Setting of MRLs for bixafen in oil seed rape, linseed, mustard seed and poppy seed 1

Transcription

1 ESA Journal 2011; 9(7):2286 REASOED OPIIO Setting of MRLs for bixafen in oil seed rape, linseed, mustard seed and poppy seed 1 European ood Safety Authority 2 European ood Safety Authority (ESA), Parma, Italy SUMMARY According to Article 6 of the Regulation (EC) o 396/2005, the United Kingdom, hereafter referred to as the Evaluating Member State (EMS), received an application from Bayer CropScience Limited to modify the existing MRL for bixafen for several oilseeds crops for which an authorisation is requested in the United Kingdom. In order to accommodate for the intended use on rape seed, linseed, mustard seed and poppy seed, it is proposed to raise the existing MRL from the value of 0.01* mg/kg to the proposed MRL of 0.02 mg/kg. The United Kingdom drafted according to Article 8 of Regulation (EC) o 396/2005 an evaluation report which was submitted to the European Commission and forwarded to ESA on 08 March It is noted that bixafen is a new active substance for which the peer review process under Directive 91/414/EEC is at an early stage. ESA bases its assessment on the Evaluation Report, the Draft Assessment Report and a previous ESA reasoned opinion on the modification of bixafen MRLs on certain cereals and products of animal origin. The toxicological profile of bixafen was assessed by the RMS in the framework of the preparation of the Draft Assessment Report. The data were sufficient to conclude on an ADI value of 0.02 mg/kg bw/day and an ARfD of 0.2 mg/kg. Since the peer review is currently ongoing for this active substance, the toxicological reference values should be considered as provisional only. The metabolism of bixafen was considered as sufficiently elucidated in primary (wheat, soybean) and rotational crops (wheat, turnip, swiss chard). Based on the results of these studies provisional residue definitions were derived: the residue definition for enforcement comprises the parent compound only, whereas the residue definition for risk assessment is established as the sum of bixafen and desmethylbixafen, expressed as bixafen. The supervised residue trials on rape seed are sufficient and adequate to derive a MRL proposal of mg/kg for the intended use of bixafen on this crop. Analytical methods are available to enforce the proposed MRL for the commodities under consideration. According to the EC guidance documents, this MRL can be extrapolated to linseed, mustard seed and poppy seed. 1 On request from the European Commission, Question o ESA-Q , issued on 30 June Correspondence: pesticides.mrl@efsa.europa.eu Suggested citation: European ood Safety Authority; Setting of MRLs for bixafen in oil seed rape, linseed, mustard seed and poppy seed. ESA Journal 2011; 9(7):2286. [31 pp.] doi: /j.efsa Available online: European ood Safety Authority, 2011

2 Under processing conditions simulating pasteurisation, baking/brewing/boiling and sterilisation bixafen residues are stable. Processing studies to address the magnitude of the residues in oilseeds processed commodities (crude and refined oil, meal) were not triggered. The rotational crop studies demonstrated that the occurrence of bixafen related residues in rotational crops grown in rotation after primary crops treated with bixafen in accordance with the intended GAP is expected to be low (below or at the LOQ). The dietary burden calculation showed that the contribution of the oilseeds crops to the total livestock exposure is insignificant. Therefore the modification of the MRLs for commodities of animal origin was not further investigated in the framework of the current application. The consumer exposure assessment was performed with revision 2 of the ESA PRIMo (Pesticide Residue Intake Model). or the chronic intake assessment, ESA used the median residue concentrations derived from the submitted supervised residue trials on rape seed and the existing MRLs as established in Commission Regulation (EC) o 396/2005. Additionally, median residue levels were available from a previous assessment on certain cereals and products of animal origin which could be used to refine the calculation of the dietary exposure. The acute intake assessment was performed only with regard to the crop under consideration applying the STMR value on rape seed as derived from the supervised residue trials. The estimated long-term and short-term exposures were compared with the toxicological reference values established for bixafen. The total calculated intake values ranged from 0.5% to 4.8% of the ADI (L child). The contribution of residues in rape seed, linseed, mustard seed and poppy seed to the total consumer exposure accounted for 0.06% of the ADI (WHO cluster diet E). o acute consumer risk was identified in relation to the MRL proposal on these crops. The calculated maximum exposure in percentage of the ARfD was <0.015% for children (DE child). ESA concludes that the intended use of bixafen on rape seed, linseed, mustard seed and poppy seed is acceptable from a consumer safety point of view; the residues expected after treatment of the crops according to the intended GAP will not lead to an exceedance of the toxicological reference values. ESA proposes to amend the current MRL on rape seed, linseed, mustard seed and poppy seed as proposed in the table below: Commodity Existing EC (a) MRL (mg/kg) Enforcement residue definition: Proposed EC MRL (mg/kg) Justification for the proposal Linseed 0.01* The proposed MRLs are Poppy seed sufficiently supported by data. The dietary risk assessment did not Rape seed reveal a potential consumer health Mustard seed concern. (a). According to Annex I of Regulation (EC) o 396/2005. (*): Indicates that the MRL is set at the limit of analytical quantification. As the Draft Assessment Report has not yet been peer reviewed, the conclusions reached in this reasoned opinion have to be considered as provisional and might have to be reconsidered once the peer review under Regulation (EU) o 188/2011 has been finalised. ESA Journal ; 9(7):2286 2

3 KEY WORDS, rape seed, linseed, mustard seed, poppy seed, MRL application, Regulation (EC) o 396/2005, consumer risk assessment ESA Journal ; 9(7):2286 3

4 TABLE O COTETS Summary... 1 Table of contents... 4 Background... 5 Terms of reference... 5 The active substance and its use pattern... 6 Assessment Methods of analysis Methods for enforcement of residues in food of plant origin Methods for enforcement of residues in food of animal origin Mammalian toxicology Residues ature and magnitude of residues in plant Primary crops Rotational crops ature and magnitude of residues in livestock Dietary burden of livestock Consumer risk assessment Conclusions and recommendations References Appendix A. Good Agricultural Practices (GAPs) Appendix B. Pesticide Residues Intake Model (PRIMo) Appendix C. Existing EU maximum residue limits (MRLs) Pesticides - Web Version - EU MRLs (ile created on 16/06/ :30) Appendix D. List of metabolites and related structural formula Abbreviations ESA Journal ; 9(7):2286 4

5 BACKGROUD Regulation (EC) o 396/2005 establishes the rules governing the setting of pesticide MRLs at Community level. Article 6 of that regulation lays down that a party requesting an authorisation for the use of a plant protection product in accordance with Directive 91/414/EEC, shall submit to a Member State, when appropriate, an application to set or modify an MRL in accordance with the provisions of Article 7 of that regulation. The United Kingdom, hereafter referred to as the evaluating Member State (EMS), received an application from the company Bayer CropScience Limited 3 to set MRLs for the active substance bixafen in oilseed rape, linseed, mustard seed and poppy seed. This application was notified to the European Commission and ESA and subsequently evaluated by the EMS in accordance with Article 8 of the Regulation. After completion, the evaluation report of the EMS was submitted to the European Commission who forwarded the application, the evaluation report and the supporting dossier to ESA on 08 March The application was included in the ESA Register of Question with the reference ESA-Q and the following subject: Application to modify the existing MRL in rape seed ESA then proceeded with the assessment of the application as required by Article 10 of the Regulation. TERMS O REERECE In accordance with Article 10 of Regulation (EC) o 396/2005, ESA shall, based on the evaluation report provided by the evaluating Member State, provide a reasoned opinion on the risks to the consumer associated with the application. In accordance with Article 11 of that Regulation, the reasoned opinion shall be provided as soon as possible and at the latest within three months (which may be extended to six months where more detailed evaluations need to be carried out) from the date of receipt of the application. Where ESA requests supplementary information, the time limit laid down shall be suspended until that information has been provided. In this particular case the calculated deadline for providing the reasoned opinion is 08 June Bayer CropScience Limited, 230 Cambridge Science Park Cambridge CB4 OWB United Kingdom ESA Journal ; 9(7):2286 5

6 THE ACTIVE SUBSTACE AD ITS USE PATTER is the ISO common name for -(3,4 -dichloro-5-fluorobiphenyl-2-yl)-3-(difluoromethyl)-1- methylpyrazole-4-carboxamide (IUPAC). Molecular weight: is a new broad spectrum fungicide belonging to the group of anilides and pyrazoles. It was developed to control leaf and stem diseases in cereals. is evaluated in the framework of Regulation (EU) o 188/ as new active substance with the United Kingdom acting as the designated Rapporteur Member State (RMS). The European Commission has confirmed the recognition of a complete application dossier from Bayer CropScience Limited in Decision 2009/700/EC 5 which entered into force on 12 September The Draft Assessment Report is available (UK, 2009). The representative uses supported by the manufacturer in the peer review are the foliar application on wheat, rye, triticale, barley and oats. The Draft Assessment Report is available and the subsequent steps of the peer review procedure are ongoing in line with Regulation (EU) o 188/2011. A final decision regarding the approval under Regulation (EC) o 1107/ is not expected within the next months. Specific bixafen MRLs have been established in Regulation o 2010/750/EC 7, taking into account the recommendations of ESA. o CXLs are established by x Alimentarius. The applicant Bayer CropScience Limited requested an authorisation for oilseed rape in the United Kingdom. The GAP for this intended use concerns two foliar applications with a spray application rate of 75 g a.s./ha and a pre harvest interval (PHI) of 56 days. The summary of the GAP is presented in Appendix A. or oilseeds, the MRLs are currently set at the limit of quantification (LOQ) of 0.01 mg/kg. According to the EMS, the same GAP as for oilseed rape is intended to be authorised also for linseed, mustard seed and poppy seed. 4 Commission Regulation (EU) o 188/2011 of 25 ebruary 2011, OJ L 53 of , p Commission Decision (EC) o 2009/700/EC of 10 September 2009, OJ L 240 of , p Regulation (EC) o 1107/2009 of the European Parliament and of the Council of 21 October 2009, OJ L 309 of , p Commission Regulation (EU) o 2010/750/EC of 7 July 2010, OJ L 220 of , p ESA Journal ; 9(7):2286 6

7 ASSESSMET ESA bases its assessment on the evaluation report submitted by the United Kingdom (UK, 2011), the Draft Assessment Report (DAR) prepared under Council Directive 91/414/EEC (UK, 2009) as well as the conclusions from the previously issued ESA reasoned opinion on bixafen. The assessment is performed in accordance with the legal provisions of the Uniform Principles for the Evaluation of the Authorization of Plant Protection Products set out in Regulation (EU) o 546/ and the currently applicable guidance documents relevant for the consumer risk assessment of pesticide residues (EC, 1996, 1997a, 1997b, 1997c, 1997d, 1997e, 1997f, 1997g, 2000, 2010a, 2010b, 2011; ESA, 2007, 2009b, OECD, 2011a, 2011b). Since the peer review under Regulation (EU) o 188/2011 has not yet been 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 peer review. 1. Methods of analysis 1.1. Methods for enforcement of residues in food of plant origin The EMS reported an analytical method for the determination of bixafen residues in samples of plant origin. After a microwave extraction with acetonitrile/water the resulting extracts are filtered and analysed by LC/MS/MS, using a C18 column. Validation data in wheat grain, wheat foliage, orange and rape seed demonstrated that a LOQ of 0.01 mg/kg is achievable. The method was also tested in an independent laboratory validation. The applicant stated that bixafen could not be determined by the German DG method S19 due to lack of sufficient sensitivity. ESA concludes that an analytical method is available for dry commodities and crops with high acid and high oil content which can be used for enforcement of MRLs according to the residue definition. However, a multi-residue method, using standard extraction techniques would be desirable Methods for enforcement of residues in food of animal origin or the determination of residues in products of animal origin an analytical method is available which has been evaluated by the RMS. The extraction depends on the matrix: for fat and cream the extraction is done with acetonitrile/hexane, followed by acetonitrile/water; liver is extracted with acetonitrile/water by microwave extraction. or other tissues and milk an extraction with acetonitrile/water is sufficient. After having cleaned the extracts with a C18-cartridge, the eluant is analysed by LC/MS/MS. The method allows separate determination of bixafen and desmethylbixafen, each compound with a LOQ of 0.01 mg/kg. Validation data for bixafen and desmethylbixafen were presented for eggs, milk, muscle, kidney, fat and liver. An independent laboratory validation was also reported. Thus, ESA concludes that for animal tissues, milk and eggs a sufficiently validated analytical method is available. 8 Commission Regulation (EU) o 546/2011 of 10 June 2011, OJ L 155 of , p ESA Journal ; 9(7):2286 7

8 2. Mammalian toxicology The toxicological properties of bixafen were assessed by the EMS in the framework of the Draft Assessment Report (UK, 2009). The EMS considered the studies sufficient to derive toxicological reference values. The proposed ADI and ARfD are reported in Table 2-1. These toxicological reference values should be considered as provisional until they are confirmed by the peer review. Table 2-1: Overview of the toxicological reference values Source Year Value Study relied upon Safety factor ADI UK mg/kg bw/d 2 year male rat feeding study 100 ARfD UK mg/kg bw Rat developmental study Residues 3.1. ature and magnitude of residues in plant Primary crops ature of residues The metabolism of bixafen in primary crops was evaluated by the RMS in the Draft Assessment Report (UK, 2009). The nature of the residues resulting from foliar applications was investigated in wheat and soybean. The studies were conducted using pyrazole-5-14 C-bixafen (pyrazol-label) and dichlorophenyl-ul- 14 C-bixafen (dichlorophenyl-label). The overview of the metabolism study designs is presented in the table below. Table 3-1: Summary of available metabolism studies in plants Group Crop Label position Application details Method, or G (a) Cereals Wheat Pyrazol- 14 C G 1 st Pulses and oilseeds Dichlorophenyl- 14 C Rate Kg a.s./ha application: nd application: 0.15 o/ Interval Sampling (1) 2 GS 38: (forage) GS 77: (hay) GS 89: (mature grain/straw) Soybean Pyrazol- 14 C G GS 70-71: (forage) Dichlorophenyl- 14 C GS 75: (hay) GS 96: (mature seed/straw) Remarks Applications performed at GS 60, 69 and 88, respectively ESA Journal ; 9(7):2286 8

9 (a): Outdoor/field use () or glasshouse/protected crops/indoor application (G) (1) : BBCH growth stage In wheat, after application of the pyrazol labelled bixafen, at harvest the TRR was 0.16 mg eq./kg and 24 mg eq./kg in the grain and straw, respectively. In the dichlorophenyl-label study, comparable TRR values were measured (0.23 mg eq./kg for grain and 23 mg eq./kg in straw). On characterisation of the extractable radioactivity one major component was identified in the grain and straw at harvest as parent bixafen, which accounted for 90-93% of the TRR. Desmethyl-bixafen 9 was the only metabolite identified. This metabolite did not represent more than 2.5% (0.004 mg /kg) and 2% (0.43 mg /kg) of the total radioactivity in the grain and straw, respectively. In forage and hay, the ratio of bixafen and desmethyl-bixafen was comparable to the results observed in grain and straw. The remaining unextractable radioactivity in grain and straw as well as in forage and hay accounted for less than or equal to 6% of the TRR. In soybean, the TRR measured in seed and straw was 0.02 mg eq./kg and 13 mg eq./kg, respectively in the pyrazole-label study. In the dichlorophenyl-label study the TRR was <0.01 mg eq./kg and 9.5 mg eq./kg for seed and straw, respectively. In straw more than 90% of the applied radioactivity was extractable with acetonitrile/water. In soybean seed, the extractability was significant lower: in the pyrazole-label study, after microwave extraction, 78% of the TRR was extractable, whereas in the dichlorophenyl-label study, using conventional extraction technique, only 53% of the TRR was extractable. In the pyrazole-label study, the major component identified in seed and straw at harvest was the parent bixafen, which accounted for 30% of the TRR (<0.01 mg/kg) and 90% of the TRR (12 mg/kg), respectively. The metabolites identified in seed were bixafen-desmethyl-pyrazole-4-carboxylic acid 10 (19% of the TRR, <0.01 mg/kg) and bixafen-pyrazolone-4-carboxylic acid 11 (12% of the TRR, <0.01 mg/kg). In straw the only metabolite detected was the desmethyl-bixafen (0.5% of the TRR, 0.06 mg /kg). In addition, several other compounds could not be identified in soybeans but these occurred at a low concentration in seed (<0.1 mg/kg) and in straw (0.06 mg/kg). In the dichlorophenyl-label study, neither the parent compound nor the metabolite desmethyl-bixafen were detected in the seed whilst in straw, bixafen was recovered at a high level (92% of TRR; 8.8 mg /kg) whilst its metabolite desmethyl-bixafen at a trace level (0.6% of TRR; 0.06 mg /kg). ESA considers that further clarification is needed on the available metabolism data on soybean since the parent compound was identified in a significant amount in soybean seed for the pyrazole labelling whereas it was not detected in the dichlorophenyl labelled treated seeds. The metabolic pattern observed in soybean was quite different compared to the metabolism depicted in wheat as besides the metabolic reaction of demethylation of the pyrazole ring to generate the desmethyl-bixafen identified in wheat grain and straw, hydrolytic cleavage of the bridge between the pyrazole ring and the dichlorophenyl ring of the parent molecule occurred in soybean and generated the bixafen-desmethyl-pyrazole-4-carboxylic acid with subsequent oxidative desalkylation to form the bixafen-pyrazolone-4-carboxylic acid. These 2 metabolites were recovered in significant amount in soybean seed only and were not detected in straw. In the rat metabolism, the most important metabolic reaction was the demethylation of the pyrazole ring to form desmethyl-bixafen and numerous desmethyl-bixafen related metabolites. The metabolites bixafen-desmethyl-pyrazole-4-carboxylic acid and bixafen-pyrazolone-4-carboxylic acid were not recovered in the rat metabolism. 9 Desmethyl-bixafen See Appendix D 10 -desmethyl-pyrazole-4-carboxylic acid See Appendix D 11 -pyrazolone-4-carboxylic acid See Appendix D ESA Journal ; 9(7):2286 9

10 Based on the plant metabolism data submitted on wheat and soybean, the EMS derived the following residue definitions for cereals and pulses/oilseeds: Residue definition for risk assessment: sum of bixafen and its metabolite desmethyl-bixafen, expressed as bixafen Residue definition for enforcement: bixafen EMS included the desmethyl-bixafen in the residue definition for risk assessment because similar toxicological properties as the parent bixafen are assumed. ESA agrees to use the residue definitions derived by the EMS on a provisional basis, but recommends that during the peer review the need to include the metabolites observed in soybeans (bixafen-desmethyl-pyrazole-4-carboxylic acid and bixafen-pyrazolone-4-carboxylic acid) in the residue definition for risk assessment should be further considered Magnitude of residues In support of the MRL application, 8 residue trials on rape seed were performed in northern Europe (United Kingdom, Belgium, orth of rance, the etherlands, Germany) which complied with the intended GAP. The samples were analysed for bixafen and desmethyl-bixafen. The results were reported for the sum of bixafen and desmethyl-bixafen and the parent bixafen separately. Thus, a MRL proposal in compliance with the enforcement residue definition can be derived. ESA derived a MRL proposal of mg/kg on rape seed. According to the EU guidance document (EC, 2008) an extrapolation to linseed, mustard seed and poppy seed is possible. The method used to analyse the samples of the supervised field trials was sufficiently validated for bixafen and its metabolite desmethyl-bixafen in commodities with high oil content (rape seed). or each analyte a LOQ of 0.01 mg/kg was achievable. The results for desmethyl-bixafen were not recalculated to bixafen, but as the difference in molecular weight of the parent bixafen and desmethylbixafen is negligible (less than 4%), a correction would not alter the results significantly. According to the proposed residue definition for monitoring and risk assessment in pulses and oilseeds, no additional validation data are requested for the metabolite desmethyl-bixafen in high oil content matrices. The storage of samples prior to analysis did not exceed 14 months. Storage stability data were submitted in the evaluation report (UK, 2011) and demonstrated that residues of bixafen and its metabolite desmethyl-bixafen are stable for up to 24 months in lettuce, potato, rape seed and wheat (foliage, grain and straw). It is concluded that the supervised field trials provided are valid regarding the storage stability and the analytical methodology applied as far as the parent compound is concerned. ESA considers that the data are sufficient to derive a MRL on rape seed with extrapolation to linseed, mustard seed and poppy seed and concludes that the MRL of mg/kg would be appropriate for the authorized use of bixafen on these crops in northern Europe (UK). The results of the residue trials, the related risk assessment input values (highest residue, median residue) and the MRL proposal for bixafen are summarized in Table 3-2. ESA Journal ; 9(7):

11 Table 3-2: Overview of the available residues trials data Commodity Region (a) Outdoor/Indoor Individual trial results (mg/kg) Median residue (mg/kg) (b) Rape seed linseed, mustard seed and poppy seed Enforcement () Risk assessment (sum of bixafen and desmethyl bixafen, expressed as bixafen) (1) Highest residue (mg/kg) (c) MRL proposal (mg/kg) Median C (d) Comments EU Outdoor 6 x <0.01; 2 x x <0.02; 2 x Rber= 0.02 mg/kg Rmax= 0.01 mg/kg OECD calculator (e) (a): EU, SEU, EU or Import (country code). In the case of indoor uses there is no necessity to differentiate between EU and SEU. (b): Median value of the individual trial results according to the enforcement residue definition. (c): Highest value of the individual trial results according to the enforcement residue definition. (d): The median conversion factor for enforcement to risk assessment is obtained by calculating the median of the individual conversion factors for each residues trial. (e) OECD calculator (OECD, 2011a,2011b) (*): Indicates that the MRL is set at the limit of analytical quantification. (1) : The results for desmethyl-bixafen were not re-calculated to bixafen since the difference in molecular weight of the parent bixafen and desmethyl-bixafen is negligible. = 0.02 mg/kg ESA Journal ; 9(7):

12 Effect of industrial processing and/or household preparation A hydrolysis study simulating conditions of pasteurisation baking/brewing/boiling and sterilisation was reported in the DAR (UK, 2009) and complied with the relevant European guidance document (European Commission, 1997d). Under the conditions tested (20 min at 90 C at ph 4, 60 min at 100 C at ph 5 and 20 min at 120 C at ph 6) and using the pyrazole labelling only no degradation occurred. Thus, it is concluded that the active substance is hydrolytically stable during the representative processing conditions. o specific processing studies were submitted to address the magnitude of the residues in oilseeds processed commodities (crude and refined oil, meal). But since the residues in rape seed are not exceeding 0.02 mg/kg and the consumer intake is below 10% of the ADI, no processing studies are triggered (EC, 1997d) Rotational crops Preliminary considerations Since the intended GAP refers to a use in crops that are grown in crop rotation, the possibility of residues in succeeding crops has to be assessed ature of residues The metabolism and distribution of bixafen in rotational crops was investigated in wheat, turnips and Swiss chard. The crops were grown in soil that had been treated with pyrazole- and dichlorophenylring labelled [C 14 ] bixafen, at a rate of 0.79 to 0.85 kg as/ha. Crops were planted 30, 138 and 285 days after application. At harvest the TRR in Swiss chard ranged between 0.03 mg eq./kg and 0.06 mg eq./kg at all plantback intervals. The level of the parent compound ranged between 26% and 37% of the TRR in the pyrazole label-study and between 52% and 71% of the TRR in the dichlorophenyl label-study. In wheat grain no radioactive residues were detected (residues below the LOQ). In wheat straw, the TRR ranged between 0.49 mg eq/kg at the shortest plant-back interval and 0.24 mg eq/kg after 285 days plant-back interval. Parent bixafen accounted for 14% to 23% of the TRR in the pyrazole labelstudy and 14% to 37% of the TRR in the dichlorophenyl label-study. In turnip roots, the TRR was in the range of 0.01 mg eq/kg and 0.05 mg eq/kg. Significant residue levels of parent bixafen above the LOQ (0.03 mg/kg) were found in the sample derived from the shortest plant-back interval corresponding to 59% of the TRR. In turnip tops the total residues ranged between 0.01 mg eq./kg and 0.08 mg eq/kg. Again, parent compound was quantifiable only in samples grown after 30 days plant-back interval (0.03 mg/kg-37% of the TRR). was extensively metabolised into numerous metabolites in wheat plant parts (forage, hay, straw) at all plant-back intervals while in Swiss chard and turnip roots the parent was recovered at a level of up to 71% and 78% of the TRR, respectively. In the different wheat plant parts (forage, hay, straw), the desmethyl-bixafen metabolite was found to be the major compound of the total residues with residue levels ranging between 44% of the TRR (0.19 mg/kg) and 73% of the TRR (0.18 mg/kg) while the other identified metabolites in wheat straw were detected at a very low level (4.7% of the TRR-0.02 mg/kg). rom the nature of the identified metabolites it was concluded that the bridge between the pyrazole ring and the dichlorophenyl ring had been broken and lead to the formation of ESA Journal ; 9(7):

13 bixafen-pyrazolone-4-carboxylic acid, bixafen-pyrazole-4-carboxamide 12, bixafen-pyrazole-4- carboxylic acid 13 and bixafen-desmethyl-pyrazole-4-carboxylic acid for the pyrazole labelling whilst only the desmethyl-bixafen and its hydroxy glycoside sulfate 14 conjugate were identified in the dichlorophenyl-label study (UK, 2011). The metabolism of bixafen showed a similar profile as in soybean with the parent bixafen being the most valid indicator of the total residues in the edible parts of the rotational crops. The provisional residue definitions for monitoring and risk assessment are also applicable for rotational crops, but may need to be revised if the peer review comes to different conclusions Magnitude of residues our residue trials were conducted to investigate the magnitude of residues in succeeding or rotational crops (UK, 2009). Winter/spring wheat, lettuce, and turnip/carrots were grown in soil which had been treated at an application rate of 0.28 kg as/ha and aged for 30 days and in soil which had been previously used to grow barley (treated with 2 foliar applications of bixafen at a combined rate of 0.28 kg as/ha. The barley crop was harvested at maturity 52 to 73 days after the last application and the soil cultivated ready for planting following crops. Rotational crops were planted into the soil at 60 to 70 and 298 to 331 days after the last application to simulate winter and spring rotations. Rotational crop samples were taken at set intervals up to maturity and analysed for bixafen and desmethylbixafen. In all samples bixafen and desmethyl-bixafen residues were below the LOQ of 0.01 mg/kg, respectively, with the exception of one sample of immature lettuce head which contained 0.05 mg/kg of bixafen and one sample of wheat straw at harvest in which desmethyl-bixafen residues were found at a concentration of 0.02 mg/kg. Based on the available information on the nature and magnitude of the residues in rotational crops, the occurrence of quantifiable residue levels in the edible parts of the rotational crops is not likely, provided that the compound is used on rape seed according to the proposed pattern. However, Member States intending to grant an authorisation for bixafen containing plant protection products should consider the need to define specific restrictions, e.g. plant back intervals, in order to avoid contamination of succeeding crops ature and magnitude of residues in livestock Since rapeseed, linseed and their by-products are used as feed items, ESA assessed whether the new uses would require an amendment of the existing MRLs for animal commodities Dietary burden of livestock The median and maximum dietary burden for livestock was calculated using the agreed European methodology (EC, 1996) considering the crops for which authorisations are already granted at EU level (i.e. cereals, ESA, 2009) and the oilseeds assessed in the framework of this report. ESA calculated two scenarios for estimating the dietary burden on livestock, estimating the impact of the new uses on oilseeds. In scenario 1 the dietary burden was calculated for the cereals and cereal products only, using the input values derived in the previous ESA opinion, whereas in scenario 2 also the oilseeds and oilseed by-products were included. The input values for the dietary burden calculation were selected according to the latest AO recommendations (AO, 2009). To refine the calculations for the oilseeds, ESA used the default processing factor of 2 for oilseeds meal. 12 -pyrazole-4-carboxamide See Appendix D 13 -pyrazole-4-carboxylic acid See Appendix D 14 Hydroxy glycoside sulphate of desmethyl-bixafen See Appendix D ESA Journal ; 9(7):

14 The input values for the dietary burden calculations are summarized in Table 3-3. Table 3-3: Input values for the dietary burden calculation Commodity Median dietary burden Maximum dietary burden Input value (mg/kg) Comment Input value (mg/kg) Risk assessment residue definition: sum of bixafen and desmethyl-bixafen, expressed as bixafen Wheat grain 0.02 median residue*c Barley grain 0.11 median residue (SEU)*C Rye grain 0.02 median residue (Wheat)*C Oats grain 0.11 median residue (barley, SEU)*C Wheat bran 0.08 median residue *C*P (4) Rye bran 0.44 median residue (SEU)*C*P (4) Wheat straw 4.14 median residue (EU)*C Barley straw 3.71 median residue (SEU)*C Rye straw 4.14 median residue (wheat. EU)*C Oats straw 3.71 median residue (barley, SEU)*C Included only in scenario 2 Comment 0.02 median residue*c 0.11 median residue (SEU)*C 0.02 median residue (Wheat)*C 0.11 median residue (barley, SEU)*C 0.08 median residue *C*P (4) 0.44 median residue (SEU)*C*P (4) HR*C 7.30 HR*C HR*C 7.30 HR*C Rape seed 0.02 median residue*c 0.02 median residue*c Rape seed meal 0.04 median residue*c * P (2) 0.04 median residue*c* P (2) Linseed 0.02 median residue*c 0.02 median residue*c Linseed meal 0.04 median residue*c *P (2) 0.04 median residue*c* P (2) In Tables 3-4 and 3-5, the results of the calculations according to scenarios 1 and 2, respectively are summarised. It was demonstrated that the expected maximum dietary burden is not significantly different in scenario 1 (considering only cereals and cereal products) and in scenario 2 (including in addition oilseeds and oilseed products). ESA Journal ; 9(7):

15 Table 3-4: Results of the dietary burden calculation - Scenario 1 Setting of MRLs for bixafen in several oilseeds Maximum dietary burden (mg/kg bw/d) Median dietary burden (mg/kg bw/d) Highest contributing commodity Max dietary burden (mg/kg DM) Risk assessment residue definition: sum of bixafen and desmethyl-bixafen, expressed as bixafen Trigger exceeded? Dairy ruminants Wheat straw Yes Meat ruminants Wheat straw Yes Poultry Barley grain o Pigs Barley grain Yes Table 3-5: Results of the dietary burden calculation - Scenario 2 Maximum dietary burden (mg/kg bw/d) Median dietary burden (mg/kg bw/d) Highest contributing commodity Max dietary burden (mg/kg DM) Risk assessment residue definition: sum of bixafen and desmethyl-bixafen, expressed as bixafen Trigger exceeded? Dairy ruminants Wheat straw Yes Meat ruminants Wheat straw 6.74 Yes Poultry Barley grain o Pigs Barley grain Yes Thus, the dietary burden is mainly driven by the existing uses on cereals (wheat, rye, triticale, barley, oat) and the contribution of the oilseeds to the total livestock exposure is insignificant. Therefore the modification of the MRLs for commodities of animal origin was not further investigated in the framework of the current application. 4. Consumer risk assessment The consumer risk assessment was performed with revision 2 of the ESA Pesticide Residues Intake Model (PRIMo). This exposure assessment model contains the relevant European food consumption data for different sub-groups of the EU population 15 (ESA, 2007). or the calculation of the chronic exposure, ESA used the median residue value as derived from the residue trials on oilseed rape (see Table 3-2), and in the previously issued ESA reasoned opinion. or the remaining commodities of plant and animal origin, the current MRL of 0.01* mg/kg was used as input values for plant matrices and the MRL of 0.02* mg/kg was set for the products of animal origin as established in Annexes IIIA of Regulation (EC) o 396/2005. The model assumptions for the long-term exposure assessment are considered to be rather conservative, assuming that all food items consumed have been treated with the active substance under consideration. In reality, it is not likely that all food consumed will contain residues at the MRL or at levels of the median residue values identified in supervised field trials. However, if this first tier exposure 15 The calculation of the long-term exposure (chronic exposure) is based on the mean consumption data representative for 22 national diets collected from MS surveys plus 1 regional and 4 cluster diets from the WHO GEMS ood database; for the acute exposure assessment the most critical large portion consumption data from 19 national diets collected from MS surveys is used. The complete list of diets incorporated in ESA PRIMo is given in its reference section (ESA, 2007). ESA Journal ; 9(7):

16 assessment does not exceed the toxicological reference value for long-term exposure (i.e. the ADI), a consumer health risk can be excluded with a high probability. The acute exposure assessment was performed only with regard to the commodities under consideration assuming the consumption of a large portion of the food items as reported in the national food surveys containing residues at the median level as observed in supervised field trials. The input values used for the dietary exposure calculation are summarized in Table 4-1. Table 4-1. Input values for the consumer dietary exposure assessment Commodity Chronic exposure assessment Acute exposure assessment Input value (mg/kg) Comment Input value (mg/kg) Risk assessment residue definition: sum of bixafen and desmethyl-bixafen, expressed as bixafen Linseed, poppy seed, rape seed, mustard seed Wheat (including triticale) 0.02 median residue*c Rye 0.02 median residue*c Barley 0.11 median residue (SEU)*C Oats 0.11 median residue (SEU)*C Bovine, sheep and goat meat median residue Bovine, sheep and goat fat median residue Bovine, sheep and goat liver median residue Bovine, sheep and goat kidney Comment 0.02 median residue*c 0.02 median residue*c 0.1 median residue Milk of cows, sheep and goat median residue Other commodities of plant origin Other commodities of animal origin EC MRL EC MRL See Appendix C See Appendix C Acute risk assessment was undertaken only with regard to the products for which a MRL proposal is requested. The estimated exposure was then compared with the toxicological reference values derived for bixafen (see Table 2-1). The results of the intake calculation are presented in Appendix B to this reasoned opinion. o long-term consumer intake concerns were identified for any of the European diets incorporated in the ESA PRIMo. The total calculated intake values ranged from 0.5% to 4.8% of the ADI (L ESA Journal ; 9(7):

17 child). The contribution of residues in rape seed, linseed, mustard seed and poppy seed to the total consumer exposure accounted for 0.06% of the ADI (WHO cluster diet E). o acute consumer risk was identified in relation to the MRL proposal for rape seed, linseed, mustard seed and poppy seed. The calculated maximum exposure in percentage of the ARfD was <0.015% for children (DE child). ESA concludes that the intended use of bixafen on rape seed, linseed, mustard seed and poppy seed is acceptable from a consumer safety point of view; the residues expected after treatment of the crops according to the intended GAP will not lead to an exceedance of the toxicological reference values. COCLUSIOS AD RECOMMEDATIOS COCLUSIOS The toxicological profile of bixafen was assessed by the RMS in the framework of the preparation of the Draft Assessment Report. The data were sufficient to conclude on an ADI value of 0.02 mg/kg bw/day and an ARfD of 0.2 mg/kg. Since the peer review is currently ongoing for this active substance, the toxicological reference values should be considered as provisional only. The metabolism of bixafen was considered as sufficiently elucidated in primary (wheat, soybean) and rotational crops (wheat, turnip, swiss chard). Based on the results of these studies provisional residue definitions were derived: the residue definition for enforcement comprises the parent compound only, whereas the residue definition for risk assessment is established as the sum of bixafen and desmethylbixafen, expressed as bixafen. The supervised residue trials on rape seed are sufficient and adequate to derive a MRL proposal of mg/kg for the intended use of bixafen on this crop. Analytical methods are available to enforce the proposed MRL for the commodities under consideration. According to the EC guidance documents, this MRL can be extrapolated to linseed, mustard seed and poppy seed. Under processing conditions simulating pasteurisation, baking/brewing/boiling and sterilisation bixafen residues are stable. Processing studies to address the magnitude of the residues in oilseeds processed commodities (crude and refined oil, meal) were not triggered. The rotational crop studies demonstrated that the occurrence of bixafen related residues in rotational crops grown in crop rotation after primary crops treated with bixafen in accordance with the intended GAP is expected to be low (below or at the LOQ). The dietary burden calculation showed that the contribution of the oilseeds crops to the total livestock exposure is insignificant. Therefore the modification of the MRLs for commodities of animal origin was not further investigated in the framework of the current application. The consumer exposure assessment was performed with revision 2 of the ESA PRIMo (Pesticide Residue Intake Model). or the chronic intake assessment, ESA used the median residue concentrations derived from the submitted supervised residue trials on rape seed and the existing MRLs as established in Commission Regulation (EC) o 396/2005. Additionally, median residue levels were available from a previous assessment on certain cereals and products of animal origin which could be used to refine the calculation of the dietary exposure. The acute intake assessment was performed only with regard to the crop under consideration applying the STMR value on rape seed as derived from the supervised residue trials. The estimated long-term and short-term exposures were compared with the toxicological reference values established for bixafen. ESA Journal ; 9(7):

18 The total calculated intake values ranged from 0.5% to 4.8% of the ADI (L child). The contribution of residues in rape seed, linseed, mustard seed and poppy seed to the total consumer exposure accounted for 0.06% of the ADI (WHO cluster diet E). o acute consumer risk was identified in relation to the MRL proposal on these crops. The calculated maximum exposure in percentage of the ARfD was <0.015% for children (DE child). ESA concludes that the intended use of bixafen on rape seed, linseed, mustard seed and poppy seed is acceptable from a consumer safety point of view; the residues expected after treatment of the crops according to the intended GAP will not lead to an exceedance of the toxicological reference values. RECOMMEDATIOS Commodity Existing EC (a) MRL (mg/kg) Enforcement residue definition: Proposed EC MRL (mg/kg) Justification for the proposal Linseed 0.01* The proposed MRLs are Poppy seed sufficiently supported by data. The dietary risk assessment did not Rape seed reveal a potential consumer health Mustard seed concern. (a). According to Annex I of Regulation (EC) o 396/2005. (*): Indicates that the MRL is set at the limit of analytical quantification. As the Draft Assessment Report has not yet been peer reviewed, the conclusions reached in this reasoned opinion have to be considered as provisional and might have to be reconsidered once the peer review under Regulation (EU) o 188/2011 has been finalised. ESA Journal ; 9(7):

19 REERECES EC (European Commission), Appendix G. Livestock eeding Studies. 7031/VI/95 rev.4. Available from: EC (European Commission), 1997a. Appendix A. Metabolism and distribution in plants. 7028/IV/95- rev.3. Available from: EC (European Commission), 1997b. Appendix B. General recommendations for the design, preparation and realization of residue trials. Annex 2. Classification of (minor) crops not listed in the Appendix of Council Directive 90/642/EEC. 7029/VI/95-rev.6. Available from: EC (European Commission), 1997c. Appendix C. Testing of plant protection products in rotational crops. 7524/VI/95-rev.2. Available from: EC (European Commission), 1997d. Appendix E. Processing studies. 7035/VI/95-rev.5. Available from: EC (European Commission), 1997e. Appendix. Metabolism and distribution in domestic animals. 7030/VI/95-rev. 3. Available from: EC (European Commission), 1997f. Appendix H. Storage stability of residue samples. 7032/VI/95- rev.5. Available from: EC (European Commission), 1997g. Appendix I. Calculation of maximum residue level and safety intervals. 7039/VI/95. Available from: EC (European Commission), Residue analytical methods. or pre-registration data requirement for Annex II (part A, section 4) and Annex III (part A, section 5 of Directive 91/414. SACO/3029/99-rev.4. Available from: EC (European Commission), 2010a. Guidance document on pesticide residue analytical methods. or post-registration control. SACO/825/00-rev.8.1 (16/11/2010). Available from: EC (European Commission), 2010b. Classes to be used for the setting of EU pesticide Maximum Residue Levels (MRLs). SACO 10634/2010 Rev. 0, finalized in the Standing Committee on the ood Chain and Animal Health at its meeting of March EC (European Commission), Appendix D. Guidelines on comparability, extrapolation, group tolerances and data requirements for setting MRLs. 7525/VI/95-rev.9. Available from: ESA (European ood Safety Authority), Pesticide Residues Intake Model for assessment of acute and chronic consumer exposure to pesticide residues-rev.2. Available from ESA (European ood Safety Authority), Reasoned opinion on the setting of new MRLs for bixafen in certain cereals and products of animal origin prepared by ESA Pesticide Risk Assessment Peer Review (PRAPeR) Unit. ESA Journal 2009; volume 7(12):1440, 32 pp. AO (ood and Agriculture Organization of the United ations), Submission and evaluation of pesticide residues data for the estimation of Maximum Residue Levels in food and feed. Pesticide Residues. 2 nd Ed. AO Plant Production and Protection Paper 197, 264 pp. ESA Journal ; 9(7):

20 Meier U, Growth Stages of mono- and dicotyledonous plants. BBCH Monograph, 2 nd Ed., ederal Biological Research Centre of Agriculture and orest. Braunschweig, Germany. Available from: OECD (Organization for Economic Co-operation and Development), 2011a. OECD MRL Calculator: User Guide. Series of pesticides o. 56, EV/JM/MOO(2011)2, 1 March In: Pesticide Publications/Publications on Pesticide Residues. Available from: OECD (Organization for Economic Co-operation and Development), 2011b. OECD MRL Calculator: spreadsheet for single data set and spreadsheet for multiple data set, 2 March In: Pesticide Publications/Publications on Pesticide Residues. Available from: United Kingdom, Draft assessment report on the active substance prepared by the rapporteur Member State UK in the framework of Council Directive 91/414/EEC, December United Kingdom, Evaluation report on the setting of MRLs for bixafen in oilseed rape (extrapolated to linseed, mustard seed and poppy seed) prepared by the evaluating Member State UK under Article 8 of Regulation (EC) o 396/2005, 23 ebruary 2011, 25 pp. ESA Journal ; 9(7):

21 Appendix A. GOOD AGRICULTURAL PRACTICES (GAPS) Crop and/or situation (a) Oilseed rape, linseed, mustard seed, poppy seed Remarks: (a) (b) (c) (d) (e) (f) (g) Member State or Country G or I (b) Pest or group of pests controlled (c) UK Stem and leaf diseases ormulation Application Application rate per treatment PHI type conc. method interval kg as/hl kg a.s./ha (days) of a.s. kind min max min max min max min max (d - f) (i) (f - h) growth stage & season (j) (k) water L/ha min max EC* 75 g/l Spray or crops, EU or other classifications, e.g.x, should be used; where relevant, the use situation should be described (e.g. fumigation of a structure) Outdoor or field use (), glasshouse application (G) or indoor application (I) e.g. biting and suckling insects, soil born insects, foliar fungi, weeds e.g. wettable powder (WP), emulsifiable concentrate (EC), granule (GR) GCP Technical Monograph o 2, 4 th Ed., 1999 or other codes, e.g. OECD/CIPAC, should be used All abbreviations used must be explained Method, e.g. high volume spraying, low volume spraying, spreading, dusting, drench (h) (i) (j) (k) (l) (m) (l) Remarks Kind, e.g. overall, broadcast, aerial spraying, row, individual plant, between the plants - type of equipment used must be indicated g/kg or g/l Growth stage at last treatment (Growth stages of mono-and dicotyledonous plants. BBCH Monograph, 2 nd Ed., 2001), including where relevant, information on season at time of application The minimum and maximum of application possible under practical conditions of use must be provided PHI - minimum pre-harvest interval Remarks may include: Extent of use/economic importance/restrictions (i.e. feeding, grazing) * is formulated with the active substances prothioconazole and tebuconazole. Prothioconazole is applied at a rate of up to 2 x 0.15 kg as/ha when in combination with bixafen, which is identical to the rate and latest timing in the approved prothiaconazole product Proline. Tebuconazole is applied at a rate of up to 2 x 0.1 kg as/ha when in combination with bixafen, which is identical to the rate and latest timing in the approved tebuconazole product Prosano. (m) ESA Journal ; 9(7):