Reasoned opinion on the modification of the existing MRLs for quizalofop-p in oilseed rape, sunflower, cotton and soybean 1

Transcription

1 EFSA Journal 2012;10(12):3008 ABSTRACT REASONED OPINION Reasoned opinion on the modification of the existing MRLs for quizalofop-p in oilseed rape, sunflower, cotton and soybean 1 European Food Safety Authority 2, European Food Safety Authority (EFSA), Parma, Italy In accordance with Article 6 of Regulation (EC) No 396/2005, Spain, hereafter referred to as the evaluating Member State (EMS), received from Nissan Chemical Europe an application to modify the existing MRLs of quizalofop-p in rapeseed, sunflower, cotton and soybean. Spain drafted an evaluation report in accordance with Article 8 of Regulation (EC) No 396/2005, which was submitted to the European Commission and forwarded to EFSA. The submitted residue trials lead to MRL proposals of 0.3 mg/kg for rapeseed and 0.4 mg/kg for sunflower. These proposals are already covered by the existing EU MRL of 0.5 mg/kg for rapeseed and by the proposals of 0.7 mg/kg made by EFSA for sunflower in an application related to the ester variant quizalofop-ptefuryl. EFSA is therefore of the opinion that the uses of quizalofop-p-ethyl on oilseed rape and sunflower do not necessitate any change to the existing EU MRLs or to the proposals done in a previous MRL application. The extrapolations to cotton and soybean are not recommended, since not in line with the rules defined in the current EU guideline. An enforcement method referenced AN34 validated to control quizalofop-p-ethyl residues in oily matrices has been submitted. This method is however an outdated method using techniques no longer in use in laboratories for routine analyses. Considering that a LC-MS/MS method corresponding to the current analytical standards has been developed to analyse the samples from the trials performed from 2007, EFSA is of the opinion that validation data, including an ILV, have to be requested for such an analytical method. Based on the risk assessment results, EFSA concludes that the proposed uses of quizalofop-p-ethyl on oilseed rape and sunflower will not result in a consumer exposure exceeding the toxicological reference value and therefore is unlikely to pose a consumer health risk. European Food Safety Authority, 2012 KEY WORDS Quizalofop-P-ethyl, oilseeds, MRL application, Regulation (EC) No 396/2005, consumer risk assessment, aryloxyphenoxypropionic herbicide. 1 On request from European Commission, Question No EFSA-Q , approved on 03 December Correspondence: pesticides.mrl@efsa.europa.eu Suggested citation: European Food Safety Authority; Reasoned opinion on the modification of the existing MRLs for quizalofop-p in oilseed rape, sunflower, cotton and soybean. EFSA Journal 2012;10(12):3008. [28 pp.] doi: /j.efsa Available online: European Food Safety Authority, 2012

2 SUMMARY In accordance with Article 6 of Regulation (EC) No 396/2005, Spain, hereafter referred to as the evaluating Member State (EMS), received from Nissan Chemical Europe an application to modify the existing MRLs for the active substance quizalofop-p in oilseed rape, sunflower, cotton and soybean. Spain drafted an evaluation report in accordance with Article 8 of Regulation (EC) No 396/2005, which was submitted to the European Commission and forwarded to EFSA on 13 September EFSA bases its assessment on the evaluation report submitted by the EMS, the Draft Assessment Reports (DAR) prepared under Council Directive 91/414/EEC for the active substances quizalofop-pethyl, quizalofop-p-tefuryl and propaquizafop, the Commission Review Report on quizalofop-p, the conclusion on the peer review of the pesticide risk assessment of the active substance quizalofop-p and propaquizafop, as well as the conclusions from a previous EFSA opinion on quizalofop-p. The toxicological profile of quizalofop-p-ethyl was assessed in the framework of the peer review under Directive 91/414/EEC and the data were sufficient to propose an ADI of mg/kg bw per day ( mg/kg bw per day when expressed as quizalofop-p equivalent). No ARfD was deemed necessary. The metabolism of quizalofop-p-ethyl in primary crops was investigated in sugar beet (root vegetables), cotton and soybean (pulses/oilseeds group). From these data and from the additional studies conducted with the other ester variants, the peer review concluded to establish a general residue definition for the different quizalofop-p esters as "sum of quizalofop-esters, quizalofop and quizalofop conjugates, expressed as quizalofop (sum of isomers)" both, for enforcement and risk assessment. Therefore EFSA concludes that the metabolism in primary crops was sufficiently addressed to support the use of quizalofop-p-ethyl on oilseeds. The enforcement residue definition established in Regulation (EC) No 396/ is set as quizalofop (including quizalofop-p). The submitted residue trials conducted with quizalofop-p-ethyl according to the intended GAPs lead to MRL proposals of 0.3 mg/kg for oilseed rape and 0.4 mg/kg for sunflower. These MRL proposals refer to the wider residue definition derived in the peer review. However, on a provisional basis these MRLs can be included in the current residue definition, noting that the MRLs are slightly overestimating the expected residues for quizalofop since also the esters and conjugates are covered by the MRLs. EFSA notes that the existing MRL for rape seed is 0.5 mg/kg; thus, the uses of quizalofop- P-ethyl on oilseed rape according to the intended GAPs do not necessitate a change to the existing EU. For sunflower seed the proposed MRL is lower than the MRL proposal of 0.7 mg/kg derived in a previous MRL assessment related to the ester variant quizalofop-p-tefuryl; this MRL proposal has not yet been taken over in EU legislation. The extrapolation of the MRL proposals derived in this assessment to cotton and soybean is not recommended by EFSA, since not in line with the extrapolation rules defined in the current EU guidelines. A validated analytical enforcement method referenced AN34 to control the residues of quizalofop-pethyl in high oil content matrices has been submitted. This method is however an outdated method using techniques no longer in use in laboratories for routine analyses, as more appropriate approaches are nowadays available. Considering that a LC-MS/MS method (AN41) corresponding to the current routine analytical standards has been recently developed by the applicant to analyse the samples from the residues trials performed from 2007, EFSA is of the opinion that full validation data including ILV, have to be requested for such an analytical method. Studies investigating the nature of quizalofop-p-ethyl residues in processed commodities are not available. Taking into account the overall consumer exposure which exceeds the trigger value of 10% of the ADI, studies investigating the nature of residues in processed food should be provided. One processing study on sunflower was submitted, providing some evidence that the residues in refined sunflower seed oil are significantly reduced. However, EFSA does not recommend the inclusion of the processing factors derived for sunflower meal and sunflower oil in Annex VI of Regulation (EC) No 396/2005, as based on one study only. EFSA Journal 2012;10(12):3008 2

3 The occurrence of quizalofop-p-ethyl residues in rotational crops was investigated in the framework of the peer review. Based on the available information on the nature and magnitude of residues in succeeding crops, it was concluded that significant residue levels are unlikely to occur in rotational crops, provided that the compound is used on oilseeds according to the proposed GAPs. Residues in commodities of animal origin were not assessed in the framework of this application, since the supported uses of quizalofop-p-ethyl on oilseed crops do not result in changes to the existing or proposed MRL values and the intended uses will not have an impact on the dietary exposure of livestock. The consumer risk assessment was performed with revision 2 of the EFSA Pesticides Residues Intake Model (PRIMo). Since information to perform a complete dietary consumer risk assessment for quizalofop-p was not available to EFSA, the calculation of chronic exposure was conducted using the MRL values currently into force under Regulation (EC) No 396/2005, except for sunflower and cotton where the MRL proposals of 0.7 mg/kg and 0.15 mg/kg made in a EFSA reasoned opinion related to the ester variant quizalofop-p-tefuryl were used as input values. Considering this worst case assessment, no long-term consumer intake concerns were identified for any of the European diets incorporated in the EFSA PRIMo, as the highest calculated intake value accounted for 90 % of the ADI (WHO Cluster B). The contribution of residues in rapeseed and sunflower to the total consumer exposure is limited to a maximum of 6 % of the ADI. Therefore, EFSA concludes that the proposed uses of quizalofop-p-ethyl on oilseed rape and sunflower will not result in a consumer exposure exceeding the toxicological reference value and therefore is unlikely to pose a consumer health risk. Since the use of quizalofop-p-ethyl on oilseed rape and sunflower according to the intended GAPs results in residue levels already covered by the existing MRLs or by the proposals already made in a former reasoned opinion, EFSA does not recommend to amend the existing MRLs or MRL proposals for quizalofop-p, as summarized in the table below. Summary table Code number (a) Commodity Existing EU MRL (mg/kg) Proposed EU MRL (mg/kg) Enforcement residue definition: quizalofop (including quizalofop-p) Sunflower seed 0.1* No new Proposal Rape seed 0.5 No new proposal Soya bean 0.1* No new Proposal Cotton seed 0.1* No new Proposal (a): According to Annex I of Regulation (EC) No 396/2005. (*): Indicates that the MRL is set at the limit of analytical quantification. Justification for the proposal No new proposal since the use of quizalofop-pethyl on sunflower according to the supported GAP leads to a proposal of 0.4 mg/kg, lower than the MRL value of 0.7 mg/kg already proposed by EFSA in a former reasoned opinion referring to the use of ester variant quizalofop-p-tefuryl on sunflower (EFSA, 2010), not yet implemented in EU legislation No new proposal since the use of quizalofop-pethyl on oilseed rape according to the supported GAP leads to a proposal of 0.3 mg/kg, lower than the existing MRL of 0.5 mg/kg already into force under Regulation (EC) No 396/2005. No proposals since extrapolation from oilseed rape and sunflower to soybean and cotton is not foreseen according to EU guidance document SANCO 7525/VI/95. Moreover, the data base on sunflower in northern EU is not complete. EFSA Journal 2012;10(12):3008 3

4 TABLE OF CONTENTS Abstract... 1 Summary... 2 Table of contents... 4 Background... 5 Terms of reference... 5 The active substance and its use pattern... 6 Assessment Method of analysis Methods for enforcement of residues in food of plant origin Methods for enforcement of residues in food of animal origin Mammalian toxicology Residues Nature and magnitude of residues in plant Primary crops Rotational crops Nature and magnitude of residues in livestock Consumer risk assessment Conclusions and recommendations References Appendices A. Good Agricultural Practice (GAPs) B. Pesticide Residues Intake Model (PRIMo ) C. Existing EU maximum residue levels (MRLs) D. List of metabolites and related structural formula Abbreviations EFSA Journal 2012;10(12):3008 4

5 BACKGROUND Regulation (EC) No 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) No 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. Spain, hereafter referred to as the evaluating Member State (EMS), received an application from the company Nissan Chemical Europe 6 to modify the existing MRLs for the active substance quizalofop- P-ethyl in oilseed rape, sunflower, cotton and soybean. This application was notified to the European Commission and EFSA, and was subsequently evaluated by the EMS in accordance with Article 8 of the Regulation. After completion, the evaluation report was submitted to the European Commission who forwarded the application, the evaluation report and the supporting dossier to EFSA on 13 September The application was included in the EFSA Register of Questions with the reference number EFSA-Q and the following subject: Quizalofop-P Application to modify the existing MRLs in oilseeds Spain proposed to raise the existing MRLs of quizalofop-p in cotton and soybean from the limit of quantification of 0.1* mg/kg to 0.3 mg/kg. On 20 April 2012 some data requirements were identified, which prevented EFSA to conclude on the consumer risk assessment. An updated evaluation report addressing these data requirements was submitted by the EMS on 21 September 2012 and taken into consideration by EFSA for finalization of this reasoned opinion. EFSA proceeded with the assessment of the application and the evaluation report as required by Article 10 of the Regulation. TERMS OF REFERENCE In accordance with Article 10 of Regulation (EC) No 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 initial deadline for providing the reasoned opinion (13 December 2011) was suspended until the updated evaluation report was provided by the EMS on 21 September Regulation (EC) No 396/2005 of the Parliament and of the Council of 23 February OJ L 70, , p Council Directive 91/414/EEC of 15 July OJ L 230, , p Regulation (EC) No 1107/2009 of the European Parliament and of the Council of 21 October OJ L 309, , p Nissan Chemical Europe S.A.R.L./FR, Parc d`affaires de Crecy, 2 rue Claude Chappe, 69370, St Didier au Mont d'or, France EFSA Journal 2012;10(12):3008 5

6 THE ACTIVE SUBSTANCE AND ITS USE PATTERN Quizalofop is the ISO common name for the racemate (RS)-2-[4-(6-chloroquinoxalin-2-yloxy) phenoxy]propionic acid (IUPAC). Quizalofop-P is the ISO common name for the R-enantiomer (R)-2- [4-(6-chloroquinoxalin-2-yloxy)phenoxy]propionic acid (IUPAC). Different ester variants of quizalofop-p, presented in the table below, are used in plant protection products. Variant of the active substance Common name Molecular weight Acid Quizalofop-P Chemical structure Ethyl-ester Quizalofop-P-ethyl Tefuryl-ester Quizalofop-P-tefuryl Isopropylideneamino ester Propaquizafop The current application refers to the uses of the ethyl ester variant (quizalofop-p-ethyl) on oilseeds. Quizalofop-P-ethyl belongs to the class of aryloxyphenoxypropionic herbicides, commonly called "fops". It is used as a post-emergence herbicide to control annual and perennial grasses in dicotyledonous crops. It is taken up by plants via both root and foliage and is translocated in the xylem and phloem and accumulates in the meristematic tissues. It acts by inhibiting the fatty acid biosynthesis by the acetyl-coa carboxylase, which is the first enzyme of the fatty acid biosynthesis. Quizalofop-P-ethyl was evaluated in the framework of Council Directive 91/414/EEC with Finland designated as rapporteur Member State (RMS). It was included in Annex I of this Directive by Directive 2009/37/EC 7 which entered into force on 1 st December 2009 for use as herbicide only. In accordance with Commission Implementing Regulation (EU) No 540/ quizalofop-p-ethyl is approved under Regulation (EC) No 1107/2009, repealing Council Directive 91/414/EEC. The representative use evaluated in the peer review and supported by the applicant was foliar application on sugar beet in northern and southern EU. The Draft Assessment Report (DAR) of quizalofop-p-ethyl has been peer reviewed by EFSA (EFSA, 2008a). 7 Commission Directive 2009/37/EC of 23 April OJ L 104, , p Commission Implementing Regulation (EU) No 540/2011 of 23 May OJ L 153, , p EFSA Journal 2012;10(12):3008 6

7 EU MRLs have been established for "quizalofop (including quizalofop-p)" in Annexe IIIA of Regulation (EC) No 396/2005 (see Appendix C). These EU MRLs cover the uses of quizalofop-pethyl and quizalofop-p-tefuryl, as the residue for enforcement has been defined as "quizalofop (including quizalofop-p)" for both ester variants under Regulation (EC) No 396/2005. The existing EU MRL for rapeseed is set at 0.5 mg/kg; for the other oilseeds under consideration (i.e. sunflower seed, cotton seed and soybeans) the MRL is set at the LOQ of 0.1* mg/kg 9. The MRL review in the framework of Article 12 of Regulation 396/2005 is in an early stage. In addition, separate MRLs are established for propaquizafop (sunflower seed: 0.2 mg/kg, rape seed and cotton seed: 0.1 mg/kg and 0.05* for soya bean), the residues being expressed as propaquizafop, although this active substance is also an ester variant of quizalofop. Quizalofop-P has not been evaluated by the JMPR and consequently, no CXLs have been established. The details of the intended GAPs for quizalofop-p-ethyl on oilseed rape, sunflower, cotton and soybean are given in Appendix A. 9 It is noted that MRL proposals for sunflower and cotton seeds (0.7 and 0.15 mg/kg respectively) derived by EFSA in a previous reasoned opinion (EFSA, 2010) are not yet implemented in an MRL Regulation so far. EFSA Journal 2012;10(12):3008 7

8 ASSESSMENT EFSA bases its assessment on the evaluation report submitted by the EMS (Spain, 2011), the Draft Assessment Reports (DAR) (and their addenda) prepared under Council Directive 91/414/EEC for the active substances quizalofop-p-ethyl (Finland, 2007a), quizalofop-p-tefuryl (Finland, 2007b) and propaquizafop (Italy, 2005), the Commission Review Report on quizalofop-p (EC, 2010c), the conclusion on the peer review of the pesticide risk assessment of the active substance quizalofop-p and propaquizafop (EFSA, 2008a, 2008b), as well as the conclusions from a previous EFSA opinion on quizalofop-p (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 Commission Regulation (EU) No 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; OECD, 2011). 1. Method of analysis 1.1. Methods for enforcement of residues in food of plant origin Analytical methods for the determination of quizalofop-p-ethyl residues in plant commodities were assessed in the DAR and during the peer review under Directive 91/414/EEC (Finland, 2007a; EFSA, 2008a) but validation data were provided for high water content matrices only. Moreover, for the provisional residue definition derived during the peer review (sum of quizalofop-esters, quizalofop and quizalofop conjugates, expressed as quizalofop (sum of isomers)) it was concluded that no validated analytical method for food and feed of plant origin is available (EFSA, 2008a). In the framework of this MRL application, the applicant proposes for enforcement purposes, the GC/NPD method referenced AN34 where quizalofop-p-ethyl and quizalofop-p (acid) residues are converted and quantified as quizalofop-p-methyl ester. This method involves an extraction with acetone:water (7:3, v:v) followed by a liquid partition of the acidified extract with ethyl acetate prior alkali hydrolysis to convert all residues to quizalofop-p. After clean up on SPE cartridge, the extract is methylated using trimethylsilyl-diazomethane to the common moiety quizalofop-p-methyl. An additional SPE clean-up is done prior to quantification by gas chromatography with nitrogen phosphorus detection (GC-NPD). The Method AN34 has been validated for quizalofop-p-ethyl and quizalofop-p in sunflower seeds achieving a LOQ of mg/kg. This method was reported by the applicant to cover quizalofop-p-ethyl and quizalofop-p including its conjugates but no validation data were provided to demonstrate that the hydrolysis step is efficient to release the conjugates. As ILV, the applicant proposed to consider the validation conducted on sugar beet and sunflower with the analytical method AN39, similar to AN34. As concluded by the EMS, EFSA agrees that the analytical method AN34 can be considered as sufficiently validated to enforce quizalofop-p and quizalofop-p-ethyl residues in high oil content matrices. However, the method AN34 is an outdated method, involving a methylation step using trimethylsilyl-diazomethane to allow the quantification of the residues by gas chromatography, technique no longer in use in laboratories for routine analyses, since more appropriate approaches are nowadays available. Considering that Nissan Chemical Europe has reported a LC-MS/MS method (AN41) to analyse the samples from the residues trials conducted on sunflower and rapeseed from 2007 and corresponding to the current routine analytical standards, EFSA is of the opinion that the applicant should develop and provide the full validation data, including ILV, for such an analytical method. 10 Commission Regulation (EU) No 546/2011 of 10 June OJ L 155, , p EFSA Journal 2012;10(12):3008 8

9 The standard multi-residue methods (QuEChERS, DFG S19) are not appropriate to analyse both, quizalofop-p-ethyl and quizalofop-p in high oil content matrices Methods for enforcement of residues in food of animal origin Analytical methods for the determination of residues in food of animal origin are not assessed in the current application, since the uses of quizalofop-p-ethyl on the oilseed crops supported in the framework of this MRL application have no impact on the overall animal intakes (see section 3.2). 2. Mammalian toxicology The toxicological profile of the different quizalofop-p ester variants was assessed in the framework of the peer review under Directive 91/414/EEC (EFSA, 2008a&b). The data were sufficient to derive toxicological reference values which are compiled in Table 2.1 below. Table 2-1: Overview of the toxicological reference values Quizalofop-P-ethyl Source Year Value Study relied upon Safety factor ADI EFSA mg/kg bw per day 2-year rat 100 ARfD EFSA 2008 Not necessary Quizalofop-P-tefuryl ADI EFSA mg/kg bw per day 2-year rat 100 ARfD EFSA mg/kg bw Rat developmental 100 Propaquizafop (isopropylideneamino ester variant) ADI EFSA mg/kg bw per day 2-year mouse 100 ARfD EFSA 2008 Not necessary It was stated in the conclusion of the peer review under Directive 91/414/EEC (EFSA, 2008a), that the lowest toxicological value has to be taken into account for the dietary consumer risk assessment. Considering that residue levels and MRLs were expressed on the acid form basis (as quizalofop-p), the lowest ADI of mg/kg bw per day has been corrected with the respective molecular weights in order to be expressed as quizalofop-p. Thus, the value of mg/kg bw per day was used to perform the chronic consumer risk assessment. Quizalofop esters have not been reviewed by the JMPR and therefore, no ADI and ARfD have been established at Codex level. EFSA Journal 2012;10(12):3008 9

10 3. Residues 3.1. Nature and magnitude of residues in plant Primary crops Nature of residues The metabolism of quizalofop-p-ethyl in primary crops was evaluated by the RMS (Finland, 2007) and reviewed by EFSA (EFSA, 2008a) in the framework of the peer review under Directive 91/414/EEC. The overview of the metabolism study designs is presented in the table below. Table 3-1: Summary of available metabolism studies in plants Group Root and tuber vegetables Pulses and oilseeds Crop Sugar beet 14 C label position phenyl & quinoxaline Rate g a.s./ha Application details No Sampling Remarks , 60 and 90 DAT Phenyl DAT Potato Phenyl DAT Cotton Soybean phenyl & quinoxaline phenyl & quinoxaline phenyl & quinoxaline quinoxaline , 7, 21 and 42 DAT , 7, 21 and 42 DAT , 7, 14, 29 and 63 DAT 340 (R/S) 160 (R & S) 1 1, 14 and 105 DAT R enantiomer racemate (R/S). Informative only considering the low application rate racemate (R/S) Racemate (R/S) Racemate (R/S) and R enantiomer Racemate (R/S) and R and S enantiomers All studies were conducted with a single application on plants grown under greenhouse conditions and using the racemate (R/S) quizalofop or the R enantiomer (quizalofop-p). In addition, in order to investigate the fate of the different isomers in plant, a study on soybean was conducted using the racemate and the S and R enantiomers, respectively. Due to the very low application rate (ca. 6 g a.s./ha) the studies on sugar beet and potato were considered as informative only. After application, the ester quizalofop-p-ethyl was detected in cotton leaves, sugar beet leaves and soya straw, accounting for 5% to 20% TRR, but was almost not observed at harvest in sugar beet root and soya bean. In contrast, the acid form quizalofop-p, was always present at harvest, accounting for 3% to ca. 20% TRR in foliage and straw and up to 14% TRR in sugar beet root (0.006 mg/kg) and 21% TRR in soya beans (0.03 mg/kg). Based on these data and the information provided by the studies conducted with the two other ester variants (Finland, 2007b; Italy, 2005), the conclusion of the peer review was that the metabolism of all quizalofop esters proceeds in a similar way, starting by the hydrolysis of the ester link to yield the acid form quizalofop, followed by the loss of the propionyl chain leading to the quizalofop-phenol metabolite. Further metabolism occurs by hydroxylation of the quinoxaline moiety giving the hydroxy-quizalofop and hydroxy-quizalofop-phenol metabolites. In addition, the presence of quinoxaline and phenoxy metabolites indicates a cleavage of the parent molecule at the oxygen bound (EFSA, 2008a, 2008b). EFSA Journal 2012;10(12):

11 Finally, as conclusion of the discussions of the expert meeting on residues of July 2008 and pending the submission of further information and clarifications regarding the toxicological relevance of the phenoxy-propionate and hydroxy-quizalofop-phenol metabolites, the following provisional residue definitions for monitoring and risk assessment were proposed for all quizalofop esters: - sum of quizalofop-esters, quizalofop and quizalofop conjugates, expressed as quizalofop (sum of isomers). Following the expert meeting and considering that conjugates were mainly detected in soya (tefuryl variant study) and in cotton (ethyl variant study) on immature plants and shortly after application (7 to 21 days), EFSA proposed in its conclusion not to include the conjugates in the residue definitions, since they were no longer identified in mature plants at harvest. However, this residue definition was derived for the representative crop assessed under the peer review and should be reconsidered in the framework the MRL review under Article 12, taking into account the actual GAPs authorised for these active substances. The current enforcement residue definition in Annex IIIA of Regulation (EC) No 396/2005 is set as quizalofop (including quizalofop-p), and does not comprise the esters or conjugates. For risk assessment, the provisional residue definition derived in the peer review should be applied Magnitude of residues Different analytical methods, summarized in the table 3-2 below, were used to generate the results from the different residue trials. Quizalofop-P-ethyl residues were analysed for either as quizalofop-p (acid) and quizalofop-p-ethyl separately, or for the total residues (sum quizalofop-p-ethyl and quizalofop-p) following conversion to a common moiety. These different analytical methods were also reported by the applicant to consider the conjugates, but no data were provided to confirm that conjugates are effectively released and taken into account by these methods. Table 3-2: Summary of the analytical methods used to generate the results of the residue trials. Analytical method LOQ Trials Year Residues analysed and quantified as: Reference type (mg/kg) (final values expressed as ethyl ester equivalent) AN30 GC-ECD 0.10 a 0.04 a Rapeseed Sunflower quizalofop-p-ethyl quantified as quizalofop- P-methyl ester and separately - quizalofop-p and conjugates quantified as quizalofop-p-methyl ester AN33 GC-NPD Sunflower quizalofop-p-ethyl, quizalofop-p and conjugates quantified all together as quizalofop-p-methyl ester AN41 LC-MS/MS 0.01 Rapeseed quizalofop-p-ethyl, quizalofop-p and 0.01 Sunflower 2007 conjugates quantified all together as quizalofop-p a : LOQ for the sum quizalofop-p and quizalofop-p-ethyl These analytical methods can be considered as sufficiently validated for preregistration purposes. However, the LOQ of 0.10 mg/kg achieved by the method AN30 is not fully appropriate to follow the residues in oilseed rape, since the latter trials using a more efficient method (AN41) have shown the residues in seeds to be mostly in the range of 0.03 to 0.08 mg/kg. It is highlighted that these analytical methods cover more components than the current residue definition for enforcement stated under Regulation (EC) No 396/2005 and defined as quizalofop (including quizalofop-p), since the ethyl ester form and, according to the applicant, the conjugates are also covered by these methods. EFSA Journal 2012;10(12):

12 Nevertheless, provisional MRLs were derived from the submitted residue trials, having in mind that they are overestimating the residue concentrations expected for the acid form only. However, with regard to the risk assessment, the values derived from these residue trials (HR and STMR) are considered to be in compliance with the residue definition for risk assessment proposed by the peer review and defined as "sum of quizalofop-esters, quizalofop and quizalofop conjugates expressed as quizalofop (sum of isomers)". The lack of validation for the conjugates is of low relevance since according to the metabolism studies, conjugates are not expected to be present in mature crops with long PHI. The results of the trials assessed are summarised in Table 3-3; they have all been recalculated to be expressed as quizalofop (acid) equivalent. a. Oilseed rape (cgap: 1x 150 g/ha, PHI 90 days in NEU and SEU, up to BBCH 65) For northern EU, the applicant provided 11 residue trials. However, two of them conducted in 1990 have to be disregarded, as the application was done at a very early growth stage (BBCH 16 and 38) which cannot be considered representative of an application at BBCH 65 (full flowering, older petals falling) as required in the cgap. The remaining trials can be considered appropriate to derive a MRL proposal of 0.3 mg/kg for rape seed. However, it should be highlighted that most of these trials were conducted with an application at an earlier growth stage (BBCH 50 to 55) than the latest growth stage supported in the cgap (BBCH 65). This could lead to a slight underestimation of the residue levels. Four trials were provided to support the use of quizalofop-p-ethyl in southern EU, all conducted in compliance with the cgap, using an application rate of 143 to 164 g a.s./ha and a PHI of 90 to 103 days. As oilseed rape is defined as a minor crop in southern EU, these four trials are sufficient to derive a MRL proposal of 0.2 mg/kg. It is noted that the MRL proposal of 0.3 mg/kg is lower than the current EU MRL of 0.5 mg/kg for rape seed. b. Sunflower (cgap: 1x 150 g/ha, PHI 90 days NEU and 45 days SEU, up to BBCH 71) For northern EU, 6 residue trials were submitted. However, three of them were conducted with an exaggerated dose rate of 300 g a.s./ha and with an application at a very early stage (BBCH 18 to 19; 8 to 9 unfolded leaves) which cannot be considered as representative of an application at stage BBCH 71 as proposed under the cgap. EFSA is therefore of the opinion that these trials have to be disregarded. The three other northern trials conducted with an application rate of 146 to 153 g a.s./ha and a pre harvest interval of 74 to 75 days, are considered as valid, but no MRL is proposed as a total of four trials is required to derive a MRL in northern EU. The eight southern trials performed with a single application at 149 to 160 g/ha and PHIs of 44 to 46 days are considered as valid according to the southern GAP, leading to a MRL proposal of 0.4 mg/kg. Although the PHIs in the northern and southern trials were in compliance with the requested PHIs of 45 and 90 days considering the 25% tolerance, it should be highlighted that only one trial was conducted with a treatment at the critical BBCH stage 71 (seeds on outer edge grey and at final size), while the other applications were done at an earlier growth stage (BBCH 59 to 65; beginning to full flowering). No MRL is proposed for sunflower in northern EU as one trial is missing. In southern EU, the submitted data set leads to a proposal of 0.4 mg/kg. EFSA notes that the MRL proposed in a previous reasoned opinion reflecting the use quizalofop-p-tefuryl in sunflower was 0.7 mg/kg (EFSA, 2010). This proposal has not yet been voted by the Standing Committee on the Food Chain and Animal Health (SCFCAH). EFSA Journal 2012;10(12):

13 The stability of quizalofop-p-ethyl and quizalofop-p in primary crops was investigated in the DAR under Directive 91/414/EEC (Finland, 2007), but on high water content matrices only (sugar beet) and residues were found to be stable for at least 16 months when stored at ca. -20 C. Stability data in various oily matrices (cotton seed, cotton oil, cotton meal, rape seed and snap bean pods) were therefore provided and evaluated by the EMS in the framework of this MRL application. Quizalofop- P-ethyl and quizalofop-p (acid) where shown to be stable up to 28 months in high oil content matrices. The EMS suggests to require additional validation data for the analytical method AMR used to analyse the samples in this stability study. However, numerous concurrent recoveries were performed on different oily matrices in the course of this study, showing acceptable recoveries at the different investigated levels, as summarized below: Mean RSD n Fortification levels - Quizalofop-P-ethyl: 91 % 13 % mg/kg (storage level) - Quizalofop-P (acid): 94 % 15 % , and 0.47 mg/kg (storage levels) Based on these results, EFSA is of the opinion that enough information is available to confirm that the analytical method AMR was sufficiently validated to investigate the stability of quizalofop-p and quizalofop-p-ethyl residues in oily matrices and therefore, that additional validation data have not to be requested. As the samples from the supervised residue trials were stored frozen 4 to 15 months at ca -20 C prior analysis, length of storage covered by the stability study results showing quizalofop residues to be stable up to 28 months, it is concluded that the residue data are valid with regard to storage stability. The results of the residue trials, the related risk assessment input values (highest residue, median residue) and the MRL proposals are summarised in Table 3-3, all values being expressed as quizalofop-p (acid) equivalent. The MRL proposals of 0.3 mg/kg for rape seed and 0.4 mg/kg for sunflower derived from the residue trials conducted according to the cgap defined for quizalofop-p-ethyl are already covered by the existing MRLs listed under Regulation (EC) No 396/2005 or by the proposals done by EFSA to accommodate the use of the tefuryl ester variant (EFSA, 2010). Therefore, EFSA concludes that the intended uses of quizalofop-p-ethyl on oilseed rape and sunflower do not necessitate any changes in the MRLs already published or being to be published. The applicant proposed to extrapolate the MRL proposals for rape seed and sunflower seed to cotton and soybean. As the GAPs defined for sunflower, cotton and soybean refer to an application up to growth stages where the consumable part of the crops has started to form (BBCH 71; 10% seeds/pods at final size to BBCH 76; 60% bolls at final size), the extrapolation is not acceptable according to the EU guidance document (EC, 2011). Moreover; - the data set for sunflower in not complete as one additional trial in northern EU is required, - different GAPs are supported for the different crops, with application up to BBCH growth stages 65, 71 or Most of the residue trials provided for oilseed rape and sunflower were conducted with an application before flowering or at the early flowering, while application is requested at a later stage, when the consumable part of the crop (pods, bolls) has started to be formed. Therefore EFSA does not recommend the extrapolation of the MRLs proposed for rape seed and sunflower to cotton and soybean. EFSA Journal 2012;10(12):

14 Table 3-3: Overview of the available residues trials data Commodity Residue region (a) Outdoor /Indoor Individual trial results (mg/kg) Enforcement (+) Risk assessment Median residue (mg/kg) (b) Highest residue (mg/kg) (c) MRL proposal (mg/kg) Median CF (d) Comments (e) Enforcement residue definition: quizalofop (including quizalofop-p) Risk assessment residue definition: quizalofop-esters, quizalofop and quizalofop conjugates, expressed as quizalofop Oilseed rape NEU Outdoor (PHI 90d) SEU Outdoor (PHI 90d) Sunflower NEU Outdoor (PHI 90d) SEU Outdoor (PHI 45d) 0.018; 0.028; 0.074; 5x <0.10 (f) ; <0.01, 0.028; 0.065; ; 0.028; 0.074; 5x <0.10 (f) ; <0.01, 0.028; 0.065; R ber = 0.19 R max = 0.21 MRL OECD = 0.23/ R ber = 0.14 R max = 0.20 MRL OECD = 0.17/ ; 0.148; ; 0.148; Insufficient number of trials to derive MRL proposal ; 0.074; 0.083; 0.092; 0.111; 0.120; 0.176; ; 0.074; 0.083; 0.092; 0.111; 0.120; 0.176; R ber = 0.32 R max = 0.28 MRL OECD = 0.33/0.40 (+): The samples were analysed with analytical methods which take into account quizalofop-p and quizalofop-p-ethyl and, according to the applicant, also quizalofop-conjugates. However, no validation data are available to estimate whether the conjugates are covered quantitatively. Thus, the results are likely to overestimate the residues for the acid (i.e. current enforcement residue definition), but are acceptable for the risk assessment residue definition. (a): NEU (Northern and Central Europe), SEU (Southern Europe and Mediterranean), EU (i.e. outdoor use) or Import (country code) (EC, 2011). (b): Median value of the individual trial results according to the enforcement residue definition. (c): Highest value of the individual trial results according to the enforcement residue definition. (d): The median conversion factor for enforcement to risk assessment is obtained by calculating the median of the individual conversion factors for each residue trial. (e): Statistical estimation of MRLs according to the EU methodology (R ber, R max ; EC, 1997g) and unrounded/rounded values according to the OECD methodology (OECD, 2011). (f): Calculated LOQ mg/kg when expressed as quizalofop-p, rounded to 0.10 mg/kg EFSA Journal 2012;10(12):

15 Effect of industrial processing and/or household preparation Modification of the existing MRLs for quizalofop-p in oilseeds Standard hydrolysis studies on the nature of the residues in processed commodities were not provided in the DAR prepared under Directive 91/414/EEC (Finland, 2007), as residues in sugar beet roots were shown to be below the LOQ. However, taking into account the overall consumer exposure which exceeds the trigger value of 10% of the ADI, studies investigating the nature of residues in processed food should be provided. One processing study on sunflower was provided in support of this MRL application and evaluated by the EMS. Sunflower seeds collected in plots treated at an exaggerated dose rate were processed to meal cake and refined oil. Total residues (quizalofop-p-ethyl and quizalofop-p) were 2.45 mg/kg in seeds (RAC), 2.87 mg/kg in meal cake and <0.05 mg/kg in refined oil respectively, leading to processing factors of 1.17 and <0.02 as summarized in the table 3-4 below. Table 3-4: Overview of the available processing studies Processed commodity Number of studies Processing Factor (PF) Conversion Factor (CF) Comments Enforcement residue definition: quizalofop-p-ethyl and quizalofop-p Sunflower meal Sunflower Oil (refined) 1 <0.02 As only one processing study is available, EFSA does not recommend the inclusion of the derived processing factors in Annex VI of Regulation (EC) No 396/ Rotational crops Oilseeds can be grown in rotation with other plants and therefore the possible occurrence of residues in succeeding crops resulting from the use on primary crops has to be assessed. The environmental fate of quizalofop-p-ethyl was investigated together with two other ester variants quizalofop-p-tefuryl and propaquizafop in the DARs prepared under Directive 91/414/EEC (Finland, 2007a, 2007b and Italy 2005) and in the conclusion of the peer review (EFSA 2008a, 2008b). The initial degradation reaction, common to all ester variants, starts with a rapid hydrolysis of the ester bound, leading to quizalofop (acid) (maximum DT 90lab for esters: 3.5 days). Once quizalofop formed, the route of degradation was seen to be similar for all three esters and the major components in rotational crops identified as quizalofop, hydroxy-quizalofop and dihydroxy-quinoxaline. Confined rotational crops studies were conducted with the three different ester variants at dose rates of 250 g/ha (tefuryl ester) to 308 g/ha (ethyl ester) and globally, the TTRs in the different plant parts investigated were limited. It was therefore concluded that no residues of quizalofop and its metabolites are expected to be present in rotational crops. Since the application rate of 150 g/ha on oilseeds supported in the framework of this MRL application is in the range of the dose rates investigated in the different rotational crop studies, EFSA concludes that quizalofop residues are not expected to occur in rotational crops when quizalofop-p-ethyl is applied on oilseeds according to the proposed GAPs Nature and magnitude of residues in livestock Since the use of quizalofop-p-ethyl on oilseed rape and sunflower results in lower MRL proposals than the values already published under Regulation (EC) No 396/2005 or than the proposals made in a previous MRL application (EFSA, 2010), no change in the overall animal burden is expected and therefore, the residues in livestock were not considered in the framework of this MRL application. EFSA Journal 2012;10(12):

16 4. Consumer risk assessment Modification of the existing MRLs for quizalofop-p in oilseeds The consumer risk assessment was performed with revision 2 of the EFSA Pesticide Residues Intake Model (PRIMo). This exposure assessment model contains the relevant European food consumption data for different sub-groups of the EU population 11 (EFSA, 2007). To perform a complete dietary consumer risk assessment for quizalofop-p-ethyl, detailed information on all critical authorised GAPs for all crops and the results of supervised field residue trials reported in compliance with the residue definition for risk assessment would be required. In addition, in a comprehensive consumer risk assessment, the different active substances that contribute to the same residue would have to be considered (i.e. the different ester variants of quizalofop). Currently, this information is not available and therefore, EFSA performed the calculation of chronic exposure using the current MRLs established in Regulation (EC) No. 396/2005 and listed hereafter in Appendix C. For sunflower and cotton seed, the MRL proposals of 0.7 mg/kg and 0.15 mg/kg made in a previous EFSA reasoned opinion related to the ester variant quizalofop-p-tefuryl (EFSA, 2010) were used as input values. The model assumptions for the long-term exposure assessment are considered to be sufficiently conservative for a first tier exposure assessment, assuming that all food items consumed contain residues at the MRL. In reality, it is not likely that all food consumed will contain residues at these high concentrations. However, if the first tier exposure assessment does not exceed the toxicological reference value for long-term exposure (i.e. the ADI), a consumer health risk can be excluded with a high probability. Table 4-1. Input values for the indicative consumer exposure assessment Commodity Input value (mg/kg) Chronic risk assessment Comment Provisional proposed risk assessment residue definition: Sum of quizalofop-esters, quizalofop and quizalofop conjugates expressed as quizalofop (sum of isomers) (EFSA, 2008) Cotton seed 0.15 MRL proposal (EFSA, 2010) Sunflower seed 0.7 MRL proposal (EFSA, 2010) Rape seed 0.5 Existing MRL Other food commodities MRL See Appendix C No long-term consumer intake concerns were identified for any of the European diets incorporated in the EFSA PRIMo. The total calculated intake values accounted for up to 90 % of the ADI (WHO Cluster B). The contribution of residues in rape seed and sunflower to the total consumer exposure is limited to a maximum of 6 % of the ADI (WHO Cluster B). The results of the intake calculation are presented in Appendix B to this reasoned opinion. No acute exposure assessment was performed as the setting of an ARfD was considered not necessary for quizalofop-p-ethyl following the peer review (EFSA, 2008a). EFSA concludes that the intended use of quizalofop-p-ethyl on oilseed rape and sunflower will not result in a consumer exposure exceeding the toxicological reference value and therefore is unlikely to pose a public health concern. 11 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 2012;10(12):

17 CONCLUSIONS AND RECOMMENDATIONS CONCLUSIONS The toxicological profile of quizalofop-p-ethyl was assessed in the framework of the peer review under Directive 91/414/EEC and the data were sufficient to propose an ADI of mg/kg bw per day ( mg/kg bw per day when expressed as quizalofop-p equivalent). No ARfD was deemed necessary. The metabolism of quizalofop-p-ethyl in primary crops was investigated in sugar beet (root vegetables), cotton and soybean (pulses/oilseeds group). From these data and from the additional studies conducted with the other ester variants, the peer review concluded to establish a general residue definition for the different quizalofop-p esters as "sum of quizalofop-esters, quizalofop and quizalofop conjugates, expressed as quizalofop (sum of isomers)" both, for enforcement and risk assessment. Therefore EFSA concludes that the metabolism in primary crops was sufficiently addressed to support the use of quizalofop-p-ethyl on oilseeds. The enforcement residue definition established in Regulation (EC) No 396/ is set as quizalofop (including quizalofop-p). The submitted residue trials conducted with quizalofop-p-ethyl according to the intended GAPs lead to MRL proposals of 0.3 mg/kg for oilseed rape and 0.4 mg/kg for sunflower. These MRL proposals refer to the wider residue definition derived in the peer review. However, on a provisional basis these MRLs can be included in the current residue definition, noting that the MRLs are slightly overestimating the expected residues for quizalofop since also the esters and conjugates are covered by the MRLs. EFSA notes that the existing MRL for rape seed is 0.5 mg/kg; thus, the uses of quizalofop- P-ethyl on oilseed rape according to the intended GAPs do not necessitate a change to the existing EU. For sunflower seed the proposed MRL is lower than the MRL proposal of 0.7 mg/kg derived in a previous MRL assessment related to the ester variant quizalofop-p-tefuryl; this MRL proposal has not yet been taken over in EU legislation. The extrapolation of the MRL proposals derived in this assessment to cotton and soybean is not recommended by EFSA, since not in line with the extrapolation rules defined in the current EU guidelines. A validated analytical enforcement method referenced AN34 to control the residues of quizalofop-pethyl in high oil content matrices has been submitted. This method is however an outdated method using techniques no longer in use in laboratories for routine analyses, as more appropriate approaches are nowadays available. Considering that a LC-MS/MS method (AN41) corresponding to the current routine analytical standards has been recently developed by the applicant to analyse the samples from the residues trials performed from 2007, EFSA is of the opinion that full validation data including ILV, have to be requested for such an analytical method. Studies investigating the nature of quizalofop-p-ethyl residues in processed commodities are not available. Taking into account the overall consumer exposure which exceeds the trigger value of 10% of the ADI, studies investigating the nature of residues in processed food should be provided. One processing study on sunflower was submitted, providing some evidence that the residues in refined sunflower seed oil are significantly reduced. However, EFSA does not recommend the inclusion of the processing factors derived for sunflower meal and sunflower oil in Annex VI of Regulation (EC) No 396/2005, as based on one study only. The occurrence of quizalofop-p-ethyl residues in rotational crops was investigated in the framework of the peer review. Based on the available information on the nature and magnitude of residues in succeeding crops, it was concluded that significant residue levels are unlikely to occur in rotational crops, provided that the compound is used on oilseeds according to the proposed GAPs. Residues in commodities of animal origin were not assessed in the framework of this application, since the supported uses of quizalofop-p-ethyl on oilseed crops do not result in changes to the existing EFSA Journal 2012;10(12):