FAO, 2010). For the remaining commodities of plant and animal origin, the existing MRLs as established in Regulation (EU) o 1004/ 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 and that these items contained residues at STMR as observed in supervised field trials (Table 4). The input values used for the dietary exposure calculation are summarised in Table 7. The estimated exposure was then compared with the toxicological reference values derived for cyproconazole (Table 2). The results of the intake calculation using the PRIMo is a key supporting document and is made publicly available as a background document to this reasoned opinion. 10 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 World Health Organization (WHO) GEMS Food database; for the acute exposure assessment, the most critical large portion consumption data from 19 national diets collected from Member States surveys are used. The complete list of diets incorporated in EFSA PRIMo is given in its reference section (EFSA, 2007). 11 EFSA used the more conservative CF derived by Codex based on the residue definition for animal commodities as cyproconazole, free and conjugated (FAO, 2010). 12 Commission Regulation (EU) o 1004/2013 of 15 October 2013 amending Annexes II and III to Regulation (EC) o 396/2005 of the European Parliament and of the Council as regards maximum residue levels for 8-hydroxyquinoline, cyproconazole, cyprodinil, fluopyram, nicotine, pendimethalin, penthiopyrad and trifloxystrobin in or on certain products. OJ L L 279, , p EFSA Journal 2016;14(7):4526

14 Table 7: Input values for the consumer dietary exposure assessment Commodity Chronic exposure assessment Acute exposure assessment Input (mg/kg) Comment Input (mg/kg) Comment Risk assessment residue definition: Plant commodities: Cyproconazole (sum of isomer) Swine, ruminant origin commodities: Cyproconazole (sum of isomers) and the metabolites M36(Z2), M38(Z1) and M9/M14 (pair of diastereomers), expressed as cyproconazole Pulses 0.01 STMR 0.01 STMR Barley grain 0.04 STMR 0.04 STMR Oat grain 0.04 STMR 0.04 STMR Swine, bovine, Liver 0.84 STMR 9 CF (a) Acute risk assessment sheep, goats, Kidney 0.84 STMR 9 CF (a) undertaken only with regard to equine other pulses, barley and oat Offal 0.84 STMR 9 CF (a) farm animals Other plant and animal commodities A long-term consumer intake concern was not identified for any of the European diets incorporated in the EFSA PRIMo. The highest chronic intake calculated accounted for 23% of the ADI (British, toddler). The contribution of residues in the crops under consideration to the total consumer exposure accounted for a maximum of 0.2% of the ADI for barley (Irish, adult). An acute consumer risk was not identified in relation to the MRL proposals for the crops under consideration. The highest acute consumer exposure was calculated to be 1% of the ARfD for barley. EFSA concludes that the intended uses of cyproconazole on pulses, barley and oat will not result in a consumer exposure exceeding the toxicological reference values and therefore are unlikely to pose a concern for public health. However, EFSA emphasises that the above assessment does not take into consideration TDMs. EFSA recommends that a separate risk assessment should be performed for TDMs as soon as the confirmatory data requested for triazole compounds in the framework of Regulation (EC) o 1107/2009 have been evaluated and a general methodology on the risk assessment of triazole compounds and their TDMs is available. Conclusions and recommendations The information submitted was sufficient to propose the MRLs summarised in the table below: Code (a) Existing EU Proposed EU Commodity MRL (mg/kg) MRL (mg/kg) Enforcement residue definition: Cyproconazole (b) Comment/justification Pulses 0.05 (c) 0.08 EU and SEU, based on SEU trials on bean Barley EU and SEU, based on SEU trials on barley Oat Extrapolation to oat EU: European Union; MRL: maximum residue level; EU: northern Europe; SEU: southern Europe. (a): Commodity code number according to Annex I of Regulation (EC) o 396/2005. (b): Fat soluble. (c): Indicates that the MRL is set at the limit of analytical quantification (LOQ). References See Table 4-1 of the Reasoned opinion on the modification of the existing MRLs for cyproconazole in mustard seed and gold of pleasure (EFSA, 2013) STMR: supervised trials median residue; CF: conversion factor; MRL: maximum residue level. (a): STMR of 0.14 mg/kg 9 CF of 6 derived for kidney from the metabolism study on goats (FAO, 2010). EFSA (European Food Safety Authority), Reasoned opinion on the potential chronic and acute risk to consumers health arising from proposed temporary EU MRLs. EFSA Journal 2007;5(3):32r, 1141 pp. doi: /j.efsa r EFSA (European Food Safety Authority), Conclusion on the peer review of the pesticide risk assessment of the active substance cyproconazole. EFSA Journal 2010;8(11):1897, 73 pp. doi: /j.efsa EFSA (European Food Safety Authority), 2011a. Conclusion of EFSA prepared by PRAPeR on the peer review of pesticide risk assessment of the active substance difenoconazole. EFSA Journal 2011;9(1):1967, 71 pp. doi: /j.efsa EFSA Journal 2016;14(7):4526

15 EFSA (European Food Safety Authority), 2011b. Reasoned opinion of EFSA: modification of the existing MRL for cyproconazole in rape seed. EFSA Journal 2011;9(5):2187, 30 pp. doi: /j.efsa EFSA (European Food Safety Authority), 2011c. Scientific support for preparing an EU position in the 43rd Session of the Codex Committee on Pesticide Residues (CCPR). EFSA Journal 2011;9(9):2360, 123 pp. doi: / j.efsa EFSA (European Food Safety Authority), Reasoned opinion on the modification of the existing MRL for cyproconazole in poppy seed. EFSA Journal 2012;10(7):2834, 26 pp. doi: /j.efsa EFSA (European Food Safety Authority), Reasoned opinion on the modification of the existing MRLs for cyproconazole in mustard seed and gold of pleasure. EFSA Journal 2013;11(4):3194, 26 pp. doi: / j.efsa EFSA (European Food Safety Authority), 2014a. Scientific support for preparing an EU position in the 46th Session of the Codex Committee on Pesticide Residues (CCPR). EFSA Journal 2014;12(7):3737, 182 pp. doi: / j.efsa EFSA (European Food Safety Authority), 2014b. Outcome of the consultation with Member States, applicant and EFSA on the pesticide risk assessment of confirmatory data submitted for the active substance cyproconazole. EFSA supporting publication 2014:E pp. European Commission, Appendix G. Livestock feeding studies. 7031/VI/95-rev.4. European Commission, 1997a. Appendix A. Metabolism and distribution in plants. 7028/IV/95-rev.3. 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. European Commission, 1997c. Appendix C. Testing of plant protection products in rotational crops. 7524/VI/95-rev.2. European Commission, 1997d. Appendix E. Processing studies. 7035/VI/95-rev.5. European Commission, 1997e. Appendix F. Metabolism and distribution in domestic animals. 7030/VI/95-rev.3. European Commission, 1997f. Appendix H. Storage stability of residue samples. 7032/VI/95-rev.5. European Commission, 1997g. Appendix I. Calculation of maximum residue level and safety intervals. 7039/VI/95. 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. 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 European Commission, 2010b. Residue analytical methods. For post-registration control. SACO/825/00-rev.8.1. European Commission, Final review report for the active substance cyproconazole finalised in the Standing Committee on the Food Chain and Animal Health at its meeting on 17 May 2013 in view of the inclusion of cyproconazole in Annex I of Directive 91/414/EEC. SACO/10344/2011 final, 17 May 2013, 7 pp. European Commission, Appendix D. Guidelines on comparability, extrapolation, group tolerances and data requirements for setting MRLs. 7525/VI/95-rev 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 Edition. FAO Plant Production and Protection Paper 197, 264 pp. FAO (Food and Agriculture Organization of the United ations), Cyproconazole. In: Pesticide Residues in Food Report of the Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Expert Group on Pesticide Residues. FAO Plant Production and Protection Paper 200, FAO (Food and Agriculture Organization of the United ations), Cyproconazole. In: Pesticide Residues in Food Report of the Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Core Assessment Group on Pesticide Residues. FAO Plant Production and Protection Paper 219, France, Evaluation report on the modification of MRLs for cyproconazole in barely, oat and pulses prepared by the evaluating Member State France under Article 8 of Regulation (EC) o 396/2005, 29 January 2016, 73 pp. Ireland, Draft Assessment Report (DAR) on the active substance cyproconazole prepared by the rapporteur Member State Ireland in the framework of Directive 91/414/EEC, February Ireland, 2010a. Additional Report to the Draft Assessment Report on the active substance cyproconazole prepared by the rapporteur Member State Ireland in the framework of Commission Regulation (EC) o 33/2008, February Ireland, 2010b. Final Addendum to the Draft Assessment Report and Additional Report on cyproconazole, compiled by EFSA, September Ireland, Addendum to the Draft Assessment Report on cyproconazole, confirmatory data, May 2014, updated in September OECD (Organisation for Economic Co-operation and Development), Guidance Document on Overview of Residue Chemistry Studies. Series on Pesticides o 32/Series on Testing and Assessment o 64, revision, published 28 July 2009, EV/JM/MOO(2009)31. In: Pesticide Publications/Publications on Pesticide Residues. Available online: EFSA Journal 2016;14(7):4526