Reasoned opinion on the modification of the existing MRLs for bromuconazole in wheat and rye 1

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1 EFSA Journal 2015;13(3):4044 ABSTRACT REASOED OPIIO Reasoned opinion on the modification of the existing MRLs for bromuconazole in wheat and rye 1 European Food Safety Authority 2 European Food Safety Authority (EFSA), Parma, Italy In accordance with Article 6 of Regulation (EC) o 396/2005, Belgium, hereafter referred to as the evaluating Member State (EMS), received an application from Sumitomo Chemical Agro Europe S.A.S. to modify the existing maximum residue levels (MRLs) for the active substance bromuconazole in wheat and rye. In order to accommodate for the intended use of bromuconazole, Belgium proposed to raise the existing MRLs from the value of 0.2 mg/kg to 0.3 mg/kg. Belgium drafted an evaluation report in accordance with Article 8 of Regulation (EC) o 396/2005 which was submitted to the European Commission and forwarded to EFSA. According to EFSA the data are sufficient to derive MRL proposals of 0.2 mg/kg for the intended use on wheat and rye, which do not require a modification of the existing MRLs. An adequate analytical enforcement method is available to control the residues of bromuconazole in cereals. Based on the risk assessment results, EFSA concludes that the proposed use of bromuconazole on wheat and rye will not result in a consumer exposure exceeding the toxicological reference values of bromuconazole and therefore is unlikely to pose a consumer health risk related to this compound. European Food Safety Authority, 2015 KEY WORDS bromuconazole, wheat and rye, MRL application, Regulation (EC) o 396/2005, consumer risk assessment, triazole fungicide 1 On request from the European Commission, Question o EFSA-Q , approved on 6 March Correspondence: pesticides.mrl@efsa.europa.eu Suggested citation: EFSA (European Food Safety Authority), Reasoned opinion on the modification of the existing MRLs for bromuconazole in wheat and rye. EFSA Journal 2015;13(3):4044, 24 pp. doi: /j.efsa Available online: European Food Safety Authority, 2015

2 SUMMARY In accordance with Article 6 of Regulation (EC) o 396/2005, Belgium, hereafter referred to as the evaluating Member State (EMS), received an application from Sumitomo Chemical Agro Europe S.A.S. to modify the existing maximum residue levels (MRLs) for the active substance bromuconazole in wheat and rye. In order to accommodate for the intended use of bromuconazole, Belgium proposed to raise the existing MRLs from the value of 0.2 mg/kg to 0.3 mg/kg. Belgium drafted an evaluation report in accordance with Article 8 of Regulation (EC) o 396/2005 which was submitted to the European Commission and forwarded to EFSA on 1 September EFSA bases its assessment on the evaluation report, the revised Draft Assessment Report (DAR) prepared under Council Directive 91/414/EEC, the Commission Review Report on bromuconazole and the conclusion on the peer review of the pesticide risk assessment of the active substance bromuconazole. The toxicological profile of bromuconazole 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 0.01 mg/kg bw per day and an acute reference dose (ARfD) of 0.1 mg/kg bw. EFSA defined toxicological reference values also for the triazole derivative metabolites (TDMs). During the peer review, the metabolism of bromuconazole was investigated on cereals (wheat) with the active substance labelled in the phenyl moiety only. An additional study using the compound labelled in the triazole moiety has been provided as confirmatory data. For the uses on wheat and rye, the residue definition for enforcement and risk assessment provisionally proposed for cereals as bromuconazole (sum of isomers) is applicable. To take into consideration the toxicological relevant metabolites TDMs, EFSA proposes a separate residue definition for risk assessment including the TDMs. Pending the conclusion of the assessment of the confirmatory data and the availability of a general methodology on the risk assessment of triazole compounds, the proposed residue definitions are still regarded as provisional. EFSA concludes that the submitted supervised residue trials are sufficient to derive MRL proposals of 0.2 mg/kg for the intended use on wheat and rye, which do not require a modification of the existing MRLs. An adequate analytical enforcement method is available to control the residues of bromuconazole in cereals at the validated limit of quantification (LOQ) of 0.01 mg/kg. Specific studies investigating the nature and magnitude of bromuconazole residues in rye and wheat processed products are not required. Since no information on residues of TDMs in the raw agricultural commodity (RAC) is available, EFSA cannot address the need for studies investigating TDM residues in processed products. The occurrence of bromuconazole residues in rotational crops was investigated in the framework of the peer review. The studies were performed using phenyl-labelled bromuconazole. Since no rotational crop metabolism study is available with triazole-labelled bromuconazole, EFSA cannot conclude on the occurrence of bromuconazole related residues in rotational crops. Pending the outcome of the evaluation of confirmatory data on the formation of TDMs in rotational crops, Member States when granting authorisations for the use of bromuconazole on wheat and rye should take appropriate risk management measures to avoid the occurrence of bromuconazole related residues in rotational crops. Cereals and their products are usually fed to livestock, therefore the possible carry-over of residues in food of animal origin has to be considered. The calculated livestock dietary burden for bromuconazole exceeded the trigger value of 0.1 mg/kg (dry matter) for ruminants. Based on the available information residues of bromuconazole above the LOQ are not expected and a modification of the MRLs for bromuconazole on commodities of animal (ruminants) origin is not required. It should be noted that the dietary burden exposure to the TDMs could not be performed as the information on the magnitude of the TDMs residues in feed items is not available. EFSA Journal 2015;13(3):4044 2

3 The consumer risk assessment for bromuconazole was performed using the revision 2 of the EFSA Pesticide Residues Intake Model (PRIMo). It is based on the assumption that different bromuconazole diastereomer ratios observed in the terminal residues do not contribute to the overall toxicological burden and no change in the ratio of enantiomers in each diastereomer occurs. Taking into account the low residue levels observed in wheat and rye at the intended application rate and that an obvious shift in the ratio was not observed in grain in the submitted trials, it is unlikely that the uncertainty significantly influence the risk assessment outcome. For the calculation of chronic exposure, EFSA used the supervised trials median residue (STMR) as derived from the residue trials for the crops under consideration and the existing MRLs as established in Annex IIIA of Regulation (EC) o 396/2005 for the remaining commodities of plant and animal origin. o long-term consumer intake concerns were identified for any of the European diets incorporated in the EFSA PRIMo. The total calculated intake accounted for up to 37 % of the ADI (Dutch child). The contribution of residues in wheat and rye to the total consumer exposure accounted for a maximum of 0.9 % and 0.4 % of the ADI for wheat and rye, respectively. o acute consumer risk was identified in relation to the MRL proposals for wheat and rye. Based on the available information, EFSA concludes that the proposed use of bromuconazole on wheat and rye will not result in a consumer exposure exceeding the toxicological reference values of bromuconazole and therefore is unlikely to pose a consumer health risk related to this compound. The consumer risk assessment related to TDMs could not be performed and will be considered further as soon as residue data of TDMs in wheat and rye and a general methodology on the risk assessment of triazole compounds is available. Thus, EFSA proposes to amend the existing MRLs as reported in the summary table. SUMMARY TABLE Code number (a) Commodity Existing EU MRL Proposed EU MRL Enforcement residue definition: Bromuconazole (sum of diasteroisomers) (F) Justification for the proposal Rye Wheat The submitted information does not require the change of the existing MRL value. The consumer risk assessment for TDMs could not be performed. (a): According to Annex I of Regulation (EC) o 396/2005. (F): Fat-soluble. EFSA Journal 2015;13(3):4044 3

4 TABLE OF COTETS Abstract... 1 Summary... 2 Background... 5 Terms of reference... 5 The active substance and its use pattern... 6 Assessment Method of analysis Methods for enforcement of residues in food of plant origin Methods for enforcement of residues in food of animal origin Mammalian toxicology Residues ature and magnitude of residues in plant Primary crops Rotational crops ature and magnitude of residues in livestock Dietary burden of livestock ature of residues Magnitude of residues Consumer risk assessment Conclusions and recommendations References Appendices Appendix A. Good Agricultural Practice (GAPs) Appendix B. Pesticide Residue Intake Model (PRIMo) Appendix C. List of metabolites and related structural formula Abbreviations EFSA Journal 2015;13(3):4044 4

5 BACKGROUD Regulation (EC) o 396/ establishes the rules governing the setting of pesticide MRLs at European Union level. Article 6 of that Regulation lays down that any party having a legitimate interest or requesting an authorisation for the use of a plant protection product in accordance with Council Directive 91/414/EEC, 4 repealed by Regulation (EC) o 1107/2009, 5 shall submit to a Member State, when appropriate, an application to modify a MRL in accordance with the provisions of Article 7 of that Regulation. Belgium, hereafter referred to as the evaluating Member State (EMS), received an application from the company Sumitomo Chemical Agro Europe S.A.S. 6 to modify the existing MRLs for the active substance bromuconazole in wheat and rye. This application was notified to the European Commission and EFSA and was evaluated by the EMS in accordance with Article 8 of the Regulation. After completion, the evaluation report was submitted to the European Commission who forwarded the application, the evaluation report and the supporting dossier to EFSA on 1 September The application was included in the EFSA Register of Questions with the reference number EFSA-Q and the following subject: Bromuconazole - Application to set new MRLs in rye and wheat (triticale). Belgium proposed to raise the existing MRLs of bromuconazole in wheat and rye from 0.2 mg/kg to 0.3 mg/kg. EFSA proceeded with the assessment of the application and the evaluation report as required by Article 10 of the Regulation. TERMS OF REFERECE In accordance with Article 10 of Regulation (EC) o 396/2005, EFSA shall, based on the evaluation report provided by the evaluating Member State, provide a reasoned opinion on the risks to the consumer associated with the application. In accordance with Article 11 of that Regulation, the reasoned opinion shall be provided as soon as possible and at the latest within three months (which may be extended to six months where more detailed evaluations need to be carried out) from the date of receipt of the application. Where EFSA requests supplementary information, the time limit laid down shall be suspended until that information has been provided. In this particular case the deadline for providing the reasoned opinion is 1 December Regulation (EC) o 396/2005 of the Parliament and of the Council of 23 February 2005 on maximum residue levels of pesticides in or on food and feed of plant and animal origin and amending Council Directive 91/414/EEC. OJ L 70, , p Council Directive 91/414/EEC of 15 July 1991 concerning the placing of plant 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 Sumitomo Chemical Agro Europe S.A.S., Parc d Affaires de Crecy, 2 Rue Claude Chappe, St-Didier Au Mont D Or, 69771, France. EFSA Journal 2015;13(3):4044 5

6 THE ACTIVE SUBSTACE AD ITS USE PATTER Bromuconazole is the ISO common name for 1-[(2RS,4RS:2RS,4SR)-4- bromo-2-(2,4-dichlorophenyl) tetrahydrofurfuryl]-1h-1,2,4-triazole (IUPAC). The compound is a mixture of two diastereomeric pairs of enantiomers (LS and LS850647), which structure is reported below. Cl Cl Cl Cl Cl Cl Cl Cl O O O O Br Br Br Br LS (2RS,4SR) LS (2RS,4RS) Molecular weight: g/mol Bromuconazole is a systemic fungicide belonging to the class of triazoles used in agriculture to control fungal diseases. Bromuconazole interferes with the metabolic pathway of fungi by blocking the ergosterol biosynthesis in cell membranes. Bromuconazole was evaluated in the framework of Council Directive 91/414/EEC with Belgium designated as rapporteur Member State (RMS). It has been included in Annex I of this Directive by Commission Directive 2010/92/EU 7 which entered into force on 1 February 2011 for use as fungicide. In accordance with Commission Implementing Regulation (EU) o 540/ bromuconazole is approved under Regulation (EC) o 1107/2009, repealing Council Directive 91/414/EEC. Confirmatory data regarding the residues of triazole derivative metabolites (TDMs) in primary crops, rotational crops, processed commodities and products of animal origin requested in the inclusion Directive were submitted by the manufacturer and are currently under consideration but a conclusion has not yet been taken. The representative use evaluated in the peer review was two spray applications at 200 g/ha on wheat in the northern Europe (EU) and the southern Europe (SEU). The Draft Assessment Report (DAR) of bromuconazole has been peer reviewed by EFSA (EFSA, 2010). The EU MRLs for bromuconazole are established in Annex IIIA of Regulation (EC) o 396/2005. The existing EU MRLs for bromuconazole on wheat and rye are set at 0.2 mg/kg. The MRL review for bromuconazole according to Article 12 of Regulation (EC) o 396/2005 is at an early stage. Codex Alimentarius has not established Codex maximum residue limits (CXLs) for bromuconazole. The details of the intended GAP for bromuconazole on wheat and rye is given in Appendix A. ASSESSMET EFSA bases its assessment on the evaluation report submitted by the EMS (Belgium, 2014), the Draft Assessment Report (DAR) and its revised version prepared under Council Directive 91/414/EEC (Belgium, 2007, 2009), the Commission Review Report on bromuconazole (EC, 2010c) and the conclusion on the peer review of the pesticide risk assessment of the active substance bromuconazole (EFSA, 2010). 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 7 Commission Directive 2010/92/EU of 21 December 2010 amending Council Directive 91/414/EEC to include bromuconazole as active substance. OJ L 338, , 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 2015;13(3):4044 6

7 Commission Regulation (EU) o 546/ and the currently applicable guidance documents relevant for the consumer risk assessment of pesticide residues (EC, 1996, 1997a-g, 2000, 2010a,b, 2011; OECD, 2011). Since the evaluation of the information on residues of TDMs in primary crops, rotational crops and products of animal origin as requested according to Commission Directive 2010/92/EU (confirmatory data) is not yet finalised, the conclusions reached in this reasoned opinion should be taken as provisional and might need to be reconsidered in the light of the outcome of the review of these confirmatory data. 1. Method of analysis 1.1. Methods for enforcement of residues in food of plant origin The multi-residue DFG S19 method assessed during the peer review was accepted for the control and monitoring of bromuconazole residues in cereals at the validated LOQ of 0.05 mg/kg (EFSA, 2010). In the framework of this MRL application, validation data in several matrices, including wheat grain and straw, for the multi-residue QuEChERS method described in the European Standard E 15662:2008 (CE, 2008) were provided. Residues of the LS diastereomer and the LS diastereomer of bromuconazole were determined in wheat and straw, by liquid chromatography coupled with tandem mass spectrum detection (LC/MS-MS), at the LOQ of mg/kg and mg/kg respectively, giving the overall LOQ of 0.01 mg/kg (as sum). According to the current requirements, the applicant should demonstrate the efficiency of the extraction procedure of the proposed enforcement method (Belgium, 2014). The deviation is of minor relevance and considered as acceptable; however, the applicant is asked to address the point in a future application. Since wheat and rye belong to the group of dry/starch commodities, EFSA concludes that a validated analytical method is available for enforcing the proposed MRLs for bromuconazole at the LOQ of 0.01 mg/kg (as sum of isomers) Methods for enforcement of residues in food of animal origin Analytical methods assessed during the peer review were accepted for control and monitoring of bromuconazole residues in food of animal origin. Residues of bromuconazole were analysed in bovine milk at the validated LOQ of 0.01 mg/kg and in bovine meat, fat, liver and kidney and in poultry eggs at the validated LOQ of 0.02 mg/kg (EFSA, 2010). EFSA concludes that sufficiently validated analytical methods for enforcing MRLs for bromuconazole in food of animal origin are available. 2. Mammalian toxicology The toxicological profile of the active substance bromuconazole was assessed in the framework of the peer review under Council Directive 91/414/EEC (EC, 2010c; EFSA, 2010). The data were sufficient to derive toxicological reference values for bromuconazole which are compiled in Table 2-1. Bromuconazole belongs to the class of triazole fungicides, which are degraded/metabolised in plants and animals to common metabolites known as TDMs, the major ones being 1,2,4-triazole, triazole alanine, triazole lactic acid and triazole acetic acid. These TDMs were initially considered of no toxicological concern, but recent evaluations indicate that they are of toxicological relevance and 9 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 2015;13(3):4044 7

8 specific toxicological reference values were agreed (EFSA, 2011). These values are reported in Table 2-1 as well. Table 2-1: Overview of the toxicological reference values bromuconazole (a) Source Year Value Study relied upon Safety factor ADI EC mg/kg bw per day Rat, 2-year (study) 100 ARfD EC mg/kg bw Rat, developmental (study) 100 1,2,4-triazole, triazole acetic acid and triazole lactic acid (b) ADI EFSA mg/kg bw per day Rat, multigeneration study 1000 ARfD EFSA mg/kg bw Rat, developmental study 500 triazole alanine ADI EFSA mg/kg bw per day Rat, developmental study 1000 ARfD EFSA mg/kg bw Rat, developmental study 500 (a): Toxicological key studies performed with an average ratio 52:45 of LS and LS isomers (EFSA, 2010). (b): For triazole lactic acid the same value as for 1,2,4-triazole was applied in absence of reproductive data (EFSA, 2011) It should be noted that information was insufficient to investigate the toxicological profile of each separate isomer. The peer review could not conclude whether the toxicological profile may differ from that supported in the DAR in case of isomerisation shift in residues of diastereomer LS against LS producing different ratios and a data gap was identified in the mammalian toxicity (EFSA, 2010). 3. Residues 3.1. ature and magnitude of residues in plant Primary crops ature of residues The metabolism of bromuconazole in primary crops was evaluated on cereals (wheat) and fruit crops (apples and bananas) 10 in the framework of the peer review under Council Directive 91/414/EEC. The studies were performed using phenyl-labelled bromuconazole (Belgium, 2007; EFSA, 2010). A new study on wheat conducted with the triazole-label was submitted as confirmatory data in 2013 and assessed by the RMS (Belgium, 2013); a conclusion on the acceptability should be taken in the framework of the evaluation of these confirmatory data. The overview of the metabolism study designs is presented in the table below. Table 3-1: Summary of available metabolism studies in plants Crop groups Crops Application (a) Sampling (b) Cereals wheat Ph-L, onto four leaf surface, 100 µg solution(c) 0, 7, 21, 42 DAT Ph-L, spray, & 200 g/ha, BBCH & 65 0, 27 days after 1st appl;. 29, 315 DALA Ph-L, spray, & 230 g/ha, BBCH 37& days after seed planting T-L, spray, g/ha, BBCH & 51 1, 21 days after 1st appl;. 85 DALA 10 The applicant did not support the use on fruits (EFSA, 2010). EFSA Journal 2015;13(3):4044 8

9 Crop groups Fruit crops Crops Application (a) Sampling (b) apple Ph-L, onto fruit surface, 0.02 mg/apple 78 DAT banana Ph-L, spray on leaf or on fruit, 375 mg/tree 0, 15, 30 DAT (a): Ph-L: phenyl-label; T-L: triazole-label (b): DAT: days after application; DALA: days after last application. (c): Pre-Good Laboratory Practice (GLP) study with tentative characterisation of residues (Belgium, 2007). Based on the metabolism studies conducted with phenyl label, the residue definition for monitoring was provisionally proposed as bromuconazole (sum of isomers) in the conclusion of the peer review, pending the submission of an additional study considering the triazole-labelling. This residue definition was restricted to cereals. The residue definition is similar to the one in Regulation (EC) o 396/2005 (bromuconazole, sum of diasteroisomers). EFSA confirms the conclusion of the peer review that further investigation to address the impact for consumers of other ratios of isomers than those tested in the toxicological studies is required (See Section 2). In addition, EFSA notes that the above metabolism studies on wheat do not investigate the possible impact of plant metabolism on the enantiomers ratio in each diastereomer of bromuconazole and further investigation on this matter are in principle required. Since guidance on the consideration of isomer ratios in the consumer risk assessment is not yet available, EFSA recommends that this issue is reconsidered when such guidance is available. For the uses on wheat and rye, EFSA confirms the residue definitions for enforcement and risk assessment as bromuconazole (sum of isomers) provisionally proposed by the peer review. To take into consideration the toxicological relevant metabolites TDMs, EFSA proposes a separate residue definition for risk assessment including the TDMs. Pending the conclusion on the assessment of the confirmatory data and the availability of a general methodology on the risk assessment of triazole compounds, the residue definitions are still regarded as provisional Magnitude of residues In support to the MRL application, the applicant submitted a total of eight EU and eight SEU GAPcompliant trials on wheat conducted over a single season (2013). Although according to the guidance document residue trials should usually be conducted in at least two growing seasons (EC, 2011), different European geographical locations have been included and the deviation is considered as acceptable. Samples were collected 30 to 50 days after application in EU and 35 to 57 days in SEU. Both, EU and SEU datasets were combined together to derive an MRL proposal of 0.2 mg/kg 11 for bromuconazole in wheat. The extrapolation to rye requested by the applicant is acceptable as EU and SEU GAPs are equivalent and a sufficient number of residue trials has been submitted. In line with the findings of the metabolism study, a shift in the diastereomer ratio of bromuconazole was observed in samples at harvest. Isomerisation was more evident in the EU and straw compared to the SEU and grain 12. Information regarding the residue levels of TDMs was not provided and is required in order to conduct the consumer risk assessment of TDMs. The results of the residue trials, the related risk assessment input values (HR, STMR) and the MRL proposals are summarised in Table 3-2. In addition, EFSA also assessed the residues expected in straw following the intended use for the livestock dietary burden calculations. 11 The EMS proposed a MRL of 0.3 mg/kg based on the single dataset of SEU residue trials (Belgium, 2014). 12 At harvest, the ratio of the two diastereomers LS850646:LS was: Grain. EU: mean 60:40 (range 29:71 to 80:20); SEU: mean 49:51 (range 21:79 to 70:30); Straw. EU: mean 73:27 (range 61:39 to 85:15); SEU: mean 61:39 (range 52:48 to 80:20). The isomer ratio of applied bromuconazole was not clearly reported in the evaluation report but it is expected to be 55:45. EFSA Journal 2015;13(3):4044 9

10 Residues of bromuconazole (LS and LS850647) were found to be stable at -18 C for up to 20 months in wheat grain and straw (EFSA, 2010). As the supervised residue trial samples were stored under conditions for which integrity of the samples was demonstrated (up to about 6 months), it is concluded that the residue data are valid with regard to storage stability. According to the EMS, the analytical method used to analyse the supervised residue trial samples (QuEChERS method reported in Section 1.1) has been sufficiently validated and was proven to be fit for the purpose (Belgium, 2014). EFSA concludes that the data are sufficient to derive a MRL proposal of 0.2 mg/kg for the intended use on wheat and rye in the EU and in the SEU. EFSA Journal 2015;13(3):

11 Table 3-2: Overview of the available residues trials data Commodity Region (a) Individual trial results (b) Comments (c) MRL proposal HR (d) STMR (e) Enforcement and risk assessment residue definition: Bromuconazole, sum of isomers (provisional) (EFSA, 2010) Wheat (grain) EU 6 <0.01; 0.01; 0.02 MRL, STMR, HR derived from the merged datasets. SEU 3 <0.01; ; 0.03; 0.06; 0.17 (f) Extrapolation to rye. MRL OECD : 0.19/ Wheat (straw) EU 0.19; 0.26; 0.33; 0.44; 0.6; 1.8; 2.3; 2.6 EU, SEU dataset not significantly different (U-test, 5%), STMR, HR derived from the SEU 0.14; 0.67; 0.74; 2.0; 2.2; 2.5; 2.7; 2.9 merged data (a): EU (orthern and Central Europe), SEU (Southern Europe and Mediterranean), EU (i.e. indoor use) or Import (country code) (EC, 2011). (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 value of the individual trial results according to the residue definition for risk assessment. (e) STMR: Median value of the individual trial results according to residue definition for risk assessment. (f): Statistically detected as potential outlier (Dixon s Q-test) but no information and no obvious defects in the trial justified the exclusion of the value from the calculation (EC, 1997g; FAO, 2009). EFSA Journal 2015;13(3):

12 Effect of industrial processing and/or household preparation Modification of the MRLs for bromuconazole in wheat and rye The effect of processing on bromuconazole residues was not investigated during the peer review as no significant residues were reached in grain for the representative use on wheat (EFSA, 2010). Since residues above the trigger value of 0.1 mg/kg (EC, 1997d) were observed in one sample only (identified as potential outlier; see Table 3-2) in wheat grain, studies on the nature and magnitude of bromuconazole residues in processed wheat or rye products are still not required. Since no information on residues of TDMs in the raw agricultural commodity (RAC) is available, EFSA cannot address the need for studies investigating TDM residues in processed products Rotational crops Preliminary considerations Cereals can be grown in a crop rotation with other plants and therefore the occurrence of residues in succeeding crops resulting from the use on primary crops has to be assessed. The soil studies demonstrate that the degradation rate of bromuconazole is slow; the maximum DT 90 was 709 days (EFSA, 2010), which is above the trigger value of 100 days. Thus, further studies investigating the nature and magnitude of the compound uptake in rotational crops are required (EC, 1997c) ature of residues The metabolism of bromuconazole in rotational crops was assessed in the peer review under Council Directive 91/414/EEC. The study was performed using phenyl-labelled bromuconazole only. Detailed assessment is reported in the DAR and the EFSA conclusion (Belgium, 2007; EFSA, 2010). The metabolic pattern with phenyl-labelled bromuconazole in rotational crops was concluded to be similar to the metabolism in cereals as primary crops (EFSA, 2010). A study in rotational crops with triazole-labelled compound has not been provided and was identified as a data gap in the conclusion of the peer review. The requested information on TDMs data is under assessment as confirmatory. A conclusion on the acceptability should be taken in the framework of the evaluation of these confirmatory data. Pending the assessment of a rotational crop study with triazolelabelled compound, the conclusion reached by the peer review is regarded as provisional Magnitude of residues Rotational crop residue trials investigated the level of bromuconazole residues in cereals was assessed in the DAR and in the conclusion of the peer review (Belgium, 2007; EFSA, 2010). The peer review concluded that residues of bromuconazole in succeeding crops are not likely to exceed 0.05 mg/kg when bromuconazole is used according to the representative GAP (namely two applications at 200 g/ha) in cereals (EFSA, 2010). Since the intended application rate on wheat and rye is less critical (one application at 200 g/ha), the conclusion reached by the peer review are applicable. Since no conclusion is currently possible on whether triazole metabolites may reach quantifiable levels in rotational crops, Member States when granting authorisations for the use of bromuconazole on wheat and rye should take appropriate risk management measures to avoid the occurrence of bromuconazole related residues in rotational crops and/or succeeding crops ature and magnitude of residues in livestock Since wheat and rye grain, straw and bran are normally fed to livestock, the nature and magnitude of bromuconazole residues in livestock should be assessed (EC, 1996). EFSA Journal 2015;13(3):

13 Dietary burden of livestock Modification of the MRLs for bromuconazole in wheat and rye The median and maximum dietary burden for livestock was calculated using the agreed European methodology (EC, 1996). The input values for the dietary burden calculation were selected according to the latest FAO recommendations (FAO, 2009) considering the livestock intake from the intended use on wheat and rye (see Table 3-2). There are no other feed products on which existing EU MRLs are set above the LOQ. A default processing factor (PF) of 8 was used for bran. The dietary burden to TDMs could not be assessed as the residue levels of TDMs in wheat and rye potentially used as feed items are not available. The input values for the dietary burden calculation are summarised in Table 3-3. Table 3-3: Input values for the dietary burden calculation Commodity Median dietary burden Maximum dietary burden Input value Comment Input value Risk assessment residue definition: Bromuconazole (sum of isomers) (provisional) Wheat, rye grain 0.01 STMR 0.01 STMR Wheat, rye straw 1.27 STMR 2.9 HR Wheat, rye bran 0.08 (0.01 8) STMR PF 0.08 STMR PF Risk assessment residue definition: TDMs (provisional) Comment Wheat, rye grain, straw, bran o data to estimate the dietary burden. The results of the dietary burden calculation for bromuconazole are summarised in the following table. Table 3-4: Results of the dietary burden calculation for bromuconazole Maximum dietary burden (mg/kg bw per d) Median dietary burden (mg/kg bw per d) Highest contributing commodity (a) Risk assessment residue definition: Bromuconazole (sum of isomers) (provisional) Max dietary burden (mg/kg DM) Trigger exceeded (Y/) Dairy ruminants Wheat straw Y Meat ruminants Wheat straw Y Poultry Rye bran Pigs Wheat straw (a): Calculated for the maximum dietary burden. The calculated dietary burden for bromuconazole indicated that the trigger value of 0.1 mg/kg dry matter (DM) for ruminants was exceeded, meaning that the occurrence of bromuconazole residues in commodities of ruminant origin has to be investigated. The data also indicated that the main contributing commodity is wheat straw ature of residues The metabolism of bromuconazole was assessed during the peer review in ruminants (goat and cow) and poultry. The studies were performed using phenyl-labelled bromuconazole and the details are reported in the DAR and the EFSA conclusion (Belgium, 2007; EFSA, 2010). A study in livestock EFSA Journal 2015;13(3):

14 with triazole-labelled compound has not been provided. The justification for non-submission of the requested information on TDMs is under assessment as confirmatory data (Belgium, 2013) and a conclusion on the acceptability should be taken in the framework of the evaluation of these confirmatory data. Based on these studies, the residue definition for enforcement and risk assessment for food of animal origin was proposed as bromuconazole (sum of isomers) in the conclusion of the peer review, provisionally pending the submission of additional information on TDMs. Considering the relevant amounts of TDMs found in the wheat metabolism study (particularly in straw), the potential carryover of TDM residues into commodities of animal origin needs to be addressed before a final conclusion on the residue definition of bromuconazole in animal origin commodities is reached. Bromuconazole was classified as fat-soluble (EFSA, 2010) Magnitude of residues Livestock feeding study on ruminant is not available. However, considering that the total radioactive residues (TRR) in the highest dose level investigated in the goat metabolism study (20 mg/kg DM, 12 study) were 0.02 mg eq/kg in liver and <0.01 mg eq/kg in kidney, EFSA concludes that, based on the intended uses on wheat and rye, residues of bromuconazole above the LOQ are not expected in commodities of ruminant origin. Having regard to LOQs of 0.01 mg/kg (milk) and 0.02 mg/kg (other animal matrices) achieved by the validated enforcement analytical method (see section 1.2), the lowering of the existing MRLs set at the LOQ of 0.05 mg/kg would be possible. However, EFSA is of the opinion that this change should be considered in the framework of the review under Article 12, when all the existing MRLs will be critically scrutinised. 4. Consumer risk assessment The consumer risk assessment for bromuconazole was performed using the 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 13 (EFSA, 2007). It is based on the assumption that different bromuconazole diastereomer ratios observed in the terminal residues do not contribute to the overall toxicological burden and no change in the ratio of enantiomers in each diastereomer occurs. Taking into account the low residues in the commodities under concern at the intended application rate (see Table 3-2) and that an obvious shift in the ratio was not observed in grain (see Footnote o 12), it is unlikely that the uncertainty significantly influence the risk assessment outcome. For the calculation of the chronic exposure, EFSA used the median residue value derived from the residue trials on wheat for wheat and rye (see Table 3-2) and the existing MRLs as established in Annex IIIA of Regulation (EC) o 396/2005 for the remaining commodities of plant and animal origin. The acute exposure assessment was performed for bromuconazole with regard to wheat and rye only, assuming the consumption of a large portion of the food items as reported in the national food surveys and that these items contained residues at the median residue level as observed in supervised field trials. o variability factor accounting for the inhomogeneous distribution on the individual items consumed was included in the calculation (EFSA, 2007). The input values used for the dietary exposure calculation are summarised in Table The calculation of the long-term exposure (chronic exposure) is based on the mean consumption data representative for 22 national diets collected from MS surveys plus 1 regional and 4 cluster diets from the WHO GEMS Food database; for the acute exposure assessment the most critical large portion consumption data from 19 national diets collected from MS surveys is used. The complete list of diets incorporated in EFSA PRIMo is given in its reference section (EFSA, 2007). EFSA Journal 2015;13(3):

15 Table 4-1: Input values for the consumer dietary exposure assessment Commodity Chronic exposure assessment Input value Modification of the MRLs for bromuconazole in wheat and rye Comment Input value Risk assessment residue definition: Bromuconazole (sum of isomers) (provisional) Acute exposure assessment Wheat, rye 0.01 STMR 0.01 STMR Comment Other commodities of plant and animal origin MRL See Regulation (EC) o 149/ Risk assessment residue definition: TDMs (provisional) o data available to perform the risk assessment. Acute risk assessment was undertaken only with regard to the crops under consideration. o long-term consumer intake concerns were identified for any of the European diets incorporated in the EFSA PRIMo. The total calculated intake accounted for up to 37 % of the ADI (Dutch child). The contribution of residues in wheat and rye to the total consumer exposure accounted for a maximum of 0.9 % of the ADI (WHO Cluster B) for wheat and 0.4 % of the ADI (Danish child) for rye. o acute consumer risk was identified in relation to the MRL proposals for wheat and rye. The calculated maximum exposure in percentage of the ARfD was 0.1 % for both cereals (British infant and 4-6 year old child diets). EFSA concludes that the proposed use of bromuconazole on wheat and rye will not result in a consumer exposure exceeding the toxicological reference values of bromuconazole and therefore is unlikely to pose a consumer health risk related to this compound. The consumer risk assessment related to TDMs will be performed as soon as residue data of TDMs after the administration of bromuconazole in wheat and rye and a general methodology on the risk assessment of triazole compounds is available. COCLUSIOS AD RECOMMEDATIOS COCLUSIOS The toxicological profile of bromuconazole 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 0.01 mg/kg bw per day and an acute reference dose (ARfD) of 0.1 mg/kg bw. EFSA defined toxicological reference values also for the triazole derivative metabolites (TDMs). During the peer review, the metabolism of bromuconazole was investigated on cereals (wheat) with the active substance labelled in the phenyl moiety only. An additional study using the compound labelled in the triazole moiety has been provided as confirmatory data. For the uses on wheat and rye, the residue definition for enforcement and risk assessment provisionally proposed for cereals as bromuconazole (sum of isomers) is applicable. To take into consideration the toxicological relevant metabolites TDMs, EFSA proposes a separate residue definition for risk assessment including the TDMs. Pending the conclusion of the assessment of the confirmatory data and the availability of a 14 Commission Regulation (EC) o 149/2008 of 29 January 2008 amending Regulation (EC) o 396/2005 of the European Parliament and of the Council by establishing Annexes II, III and IV setting maximum residue levels for products covered by Annex I thereto. OJ L58, , p ; Corrigendum to Commission Regulation (EC) o 149/2008. OJ L240, , p EFSA Journal 2015;13(3):

16 general methodology on the risk assessment of triazole compounds, the proposed residue definitions are still regarded as provisional. EFSA concludes that the submitted supervised residue trials are sufficient to derive MRL proposals of 0.2 mg/kg for the intended use on wheat and rye, which do not require a modification of the existing MRLs. An adequate analytical enforcement method is available to control the residues of bromuconazole in cereals at the validated limit of quantification (LOQ) of 0.01 mg/kg. Specific studies investigating the nature and magnitude of bromuconazole residues in rye and wheat processed products are not required. Since no information on residues of TDMs in the raw agricultural commodity (RAC) is available, EFSA cannot address the need for studies investigating TDM residues in processed products. The occurrence of bromuconazole residues in rotational crops was investigated in the framework of the peer review. The studies were performed using phenyl-labelled bromuconazole. Since no rotational crop metabolism study is available with triazole-labelled bromuconazole, EFSA cannot conclude on the occurrence of bromuconazole related residues in rotational crops. Pending the outcome of the evaluation of confirmatory data on the formation of TDMs in rotational crops, Member States when granting authorisations for the use of bromuconazole on wheat and rye should take appropriate risk management measures to avoid the occurrence of bromuconazole related residues in rotational crops. Cereals and their products are usually fed to livestock, therefore the possible carry-over of residues in food of animal origin has to be considered. The calculated livestock dietary burden for bromuconazole exceeded the trigger value of 0.1 mg/kg (dry matter) for ruminants. Based on the available information residues of bromuconazole above the LOQ are not expected and a modification of the MRLs for bromuconazole on commodities of animal (ruminants) origin is not required. It should be noted that the dietary burden exposure to the TDMs could not be performed as the information on the magnitude of the TDMs residues in feed items is not available. The consumer risk assessment for bromuconazole was performed using the revision 2 of the EFSA Pesticide Residues Intake Model (PRIMo). It is based on the assumption that different bromuconazole diastereomer ratios observed in the terminal residues do not contribute to the overall toxicological burden and no change in the ratio of enantiomers in each diastereomer occurs. Taking into account the low residue levels observed in wheat and rye at the intended application rate and that an obvious shift in the ratio was not observed in grain in the submitted trials, it is unlikely that the uncertainty significantly influence the risk assessment outcome. For the calculation of chronic exposure, EFSA used the supervised trials median residue (STMR) as derived from the residue trials for the crops under consideration and the existing MRLs as established in Annex IIIA of Regulation (EC) o 396/2005 for the remaining commodities of plant and animal origin. o long-term consumer intake concerns were identified for any of the European diets incorporated in the EFSA PRIMo. The total calculated intake accounted for up to 37 % of the ADI (Dutch child). The contribution of residues in wheat and rye to the total consumer exposure accounted for a maximum of 0.9 % and 0.4 % of the ADI for wheat and rye, respectively. o acute consumer risk was identified in relation to the MRL proposals for wheat and rye. Based on the available information, EFSA concludes that the proposed use of bromuconazole on wheat and rye will not result in a consumer exposure exceeding the toxicological reference values of bromuconazole and therefore is unlikely to pose a consumer health risk related to this compound. The consumer risk assessment related to TDMs could not be performed and will be considered further as soon as residue data of TDMs in wheat and rye and a general methodology on the risk assessment of triazole compounds is available. EFSA Journal 2015;13(3):

17 RECOMMEDATIOS Code number (a) Commodity Existing EU MRL Proposed EU MRL Enforcement residue definition: Bromuconazole (sum of diasteroisomers) (F) Justification for the proposal Rye Wheat The submitted information does not require the change of the existing MRL value. The consumer risk assessment for TDMs could not be performed. (a): According to Annex I of Regulation (EC) o 396/2005. (F): Fat-soluble. REFERECES CE (European Committee for Standardisation), Foods of plant origin - Determination of pesticide residues using GC-MS and/or LC-MS/MS following acetonitrile extraction/partitioning and clean-up by dispersive SPE. QuEChERS-method. E ovember Belgium, Draft Assessment Report (DAR) on the active substance bromuconazole prepared by the rapporteur Member State Belgium in the framework of Council Directive 91/414/EEC, June Belgium, Revised Draft Assessment Report on the active substance bromuconazole, prepared by the rapporteur Member State Belgium in the framework of Commission Regulation (EC) o 33/2008, October Belgium, Bromuconazole Addendum confirmatory data B.7 Residue data B.9 Ecotoxicology, prepared by the rapporteur Member State Belgium, 30 July Belgium, Evaluation report on the modification of MRLs for bromuconazole in wheat (tirade) and rye prepared by the evaluating Member State Belgium under Article 8 of Regulation (EC) o 396/2005, 3 July, 2014, 47 pp. EC (European Commission), Appendix G. Livestock Feeding Studies. 7031/VI/95-rev.4. EC (European Commission), 1997a. Appendix A. Metabolism and distribution in plants. 7028/IV/95- rev.3. EC (European Commission), 1997b. Appendix B. General recommendations for the design, preparation and realisation of residue trials. Annex 2. Classification of (minor) crops not listed in the Appendix of Council Directive 90/642/EEC. 7029/VI/95-rev.6. EC (European Commission), 1997c. Appendix C. Testing of plant protection products in rotational crops. 7524/VI/95-rev.2. EC (European Commission), 1997d. Appendix E. Processing studies. 7035/VI/95-rev.5. EC (European Commission), 1997e. Appendix F. Metabolism and distribution in domestic animals. 7030/VI/95-rev.3. EC (European Commission), 1997f. Appendix H. Storage stability of residue samples. 7032/VI/95- rev.5. EC (European Commission), 1997g. Appendix I. Calculation of maximum residue level and safety intervals. 7039/VI/95. EC (European Commission), Residue analytical methods. For pre-registration data requirement for Annex II (part A, section 4) and Annex III (part A, section 5 of Directive 91/414). SACO/3029/99-rev.4. EFSA Journal 2015;13(3):

18 EC (European Commission), 2010a. Classes to be used for the setting of EU pesticide Maximum Residue Levels (MRLs). SACO 10634/2010 Rev. 0, finalised in the Standing Committee on the Food Chain and Animal Health at its meeting of March EC (European Commission), 2010b. Residue analytical methods. For post-registration control. SACO/825/00-rev.8.1. EC (European Commission), 2010c. Review report for the active substance bromuconazole. Finalised in the Standing Committee on the Food Chain and Animal Health at its meeting on 23 ovember 2010 in view of the inclusion of bromuconazole in Annex I of Council Directive 91/414/EEC. SACO/12620/2010-Final, 23 ovember 2010, 9 pp. EC (European Commission), Appendix D. Guidelines on comparability, extrapolation, group tolerances and data requirements for setting MRLs. 7525/VI/95-rev.9. EFSA (European Food Safety Authority), Reasoned opinion on the potential chronic and acute risk to consumers health arising from proposed temporary EU MRLs. The EFSA Journal 2007, 32r, Available online: EFSA (European Food Safety Authority), Conclusion on the peer review of the pesticide risk assessment of the active substance bromuconazole. EFSA Journal 2010;8(8):1704, 84 pp. doi: /j.efsa EFSA (European Food Safety Authority), Conclusion on the peer review of the pesticide risk assessment of the active substance difenoconazole. EFSA Journal 2011;9(1):1967, 71 pp. doi: /j.efsa OECD (Organisation for Economic Co-operation and Development), OECD MRL Calculator: spreadsheet for single data set and spreadsheet for multiple data set, 2 March In: Pesticide Publications/Publications on Pesticide Residues. EFSA Journal 2015;13(3):