Modification of the existing maximum residue levels for prothioconazole in sunflower seeds

REASOED OPIIO APPROVED: 10 December 2015 PUBLISHED: 21 December 2015 doi:10.2903/j.efsa.2016.4371 Modification of the existing maximum residue levels for prothioconazole in sunflower seeds Abstract European Food Safety Authority (EFSA) In accordance with Article 6 of Regulation (EC) o 396/2005, the evaluating Member State (EMS) Hungary received an application from Bayer Crop Science to set a new maximum residue level (MRL) for the active substance prothioconazole in sunflower seeds. Hungary 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 submitted data are sufficient to derive a MRL proposal of 0.2 mg/kg for prothioconazole on sunflower. Adequate analytical enforcement methods are available. Based on the risk assessment results, EFSA concludes that the proposed use of prothioconazole on sunflower will not result in a consumer exposure exceeding the toxicological reference values and therefore is unlikely to pose a consumer health risk. European Food Safety Authority, 2015 Keywords: prothioconazole, sunflower seeds, MRL application, consumer risk assessment Requestor: European Commission Question number: EFSA-Q-2015-00416 Correspondence: pesticides.mrl@efsa.europa.eu www.efsa.europa.eu/efsajournal EFSA Journal 2015;13(12):4371

Suggested citation: EFSA (European Food Safety Authority), 2015. Reasoned opinion on the modification of the existing maximum residue levels for prothioconazole in sunflower seeds. EFSA Journal 2015;13(12):4371, 24 pp. doi:10.2903/j.efsa.2015.4371 ISS: 1831-4731 European Food Safety Authority, 2015 Reproduction is authorised provided the source is acknowledged. The EFSA Journal is a publication of the European Food Safety Authority, an agency of the European Union. www.efsa.europa.eu/efsajournal 2 EFSA Journal 2015;13(12):4371

Summary In accordance with Article 6 of Regulation (EC) o 396/2005, the evaluating Member State (EMS) Hungary received an application from Bayer Crop Science to modify the existing maximum residue level (MRL) for the active substance prothioconazole in sunflower seeds in order to accommodate the intended southern Europe (SEU) and northern Europe (EU) uses. Hungary 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 7 July 2015. EFSA bases its assessment on the evaluation report submitted by the EMS, the draft assessment report (DAR) (and its addendum) prepared under Directive 91/414/EEC, the conclusion on the peer review of the pesticide risk assessment of the active substance prothioconazole, as well as the conclusions from previous EFSA reasoned opinions on prothioconazole, including the opinion on the review of existing MRLs according to Article 12 of Regulation (EC) o 396/2005 (here after Article 12 MRL review). The toxicological profile of prothioconazole and prothioconazole-desthio was assessed in the framework of the peer review under Directive 91/414/EEC and the data were sufficient to derive an acceptable daily intake (ADI) of 0.05 and 0.01 mg/kg (body weight) bw per day, respectively, and an acute reference dose (ARfD) of 0.2 and 0.01 mg/kg bw, respectively. The metabolism of prothioconazole was investigated by foliar application on the root, pulses/oilseeds and cereal/grass crop groups. Based on these studies, the residue definition for enforcement was set as prothioconazole-desthio in the conclusion of the peer review and confirmed during the Article 12 MRL review. The residue for risk assessment was defined as the sum of prothioconazole-desthio and all metabolites containing the 2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl-2H-1,2,4- triazole moiety, expressed as prothioconazole-desthio (sum of isomers). Adequate analytical enforcement methods are available. EFSA concludes that the submitted supervised residue trials on sunflower are sufficient to derive a MRL proposal of 0.2 mg/kg for prothioconazole in sunflower seeds. As residue trials indicated no presence of the five hydroxy metabolites analysed for, EFSA suggests for risk assessment to use the conversion factor of 2 derived from the metabolism studies and proposed under the Article 12 MRL review. ew studies on the storage stability of prothioconazole-hydroxy-desthio metabolites were assessed in the framework of this MRL application and confirm the stability of these components under frozen storage conditions for 24 months in high water, high starch-, high acid- and high oil content matrices. This study addresses the data requirement raised by the Article 12 MRL review. Prothioconazole and prothioconazole-desthio were shown to be stable under standard hydrolysis conditions. Therefore for processed commodities the same residue definitions as for primary crops are applicable. ew processing studies with sunflower seed have not been submitted and are not necessary considering that the total theoretical maximum daily intake (TMDI) amounts to less than 10% of the ADI The metabolism of prothioconazole in primary and rotational crops was found to be similar and a specific residue definition for rotational crops is not deemed necessary. Considering the application rates of prothioconazole on sunflower, it can be concluded that prothioconazole residue levels in rotational crops are expected to be covered by the residue levels in primary crops and no risk mitigation measures need to be proposed. Sunflower seeds and their by-products can be fed to livestock and therefore a potential carry-over of residues into food of animal origin was assessed. The dietary burdens for livestock were recently calculated under Article 12 MRL review and were now updated with residues in sunflower seed and meal, resulting from the intended use. Since residues in sunflower seed do not affect the calculated dietary burdens, a modification of the MRLs proposed for animal commodities under Article 12 MRL review is not necessary. The EMS submitted validation data (and independent laboratory validation (ILV)) for the analytical method for the determination of prothioconazole-desthio in animal matrices, including eggs. The method was considered sufficiently validated and thus the data requirement raised by the Article 12 MRL review on a need for a fully validated analytical method for the determination of prothioconazole-desthio in eggs is considered addressed. www.efsa.europa.eu/efsajournal 3 EFSA Journal 2015;13(12):4371

The consumer risk assessment was performed with revision 2 of the EFSA Pesticide Residues Intake Model (PRIMo). In the framework of the Article 12 MRL review a comprehensive long-term exposure assessment was performed which was now updated with the median residue levels in sunflower seeds. The acute exposure assessment was performed only with regard to sunflower seed. A conversion factor (CF) of 2 which was established during the peer review and tentatively supported by Article 12 MRL review, was applied to consider all metabolites included in the residue definition for risk assessment. Under the assumption that the MRLs will be amended as proposed in the Article 12 MRL review, longterm consumer intake concerns were not identified for any of the European diets incorporated in the EFSA PRIMo. The total calculated chronic intake accounted for up to 6% of the ADI (WHO uster diet B). The contribution of residues in sunflower seed to the total consumer exposure accounted for a maximum of 0.15% of the ADI (WHO uster B). An acute consumer risk was not identified in relation to the MRL proposal for sunflower seed (8% of the ARfD). EFSA concludes that the intended use of prothioconazole on sunflower will not result in a consumer exposure exceeding the toxicological reference values and therefore is unlikely to pose a health risk to consumer. EFSA emphasises that the above assessment does not take into consideration triazole derivative metabolites (TDMs). As these metabolites may be generated by several pesticides belonging to the group of triazole fungicides, 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. EFSA proposes to amend the existing MRL as reported in the summary table below. Code(a) Commodity Existing EU MRL Proposed EU MRL Comment/Justification Enforcement residue definition: Prothioconazole (prothioconazole-desthio) 0401050 Sunflower seeds 0.05 0.2 Derived from EU trials and covering EU and SEU uses (a): Commodity code number according to Annex I of Regulation (EC) o 396/2005 www.efsa.europa.eu/efsajournal 4 EFSA Journal 2015;13(12):4371

Table of contents Abstract... 1 Summary... 3 Background... 6 The active substance and its use pattern... 6 Assessment... 7 1. Method of analysis... 8 1.1. Methods for enforcement of residues in food of plant origin... 8 1.2. Methods for enforcement of residues in food of animal origin... 8 2. Mammalian toxicology... 8 3. Residues... 9 3.1. ature and magnitude of residues in plant... 9 3.1.1. Primary crops... 9 3.1.2. Rotational crops... 12 3.2. ature and magnitude of residues in livestock... 13 3.2.1. Dietary burden of livestock... 13 4. Consumer risk assessment... 14 Conclusions and recommendations... 15 References... 16 Abbreviations... 18 Appendix A Good Agricultural Practice (GAPs)... 20 Appendix B Pesticide Residue Intake Model (PRIMo)... 21 Appendix C Used compound codes... 23 www.efsa.europa.eu/efsajournal 5 EFSA Journal 2015;13(12):4371

Background Regulation (EC) o 396/2005 1 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 Council Directive 91/414/EEC, 2 repealed by Regulation (EC) o 1107/2009, 3 shall submit to a Member State, when appropriate, an application to set or to modify a MRL in accordance with the provisions of Article 7 of the Regulation. Hungary, hereafter referred to as the evaluating Member State (EMS), received an application from Bayer Crop Science 4 to set a new maximum residue level (MRL) for the active substance prothioconazole in sunflower seeds. In order to accommodate for the intended southern Europe (SEU) and northern Europe (EU) uses of prothioconazole, Hungary proposed to raise the existing MRL from 0.05 mg/kg to 0.2 mg/kg. 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 7 July 2015. The application was included in the EFSA Register of Questions with the reference number EFSA-Q- 2015-00416 and the following subject: Prothioconazole: Setting new MRLs in sunflower seed Hungary proposed to raise the existing MRL of prothioconazole in sunflower seed from 0.05 mg/kg to 0.2 mg/kg. 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. In accordance with Article 11 of the 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, 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 Prothioconazole is the ISO common name for (RS)-2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2- hydroxypropyl]-2,4-dihydro-1,2,4-triazole-3-thione (IUPAC). The active substance used in the pesticide formulations is a racemic mixture of the two stereoisomers (R- and S-enantiomer). The chemical structures of the active substance and its main metabolites are reported in Appendix C. Prothioconazole belongs to the class of fungicides which are commonly referred to as the triazoles. It is a systemic fungicide. Prothioconazole was evaluated in the framework of Council Directive 91/414/EEC with United Kingdom designated as rapporteur Member State (RMS). The representative uses supported for the peer review process were outdoor foliar applications on cereals and rape seeds. Following the peer review, which was carried out by EFSA, prothioconazole was included in Annex I of this Directive by Commission Directive 2008/44/EC 5 which entered into force on 1 August 2008 for use 1 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, 16.03.2005, p. 1 16. 2 Council Directive 91/414/EEC of 15 July 1991 concerning the placing of plant protection products on the market. OJ L 230, 19.08.1991, p. 1 32. 3 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, 24.11.2009, p. 1 50. 4 Bayer Crop Science, Alfred obel Str.50, Monheim an Rhein, D-40789, Germany www.efsa.europa.eu/efsajournal 6 EFSA Journal 2015;13(12):4371

as a fungicide. In accordance with Commission Implementing Regulation (EU) o 540/2011 5 prothioconazole is approved under Regulation (EC) o 1107/2009. The EFSA conclusion is available (EFSA, 2007b). The EU MRLs for prothioconazole are established as prothioconazole-desthio in Annex IIIA of Regulation (EC) o 396/2005. Since the entry into force of the abovementioned regulation, EFSA has issued several reasoned opinions on the modification of MRLs for prothioconazole and these proposals have been considered in the EU legislation. The review of prothioconazole MRLs according to Article 12 of Regulation (EC) o 396/2005 (here after Article 12 MRL review) has been finalised (EFSA, 2014), but the regulation considering this assessment has not been published yet. Similarly, the MRL proposal for prothioconazole in shallots assessed in the last EFSA reasoned opinion has been voted at the Standing Committee on Plants, Animals, Food and Feed (SCPAFF) in September 2015, but so far not legally implemented. An overview of the MRL changes that occurred is provided in the Table 1. 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, 2009) (EC) o 1050/2009 Head cabbage, Brussels sprouts. Implementation of CXLs (EU) o 459/2010 CAC 2009 Art. 10 (EFSA, 2010a) (EU) o 893/2010 Broccoli, cauliflower. Art. 10 (EFSA, 2010b) (EU) o 508/2011 Various root vegetables. Implementation of CXLs (EU) o 520/2011 CAC 2010 Art. 10 (EFSA, 2012) (EU) o 834/2013 Rape seed, linseed, poppy seed, mustard seed. Art. 12 (EFSA, 2014) ot implemented Review of existing MRLs for prothioconazole (SACO/11481/2014 (ovember)) Art.10 (EFSA, 2015) ot implemented (SATE/11195/2015 (September)) Shallots CXLs: Codex maximum residue limits (Codex MRL) (a): Article 10: Assessment of MRL application according to Article 6 to 10 of Regulation (EC) o 396/2005 Article 12: Review of the existing MRLs according to Article 12 of Regulation (EC) o 396/2005 Codex Alimentarius has established CXLs for a number of commodities, but no CXL has been set for sunflower seeds. The details of the intended SEU and EU GAPs for prothioconazole on sunflower are given in Appendix A. Assessment EFSA bases its assessment on the evaluation report submitted by the EMS (Hungary, 2015), the DAR (and its addendum/addenda) prepared under Directive 91/414/EEC (The United Kingdom, 2004, 2007), the Commission review report on prothioconazole (European Commission, 2007), the conclusion on the peer review of the pesticide risk assessment of the active substance prothioconazole (EFSA, 2007b), the Joint FAO/WHO Meeting on Pesticide Residues (JMPR) evaluation report (FAO, 2009) as well as the conclusions from previous EFSA opinion on prothioconazole (EFSA, 2014, 2015). 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 546/2011 6 and the currently applicable guidance documents relevant for the consumer risk assessment of pesticide residues (European Commission, 1996, 1997a g, 2000, 2010a, b, 2011; OECD, 2011). 5 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, 11.06.2011, p. 1 186. 6 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, 11.06.2011, p. 127 175. www.efsa.europa.eu/efsajournal 7 EFSA Journal 2015;13(12):4371

1. Method of analysis 1.1. Methods for enforcement of residues in food of plant origin During the peer review under Directive 91/414/EEC an analytical method using GC-MS and its ILV were evaluated and validated for the determination of prothioconazole-desthio with an LOQ of 0.02 mg/kg in high water (tomato), high oil (rape seed), high acid (orange), dry/high starch (wheat grain) matrices and with an LOQ of 0.05 mg/kg in straw (EFSA, 2007b). In addition, a confirmatory method using HPLC-MS/MS was fully validated for the determination of prothioconazole-desthio in straw and in high water content commodities at an LOQ of 0.05 mg/kg and in high oil and dry commodities at an LOQ of 0.01 mg/kg (United Kingdom, 2004). The analytical methods are not enantioselective, hence the sum of isomers is analysed. It is concluded that prothioconazole-desthio can be enforced in food of plant origin with an LOQ of 0.02 mg/kg in high oil content and dry commodities and with an LOQ of 0.05 mg/kg in high water content commodities and in straw taking into account the highest LOQ of both methods (EFSA, 2014). As sunflower seeds are a commodity of high oil content, EFSA concludes that sufficiently validated analytical methods are available to control prothioconazole residues in sunflower seeds according to the enforcement residue definition, which is established as prothioconazole (prothioconazole-desthio) in Regulation (EC) o 396/2005. 1.2. Methods for enforcement of residues in food of animal origin The enforcement residue definition established for commodities of animal origin in the Regulation (EC) o 396/2005 refers to the sum of prothioconazole-desthio and its glucuronide conjugate, expressed as prothioconazole-desthio (EFSA, 2007b). The Article 12 MRL review proposed to establish the enforcement residue definition in animal commodities as prothioconazole-desthio (sum of isomers). During the peer review under Directive 91/414/EEC, an analytical method using HPLC-MS/MS and its ILV were evaluated and validated for the determination of prothioconazole-desthio in food of animal origin with an LOQ of 0.004 mg/kg in milk and an LOQ of 0.01 mg/kg in muscle, fat, liver and kidney (United Kingdom, 2004; EFSA, 2007b). This method has not been validated for the determination of prothioconazole-desthio in eggs. In the framework of previous assessments of prothioconazole according to Article 10 of Regulation (EC) o 396/2005, validation data were submitted for the determination of prothioconazole-desthio, prothioconazole 3-hydroxy-desthio and prothioconazole 4-hydroxy-desthio in animal matrices, including eggs (France, 2012). The ILV data have been submitted for meat, milk and eggs and confirm that the method is sufficiently validated for the determination prothioconazole-desthio in all animal matrices, including eggs, at the LOQ of 0.01 mg/kg. EFSA notes that this study addresses the data requirement raised by the Article 12 MRL review regarding the need for a fully validated analytical method for the determination of prothioconazole-desthio in eggs. EFSA concludes that prothioconazole-desthio can be enforced in food of animal origin with an LOQ of 0.004 mg/kg in milk and an LOQ of 0.01 mg/kg in muscle, fat, liver, eggs and kidney. However, none of the available methods has been validated for the determination of prothioconazole glucuronide conjugate in animal commodities. 2. Mammalian toxicology The toxicological profile of the active substance prothioconazole and prothioconazole-desthio was assessed in the framework of the peer review under Directive 91/414/EEC and the toxicological reference values were established by EFSA (EFSA, 2007b). They apply to the racemic mixture (50:50) of the constituent isomers of prothioconazole and prothioconazole-desthio, respectively. The derived toxicological reference values are compiled in Table 2. www.efsa.europa.eu/efsajournal 8 EFSA Journal 2015;13(12):4371

Table 2: Overview of the toxicological reference values Source Year Value Study Safety factor Prothioconazole ADI EFSA 2007 0.05 mg/kg bw per day Rat, 2 year study; dog, 2 year study 100 ARfD EFSA 2007 0.2 mg/kg bw Rat, developmental study 100 Prothioconazole-desthio ADI EFSA 2007 0.01 mg/kg bw per day Rat, carcinogenicity study 100 ARfD EFSA 2007 0.01 mg/kg bw Rat, developmental study 100 3. Residues 3.1. ature and magnitude of residues in plant 3.1.1. Primary crops 3.1.1.1. ature of residues In the framework of the peer review under Directive 91/414/EEC, the metabolism of prothioconazole was investigated by foliar applications on the root (sugar beet), pulses/oilseeds (peanut) and cereal/grass (wheat) crop groups and by seed treatment on cereal (wheat)(efsa, 2007b, 2014). An overview of the available metabolism studies is presented in Table3. Table 3: Summary of available metabolism studies in plants Crop group Crops Application Sampling (a) Comments (day, DAT) Root Sugar beet Foliar (4x 290 g/ha) 7 DAT 4 - Cereal/Grass Wheat Foliar (2x 220 g/ha, BBCH 32-65) 6, 26, 48 DAT 2 - Foliar (2x 250 g/ha; 31-59) 0, 14, 48 DAT 2 - Foliar (2x 180 and 290 g/ha; BBCH 32-65) n.r. - Seed (1x 20 or 100 g/100 kg seed) 57, 110, 153 DAT - Pulses/Oilseeds Peanuts Foliar (3x 300 g/ha) 14 DAT 3 - (a): DATx, days after treatment x, e.g. DAT 2; n.r.: not reported The residue definition for enforcement, proposed as prothioconazole-desthio in the conclusion of the peer review, was confirmed by the Article 12 MRL review. However, EFSA proposed that this residue definition refers to the sum of isomers, since no enantiospecific analytical methods are available (EFSA, 2014). The current residue definition set in Regulation (EC) o 396/2005 is similar and refers to prothioconazole-desthio. The residue for risk assessment was defined as the sum of prothioconazole-desthio and all metabolites containing the 2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl-2H-1,2,4- triazole moiety, expressed as prothioconazole-desthio (sum of isomers), assuming that all metabolites have a toxicological profile similar to prothioconazole-desthio (EFSA, 2007b). EFSA already highlighted that the possible isomer ratio change of prothioconazole was not investigated in plant metabolism and should be considered when a specific guidance is available. Furthermore, the above residue definitions do not take into consideration the triazole derivative metabolites (TDMs), which were present in the crops from the use of prothioconazole and which are common metabolites of other triazole fungicides. Pending the general approach to assess TDMs, the residue definitions should be regarded as provisional. For the uses on sunflower EFSA concludes that the metabolism of prothioconazole is sufficiently addressed and the derived residue definitions for enforcement and risk assessment are applicable. www.efsa.europa.eu/efsajournal 9 EFSA Journal 2015;13(12):4371

3.1.1.2. Magnitude of residues In support to the intended uses the applicant submitted 10 northern residue trials (Greece, France, Spain, Italy and Portugal) and 8 southern trials (Germany, Belgium, France and Hungary) on sunflower performed during the growing seasons 2010, 2011 and 2012. Seed samples were analysed for prothioconazole-desthio and five hydroxy metabolites (prothioconazole-α-hydroxy-desthio, prothioconazole-3-hydroxy-desthio, prothioconazole-4-hydroxydesthio, prothioconazole-5-hydroxy-desthio and prothioconazole-6-hydroxy-desthio). Residue levels were all expressed as prothioconazole-desthio. Seed samples were not analysed for TDMs. Prothioconazole-desthio residue levels were within the range of <0.01 to 0.035 mg/kg in southern trials and of <0.01 to 0.13 mg/kg in the northern ones, resulting in MRL proposals of 0.05 mg/kg and 0.2 mg/kg respectively. All metabolites were individually below the LOQ, except for prothioconazole-3-hydroxy-desthio which accounted for 0.014 mg/kg in one southern trial at a PHI of 35 days. Considering that hydroxymetabolites were almost never detected in sunflower seeds, EFSA suggests for the risk assessment to use the conversion factor of 2 derived from the metabolism studies and proposed under the Article 12 MRL review (EFSA, 2014), instead of summing the individual LOQs achieved for each of the six components analysed for. The results of the residue trials and the MRL proposals are summarised in Table 4. In the framework of the peer review, storage stability of prothioconazole-desthio residues was demonstrated at -18 C for 18 months in high water content commodities (wheat green matter), dry/starch content commodities (cereal grain) and straw (EFSA, 2014). Furthermore, storage stability of prothioconazole-desthio residues was subsequently demonstrated at -18 C for a period of 24 months in high water (spinach, tomatoes), high water/starch (sugar beet), high oil (canola seeds) and in dry/protein content commodities (peas) and canola straw (EFSA, 2014). The Article 12 MRL review requested further storage stability data for at least one hydroxylated metabolite included in the risk assessment residue definition (EFSA, 2014). In the framework of the current application, the applicant submitted a study performed in 2011, where the stability of the hydroxy metabolites - prothioconazole-α-hydroxy-desthio, prothioconazole- 3-hydroxy-desthio, prothioconazole-4-hydroxy-desthio, prothioconazole-5-hydroxy-desthio and prothioconazole-6-hydroxy-desthio - was investigated in matrices with high water (tomato), high water/starch (potato), high oil (soybean, rape seed) and high acid (orange) content. The crops were stored frozen for a maximum period of 24 months and samples were analysed at intervals of 30, 60, 90, 180, 360, 540 and 720 days. The samples were fortified with the mixture of metabolites, which is in this case acceptable, considering that the risk assessment residue definition refers to a moiety of compounds. The crops were analysed for each component separately. Results showed that prothioconazole-desthio hydroxy metabolites are stable over the storage period of 24 months in the matrices with high water/starch content (potatoes), high water content (tomatoes), high acid content (oranges) and high oil content (rape seed and soybean). EFSA also notes that this study addresses the data requirement raised by the Article 12 MRL review for the need of a storage stability data for at least one hydroxylated metabolite. As the trial samples were stored for a maximum period of ca. 13 months under conditions for which integrity of the samples was demonstrated, it is concluded that the residue data are valid with regard to the storage stability. According to the EMS, the analytical method used to analyse the residue trial samples has been sufficiently validated and was proven to be fit for the purpose (Hungary, 2015). EFSA concludes that the data are sufficient to derive the following MRL proposal: 0.2 mg/kg sunflower seed, covering EU and SEU uses of prothioconazole on sunflower www.efsa.europa.eu/efsajournal 10 EFSA Journal 2015;13(12):4371

Table 4: Overview of the available residues trials data Crop (GAPs) Sunflower (2x 125g/ha, PHI 28 d) Region/ Indoor (a) Residue levels observed in the supervised residue trials (b) SEU Prothioconazole-desthio: 2 x <0.01; <0.01; 0.01; 2 x 0.01; 0.017; 2 x 0.02; 0.035 Prothioconazole-α-hydroxy-desthio: 10x <0.01 Prothioconazole-3-hydroxy-desthio: 10x <0.01 Prothioconazole-4-hydroxy-desthio: 10x <0.01 Prothioconazole-5-hydroxy-desthio: 10x <0.01 Prothioconazole-6-hydroxy-desthio: 10x <0.01 EU Prothioconazole-desthio: 6 x <0.01; 0.043; 0.125 Prothioconazole-α-hydroxy-desthio: 8x <0.01 Prothioconazole-3-hydroxy-desthio: 7x <0.01; 0.014 Prothioconazole-4-hydroxy-desthio: 8x <0.01 Prothioconazole-5-hydroxy-desthio: 8x <0.01 Prothioconazole-6-hydroxy-desthio: 8x <0.01 Recommendations/comments (c) Underlined value refers to the average of analytical replicates MRL OECD : 0.05/0.05 Underlined value refers to the average of analytical replicates Underlined values: sample with higher residues at a longer PHI of 35 days MRL OECD : 0.19/0.20 (*): Indicates that the MRL is proposed at the limit of analytical quantification (LOQ). (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 considered for MRL calculation are reported in ascending order (c): Any information/comment supporting the decision and OECD MRL calculation (unrounded/rounded values) (d): HR: Highest residue level according to the residue definition for monitoring. (e): STMR: Median residue level according to residue definition for monitoring. MRL proposal HR (d) STMR (e) 0.05 0.035 0.01 0.2 0.125 0.01 www.efsa.europa.eu/efsajournal 11 EFSA Journal 2015;13(12):4371

3.1.1.3. Effect of industrial processing and/or household preparation The effect of processing on the nature of prothioconazole residues was not investigated in the framework of the peer review. evertheless, standard hydrolysis studies have been assessed by the JMPR in 2008, and it was concluded that prothioconazole is stable under processing conditions representative of pasteurisation and boiling but slightly degraded ( 11%) to prothioconazole-desthio under sterilisation (EFSA, 2014). Additionally, the Article 12 MRL review refers to a study where the effect of processing on the nature of prothioconazole-desthio was investigated. Results indicated that prothioconazole-desthio is stable under standard hydrolysis conditions (EFSA, 2014). The Article 12 MRL review concluded that other compounds, which are included in the risk assessment residue definition and contains the 2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl-2H- 1,2,4-triazole moiety, due to their similar structure to the parent compound and/or prothioconazoledesthio, are expected to remain stable under hydrolysis. The residue definitions in raw and processed crops are therefore concluded to be the same. ew studies investigating the effect of processing on the magnitude of prothioconazole residues during the processing of sunflower seed have not been submitted and are not necessary considering that the total theoretical maximum daily intake (TMDI) amounts to less than 10% of the ADI (European Commission, 1997d). The applicant submitted a processing study with rape seed, which was not further considered by EFSA in this assessment. 3.1.2. Rotational crops Sunflower can be grown in a crop rotation. According to the soil degradation studies evaluated in the framework of the peer review, DT 90field values of prothioconazole and prothioconazole-desthio range between 4.4 9.3 days (median: 5.5 days) and 54 240 days (median: 140 days), respectively. The DT 90field value of prothioconazole-desthio is therefore higher than the trigger value of 100 days (EFSA, 2007b). According to the European guidelines on rotational crops (European Commission, 1997c), further investigation of the nature of the residues in rotational crops is relevant. 3.1.2.1. ature of residues Studies on the nature of prothioconazole residues in rotational crops were assessed in the framework of the peer review and it was concluded that the residue definitions set for primary crops are also applicable to rotational crops (EFSA, 2007b). However, rotational crop studies with prothioconazole radiolabelled on the triazole ring were not assessed in the framework of the peer review but such studies were reported and assessed by the JMPR in 2008 and indicated a cleavage of the triazole linkage with the formation of the major metabolites found in all rotational crop matrices as triazole alanine, triazole lactic acid and triazole acetic acid (FAO, 2009). Both the parent prothioconazole and prothioconazole-desthio were identified as minor metabolites (EFSA, 2014). oting that TDMs may be generated by several pesticides belonging to the group of triazole fungicides, EFSA recommends that a separate risk assessment should be performed for TDMs in rotational crops 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. 3.1.2.2. Magnitude of residues In the confined rotational crop study conducted with an application rate of 580 g/ha, residues of prothioconazole-desthio in edible part of Swiss chard and turnip were 0.01 mg/kg at plant back intervals (PBI) of 28 and 146 days and the total amount of all metabolites containing the prothioconazole-desthio common structural moiety was around 0.03 mg/kg (EFSA, 2007b). Since the maximum seasonal application rate of prothioconazole on sunflower is 125 g/h only (0.4 ), EFSA concludes that significant residues are not expected in rotational crops when the active substance is applied on sunflower according to the proposed GAPs. www.efsa.europa.eu/efsajournal 12 EFSA Journal 2015;13(12):4371

3.2. ature and magnitude of residues in livestock Sunflower seed and their by-products are fed to livestock and therefore the nature and magnitude of prothioconazole residues in livestock has to be further assessed (European Commission, 1996). 3.2.1. Dietary burden of livestock The median and maximum dietary burden for livestock was recently calculated under Article 12 MRL review using the agreed European methodology (European Commission, 1996) and considering livestock intake of all feed products containing prothioconazole residues resulting from all authorized uses of prothioconazole in Europe (EFSA, 2014). EFSA now updated the dietary burden calculated in the Article 12 MRL review with residues in sunflower seed and meal, resulting from the intended use and reported in Table 4. In order to account for the concentration of residues in seed meal, a default processing factor (PF) of 2 was applied. A conversion factor (CF) of 2 from enforcement to risk assessment as tentatively proposed under Article 12 MRL review was applied to input values for sunflower seed and meal. The input values for the livestock 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 Comment Input Comment Risk assessment residue definition: sum of prothioconazole-desthio and all metabolites containing the 2- (1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl-2H-1,2,4-triazole moiety, expressed as prothioconazole -desthio (sum of isomers) Sunflower seed 0.02 STMR (Table 4)*CF 0.02 STMR (Table 4)*CF Sunflower seed meal 0.04 STMR*CF*PF 0.04 STMR*CF*PF Head cabbage, maize silage and grain, barley, oats, rye and wheat grain and See Table 3-4 of the EFSA reasoned opinion on the Article 12 MRL review (EFSA, 2014). straw, dry peas and beans, potatoes, turnips and swedes, rape seed and linseed meal The estimated animal dietary intakes are summarised in Table 6. Table 6: Results of the dietary burden calculation Animal Median burden (mg/kg bw) Maximum burden (mg/kg bw) Maximum burden (mg/kg DM) >0.1 mg /kg DM (Y/) Highest contributing commodity (a) Previous assessment (Max. burden) Risk assessment residue definition: sum of prothioconazole-desthio and all metabolites containing the 2-(1- chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl-2h-1,2,4-triazole moiety, expressed as prothioconazoledesthio (sum of isomers) Dairy cattle 0.028 0.086 2.4 Y Barley straw 0.028 Beef cattle 0.069 0.208 4.8 Y Barley straw 0.069 Poultry 0.011 0.018 0.3 Y Turnips 0.011 Pigs 0.017 0.031 0.77 Y Turnips 0.017 (a): Considering the maximum dietary animal burden Since residues in sunflower seed from the new intended use have no impact on the dietary burdens calculated in the framework of the Article 12 MRL review, modification of the MRLs proposed for animal commodities under the MRL review is not necessary. www.efsa.europa.eu/efsajournal 13 EFSA Journal 2015;13(12):4371

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 (EFSA, 2007). 7 In the framework of the review of the existing MRLs for prothioconazole according to Article 12 of Regulation (EC) o 396/2005, a comprehensive long-term exposure assessment was performed taking into account the existing uses at the EU level and the acceptable CXLs (EFSA, 2014). EFSA updated this risk assessment with the median residue levels (STMR) derived from the residue trials conducted on sunflower (see Table 4). In addition, the risk assessment value for shallots, as derived in the previous EFSA reasoned opinion was used as an input value (EFSA, 2015). Those food commodities, for which no uses were reported in the framework of the Article 12 MRL review, were excluded from the exposure calculation, assuming that there is no use of prothioconazole on these crops. The acute exposure assessment was performed only with regard to sunflower seed assuming the consumption of a large portion of the food item as reported in the national food surveys and that this item contained residues at the highest residue level (HR) as observed in supervised field trials (see Table 4). A variability factor accounting for the inhomogeneous distribution on the individual items consumed was included in the calculation, when required (EFSA, 2007a). The conversion factor (CF) of 2 from enforcement to risk assessment as tentatively derived by the Article 12 MRL review for oilseeds (EFSA, 2014), was applied to input values for sunflower seed. The input values used for the dietary exposure calculation are summarised in Table 7. Table 7: Input values for the consumer dietary exposure assessment Commodity Chronic exposure assessment Acute exposure assessment Input Comment Input Comment Risk assessment residue definition: the sum of prothioconazole-desthio and all metabolites containing the 2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl-2H-1,2,4-triazole moiety, expressed as prothioconazole-desthio (sum of isomers) Sunflower seeds 0.02 STMR (Table 4)* CF 0.25 HR (Table 4)*CF Shallots 0.02 STMR (EFSA, 2015) Acute risk assessment undertaken Other plant and animal commodities STMR Table 4-2 of the EFSA reasoned opinion on Article 12 MRL review (EFSA, 2014) only with regard to sunflower seed The estimated exposure was then compared with the toxicological reference values derived for prothioconazole-desthio (see Table 2). The results of the intake calculation are presented in Appendix B of this reasoned opinion. Under the assumption that the MRLs will be amended as proposed in the Article 12 MRL review, longterm consumer intake concerns were not identified for any of the European diets incorporated in the EFSA PRIMo. The total calculated chronic intake accounted for up to 6% of the ADI (WHO uster diet B). The contribution of residues in sunflower seed to the total consumer exposure accounted for a maximum of 0.15% of the ADI (WHO uster diet B). An acute consumer risk was not identified in relation to the MRL proposal for sunflower seed. The highest acute consumer exposure was calculated to be 8% of the ARfD. EFSA concludes that the intended use of prothioconazole on sunflower will not result in a consumer exposure exceeding the toxicological reference values and therefore is unlikely to pose a consumer health risk. EFSA emphasises that the consumer exposure assessment does not take into consideration triazole derivative metabolites (TDMs). As these metabolites may be generated by several pesticides 7 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). www.efsa.europa.eu/efsajournal 14 EFSA Journal 2015;13(12):4371

belonging to the group of triazole fungicides, 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 MRL summarised in the table below: Code (a) Commodity Existing EU MRL Proposed EU MRL Comment/Justification Enforcement residue definition: Prothioconazole (prothioconazole-desthio) 0401050 Sunflower seeds 0.05 0.2 Derived from EU trials and covering EU and SEU uses (a): Commodity code number according to Annex I of Regulation (EC) o 396/2005 www.efsa.europa.eu/efsajournal 15 EFSA Journal 2015;13(12):4371

References European Commission, 1996. 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. assification 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, 2000. 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. asses 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 23 24 March 2010. European Commission, 2010b. Residue analytical methods. For post-registration control. SACO/825/00-rev.8.1. European Commission, 2011. Appendix D. Guidelines on comparability, extrapolation, group tolerances and data requirements for setting MRLs. 7525/VI/95-rev.9. European Commission, 2007. Review report for the active substance prothioconazole. Finalised in the Standing Committee on the Food Chain and Animal Health at its meeting on 22 January 2008 in view of the inclusion of prothioconazole in Annex I of Council Directive 91/414/EEC. SACO/3923/07-Final, 10 December 2007, 10 pp. EFSA (European Food Safety Authority), 2007a. Reasoned opinion on the potential chronic and acute risk to consumers health arising from proposed temporary EU MRLs. The EFSA Journal 2007, 32r, 1-1141. doi:10.2903/j.efsa.2007.32r EFSA (European Food Safety Authority), 2007b. Conclusion on the peer review of the pesticide risk assessment of the active substance prothioconazole. EFSA Scientific Report (2007) 106, 1-98 pp. doi:102903/j.efsa.2007.106r EFSA (European Food Safety Authority), 2009. Reasoned opinion on the modification of the existing MRLs for prothioconazole in head cabbage and Brussels sprouts. EFSA Scientific Report 2009, 261, 1-24, doi:10.2903/j.efsa.2009.261r EFSA (European Food Safety Authority), 2010a. Reasoned opinion on the modification of the existing MRLs for prothioconazole in cauliflower and broccoli. EFSA Journal 2010;8(4):1577, 22 pp. doi:10.2903/j.efsa.2010.1577 EFSA (European Food Safety Authority), 2010b. Reasoned opinion on the modification of the existing MRLs for prothioconazole in various root vegetables. EFSA Journal 2010;8(7):1675, 28 pp. doi:10.2903/j.efsa.2010.1675 EFSA (European Food Safety Authority), 2011. 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:10.2903/j.efsa.2011.1967 www.efsa.europa.eu/efsajournal 16 EFSA Journal 2015;13(12):4371

EFSA (European Food Safety Authority), 2012. Reasoned opinion on the modification of the existing MRLs for prothioconazole in rape seed, linseed, poppy seed and mustard seed. EFSA Journal 2012;10(11):2952, 35 pp. doi:102903/j.efsa.2012.2952 EFSA (European Food Safety Authority), 2014. Reasoned opinion on the review of the existing maximum residue levels (MRLs) for prothioconazole according to Article 12 of Regulation (EC) o 396/2005. EFSA Journal 2014; 12(5):3689, 72 pp. doi:102903/j.efsa.2014.3689 EFSA (European Food Safety Authority), 2015. Reasoned opinion on the modification of the existing MRL for prothioconazole in shallots. EFSA Journal 2015; 13(5):4105, 20 pp. doi:102903/j.efsa.2015.4105 FAO (Food and Agriculture Organization of the United ations), 2009. Prothioconazole. In: Pesticide residues in food 2008. Evaluations. Part I. Residues. FAO Plant Production and Protection Paper 194. France, 2012. Evaluation report on MRLs for prothioconazole in oilseeds prepared by the evaluating Member State France under Article 8 of Regulation (EC) o 396/2005, 5 January 2012, 74 pp. Hungary, 2015. Evaluation report on the modification of MRLs for prothioconazole in sunflower prepared by the evaluating Member State Hungary under Article 8 of Regulation (EC) o 396/2005, 19 October 2015, 122 pp. OECD (Organisation for Economic Co-operation and Development), 2011. OECD MRL calculator: spreadsheet for single data set and spreadsheet for multiple data set, 2 March 2011. In: Pesticide Publications/Publications on Pesticide Residues. Available online: http://www.oecd.org United Kingdom, 2004. Draft assessment report on the active substance prothioconazole prepared by the rapporteur Member State United Kingdom in the framework of Council Directive 91/414/EEC, October, 2004 United Kingdom, 2007. Final addendum to the additional report and the draft assessment report on the active substance prothioconazole prepared by the rapporteur Member State United Kingdom in the framework of Council Regulation (EC) o 33/2008, compiled by EFSA, May 2007. www.efsa.europa.eu/efsajournal 17 EFSA Journal 2015;13(12):4371

Abbreviations a.s. ADI ARfD BBCH bw CF CXL DAR DAT DM DT90 EFSA EMS eq FAO GAP GC GCPF HPLC HR ILV ISO IUPAC JMPR LOQ MRL MS MS MS/MS MW EU OECD PF PHI PRIMo RD Mo active substance acceptable daily intake acute reference dose growth stages of mono- and dicotyledonous plants body weight conversion factor for enforcement to risk assessment residue definition Codex maximum residue limit (Codex MRL) draft assessment report days after treatment dry matter period required for 90% dissipation European Food Safety Authority evaluating Member State residue expressed as a.s. equivalent Food and Agriculture Organization of the United ations good agricultural practice gas chromatography Global Crop Protection Federation (formerly International Group of ational Associations of Manufacturers of Agrochemical Products (GIFAP)) high performance liquid chromatography highest residue independent laboratory validation International Organisation for Standardisation International Union of Pure and Applied Chemistry Joint FAO/WHO Meeting on Pesticide Residues limit of quantification maximum residue level Member States mass spectrometry detector tandem mass spectrometry detector molecular weight northern Europe Organisation for Economic Co-operation and Development processing factor pre-harvest interval (EFSA) Pesticide Residues Intake Model residue definition for monitoring www.efsa.europa.eu/efsajournal 18 EFSA Journal 2015;13(12):4371

RD RA RMS SCPAFF SEU SE STMR TDMs TMDI WHO residue definition for risk assessment rapporteur Member State Standing Committee on Plants, Animals, Food and Feed (formerly: Standing Committee on the Food Chain and Animal Health; SCFCAH) southern Europe suspo-emulsion supervised trials median residue triazole derivative metabolites theoretical maximum daily intake World Health Organization www.efsa.europa.eu/efsajournal 19 EFSA Journal 2015;13(12):4371