Review of the existing maximum residue levels (MRLs) for fludioxonil according to Article 12 of Regulation (EC) No 396/2005 1

EFSA Journal 2011;9(8):2335 REASONED OPINION Review of the existing maximum residue levels (MRLs) for fludioxonil according to Article 12 of Regulation (EC) No 396/2005 1 European Food Safety Authority 2, 3 European Food Safety Authority (EFSA), Parma, Italy SUMMARY Fludioxonil was included in Annex I to Directive 91/414/EEC on 01 November 2008, which is after the entry into force of Regulation (EC) No 396/2005 on 02 September 2008. 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 afore mentioned regulation. In order to collect the relevant pesticide residues data, EFSA asked Denmark, as the designated rapporteur Member State (RMS), to complete the Pesticide Residues Overview File (PROFile) and to prepare a supporting evaluation report. The requested information was submitted to EFSA on 02 March 2010 and, after having considered several comments made by EFSA, the RMS provided on 14 January 2011 a revised PROFile. Based on the conclusions derived by EFSA in the framework of Directive 91/414/EEC, the MRLs established by the Codex Alimentarius Commission and the additional information provided by the RMS, EFSA issued on 16 March 2011 a draft reasoned opinion that was circulated to Member State experts for consultation. Comments received by 20 May 2011 were considered for finalisation of this reasoned opinion. The following conclusions are derived. The toxicological profile of fludioxonil was evaluated in the framework of Directive 91/414/EEC, which resulted in an ADI of 0.37 mg/kg bw/d. No ARfD was deemed necessary. Primary crop metabolism of fludioxonil was investigated in three different crop groups following foliar applications, and in three different crop groups following seed applications. Metabolic patterns in the different studies were shown to be similar and the relevant residue for enforcement in all crops supported in the framework of this review is proposed as parent fludioxonil. For risk assessment, the residue was defined as the sum of fludioxonil and its metabolites oxidized to metabolite 2,2-difluorobenzo[1,3]dioxole-4 carboxylic, expressed as fludioxonil. A conversion factor of 2.8 from enforcement to risk assessment is proposed for root vegetables after foliar application. No studies investigating the metabolism of fludioxonil following post-harvest treatment are available. However, as a more extensive metabolism of the active substance is not expected in the post-harvest use, EFSA concludes that the same residue definitions apply. Validated analytical methods for enforcement of 1 On request from EFSA, Question No EFSA-Q-2009-00024, issued on 22 August 2011. 2 Correspondence: pesticides.mrl@efsa.europa.eu 3 Acknowledgement: EFSA wishes to thank the rapporteur Member State Denmark for the preparatory work on this scientific output. Suggested citation: European Food Safety Authority; Review of the existing maximum residue levels (MRLs) for fludioxonil according to Article 12 of Regulation (EC) No 396/2005. EFSA Journal 2011;9(8):2335. [86 pp.] doi:10.2903/j.efsa.2011.2335. Available online: www.efsa.europa.eu/efsajournal European Food Safety Authority, 2011

the residue definition in foods of plant origin are available with a LOQ of 0.01 mg/kg in high water content, high oil content, ic and dry commodities. Regarding the magnitude of residues in most crops reported by the RMS, at least one GAP or import tolerance was supported by a sufficient number of supervised residue trials, which allowed EFSA to estimate the expected residue concentrations in the relevant plant commodities and to derive appropriate MRLs, except for citrus fruits, pistachios, stone fruits and strawberries where data were sufficient to derive tentative MRLs only. For cucurbits with inedible peel and celery, the number of residue trials was not compliant with the minimum data requirements defined by EU guidance documents. EFSA was therefore not able to derive reliable MRL proposals in the above mentioned crops and further residue trials are required. In processed commodities, parent fludioxonil was shown to be stable during pasteurisation, cooking, boiling/brewing/baking and sterilisation and no formation of toxicologically relevant metabolites occurs. Magnitude of residues in processed commodities was also investigated and robust processing factors could be derived for carrots (canned, cooked, juice), wine grapes (juice, must, wine), table grapes (raisin) and peeled passion fruits. Further processing studies are not required as they are not expected to affect the outcome of the risk assessment. However, if there would be the intention to derive more robust processing factors, in particular for enforcement purposes, additional processing studies would be required. The potential incorporation of soil residues into succeeding and rotational crops was investigated in lettuce, winter and spring wheat, sugar beets, corn, mustard, turnips and radishes. These studies showed a comparable metabolism to the primary crops and significant residues in rotational crops are not expected, provided that fludioxonil is applied according to the GAPs supported in the framework of this review. Based on the uses reported by the RMS, significant exposures to fludioxonil are expected for dairy ruminants, meat ruminants and pigs. Metabolism in lactating ruminants and poultry was sufficiently investigated and findings can be extrapolated to pigs as well. The relevant residue definition for enforcement and risk assessment was defined as the sum of fludioxonil and its metabolites oxidized to metabolite 2,2-difluoro-benzo[1,3]dioxole-4 carboxylic, expressed as fludioxonil. A validated analytical method for enforcement of the residue definition is also available with a LOQ of 0.01 mg/kg in milk and meat and a LOQ of 0.05 mg/kg in liver, kidney, fat and eggs. The available livestock feeding study demonstrated that residues of fludioxonil are not expected in milk or in any edible matrix of pigs and MRLs in these commodities can be set at the LOQ. Yet the livestock dietary intake for meat ruminants exceeds the highest dose level of the feeding study. Tentative MRLs for these commodities can be proposed, based on extrapolation from the highest available dosing level but a new feeding study including a higher dosing level is still required. MRLs are not required for poultry products because poultry is not expected to be exposed to significant levels of fludioxonil residues. Chronic consumer exposure resulting from the MRLs proposed in the framework of this review was calculated. The highest chronic exposure represented 16.5 % of ADI (German child). Acute exposure calculations were not carried out because an ARfD was not deemed necessary for this active substance. Apart from the MRLs evaluated in the framework of this review, internationally recommended CXLs have also been established for fludioxonil. Additional calculations of the chronic consumer exposure, including these CXLs, were therefore performed. The highest chronic exposure represented 15.8 % of the ADI (German child). Based on the above assessment, EFSA does not recommend inclusion of this active substance in Annex IV to Regulation (EC) No 396/2005. MRL recommendations were derived in compliance with EFSA Journal 2011;9(8):2335 2

the decision tree reported in Appendix D (see table below for a summary). All MRL values listed in the table as Recommended are sufficiently supported by data and 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 table footnotes for details). In particular, certain tentative MRLs and existing EU MRLs still need to be confirmed by the following data: 6 additional residue trials supporting the northern outdoor GAP, 4 additional residue trials supporting the southern outdoor GAP and 6 residue trials supporting the indoor GAP on strawberries; 8 residue trials on melons supporting the import tolerance GAP on cucurbits with inedible peel (currently ongoing); 3 additional residue trials supporting the northern outdoor GAP and 3 additional residue trials supporting the southern outdoor GAP on celery (currently ongoing); a livestock feeding study for meat ruminants at higher dose levels, taking into account the calculated dietary burdens where levels of fludioxonil and metabolites containing the 2,2- difluorobenzo [1,3]dioxole-4 carboxylic moiety are preferably reported separately (currently ongoing). It is highlighted, however, that some of the Recommended MRLs result from a CXL or from a GAP in one climatic zone only, while other GAPs reported by the RMS were not fully supported by data. EFSA therefore identified the following data gaps which are not expected to impact on the recommended MRLs but which might have an impact on national authorisations: 2 additional residue trials on oranges supporting the post-harvest EU GAP on citrus fruits; 1 additional residue trial supporting the import tolerance GAP on pistachios; 1 additional residue trial on plums supporting the import tolerance GAP on apricots and plums; 3 additional residue trials on raspberries complying with the southern outdoor GAP on raspberries and blackberries; 8 residue trials on currants complying with the southern outdoor GAP on blueberries, cranberries, currants and gooseberries; 6 additional residue trials on tomatoes supporting the northern outdoor GAP, 6 additional residue trials on tomatoes supporting the southern outdoor GAP and 8 residue trials on tomatoes supporting the import tolerance GAP on tomatoes and aubergines; 8 residue trials complying with the import tolerance GAP on peppers; 8 residue trials on cucumbers and/or courgettes supporting the northern outdoor GAP, 4 additional residue trials on cucumbers supporting the southern outdoor GAP and 8 residue trials on cucumbers and/or courgettes supporting the import tolerance GAP on cucurbits with edible peel; 6 additional residue trials on fresh beans with pods complying with the northern outdoor GAP on fresh beans and fresh peas with pods; EFSA Journal 2011;9(8):2335 3

4 residue trials complying with the northern outdoor GAP on fennel; residue trials including both pre- and post-harvest treatments to assess the combined effect of both treatments on the residue levels (pome fruits). 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 recommended MRLs or on the national authorisations. The following data are therefore considered desirable but not essential: development of a more efficient analytical method for enforcement of commodities of animal origin, less laborious than the current one, and preferably analysing the for the parent compound only in muscle, fat and liver; 1 additional residue trial complying with the northern outdoor GAP on potatoes; 2 trials complying with the northern outdoor GAP on sugar beet; residues trials supporting the GAPs on bulb vegetables, witloof, fresh beans, fresh peas, oilseeds, cereals grains and sweet corn carried out with analytical methods achieving a LOQ of 0.01 mg/kg. Code number Commodity Enforcement residue definition: fludioxonil Existing EU MRL Existing CXL MRL Outcome of the review Comment 110010 Grapefruit 10 10 10 Recommended (e) 110020 Oranges 7 10 10 Recommended (e) 110030 Lemons 7 10 10 Recommended (e) 110040 Limes 7 10 10 Recommended (e) 110050 Mandarins 7 10 10 Recommended (e) 120100 Pistachios 0.05* 0.2 0.2 Recommended (i) 130000 Pome fruit 5 5 5 Recommended (h) 140010 Apricots 5 5 5 Recommended (i) 140020 Cherries 5 5 5 Recommended (h) 140030 Peaches 7 5 10 Recommended (e) 140040 Plums 0.5 5 5 Recommended (i) 151010 Table grapes 2 2 5 Recommended (e) 151020 Wine grapes 2 2 4 Recommended (e) 152000 Strawberries 3 3 4 Further consideration needed (f) 153010 Blackberries 5 5 5 Recommended (h) 153020 Dewberries 0.05* 5 5 Recommended (j) EFSA Journal 2011;9(8):2335 4

Code number Commodity Existing EU MRL Existing CXL MRL Outcome of the review Comment 153030 Raspberries 5 5 5 Recommended (h) 154010 Blueberries 3 2 2 Recommended (e) 154020 Cranberries 1-2 Recommended (a) 154030 Currants (red, black and white) 3-2 Recommended (a) 154080 Elderberries 2-0.8 Recommended (a) 154040 Gooseberries 3-2 Recommended (a) 162010 Kiwi 20 15 15 Recommended (e) 163030 Mangoes 0.05* - 1 Recommended (a) 163050 Pomegranate 3 2 3 Recommended (e) 211000 Potatoes 1 0.02 0.06 Recommended (e) 212020 Sweet potatoes 0.05* 10 10 Recommended (e) 212030 Yams 0.05* 10 10 Recommended (e) 213010 Beetroot 1-1 Recommended (a) 213020 Carrots 1 0.7 1 Recommended (e) 213030 Celeriac 0.2-0.2 Recommended (a) 213040 Horseradish 1-1 Recommended (a) 213060 Parsnips 1-1 Recommended (a) 213070 Parsley root 1-1 Recommended (a) 213090 Salsify 1-1 Recommended (a) 220010 Garlic 0.05* - 0.02 Recommended (a) 220020 Onions 0.1 0.5 0.5 Recommended (h) 220030 Shallots 0.05* - 0.02 Recommended (a) 220040 Spring onions 0.3 5 5 Recommended (h) 231010 Tomatoes 1 0.5 0.9 Recommended (e) 231020 Peppers 2 1 1 Recommended (e) 231030 Aubergines (egg plants) 1 0.3 0.4 Recommended (e) 232010 Cucumbers 1 0.3 0.4 Recommended (e) 232020 Gherkins 0.5-0.4 Recommended (a) 232030 Courgettes 1 0.3 0.4 Recommended (e) 233010 Melons 0.05* 0.03 0.05 Further consideration needed (g) 233020 Pumpkins 0.05* - 0.05 Further consideration needed (c) 233030 Watermelons 0.05* - 0.05 Further consideration needed (c) 234000 Sweet corn 0.05* 0.01* 0.01* Recommended (e) 241010 Broccoli 0.05* 0.7 0.7 Recommended (j) 242020 Head cabbage 0.05* 2 2 Recommended (j) EFSA Journal 2011;9(8):2335 5

Code number Commodity Existing EU MRL Existing CXL MRL Outcome of the review Comment 243010 Chinese cabbage 0.05* 10 10 Recommended (j) 0251010 Lamb s lettuce 10-3 Recommended (a) 251020 Lettuce 10 10 12 Recommended (e) 251030 Scarole (broad-leaf endive) 10-12 Recommended (a) 0251040 Cress 10-3 Recommended (a) 0251050 Land cress 10-3 Recommended (a) 0251060 Rocket, rucola 10-3 Recommended (a) 0251070 Red mustard 10-3 Recommended (a) 0251080 Leaves and sprout of brassica spp 10-3 Recommended (a) 252010 Spinach 7-8 Recommended (a) 252030 Beet leaves (chard) 7-8 Recommended (a) 254000 Water cress 0.05* 10 10 Recommended (j) 255000 Witloof 0.05* - 0.02 Recommended (a) 256020 Chives 1 10 10 Recommended (e) 256080 Basil 1 10 10 Recommended (e) 260010 Beans (fresh, with pods) 1 0.3 1 Recommended (e) 260020 Beans (fresh, without pods) 0.2 0.03 0.05 Recommended (e) 260030 Peas (fresh, with pods) 0.2 0.3 1 Recommended (e) 260040 Peas (fresh, without pods) 0.05* 0.03 0.05 Recommended (e) 260050 Lentils (fresh) 0.05* - 0.05 Recommended (a) 270010 Asparagus 0.05* - 0.01* Recommended (a) 270030 Celery 0.05* - 0.05 Further consideration needed (c) 270040 Fennel 0.1-0.05 Recommended (a) 300010 Beans (dry) 0.05* 0.07 0.4 Recommended (k) 300020 Lentils (dry) 0.05* - 0.4 Recommended (a) 300030 Peas (dry) 0.05* 0.07 0.4 Recommended (k) 300040 Lupins (dry) 0.05* - 0.4 Recommended (a) 401030 Poppy seed 0.05* - 0.01* Recommended (a) 401050 Sunflower seed 0.05* - 0.01* Recommended (a) 401060 Rape seed 0.05* 0.02* 0.01* Recommended (k) 401070 Soya bean 0.05* - 0.01* Recommended (a) 401090 Cotton seed 0.05* 0.05* 0.01* Recommended (k) 500010 Barley grain 0.05* 0.05* 0.01* Recommended (k) 500020 Buckwheat grain 0.05* 0.05* 0.01* Recommended (l) EFSA Journal 2011;9(8):2335 6

Code number Commodity Existing EU MRL Existing CXL MRL Outcome of the review Comment 500030 Maize grain 0.1 0.05* 0.01* Recommended (k) 500040 Millet grain 0.05* 0.05* 0.01* Recommended (l) 500050 Oats grain 0.05* 0.05* 0.01* Recommended (k) 500060 Rice grain 0.05* 0.05* 0.01* Recommended (l) 500070 Rye grain 0.05* 0.05* 0.01* Recommended (k) 500080 Sorghum grain 0.05* 0.05* 0.01* Recommended (l) 500090 Wheat grain 0.2 0.05* 0.01* Recommended (k) 633000 Herbal infusions (dried, roots) 1-1 Recommended (a) 840000 Spices (roots and rhizome) 1-1 Recommended (a) 900010 Sugar beet (roots) 0.05* 0.01* Recommended (a) - Others products of plant origin See App. C.1 - - Further consideration needed (d) Enforcement residue definition: the sum of fludioxonil and its metabolites oxidized to metabolite 2,2- difluoro-benzo[1,3]dioxole-4 carboxylic (CGA 192155), expressed as fludioxonil 1011010 Swine meat 0.05* 0.01* 0.05* (F) Recommended (e) 1011020 Swine fat (free of lean meat) 0.05* - 0.05* Recommended (a) 1011030 Swine liver 0.05* 0.05* 0.05* Recommended (e) 1011040 Swine kidney 0.05* 0.05* 0.05* Recommended (e) 1012010 Bovine meat 0.05* 0.01* 0.2 (F) Further consideration needed (f) 1012020 Bovine fat 0.05* - 0.2 Further consideration needed (b) 1012030 Bovine liver 0.05* 0.05* 0.2 Further consideration needed (f) 1012040 Bovine kidney 0.05* 0.05* 0.2 Further consideration needed (f) 1013010 Sheep meat 0.05* 0.01* 0.2 (F) Further consideration needed (f) 1013020 Sheep fat 0.05* - 0.2 Further consideration needed (b) 1013030 Sheep liver 0.05* 0.05* 0.2 Further consideration needed (f) 1013040 Sheep kidney 0.05* 0.05* 0.2 Further consideration needed (f) 1014010 Goat meat 0.05* 0.01* 0.2 (F) Further consideration needed (f) 1014020 Goat fat 0.05* - 0.2 Further consideration needed (b) 1014030 Goat liver 0.05* 0.05* 0.2 Further consideration needed (f) 1014040 Goat kidney 0.05* 0.05* 0.2 Further consideration needed (f) 1016010 Poultry meat 0.05* 0.01* 0.01* Recommended (j) 1016030 Poultry liver 0.05* 0.05* 0.05* Recommended (j) 1016040 Poultry kidney 0.05* 0.05* 0.05* Recommended (j) 1020010 Cattle milk 0.05* 0.01 0.01 Recommended (e) 1020020 Sheep milk 0.05* 0.01 0.01 Recommended (e) EFSA Journal 2011;9(8):2335 7

Code number Commodity Existing EU MRL Existing CXL MRL Outcome of the review Comment 1020030 Goat milk 0.05* 0.01 0.01 Recommended (e) 1030000 Birds' eggs 0.05* 0.05* 0.05* Recommended (j) - Others products of animal origin See App. C.1 - - Further consideration needed (d) (*): Indicates that the MRL is set at the limit of analytical quantification. (F): MRL is expressed as mg/kg of fat contained in the whole product. (a): 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). (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 could be identified; no CXL is available (combination E-I in Appendix D). (c): GAP evaluated at EU level is not supported by data but no risk to consumers could be identified for the existing EU MRL; no CXL is available (combination C-I in Appendix D). (d): There are no relevant authorisations or import tolerances reported at EU level; no CXL is available. Either the specific LOQ or the default MRL of 0.01 mg/kg may be considered (combination A-I in Appendix D). (e): 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; existing CXL is covered by the recommended MRL (combination G-III in Appendix D). (f): 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 could be identified; existing CXL is covered by the tentative MRL (combination E-III in Appendix D). (g): GAP evaluated at EU level is not supported by data but no risk to consumers could be identified for the existing EU MRL; existing CXL is covered by the existing EU MRL (combination C-III in Appendix D). (h): MRL is derived from the existing CXL, which is supported by data and for which no risk to consumers is identified; GAP evaluated at EU level, which is also fully supported by data, leads to a lower MRL (combination G-VII in Appendix D). (i): (j): MRL is derived from the existing CXL, which is supported by data and for which no risk to consumers is identified; GAP evaluated at EU level, which is not fully supported by data, leads to a lower tentative MRL (combination E-VII in Appendix D). MRL is derived from the existing CXL, which is supported by data and for which no risk to consumers is identified; there are no relevant authorisations or import tolerances reported at EU level (combination A-VII in Appendix D). (k): 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; existing CXL is covered by the recommended MRL when the European enforcement LOQ of 0.01 mg/kg is assumed (combination G-III in Appendix D). (l): MRL is derived from the existing CXL but considering the European enforcement LOQ of 0.01 mg/kg (supported by data and no risk to consumers identified); there are no relevant authorisations or import tolerances reported at EU level (combination A-VII in Appendix D). KEY WORDS Fludioxonil, MRL review, Regulation (EC) No 396/2005, consumer risk assessment, phenylpyrrole, fungicide, 2,2-difluoro-benzo[1,3]dioxole-4 carboxylic. EFSA Journal 2011;9(8):2335 8

TABLE OF CONTENTS Summary... 1 Table of contents... 9 Background... 10 Terms of reference... 11 The active substance and its use pattern... 11 Assessment... 12 1. Methods of analysis... 12 1.1. Methods for enforcement of residues in food of plant origin... 12 1.2. Methods for enforcement of residues in food of animal origin... 13 2. Mammalian toxicology... 13 3. Residues... 14 3.1. Nature and magnitude of residues in plant... 14 3.1.1. Primary crops... 14 3.1.2. Rotational crops... 38 3.2. Nature and magnitude of residues in livestock... 40 3.2.1. Dietary burden of livestock... 40 3.2.2. Nature of residues... 42 3.2.3. Magnitude of residues... 43 4. Consumer risk assessment... 46 4.1. Consumer risk assessment without consideration of the existing CXLs... 46 4.2. Consumer risk assessment with consideration of the existing CXLs... 49 Conclusions and recommendations... 53 Documentation provided to EFSA... 60 References... 60 Appendix A Good Agricultural Practices (GAPs)... 63 Appendix B Pesticide Residues Intake Model (PRIMo)... 70 Appendix C Existing EU maximum residue limits (MRLs) and Codex Limits (CXLs)... 73 Appendix D Decision tree for deriving MRL recommendations... 82 Appendix E List of metabolites and related structural formula... 84 Abbreviations... 85 EFSA Journal 2011;9(8):2335 9

BACKGROUND Regulation (EC) No 396/2005 4 establishes the rules governing the setting as well as the review of pesticide MRLs at Community level. Article 12(1) of that regulation lays down 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 fludioxonil was included in Annex I to the above mentioned directive on 01 November 2008, EFSA initiated the review of all existing MRLs for that active substance and a task with the reference number EFSA-Q-2009-00024 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) No 396/2005 should accommodate for all uses authorised within the EC as well as uses authorised in third countries having 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 have an overview on the pesticide residues data that have been considered for the setting of the existing MRLs, EFSA developed the Pesticide Residue Overview File (PROFile). The PROFile is an electronic inventory of all pesticide residues data relevant to the risk assessment as well as the 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. Denmark, the designated rapporteur Member State (RMS) in the framework of Directive 91/414/EEC, was asked to complete the PROFile for fludioxonil and to prepare a supporting evaluation report. The requested information was submitted to EFSA on 02 March 2010 and subsequently checked for completeness. On 14 January 2011, after having clarified some issues with EFSA, the RMS provided a revised PROFile. A draft reasoned opinion was issued by EFSA on 16 March 2011 and submitted to Member States (MS) for commenting. All MS comments received by 20 May 2011 were considered by EFSA for finalization of the reasoned opinion. 4 Commission Regulation (EC) No 396/2005 of 23 February 2005. OJ L 70, 16.3.2005, p. 1-16. 5 Council Directive 91/414/EEC of 15 July 1991, OJ L 230, 19.8.1991, p. 1-32. EFSA Journal 2011;9(8):2335 10

TERMS OF REFERENCE According to Article 12 of Regulation (EC) No 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 SUBSTANCE AND ITS USE PATTERN Fludioxonil is the ISO common name for 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-pyrrole-3-carbonitrile (IUPAC). F O F O N N Fludioxonil belongs to the group of phenylpyrrole compounds which are used as fungicide. Its mode of action is the inhibition of a mitogen-activated protein (MAP) kinase in signal transduction of osmoregulation (glycerol synthesis). Fludioxonil is used as foliar and seed treatment applications to control diseases caused by fungi in the class of Ascomycetes, Basidiomycetes and Fungi imperfecti. Fludioxonil was evaluated in the framework of Directive 91/414/EEC with Denmark being the designated rapporteur Member State (RMS). The representative uses supported for the peer review process cover foliar applications on wine and table grapes and seed treatment of wheat grain. 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 2007/76/EC 6, entering into force on 01 November 2008. The Annex I inclusion of fludioxonil is restricted to uses as fungicide only. EU MRLs for fludioxonil in products of plant and animal origin have been set for the first time in 2008 by means of Commission Regulation (EC) No 149/2008 7 establishing Annexes II, III and IV of Regulation (EC) No 396/2005. These temporary MRLs were derived from the MRLs that have been set at national level before Regulation (EC) No 396/2005 entered into force. EFSA recently recommended the modification of existing MRLs for pomegranates, spinach and beet leaves, celeriac as well as for various root vegetables (carrots, beetroots, salsify, horseradish, parsnips, parsley roots, roots of herbal infusions and roots of spices) (EFSA, 2008, 2009a, 2009b, 2009c) which were legally implemented in Regulations 2009/256/EC 8, 2009/822/EC 9 and 2010/750/EC 10, and for sweet potatoes, yams, table and wine grapes (EFSA, 2010) which were already approved by the meeting of the Standing Committee on the Food Chain and Animal Health held on 23-24 March 2011 but which are not yet legally implemented. All existing EU MRLs, which are established for the parent compound 6 Commission Directive 2007/76/EC of 20 December 2007, OJ L 337, 21.2.2007, p. 100-104. 7 Commission Regulation (EC) No 149/2008 of 29 January 2008. OJ L 58, 1.3.2008, p. 1-398. 8 Commission Regulation 2009/256/EC of 23 March 2009, OJ L 81, 27.3.2009, p. 3-14 9 Commission Regulation 2009/822/EC of 27 August 2009, OJ L 239, 10.9.2009, p. 5-45 10 Commission Regulation (EU) No750/2010 of 7 July 2010. OJ L 220, 21.08.2010, p. 1-56. EFSA Journal 2011;9(8):2335 11

only, are summarized in Appendix C.1 to this document. CXLs for fludioxonil were also established by the Codex Alimentarius Commission (CAC) and are reported in Appendix C.2 to this reasoned opinion. These CXLs refer to parent compound only for products of plant origin, and to the sum of fludioxonil and its determined as 2,2-difluoro-benzo[1,3]dioxide-4- carboxylic, for products of animal origin. For the purpose of this MRL review, the critical uses of fludioxonil currently authorized within the EU as well as uses authorised in third countries that might have a significant impact on international trade, have been collected by the RMS and reported in the PROFile (see Appendix A). Uses of fludioxonil previously evaluated by EFSA were also considered (EFSA, 2008, 2009a, 2009b, 2009c, 2010). According to the reported GAPs, fludioxonil is applied on a wide range of crops either by foliar spraying, seed treatment or post-harvest treatment, both indoor and outdoor. PHIs may vary between 1 and 28 days. ASSESSMENT EFSA bases its assessment on the PROFile submitted by the RMS, the evaluation report accompanying the PROFile (Denmark, 2010), the Draft Assessment Report (DAR) and its addenda prepared under Council Directive 91/414/EEC (Denmark, 2005, 2007), the conclusion on the peer review of the pesticide risk assessment of the active substance fludioxonil (EFSA, 2007), the JMPR Evaluation report (FAO, 2004, 2006, 2010), the previous reasoned opinions on fludioxonil (EFSA, 2008, 2009a, 2009b, 2009c, 2010) and the evaluation reports submitted during the Member States consultation (Austria, 2001; Belgium, 2011; Denmark, 2011; Finland, 2011; France, 2011; Germany, 2011; The Netherlands, 2011; The United Kingdom, 2007 and 2010). The assessment is performed in accordance with the legal provisions of the Uniform Principles for the Evaluation of the Authorization of Plant Protection Products adopted by Commission Regulation (EU) No 546/2011 11 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, 2004, 2010, 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-UV was evaluated and validated for the determination of parent fludioxonil with a LOQ of 0.02 mg/kg in high water content (strawberries), high content (grapes, apples) and dry (wheat grain) commodities and a LOQ of 0.05 mg/kg in wine (Denmark, 2005). A confirmatory method was not available. Additionally, the multi-residue analytical method DFG S19 using HPLC-MS/MS and its ILV were evaluated and validated for the determination of parent fludioxonil with a LOQ of 0.01 mg/kg in high oil content (avocados), ic (kiwi, citrus) and dry (wheat) commodities (Denmark, 2005; EFSA, 2007b). The multi-residue QuEChERS method using HPLC-MS/MS described in the European Standard EN 15662:2008 validated with a LOQ of 0.01 mg/kg for the determination of residues in high water content and ic commodities is also applicable. 11 Regulation (EU) No 546/2011 of 10 June 2011. OJ L 155, 11.06.2011, p. 127-175. EFSA Journal 2011;9(8):2335 12

Table 1-1: Recovery data for the analysis of fludioxonil in different crop groups using the QuEChERS method in combination with LC-MS/MS (CEN, 2008) Commodity group Spiking levels Recoveries Mean (%) RSD (%) n No of labs Acidic 0.01 0.025 0.1 0.25 98 104 100 102 7 10 7 10 15 20 14 25 3 4 3 5 Watery 0.01 0.025 0.1 0.25 96 97 97 103 4 5 6 8 15 40 15 55 3 5 3 6 Hence, according to the peer review and the CEN, it is concluded that parent fludioxonil can be enforced in food of plant origin with a LOQ of 0.01 mg/kg in high water content, high oil content, ic and dry commodities. 1.2. Methods for enforcement of residues in food of animal origin During the peer review under Directive 91/414/EEC, an analytical method using HPLC-UV, confirmed by the use of an alternative column in the HPLC system, and its ILV were evaluated and validated for the determination of the sum of fludioxonil and its metabolites that can be oxidised to metabolite CGA 192155 12, expressed as fludioxonil, with a LOQ of 0.01 mg/kg in milk and meat and a LOQ of 0.05 mg/kg in liver, kidney, fat and eggs (FAO, 2004; Denmark, 2005). However, as the method is very complex, involving a laborious extraction method, the development of a more efficient method is still desirable. Hence, it is concluded that the sum of fludioxonil and its metabolites that can oxidised to metabolite CGA 192155, expressed as fludioxonil, can be enforced in products of animal origin with a LOQ of 0.01 mg/kg in milk and meat and a LOQ of 0.05 mg/kg in liver, kidney, fat and eggs. 2. Mammalian toxicology The toxicological assessment of fludioxonil was peer reviewed under Directive 91/414/EEC and toxicological reference values were established by EFSA (2007b). These toxicological reference values are summarized in Table 2-1. 12 CGA 192155: 2,2-difluoro-benzo[1,3]dioxole-4 carboxylic. See Appendix E. EFSA Journal 2011;9(8):2335 13

Table 2-1: Overview of the toxicological reference values Fludioxonil Source Year Value Study relied upon Safety factor ADI EFSA 2007 0.37 mg/kg bw/d Rat, acute neurotoxicity 100 ARfD EFSA 2007 Not necessary 3. Residues 3.1. Nature and magnitude of residues in plant 3.1.1. Primary crops 3.1.1.1. Nature of residues Metabolism of fludioxonil was investigated for foliar application on fruits and fruiting vegetables (grape, peach, tomato), on leafy vegetables (lettuce) and on root and tuber vegetables (spring onion) as well as for seed treatment on root and tuber vegetables (potato), pulses and oilseeds (cotton, soybean) and cereals (wheat, rice) using both pyrrole-4-14 C labelled and phenyl-u- 14 C labelled fludioxonil (Denmark, 2005). Available studies are summarized in table 3-1. When applied on leaves or on seeds, fludioxonil is metabolised mainly through oxidation followed by conjugation of metabolites with sugars. Following foliar application, the major component was parent fludioxonil, accounting for 22 % of the TRR in peach and up to 73.2 % of the TRR in tomatoes. Following seed application, uptake and translocation of fludioxonil was low, TRR ranged from <0.002 mg/kg in rice grain to 0.015 mg/kg in dry soybean seeds. Cleavage of the pyrrole ring results in the formation of 2,2-difluoro-benzo[1,3]dioxole metabolites. The peer review concluded that the metabolic pattern is qualitatively similar in all crop groups investigated, but in root vegetables (study in spring onions) after foliar application higher rates of metabolites (but less than 7% of the TRR) have been observed in whole plant, while parent fludioxonil remained the major residue (11.5 % to 31 % of the TRR). Table 3-1: Summary of available metabolism studies in plants Group Crop Label position Fruits and fruiting vegetable Grape [pyrrole-4-14 C] Foliar, F Application and sampling details Method, Rate No Sampling F or G (a) (DAT) 0.50 kg a.s./ha 3 After 1 st appl.: 0, 26 After 3 rd appl.: 0, 14 and at maturity Remarks EFSA Journal 2011;9(8):2335 14

Group Crop Label position Leafy vegetables Root and tuber vegetables Pulses and oilseeds Cereals Peach [phenyl-u- 14 C] Application and sampling details Method, Rate No Sampling F or G (a) (DAT) Foliar, F Tomato [pyrrole-4-14 C] Foliar, G Lettuce [pyrrole-4-14 C] Foliar, F Spring onion [phenyl-u- 14 C] Foliar Potato [pyrrole-4-14 C] Seed, F Cotton [pyrrole-4-14 C] Seed, G Soybean [pyrrole-4-14 C] Seed, G Wheat [pyrrole-4-14 C] Seed, G, F Rice [pyrrole-4-14 C] Seed 0.84 or 8.40 kg a.s./ha (total) 8.40 kg a.s./ha (total) 0.75 kg a.s./ha 0.20 kg a.s./ha or 0.60 kg a.s./ha 0.12 kg a.s./ha (total) or 6.17 kg a.s./ha (total) 2.50 g a.s./100 kg seed 2.50 g a.s./100 kg 5.0 g a.s./100kg seed 5.00 g a.s./100 kg seed 6.40 g a.s./100 kg seed (G) 7.30 g a.s./100 kg seed (F) 6.50 g a.s./100 kg seed (a): Outdoor/field application (F) or glasshouse/protected/indoor application (G) 3 2 3 28 30, 114 After 1 st appl.: 0 After 3 rd appl.: 0, 40 3 0, 6, 13 2 0, 7, 14, 28 1 0, 40, 71, 95 1 186 1 28, 38, 133 1 11, 18, 25, 32, 39, 46, 53 48, 83, 106 1 38, 76, 152 Remarks EFSA Journal 2011;9(8):2335 15

Consequently, the residue definition for enforcement is set as fludioxonil for all plant commodities. The risk assessment residue definition was set as the sum of fludioxonil and its metabolites oxidized to metabolite 2,2-difluoro-benzo[1,3]dioxole-4 carboxylic (CGA 192155), expressed as fludioxonil (EFSA, 2007b). Validated analytical methods for enforcement of the proposed residue definition are available (see also section 1.1). For cereals (seed treatment), fruits and leafy vegetables, pulses and oilseeds, the conversion factor of 1 between residue definitions for enforcement and risk assessment was derived which reflects the fact that no significant concentrations of metabolites containing the 2,2-difluoro-benzo[1,3]dioxole-4 carboxylic moiety are expected. For root vegetables after foliar application the conversion factor of 2.8 (derived from the metabolism study on spring onions) from enforcement to risk assessment residue definition is proposed (EFSA, 2009a). No studies investigating the metabolism of fludioxonil following post-harvest treatment are available. However, as a more extensive metabolism of the active substance is not expected in the post-harvest use, EFSA concludes that for all plant commodities and all types of application, the same residue definition as established by the peer review should apply. It is noted that the JMPR has established both the risk assessment and enforcement residue definitions for plant commodities as parent fludioxonil only (FAO, 2004) but according to EFSA the residue definition derived by JMPR will underestimate the toxicological burden of fludioxonil residues, in root and tuber vegetables in particular. 3.1.1.2. Magnitude of residues According to the RMS, the active substance fludioxonil is authorised for foliar and seed treatments in northern and southern Europe on a large number of crops, both under outdoor and indoor conditions (see Appendix A). To assess the magnitude of fludioxonil residues resulting from these GAPs, EFSA considered all residues trials reported in the PROFile (Denmark, 2010), including residues trials evaluated in the framework of the peer review (Denmark, 2005) or in the framework of MRLs applications (EFSA, 2008, 2009a, 2009b, 2009c, 2010) and additional data submitted during the Member State consultation (Austria, 2011; Denmark, 2011; Finland, 2011; France, 2011; Germany, 2011; The Netherlands, 2011; The United Kingdom, 2007 and 2010). All available residue trials that comply with the authorised GAPs, are summarized in Table 3-2. The number of residues trials and extrapolations were evaluated in view of the European guidelines on comparability, extrapolation, group tolerances and data requirements for setting MRLs (EC, 2011). A sufficient number of trials complying with the GAP was reported by the RMS for all crops under assessment, except in the following cases: Citrus fruit: the number of residues trials compliant with the post-harvest uses of fludioxonil in southern Europe is not compliant with the data requirements for these crops. Although appropriate MRL and risk assessment values can be derived from the import tolerance data, 2 additional trials on oranges for the post-harvest use in the EU are still required. Pistachios: the number of residue trials compliant with the import tolerance of fludioxonil is not compliant with the data requirements for this crop. Tentative MRL and risk assessment values can be derived from the import tolerance data but 1 additional trial is still required. Apricots and plums: the number of residues trials supporting the import tolerance (postharvest uses) of fludioxonil is not compliant with the data requirements for these crops. Tentative MRL and risk assessment values can be derived but 1 additional residue trial on EFSA Journal 2011;9(8):2335 16

plums is still required to support the import tolerance in plums as well as the extrapolation to apricots. Strawberries: the number of residue trials supporting the northern, southern and indoor uses of fludioxonil is not compliant with the data requirements for this crop. EFSA used values from 0 d PHI or 3 d PHI to derive tentative MRLs. However, considering that interpolations are not supported, additional residue trials representing the residue situation at the PHI of 1 day are still required for each area: 6 for the northern use, 4 for the southern use and 6 for the indoor use. Blackberries and raspberries: the number of residues trials supporting the southern use of fludioxonil is not compliant with the data requirements for these crops. Although appropriate MRL and risk assessment values can be derived from the northern outdoor data, 3 additional residues trials on raspberries complying with the southern GAP for these two crops are still required. Blueberries, cranberries, currants and gooseberries: no trials are available to support the southern use of fludioxonil. Although appropriate MRL and risk assessment values can be derived from the northern outdoor data, 8 trials complying with the southern GAP for these crops are still required, with a minimum of 4 trials on currants. Elderberries: trials were carried out with a PHI of 14 days while a PHI of 21 days is authorised in Austria. Although only deviations of 25% are normally allowed, this deviation of 33 % is accepted in this case because elderberries are classified a very minor crop, because fludioxonil has a low acute toxicity (no ARfD was established) and because this deviation is expected to overestimate residues and risk to consumers. Potatoes: no sufficient trials are available to support the northern use of fludioxonil. Although appropriate MRL and risk assessment values can be derived from the southern outdoor data, 1 additional trial complying with the northern GAPs would be desirable. Tomatoes and aubergines: the number of residues trials supporting the northern, southern and import tolerance uses of fludioxonil is not compliant with the data requirements for these crops. Although appropriate MRL and risk assessment values can be derived from the indoor data, additional residue trials on tomatoes complying with the GAPs for these two crops are still required for each area: 6 for northern use, 6 for southern use and 8 for import tolerance. Peppers: no trials are available to support the import tolerance of fludioxonil. Although appropriate MRL and risk assessment values can be derived from the indoor data, 8 trials complying with the import tolerance GAP are still required. Cucurbits with edible peel: the number of residues trials supporting the northern, southern and import tolerance uses of fludioxonil is not compliant with the data requirements for these crops. Although appropriate MRL and risk assessment values can be derived from the indoor data, residue trials on cucumbers and/or courgettes complying with the GAPs for these crops are still required for each area: 8 for northern use, 4 for southern use and 8 for import tolerance. Cucurbits with inedible peel: no trials are available to support the import tolerance of fludioxonil. At least 8 representative trials on melons would have to be submitted to support a group tolerance; no MRL is proposed due to the insufficient dataset. The RMS highlighted that residues trials are ongoing but these trials cannot be considered by EFSA as long as they are not finalised. EFSA Journal 2011;9(8):2335 17

Sweet corn: a data requirement of 4 residue trials normally applies while only 3 trials on immature maize are available in each area. Considering however that all residue levels are below the LOQ, indicating a no residue situation, further residue trials are not required. Fresh beans and fresh peas with pods: the number of residues trials supporting the northern use of fludioxonil is not compliant with the data requirements for these crop. Although appropriate MRL and risk assessment values can be derived from the indoor data, 6 additional trials on fresh beans with pods complying with the northern GAP for these two crops are still required. Celery: available trials are not sufficient to support the northern and southern outdoor uses of fludioxonil. At least 3 representative trials on celery are required for each area; no MRL is proposed due to the insufficient dataset. The RMS highlighted that residues trials are ongoing but these trials cannot be considered by EFSA as long as they are not finalised. Fennel: no trials are available to support the northern use of fludioxonil. Although appropriate MRL and risk assessment values can be derived from the southern outdoor data, 4 trials on fennel complying with the northern GAP are still required. Oilseeds: the number of residues trials in each area is not compliant with the data requirements for these crops but the reduced number of trials was considered acceptable by EFSA because residues levels after the seed treatment were demonstrated to be below the LOQ. Maize: the value of 0.05 mg/kg would be identified as an outlier according to the Dixon Q test. Based on the metabolism studies and residue trials on cereals, this value was excluded from the MRL calculation. Bulb vegetables, wiltoof, fresh beans and peas (without pods): a MRL of 0.02 mg/kg is proposed because all residue levels were found to be below the LOQ of 0.02 mg/kg that was used in the residues trials. Considering however that a LOQ of 0.01 mg/kg can be achieved for enforcement purposes (see also section 1.1), the elaboration of residues trials with a LOQ of 0.01 mg/kg is desirable. Oilseeds, cereals grains and sweet corn: there is a lack of residues trials compliant with the LOQ for enforcement (0.01 mg/kg). However, residues resulting from the seed treatment are expected to be below this LOQ (supported by the metabolism studies). In these cases MRLs are set at 0.01* mg/kg. Sugar beet: considering that it is a seed treatment, that fludioxonil is not a systemic substance, and that no residues are expected in succeeding crops, residues exceeding the enforcement LOQ of 0.01 mg/kg are not expected. However, at least 2 residues trials demonstrating that residue levels are below the LOQ are desirable. The combined effect of a pre-harvest and a post-harvest treatment on the total residue in a given crop could not be assessed by EFSA as there are no residue trials available combining both modes of application. Member States are therefore recommended to take the appropriate measures for avoiding this kind of combined treatments. The demonstrated storage stability of fludioxonil in treated crops was evaluated under the peer review of Directive 91/414/EEC (Denmark, 2005). Studies demonstrated storage stability of fludioxonil in commodities with high water, high, high oil and dry content for up to 24 months when stored deep frozen. All available residue trials samples were stored for not more than 24 months. EFSA Journal 2011;9(8):2335 18

Table 3-2: Overview of the available residues trials data Commodity Region (a) Outdoor /Indoor Citrus fruits EU Indoor (postharvest) Pistachios Import (US, CA) Import (US) Indoor (postharvest) Individual trial results Enforcement (fludioxonil) Oranges: 1.5; 1.26 Mandarins: 1.84; 2.23; 1.91; 1.46 Oranges: 2.9; 3.5; 4; 4.4; 4.6; 5; 7.2 Mandarins: 2.9; 2x5.6; 5.8; 7; 2x7.8 Risk assessment (sum of fludioxonil and its metabolites oxidized to metabolite CGA 192155, expressed as fludioxonil) (f) Median residue (b) Highest residue (c) MRL proposal Median CF (d) Comments - 1.67 2.23 4 1.00 EU GAP compliant residue trials on oranges (2) and mandarins (4). R ber = 3.98 R max = 3.02-5.30 7.80 10 1.00 US GAP compliant residue trials on oranges (7) and mandarins (7) (FAO, 2010). R ber = 14.10 R max = 9.72 Outdoor 0.04; 0.06; 0.08-0.06 0.08 0.2 (tentative) Pome fruits NEU Outdoor 0.45; 0.19; 0.33; 0.26; 0.18; 0.16; 0.6; 0.18; 0.19; 0.11 1.00 GAP compliant residue trials on pistachios. R ber = - R max = 0.21-0.19 0.60 0.8 1.00 GAP compliant residue trials on apples (7) and pears (3) were combined. Only authorised for use on apples and pears. R ber = 0.72 R max = 0.71 EFSA Journal 2011;9(8):2335 19

Commodity Region (a) Outdoor /Indoor Individual trial results Enforcement (fludioxonil) SEU Outdoor 0.35; 0.14; 0.15; 0.19; 0.22; 0.23; 0.24; 0.29; 0.39; 0.42 EU Import (US) Indoor (postharvest) Indoor (postharvest) Risk assessment (sum of fludioxonil and its metabolites oxidized to metabolite CGA 192155, expressed as fludioxonil) (f) Median residue (b) Highest residue (c) MRL proposal Median CF (d) Comments - 0.24 0.42 0.8 1.00 GAP compliant residue trials on pears (2) and apples (8) were combined. Only authorised for use on apples and pears. R ber = 0.72 R max = 0.55 - - 2.30 2.80 4 1.00 GAP compliant residue trials on pears (4) and apples (4) carried out in the US can be used for the 1.1; 1.2; 1.6; 2.8; 2.2; 2.4; 2.4; 2.6 Apricots NEU Outdoor 0.15; 0.48; 0.17; 0.33 SEU Outdoor 0.06; 0.08; 0.11; 0.19; 0.31; 0.36; 0.37; 0.5 Import (JP, AU, CL, US) Indoor (postharvest) - EU GAP as well (one worldwide zone for post-harvest applications). R ber = 5.10 R max = 4.11-0.25 0.48 1 1.00 Extrapolation from the northern outdoor GAP on peaches. - 0.25 0.50 0.8 1.00 Extrapolation from the northern outdoor GAP on peaches. 0.4; 1.06;1.90-1.06 1.90 5 (tentative) 1.00 Extrapolation from the post harvest use on plums. EFSA Journal 2011;9(8):2335 20