Reasoned opinion on the review of the existing maximum residue levels (MRLs) for metazachlor according to Article 12 of Regulation (EC) No 396/2005 1

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1 EFSA Journal 2014;12(4):3634 REASED PII Reasoned opinion on the review of the existing maximum residue levels (MRLs) for metazachlor according to Article 12 of Regulation (EC) o 396/ European Food Safety Authority 2, 3 European Food Safety Authority (EFSA), Parma, Italy This reasoned opinion, published on 20 June 2014, replaces the earlier version published on 07 April 2014* ABSTRACT According to Article 12 of Regulation (EC) o 396/2005, the European Food Safety Authority (EFSA) has reviewed the Maximum Residue Levels (MRLs) currently established at European level for the pesticide active substance metazachlor. In order to assess the occurrence of metazachlor residues in plants, processed commodities, rotational crops and livestock, EFSA considered the conclusions derived in the framework of Directive 91/414/EEC as well as the European authorisations reported by Member States (incl. the supporting residues data). Based on the assessment of the available data, MRL proposals were derived and a consumer risk assessment was carried out. Although no apparent risk to consumers was identified, some information required by the regulatory framework was found to be missing. Hence, the consumer risk assessment is considered indicative only and some MRL proposals derived by EFSA still require further consideration by risk managers. European Food Safety Authority, 2014 KEY WRDS metazachlor, MRL review, Regulation (EC) o 396/2005, consumer risk assessment, chloroacetanilide, herbicide 1 n request from EFSA, Question o EFSA-Q , approved on 01 April Correspondence: pesticides.mrl@efsa.europa.eu 3 Acknowledgement: EFSA wishes to thank the rapporteur Member State the United Kingdom for the preparatory work on this scientific output. * Minor changes of editorial nature were made. The changes do not affect the contents of this report. To avoid confusion, the original version of the opinion has been removed from the website, but is available on request, as is a version showing all the changes made. Suggested citation: European Food Safety Authority, Reasoned opinion on the review of the existing maximum residue levels (MRLs) for metazachlor according to Article 12 of Regulation (EC) o 396/2005. EFSA Journal 2014;12(4):3634, 51 pp. doi: /j.efsa Available online: European Food Safety Authority, 2014

2 SUMMARY Metazachlor was included in Annex I to Directive 91/414/EEC on 01 August 2009, which is after the entry into force of Regulation (EC) o 396/2005 on 02 September EFSA is therefore required to provide a reasoned opinion on the review of the existing MRLs for that active substance in compliance with Article 12(1) of the aforementioned regulation. In order to collect the relevant pesticide residues data, EFSA asked the United Kingdom, as the designated rapporteur Member State (RMS), to complete the Pesticide Residues verview File (PRFile) and to prepare a supporting evaluation report. The requested information was submitted to EFSA on 18 January 2011 and, after having considered several comments made by EFSA, the RMS provided on 18 December 2012 a revised PRFile. Based on the conclusions derived by EFSA in the framework of Directive 91/414/EEC and the additional information provided by the RMS, EFSA issued on 14 ctober 2013 a draft reasoned opinion that was circulated to Member States experts for consultation. Comments received by 13 December 2013 were considered in the finalisation of this reasoned opinion. The following conclusions are derived. The toxicological profile of metazachlor was evaluated in the framework of Directive 91/414/EEC, which resulted in an ADI and an ARfD being established at 0.08 mg/kg bw per d and 0.5 mg/kg bw, respectively. Primary crop metabolism of metazachlor was investigated in cereals, pulses and oilseeds and leafy vegetables following soil or foliar application. Based on these studies, EFSA proposes to define the residue for risk assessment in plants as the sum of metazachlor and its metabolites containing the 2,6-dimethylaniline moiety, expressed as metazachlor. For enforcement purposes the major metabolites 479M04, 479M08 and 479M16 are deemed to be sufficient markers. Validated analytical methods for enforcement of this residue definition are available. Regarding the magnitude of residues, the available data were sufficient to derive tentative MRLs for all commodities under evaluation, except for oranges, lemons, tree nuts, pome fruits, stone fruits, berries and small fruits, potatoes, rocket and asparagus where residues data were insufficient to derive MRLs and risk assessment values and for garlic, Brussels sprouts, globe artichokes, leek and oilseeds, where data were sufficient to derive appropriate MRLs and risk assessment values. The effect of industrial and/or household processing on the nature of metazachlor residues was investigated. Pasteurisation, baking/brewing/boiling and sterilisation are not expected to have a significant impact on the composition of residues in matrices of plant origin. Further processing studies are not required as they are not expected to affect the outcome of the risk assessment. However, if more robust processing factors were to be required by risk managers, in particular for enforcement purposes, additional processing studies would be needed. The potential incorporation of soil residues into succeeding and rotational crops was investigated in leafy vegetables, root and tuber vegetables and cereals during the peer review and the residue definition set for the primary crops also applies to the rotational crops. Magnitude of residues in succeeding and rotational crops was also investigated. Significant residues were recovered in straw from cereal grown in rotation; however these residues are not expected to impact MRLs for plant and animal products, provided that metazachlor is applied in compliance with the GAPs supported in the framework of this review. Based on the uses reported by the RMS, significant intakes were calculated for poultry, ruminants and pigs. Metabolism of metazachlor in lactating ruminants was shown to be extensive. The general metabolic pathways in rodents and ruminants were found to be comparable and the findings in ruminants can therefore be extrapolated to pigs. Metabolism in poultry was also investigated and it was demonstrated that no significant residues (i.e. above 0.01 mg/kg) are expected in eggs or tissues at EFSA Journal 2014;12(4):3634 2

3 the maximum dietary burden. Therefore, EFSA concludes that the residue definition proposed for monitoring and risk assessment in animal commodities should be the sum of metazachlor and its metabolites containing the 2,6-dimethylaniline moiety, expressed as metazachlor. Validated analytical methods for enforcement of the proposed residue definition in food of animal origin are available. MRLs are proposed for liver of ruminants and pigs based on the reported cow feeding study performed with metazachlor. MRLs in other ruminant and pig matrices, in milk and in poultry commodities can be established at the LQ. Chronic and acute consumer exposure resulting from the authorised uses reported in the framework of this review was calculated using revision 2 of the EFSA PRIMo. For those commodities where data were insufficient to derive an MRL, EFSA considered the existing EU MRL for an indicative calculation. The highest chronic exposure was calculated for Dutch children, representing 4.5 % of the ADI, and the highest acute exposure was calculated for potatoes, representing 9.2 % of the ARfD. Based on the above assessment, EFSA does not recommend inclusion of this active substance in Annex IV to Regulation (EC) o 396/2005. MRL recommendations were derived in compliance with the decision tree reported in Appendix D of the reasoned opinion (see summary table). All MRL values listed as Recommended in the table are sufficiently supported by data and are therefore proposed for inclusion in Annex II to the Regulation. The remaining MRL values listed in the table are not recommended for inclusion in Annex II because they require further consideration by risk managers (see summary table footnotes for details). In particular, some tentative MRLs or existing EU MRLs need to be confirmed by the following data: 8 residue trials on oranges or lemons, supporting the southern outdoor GAP for citrus fruit; 4 residue trials on apples, 4 trials on a stone fruit supporting the northern outdoor GAP for tree nuts, pome fruits and stone fruits; 4 residue trials on strawberries and 4 residue trials on either grapes, currant or another type of berries, supporting the northern outdoor GAP for berries & small fruits; 8 residue trials supporting the northern outdoor GAP for potatoes; 8 residue trials supporting the southern outdoor GAP for potatoes; 4 residue trials supporting the northern outdoor GAP for radish; 4 residue trials supporting the indoor GAP for radish; 4 residue trials on turnips supporting the northern outdoor GAP for turnips, swedes and horseradish; 8 residue trials (4 on cauliflower and 4 on broccoli) supporting the northern outdoor GAP for flowering brassica; 8 residue trials (4 on cauliflower and 4 on broccoli) supporting the southern outdoor GAP on flowering brassica; 8 residue trials supporting the northern outdoor GAP for head cabbage; 4 residue trials supporting the southern outdoor GAP for head cabbage; 4 residue trials on kale supporting the northern outdoor GAP for leafy brassica; 4 residue trials on kale supporting the southern outdoor GAP on leafy brassica; 4 residue trials supporting the northern outdoor GAP for kohlrabi; 4 residue trials supporting the northern outdoor GAP for rocket; 4 residue trials supporting the northern outdoor GAP for asparagus. 4 residue trials supporting the northern outdoor GAP for rape forage. EFSA Journal 2014;12(4):3634 3

4 All required residue trials should include results compliant with the proposed residue definition for enforcement. It is highlighted that, when submitting residue trials compliant with the residue definition for enforcement, a storage stability study on metabolites 479M08 and 479M04 in high oil content, dry and acidic commodities would also be required. If the above reported data gaps are not addressed in the future, Member States are recommended to withdraw or modify the relevant authorisations at national level. Minor deficiencies were also identified in the assessment but these deficiencies are not expected to impact either on the validity of the MRLs derived or on the national authorisations. The following actions and data are therefore considered desirable but not essential: clarification on the origin of the metabolite 2-hydroxymethyl-6-methylaniline observed in liver and kidney during the metabolism study and confirmation on samples extraction in the livestock feeding studies. SUMMARY TABLE Code number Commodity Existing EU MRL MRL utcome of the review Comment Enforcement residue definition (existing): metazachlor Enforcement residue definition (proposed): sum of metabolites 479M04, 479M08, 479M16, expressed as metazachlor ranges Further consideration needed (a) Lemons Further consideration needed (a) Tree nuts Further consideration needed (a) Pome fruits Further consideration needed (a) Stone fruits Further consideration needed (a) Berries and small fruits Further consideration needed (a) Potatoes Further consideration needed (a) Horseradish 0.15 Further consideration needed (b) Radishes 0.4 Further consideration needed (b) Swedes 0.15 Further consideration needed (b) Turnips 0.15 Further consideration needed (b) Garlic 0.06* Recommended (c) Flowering brassica 0.4 Further consideration needed (b) Brussels sprouts 0.06* Recommended (c) Head cabbage 0.4 Further consideration needed (b) Leafy brassica 0.2 Further consideration needed (b) Kohlrabi Further consideration needed (b) Rocket, Rucola Further consideration needed (a) Asparagus Further consideration needed (a) Globe artichokes 0.06* Recommended (c) Leek 0.06* Recommended (c) Linseed 0.1* 0.06* Recommended (c) EFSA Journal 2014;12(4):3634 4

5 Code number Commodity Existing EU MRL MRL utcome of the review Sunflower seed 0.1* 0.06* Recommended (c) Rape seed * Recommended (c) Mustard seed 0.1* 0.06* Recommended (c) Borage 0.1* 0.06* Recommended (c) Gold of pleasure 0.1* 0.06* Recommended (c) - ther products of plant origin See App. C Comment - Further consideration needed (d) Enforcement residue definition (existing): metazachlor including degradation and reaction products, which can be determined as 2,6-dimethylaniline, calculated in total as metazachlor Enforcement residue definition (proposed): sum of metazachlor and its metabolites containing the 2,6-dimethylaniline moiety, expressed as metazachlor Swine muscle 0.05* 0.05* Recommended (c) Swine fat (free of lean meat) 0.05* 0.05* Recommended (c) Swine liver Recommended (c) Swine kidney 0.05* 0.05* Recommended (c) Bovine muscle 0.05* 0.05* Recommended (c) Bovine fat 0.05* 0.05* Recommended (c) Bovine liver Recommended (c) Bovine kidney 0.05* 0.05* Recommended (c) Sheep muscle 0.05* 0.05* Recommended (c) Sheep fat 0.05* 0.05* Recommended (c) Sheep liver Recommended (c) Sheep kidney 0.05* 0.05* Recommended (c) Goat muscle 0.05* 0.05* Recommended (c) Goat fat 0.05* 0.05* Recommended (c) Goat liver Recommended (c) Goat kidney 0.05* 0.05* Recommended (c) Poultry muscle 0.05* 0.05* Recommended (c) Poultry fat 0.05* 0.05* Recommended (c) Poultry liver 0.05* 0.05* Recommended (c) Cattle milk 0.05* 0.01* Recommended (c) Sheep milk 0.05* 0.01* Recommended (c) Goat milk 0.05* 0.01* Recommended (c) Birds' eggs 0.05* 0.05* Further consideration needed (b) - ther product of animal origin See App. C - Further consideration needed (d) (*): Indicates that the MRL is set at the limit of analytical quantification. (a): GAP evaluated at EU level is not supported by data but no risk to consumers was identified for the existing EU MRL (also assuming the existing residue definition); no CXL is available (combination C-I in Appendix D). EFSA Journal 2014;12(4):3634 5

6 (b): Tentative MRL is derived from a GAP evaluated at EU level, which is not fully supported by data but for which no risk to consumers was identified (assuming the existing residue definition); no CXL is available (combination E-I in Appendix D). (c): MRL is derived from a GAP evaluated at EU level, which is fully supported by data and for which no risk to consumers is identified; no CXL is available (combination G-I in Appendix D). (d): There are no relevant authorisations or import tolerances reported at EU level; no CXL is available. Either a specific LQ or the default MRL of 0.01 mg/kg may be considered (combination A-I in Appendix D). EFSA Journal 2014;12(4):3634 6

7 TABLE F CTETS Abstract... 1 Summary... 2 Table of contents... 7 Background... 8 Terms of reference... 9 The active substance and its use pattern... 9 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 ature of residues Magnitude of residues Consumer risk assessment Conclusions and recommendations Documentation provided to EFSA References Appendix A Good Agricultural Practices (GAPs) Appendix B Pesticide Residues Intake Model (PRIMo) Appendix C Existing EU maximum residue limits (MRLs) Appendix D Decision tree for deriving MRL recommendations Appendix E List of metabolites and related structural formula Abbreviations EFSA Journal 2014;12(4):3634 7

8 BACKGRUD Regulation (EC) o 396/ establishes the rules governing the setting and the review of pesticide MRLs at European level. Article 12(1) of that regulation stipulates that EFSA shall provide, within 12 months from the date of the inclusion or non-inclusion of an active substance in Annex I to Directive 91/414/EEC 5 a reasoned opinion on the review of the existing MRLs for that active substance. As metazachlor was included in Annex I to the above mentioned directive on 01 August 2009, EFSA initiated the review of all existing MRLs for that active substance and a task with the reference number EFSA-Q was included in the EFSA Register of Questions. According to the legal provisions, EFSA shall base its reasoned opinion in particular on the relevant assessment report prepared under Directive 91/414/EEC. It should be noted, however, that in the framework of Directive 91/414/EEC only a few representative uses are evaluated, while MRLs set out in Regulation (EC) o 396/2005 should accommodate all uses authorised within the EU, and uses authorised in third countries that have a significant impact on international trade. The information included in the assessment report prepared under Directive 91/414/EEC is therefore insufficient for the assessment of all existing MRLs for a given active substance. In order to gain an overview of the pesticide residues data that have been considered for the setting of the existing MRLs, EFSA developed the Pesticide Residues verview File (PRFile). The PRFile is an inventory of all pesticide residues data relevant to the risk assessment and MRL setting for a given active substance. This includes data on: the nature and magnitude of residues in primary crops; the nature and magnitude of residues in processed commodities; the nature and magnitude of residues in rotational crops; the nature and magnitude of residues in livestock commodities and; the analytical methods for enforcement of the proposed MRLs. United Kingdom, the designated rapporteur Member State (RMS) in the framework of Directive 91/414/EEC, was asked to complete the PRFile for metazachlor and to prepare a supporting evaluation report. The requested information was submitted to EFSA on 18 January 2011 and subsequently checked for completeness. n 17 December 2012, after having clarified some issues with EFSA, the RMS provided a revised PRFile. A draft reasoned opinion was issued by EFSA on 14 ctober 2013 and submitted to Member States (MS) for commenting. All MS comments received by 13 December 2013 were considered by EFSA in the finalisation of the reasoned opinion. 4 Regulation (EC) o 396/2005 of the European Parliament and of the Council of 23 February 2005 on maximum residue levels of pesticides in or on food and feed of plant and animal origin and amending Council Directive 91/414/EEC. J L 70, , p Council Directive 91/414/EEC of 15 July 1991 concerning the placing of plant protection products on the market. J L 230, , p EFSA Journal 2014;12(4):3634 8

9 TERMS F REFERECE According to Article 12 of Regulation (EC) o 396/2005, EFSA shall provide a reasoned opinion on: the inclusion of the active substance in Annex IV to the Regulation, when appropriate; the necessity of setting new MRLs for the active substance or deleting/modifying existing MRLs set out in Annex II or III of the Regulation; the inclusion of the recommended MRLs in Annex II or III to the Regulation; the setting of specific processing factors as referred to in Article 20(2) of the Regulation. THE ACTIVE SUBSTACE AD ITS USE PATTER Metazachlor is the IS common name for 2-chloro--(pyrazol-1-ylmethyl)acet-2',6'-xylidide (IUPAC). Metazachlor belongs to the group of chloroacetanilide and pyrazole compounds which are used as herbicides. It acts as an inhibitor in the lipid biosynthesis, having effect on cell division and tissue differentiation. Metazachlor is mainly taken up via the roots, the hypocotyls and the cotyledons of the germinating and emerging weeds. Metazachlor was evaluated in the framework of Directive 91/414/EEC with the United Kingdom being the designated rapporteur Member State (RMS). The representative uses supported for the peer review process were pre- and early post-emergence applications on spring and winter rape and early post-emergence applications on several ornamental bushes. Following the peer review, which was carried out by EFSA, a decision on inclusion of the active substance in Annex I to Directive 91/414/EEC was published by means of Commission Directive 2008/116/EC 6, which entered into force on 01 August According to Regulation (EU) o 540/2011 7, amended by Regulation (EU) o 127/2012 8, metazachlor is deemed to have been approved under Regulation (EC) o 1107/ This approval is restricted to uses as herbicide only and the total dose shall not exceed 1 kg metazachlor/ha in a three-year period on the same field. The EU MRLs for metazachlor are established in Annexes IIIA of Regulation (EC) o 396/2005. Since the entry into force of that regulation, EFSA recommended the modification of the existing 6 Commission Directive 2008/116/EC of 15 December 2008 amending Council Directive 91/414/EEC to include aclonifen, imidacloprid and metazachlor as active substances. J L 337, , p Commission Implementing Regulation (EU) o 540/2011 of 25 May 2011 implementing Regulation (EC) o 1107/2009 of the European Parliament and of the Council as regards the list of approved active substances. J L 153, , p Commission Implementing Regulation (EU) o 127/2012 of 14 February 2012 amending Implementing Regulation (EU) o 540/2011 as regards an extension of the use of the active substance metazachlor. J L 41, , p Regulation (EC) o 1107/2009 of the European Parliament and of the Council of 21 ctober 2009 concerning the placing of plant protection products on the market and repealing Council Directives 79/117/EEC and 91/414/EEC. J L309, , p EFSA Journal 2014;12(4):3634 9

10 MRLs for ruminants and pig liver (EFSA, 2009) which was legally implemented in Regulation (EU) o 459/ All existing EU MRLs, which are established for the parent compound only in plant commodities and for metazachlor including degradation and reaction products, which can be determined as 2,6-dimethylaniline, expressed as metazachlor in animal commodities, are summarised in Appendix C to this document. CXLs for metazachlor are not available. For the purpose of this MRL review, the critical uses of metazachlor currently authorised within the EU, have been collected by the RMS and reported in the PRFile. The additional GAPs reported during the consultation of Member States were also considered (see Appendix A). Metazachlor is authorised for soil application in orchards and vineyard and for foliar application on root and tuber vegetables, leafy vegetables, stem vegetables and oilseeds. All authorised uses are under outdoor conditions, except for one indoor use on radish. The RMS did not report any use authorised in third countries that might have a significant impact on international trade. ASSESSMET EFSA bases its assessment on the PRFile submitted by the RMS, the evaluation report accompanying the PRFile (United Kingdom, 2011), the Draft Assessment Report (DAR) and its addendum prepared under Council Directive 91/414/EEC (United Kingdom, 2005, 2007), the conclusion on the peer review of the pesticide risk assessment of the active substance metazachlor (EFSA, 2008), the previous reasoned opinion on metazachlor (EFSA, 2009) as well as the evaluation reports submitted during the consultation of Member States (Belgium, 2013; Finland, 2013; France, 2013; Germany, 2013; Italy, 2013; etherlands, 2013a, 2013b; United Kingdom, 2013). The assessment is performed in accordance with the legal provisions of the Uniform Principles for Evaluation and Authorisation of Plant Protection Products adopted by Commission 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 and ECD, 2011). 1. Methods of analysis 1.1. Methods for enforcement of residues in food of plant origin During the peer review under Directive 91/414/EEC, an analytical method using HPLC-MS/MS, confirmed by another analytical method using HPLC-MS/MS, and its ILV were evaluated and fully validated for the determination of the metabolites 479M04 12, 479M08 13 and 479M16 14 in plant matrices with, for each individual analyte, an LQ of 0.02 mg/kg in high water content, high oil content and acidic commodities (carrot, lettuce, rape seed, orange and lemon) (United Kingdom, 2005, 2007). The multi-residue QuEChERS method in combination with HPLC-MS/MS as described by CE (2008) is also available to analyse parent metazachlor but validation data were not evaluated as metazachlor is not included in the residue definition (see section ). Hence it is concluded that metabolites 479M04, 479M08 and 479M16 can be enforced in food of plant origin with, for each analyte, an LQ of 0.02 mg/kg in high water content, high oil content and acidic commodities. 10 Commission Regulation (EU) o 459/2010 of 27 May 2010 amending Annexes II, III and IV to Regulation (EC) o 396/2005 of the European Parliament and of the Council as regards maximum residue levels for certain pesticides in or on certain products. J L 129, , p Commission Regulation (EU) o 546/2011 of 10 June 2011 implementing Regulation (EC) o 1107/2009 of the European Parliament and of the Council as regards uniform principles for evaluation and authorisation of plant protection products. J L 155, , p M04: [(2,6-dimethylphenyl)(1H-pyrazol-1-ylmethyl)amino](oxo)acetic acid. See Appendix E M08: 2-[(2,6-dimethylphenyl)(1H-pyrazol-1-ylmethyl)amino]-2-oxoethanesulfonic acid. See Appendix E M16: 3-({2-[(2,6-dimethylphenyl)(1H-pyrazol-1-ylmethyl)amino]-2-oxoethyl}sulfinyl)-2-hydroxypropanoic acid. See Appendix E. EFSA Journal 2014;12(4):

11 1.2. Methods for enforcement of residues in food of animal origin Review of the existing MRLs for metazachlor During the peer review under Directive 91/414/EEC, an analytical method using HPLC-MS/MS and its ILV were evaluated and validated for the determination of metazachlor and its metabolites containing the 2,6-dimethylaniline moiety in food of animal origin with LQs of 0.01 mg/kg in milk and 0.05 mg/kg in meat, fat, liver and eggs (United Kingdom, 2005). evertheless, a confirmatory method is not available. In addition, after Annex I inclusion, the RMS also evaluated a HPLC-MS/MS method which is fully validated for the determination of metazachlor and its metabolite containing the 2,6-dimethylaniline moiety with LQs of 0.01 mg/kg in milk and 0.05 mg/kg in meat, eggs, liver, kidney and fat (United Kingdom, 2013). Hence it is concluded that metazachlor and its metabolites containing the 2,6-dimethylaniline moiety can be enforced in food of animal origin with LQs of 0.01 mg/kg in milk and 0.05 mg/kg in meat, fat, liver kidney and eggs. 2. Mammalian toxicology The toxicological assessment of metazachlor was peer reviewed under Directive 91/414/EEC and toxicological reference values were established by EFSA (2008). These toxicological reference values are summarised in Table 2-1. Table 2-1: verview of the toxicological reference values Metazachlor Source Year Value Study relied upon Safety factor ADI EFSA mg/kg bw per d Rat, chronic study 100 ARfD EFSA mg/kg bw Rat, developmental study 100 Although the metabolic pathways in plants and rat show some differences, the toxicological information provided on several plant metabolites (including the main metabolites in primary and rotational crops 479M04, 479M08 and 479M16) suggests that these metabolites are of comparable toxicity to the parent compound. 3. Residues 3.1. ature and magnitude of residues in plant Primary crops ature of residues The metabolism of metazachlor was investigated for foliar application or soil application on cereals (maize), on pulses and oilseeds (rape seed) and on leafy vegetables (cabbage), using 14 C-phenyl-labelled metazachlor (United Kingdom, 2005, 2007). The characteristics of these studies are summarised in Table 3-1. EFSA Journal 2014;12(4):

12 Table 3-1: Summary of available metabolism studies in plants Group Crop Label position Leafy vegetables Pulses and oilseeds Cabbage ilseed rape Method, F or G (a) 14 C-phenyl Foliar spraying, G 14 C-phenyl Soil treatment, G Foliar spraying, G Foliar spraying Cereals Maize 14 C-phenyl Soil treatment, G Review of the existing MRLs for metazachlor Application and sampling details Rate (kg a.s./ha) (a): utdoor/field application (F) or glasshouse/protected/indoor application (G) o Sampling (DAT) Remarks , , , , , 118, Cabbage In cabbage, TRR levels were 3 mg eq/kg 34 DAT and 0.15 mg eq/kg 147 DAT. Parent was not detected in any sample. In 34 DAT sample, 479M16 was the most abundant component, accounting for 48 % TRR (1.1 mg eq/kg) under its free form and for 5 % TRR (0.12 mg eq/kg) under glycoconjugated forms. 479M17 15 under conjugated form accounted for 19 % TRR (0.45 mg eq/kg), 479M61 16 for 12 % TRR (0.27 mg eq/kg), and 479M for 3 % TRR (0.08 mg eq/kg). 10 % TRR (0.2 mg eq/kg) was further characterised and was composed of several compounds, none representing more than 5 % of the TRR (0.1 mg eq/kg). In the 147 DAT sample, 479M04 was the most abundant component, accounting for 28 % TRR (0.05 mg eq/kg). 479M16 accounted for 17.5 % TRR (0.03 mg eq/kg) under its free form and 479M17 accounted for 8 % TRR (0.01 mg eq/kg) under conjugated forms. 38 % TRR was further characterised and was composed of several compounds, none quantified at levels above 0.01 mg eq/kg. Rape seed Post-emergence: The highest TRR following post emergence treatment was identified in 0 DAT forage (53.2 mg eq/kg) and in straw (16.5 mg eq/kg). TRR in 22 DAT forage (2.4 mg eq/kg) and in seeds (0.27 mg eq/kg) were significantly lower. In 22 DAT forage, 479M16 was the major compound (55 % TRR; 1.3 mg eq/kg) and 479M61 and 479M17 under conjugated form accounted each for 10 % TRR (0.2 mg eq/kg). 479M16 was also the M17: 3-({2-[(2,6-dimethylphenyl)(1H-pyrazol-1-ylmethyl)amino]-2-oxoethyl}sulfanyl)-2-hydroxypropanoic acid. See Appendix E M61: S-{2-[(2,6-dimethylphenyl)(1H-pyrazol-1-ylmethyl)amino]-2-oxoethyl}cysteine. See Appendix E M145: 3-({2-[(2,6-dimethylphenyl)(1H-pyrazol-1-ylmethyl)amino]-2-oxoethyl}sulfonyl)-2-hydroxypropanoic acid. See Appendix E. EFSA Journal 2014;12(4):

13 major compound in both straw and seeds, accounting for 51 % TRR (8.4 mg eq/kg) and 26 % TRR (0.07 mg eq/kg), respectively. 479M and 479M accounted together for 13 % TRR (2 mg eq/kg) in straw. In straw and seeds, no other compound was detected at levels above 10 % TRR. A second study, conducted with a lower application rate, was also reported in the DAR. It confirmed 479M16 as the main compound in forage (50 % TRR; 1.8 mg eq/kg), straw (40 % TRR; 2.7 mg eq/kg) and seed (25 % TRR; 0.8 mg eq/kg). The metabolite 479M08, not detected in none of the other studies, accounted for 16 % TRR (0.5 mg eq/kg) in forage, for 14 % TRR (0.8 mg eq/kg) in straw and for 4 % TRR (0.1 mg eq/kg) in seed. The metabolite 479M04, not observed in the pre-emergence study, accounted for 6 % TRR (0.16 mg eq/kg) in forage and for 7 % TRR ( mg eq/kg) in straw. Pre-emergence: The highest TRR following pre-emergence treatment was identified in straw (1 mg eq/kg). TRRs were 0.5 mg eq/kg in forage and 0.1 mg eq/kg in seeds. 479M16 was the major compound in all forage, straw and seeds, accounting for 22 % TRR (0.1 mg eq/kg), 36 % TRR (0.4 mg eq/kg) and 22 % TRR (0.03 mg eq/kg), respectively. o other compound was detected at levels above 10 % TRR in seeds. 479M61 accounted for % TRR in forage (0.05 mg eq/kg) and straw (0.1 mg eq/kg). All other components were detected at levels below 10 % TRR. Maize TRR in grain was 0.02 mg eq/kg in 118 DAT samples and 0.04 mg eq/kg in 146 DAT samples. o single compound or fraction accounted for more than 0.01 mg eq/kg in both grain samples. TRR values were 0.24 mg eq/kg in 78 DAT forage, 0.47 mg eq/kg in 118 DAT forage and 0.05 mg eq/kg in 118 DAT flags, 1.52 mg eq/kg in 146 DAT straw and 0.25 mg eq/kg in 146 DAT flags. o further analysis on 118 DAT forage was reported in the DAR (United Kingdom, 2005) and no single compound or fraction accounted for more than 0.05 mg eq/kg in 118 DAT flags. 479M04 was the major compound in all maize feed items, accounting for % TRR (0.08 mg eq/kg in 78 DAT forage, 0.45 mg eq/kg in 146 DAT straw and 0.09 mg eq/kg in 146 DAT flags). 479M16 was the second most abundant compound, representing % TRR in forage (0.05 mg eq/kg), straw (7 mg eq/kg) and mature flags (0.05 mg eq/kg). 479M17 was also identified in significant amounts: 27 % TRR (0.06 mg eq/kg) in forage, 14 % TRR (0.04 mg eq/kg) in mature flags and 7 % TRR in straw (0.11 mg eq/kg). Parent metazachlor was not detected. The most abundant unidentified compound accounted for 0.05 mg eq/kg (4 % TRR) in straw. Therefore, no further investigation is deemed necessary. verall assessment Metabolites 479M16 and 479M04 are the most important compounds in all crops. Metabolite 479M08 was also found at significant levels in rapeseed. The metabolism of metazachlor in plants involves substitution of the chlorine by glutathion to form 479M22 20, followed by an enzymatic cleavage and oxidation of the sulphur and/or the carbons, to form 479M16 or 479M08. Chlorine can also be substituted by an hydroxyl group and be further oxidised to form 479M04. Hydroxylated metabolites can also form glycoconjugates M154: 2-hydroxy-3-[(2-{[2-(hydroxymethyl)-6-methylphenyl](1H-pyrazol-1-ylmethyl)amino}-2-oxoethyl)sulfinyl] propanoic acid. See Appendix E M155: 3-[(2-{(2,6-dimethylphenyl)[(4-hydroxy-1H-pyrazol-1-yl)methyl]amino}-2-oxoethyl)sulfinyl]- 2-hydroxy propanoic acid. See Appendix E M22: γ-glutamyl-s-{2-[(2,6-dimethylphenyl)(1h-pyrazol-1-ylmethyl)amino]-2-oxoethyl}cysteinylglycine. See Appendix E. EFSA Journal 2014;12(4):

14 Based on the above findings, EFSA already concluded that following soil or foliar applications the residue definition proposed for risk assessment is sum of metazachlor and its metabolites containing the 2,6-dimethylaniline moiety, expressed as metazachlor (EFSA, 2008). For enforcement purposes the major metabolites 479M04, 479M08 and 479M16 are deemed to be sufficient markers. Validated analytical methods for enforcement of the proposed residue definition are available (see also section 1.1) Magnitude of residues According to the RMS, the active substance metazachlor is authorised in northern and southern Europe for soil treatment of orchards and vineyards and for pre- and early post- emergence application on root and tuber vegetables, leafy vegetables, stem vegetables and oilseeds. All authorised uses are under outdoor conditions, except for one indoor use on radish (see Appendix A). To assess the magnitude of metazachlor residues resulting from the authorised GAPs, EFSA considered all residue trials reported in the PRFile, including residue trials evaluated in the framework of the peer review (EFSA, 2008) or in the framework of a previous MRL application (EFSA, 2009) and additional data submitted during the consultation of Member States (Belgium, 2013; Germany, 2013; Italy, 2013; etherlands, 2013a; United Kingdom, 2013). All available residue trials that, according to the RMS, comply with the authorised GAPs, are summarised in Table 3-2. The number of residue trials and extrapolations were evaluated in accordance with the European guidelines on comparability, extrapolation, group tolerances and data requirements for setting MRLs (EC, 2011). For several reported GAPs, no residue trials are available. Consequently, neither MRLs nor risk assessment values can be derived for the crops listed below and the following data gaps were identified: ranges, lemons: considering that they are major crops in southern Europe, 8 residue trials on oranges compliant with the southern outdoor GAP are required; Tree nuts, pome fruits and stone fruits: considering that the application is done before consumable parts of the crops have started to form, 4 residue trials on apples and 4 trials on a stone fruit, all compliant with the northern outdoor GAP, are required; Berries & small fruits: considering that the application is done before consumable parts of the crops have started to form, 4 trials on strawberries and 4 trials on either grapes, currant or another type of berries, all compliant with the northern outdoor GAP, are required; Rocket and asparagus: considering that they are minor crops in northern Europe, 4 residue trials on each crop compliant with the northern outdoor GAP are required; Potatoes: considering that it is a major crop in northern and southern Europe, 8 residue trials compliant with the northern outdoor GAP and 8 residue trials compliant with the southern outdoor GAP are required; For the remaining GAPs, sufficient trials are available to derive (tentative) MRLs and risk assessment values. However, all samples from residue trials were analysed only for the sum of metazachlor and its metabolites containing the 2,6-dimethylaniline moiety, expressed as metazachlor which is in accordance with the residue definition for risk assessment. For garlic, globe artichokes, leek, linseed, rape seed, sunflower seed, mustard seed, borage and gold of pleasure, as measured residues were always below the LQ, metabolites included in the residue definition for enforcement are also expected to be below the LQ. Therefore, appropriate MRL and risk assessment values can be derived from the available data and no further trials are required for these crops. EFSA Journal 2014;12(4):

15 For all other commodities, as the level of residues according to the risk assessment residue definition is not expected to be significantly different from the residue levels expressed according to the enforcement residue definition, tentative MRLs can be proposed on the basis of the risk assessment values derived for available data and the following additional considerations were made by EFSA: Radishes: no residue trials are available to support the northern use. Although appropriate risk assessment values and a tentative MRL can be derived from the available indoor data, 4 residue trials compliant with the northern outdoor GAP and 4 residue trials compliant with the indoor GAP are still required; Turnips, swedes and horseradish: although appropriate risk assessment values can be derived from the available data, 4 trials on turnips compliant with the northern GAP on turnips, swedes and horseradish are still required to derive appropriate MRLs. Moreover it is noted that the GAP for turnips (application at pre-emergence) differs from the GAPs for swedes and horseradish (application at post-transplanting); however, application at early post-emergence is not expected to result in significant higher residue levels (EFSA, 2009) and the extrapolation from turnips to swedes and horseradish is deemed acceptable; Cauliflower, broccoli: only 6 residue trials are available to support the northern outdoor use. Moreover the number of trials on cauliflower and broccoli, supporting northern and southern GAPs, is not compliant with the data requirement for extrapolation to the group of flowering brassica (4 trials on each crop are normally required). Although tentative MRLs and risk assessment values can be derived from the available data, 8 trials (4 on cauliflower and 4 on broccoli) compliant with the northern GAP and 8 trials (4 on cauliflower and 4 on broccoli) compliant with the southern GAP are still required; Brussels sprouts: the number of residue trials supporting the southern GAP is not compliant with the data requirements (2 instead of 4). However, as measured residues were always below the LQ in both northern and southern trials, the reduced number of trials is deemed acceptable. Therefore, appropriate MRL and risk assessment values can be derived from the available data and no further data are required; Head cabbage: the numbers of residue trials supporting the northern and southern GAPs are not compliant with the data requirement for this crop (4 northern trials instead of 8 and 2 southern trials instead of 4). The residue levels in the 2 southern trials are below the LQ; however, as quantifiable residue levels (up to 0.16 mg/kg) were observed for the same GAP in northern trials, a no-residue situation cannot be confirmed. Therefore, although tentative MRL and risk assessment values can be derived from the northern data, 8 trials compliant with the northern GAP and 4 trials compliant with the southern GAP are still required; Leafy brassica: the number of residue trials supporting the southern GAP is not compliant with the data requirement on this crop (2 trials instead of 4). Although tentative MRLs and risk assessment values can be derived from the northern data, 4 trials on kale compliant with the northern GAP and 4 trials on kale compliant with the southern GAP are still required; Rape forage: nine of the available trials are overdosed. Although the setting of MRL in feed items is currently not mandatory, 4 residue trials compliant with the northern GAP are desirable. Meanwhile, tentative MRL and risk assessment values are derived on the basis of the available data. The potential degradation of residues during storage of the residue trials samples was also assessed. In the framework of the peer review, storage stability of metazachlor and its metabolites containing the 2,6-dimethylaniline moiety, expressed as metazachlor, was demonstrated for a period of 24 months at - 18 C in high water content (cabbage, maize forage), high oil content (rape seed) and dry commodities (maize grain) (United Kingdom, 2005). In addition, stability of the metabolite 479M16 EFSA Journal 2014;12(4):

16 was demonstrated for a period of 13 months at -18 C in commodities with high water content (rape seed forage) and high oil content (rape seed) (United Kingdom, 2007) and stability of 479M08 and 479M04 was demonstrated for 18 months in high water commodities (United Kingdom, 2013). EFSA considers that supplementary data on the storage stability of the metabolites 479M08 and 479M04 in high oil content, dry and acidic commodities would be required only when trials analysing residues according to the enforcement residue definition would be submitted. Most of the residue trials reported during the MSs consultation were claimed to be covered by the demonstrated periods of stability (Germany, 2013; Italy, 2013). The storage conditions for all residue trials reported by the RMS were not available, however, since the storage stability has been demonstrated for 24 months, degradation of the residues during storage of the trials samples is not expected to have occurred and no further data are required. Consequently, the available data were sufficient to derive tentative MRLs for all commodities under evaluation, except for oranges, lemons, tree nuts, pome fruits, stone fruits, berries and small fruits, potatoes, rocket and asparagus where residues data were insufficient to derive MRLs and risk assessment values and for garlic, Brussels sprouts, globe artichokes, leek and oilseeds, where data were sufficient to derive appropriate MRLs and risk assessment values (see also Table 3-2). Where several uses are authorised for one commodity, the final MRL proposal was derived from the most critical use and indicated in bold in Table 3-2. Tentative MRLs were also derived for feed crops (rape forage) in view of the future need to set MRLs in feed items. EFSA Journal 2014;12(4):

17 Table 3-2: verview of the available residue trials data Commodity Residue region (a) utdoor /Indoor Individual trial results Enforcement Risk assessment Median residue (b) Highest residue (c) MRL proposal Median CF (d) Comments Enforcement residue definition: sum of metabolites 479M04, 479M08, 479M16, expressed as metazachlor. Risk assessment residue definition: sum of metazachlor and its metabolites containing the 2,6-dimethylaniline moiety, expressed as metazachlor. ranges, lemons SEU utdoor o trials available. Tree nuts Pome fruits Stone fruits Berries & small fruits EU utdoor o trials available. EU utdoor o trials available. Potatoes EU utdoor o trials available. SEU utdoor Radishes EU utdoor o trials available. Turnips Swedes Horseradish EU Indoor ; 0.05; 0.12; 0.14 EU utdoor - 6x<0.05; 0.06; 0.06; (tentative) (tentative) 1.0 (e) Trials on radish compliant with GAP (Germany, 2013). 1.0 (e) Trials on turnips compliant with GAP (application done at pre-emergence). Extrapolation to swedes and horseradish possible; see body text. R ber = 0.12 R max = 0.09 MRL ECD = 0.1 Garlic SEU utdoor - 12x< * 1.0 (e) Combined data set on garlic (8) and onion (4) compliant with GAP on garlic. EFSA Journal 2014;12(4):

18 Commodity Residue region (a) utdoor /Indoor Individual trial results Enforcement Risk assessment Median residue (b) Highest residue (c) MRL proposal Median CF (d) Comments Cauliflower Broccoli EU utdoor - <0.05; <0.05; <0.03; <0.03; 0.06; 0.21 SEU utdoor - <0.05; <0.05; <0.05; <0.05; <0.05; <0.05; <0.05; 0.12; (tentative) (tentative) 1.0 (e) Trials on broccoli (1) and cauliflower (5) compliant with GAP on flowering brassica (Germany, 2013; United Kingdom, 2013). R ber = 0.20 R max = 3 MRL ECD = (e) Trials on cauliflower (7) and broccoli (2) compliant with GAP on flowering brassica (Italy, 2013). R ber = 0.17 R max = 0.24 MRL ECD = 0 Brussels sprouts EU utdoor - 10x< * 1.0 (e) Residue trials on Brussels sprouts compliant with GAP (Germany, 2013; United Kingdom, 2013). SEU utdoor - 2x< * 1.0 (e) Residue trials on Brussels sprouts compliant with GAP (Italy, 2013). Head cabbage EU utdoor - 3x<0.05; 0.14; (tentative) 1.0 (e) Residue trials on head cabbage compliant with GAP (Germany, 2013; United Kingdom, 2013). R ber = 0 R max = 2 MRL ECD = 1 SEU utdoor - 2x< Residue trials on head cabbage compliant with GAP (Italy, 2013). EFSA Journal 2014;12(4):

19 Commodity Residue region (a) utdoor /Indoor Individual trial results Enforcement Risk assessment Median residue (b) Highest residue (c) MRL proposal Median CF (d) Comments Kale Chinese cabbage EU utdoor - <0.05; <0.05; <0.05; <0.05; 0.06; 0.14 (f) (tentative) 1.0 (e) Trials on kale compliant with GAP (Germany, 2013; United Kingdom, 2013). R ber = 0.16 R max = 0.20 MRL ECD = 0.21 SEU utdoor ; Trials on kale compliant with GAP (Italy, 2013). Kohlrabi EU utdoor - <0.05; <0.05; 0.09; 0.08 (f) ; 0.14 (f) (tentative) 1.0 (e) Trials on kohlrabi compliant with GAP (Germany, 2013). R ber = 0.23 R max = 0.24 MRL ECD = 0.23 Rocket, rucola EU utdoor o trials available. Asparagus EU utdoor o trials available. Globe artichokes SEU utdoor - 11x< * 1.0 (e) Trials compliant with GAP. Leek EU utdoor - 9x< * 1.0 (e) Trials compliant with GAP (etherlands, 2013a; United Kingdom, 2013). Linseed Rape seed Sunflower seed Mustard seed Borage Gold of pleasure Rape seed Sunflower seed EU utdoor - 12x< * 1.0 (e) Trials on rapeseed compliant with GAP. SEU utdoor - 12x< * 1.0 (e) Trials on rapeseed compliant with GAP. EFSA Journal 2014;12(4):

20 Commodity Residue region (a) utdoor /Indoor Individual trial results Enforcement Risk assessment Median residue (b) Highest residue (c) MRL proposal Median CF (d) Comments Rape forage EU utdoor ; 0.23; 0.23; 0; 2; 0.49; 0.56; 1.05; 1.24; 0.51; 0.82; (tentative) 1.0 (e) First 9 trials overdosed (1.17 kg/ha). ther trials compliant with GAP. Residues measured as 'total metazachlor'. R ber = 1.86 R max = 1.57 MRL ECD = 2.03 (a): EU (orthern 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 residues trial. (e): Although no data are available to derive a conversion factor, a factor of 1 is assumed. (f): This value, referring to 479M16 only and not total metazachlor (also analysed in the same trial), was included in the dataset because higher than total metazachlor residues. (*): Indicates that the MRL is set at the limit of analytical quantification. EFSA Journal 2014;12(4):

21 Effect of industrial processing and/or household preparation The effect of processing on the nature of 479M16 was investigated in the framework of the peer review. Studies were conducted simulating representative hydrolytic conditions for pasteurisation (20 minutes at 90 C, ph 4), boiling/brewing/baking (60 minutes at 100 C, ph 5) and sterilisation (20 minutes at 120 C, ph 6). From these studies, it was concluded that processing by pasteurisation, baking/brewing/boiling and sterilisation is not expected to have a significant impact on the composition of residues in matrices of plant origin (United Kingdom, 2005). The relevant residues for enforcement and risk assessment in processed commodities are therefore expected to be the same as for primary crops. Further investigation on the effect of processing on metabolites 479M04, 479M08 is desirable but not essential considering the low exposure to metazachlor resulting from the risk assessment (see section 4). Further processing studies are not required as they are not expected to affect the outcome of the risk assessment. However, if more robust processing factors were to be required by risk managers, in particular for enforcement purposes, additional processing studies would be needed Rotational crops Preliminary considerations All crops under consideration, except permanent crops (citrus, pome and stone fruits), may be grown in rotation. According to the soil degradation studies evaluated in the framework of the peer review, DT 90 values of the metazachlor relevant soil metabolites 479M04 and 479M08, are expected to range between days and days, respectively (EFSA, 2008). According to the European guidelines on rotational crops (EC, 1997c), further investigation of residues in rotational crops is relevant ature of residues The metabolism of metazachlor in rotational crops - lettuce, spinach, cabbage, white radish, carrot, wheat - has been evaluated in the framework of the peer review (United Kingdom, 2005, 2007). Two confined rotational crop studies investigating the nature of residues following different plant-back intervals are available. The characteristics of these studies are summarised in Table 3-3. Leafy vegetables TRR in lettuce was 0.2 mg eq/kg in 30 and 120 DAT samples and 0.02 mg eq/kg in 366 DAT sample. TRR in spinach ranged from 0.05 to 0.08 mg eq/kg and TRR in cabbage amounted mg eq/kg for 30 DAT samples. In 30 DAT cabbage, 479M04 was the major compound (23-30 % TRR; mg eq/kg), along with 479M16 (10-19 % TRR; mg eq/kg) and 479M08 (12-17 % TRR; mg eq/kg). In 30 and 120 DAT mature lettuce samples, 479M04/08 21 accounted for 56 % TRR (0.12 mg eq/kg) and 479M10 22 for % TRR ( mg eq/kg). o single compound was detected at levels above 0.01 mg eq/kg in 366 DAT sample. Root and tuber vegetables TRR in radish root decreased from mg eq/kg in 30 DAT sample to 0.03 mg eq/kg in 366 DAT sample. 479M04/08 accounted for 60 % TRR (0.07 mg eq/kg) in 30 DAT mature samples, for 57 % 21 The analytical method used in the study did not allow to quantify these compounds separately, therefore only the sum, identified as 479M04/08, is reported M10: -(2,6-dimethylphenyl)-2-(methylsulfonyl)--(1H-pyrazol-1-ylmethyl)acetamide. See Appendix E. EFSA Journal 2014;12(4):