Modification of the existing MRLs for propiconazole in table and wine grapes, apples and stone fruits (apricots, peaches and nectarines) 1

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1 REASONED OPINION Modification of the existing MRLs for propiconazole in table and wine grapes, apples and stone fruits (apricots, peaches and nectarines) 1 European Food Safety Authority 2 European Food Safety Authority (EFSA), Parma, Italy SUMMARY According to Article 6 of the Commission Regulation (EC) No 396/2005, Finland, herewith referred as the evaluating Member State (EMS), received an application from Makhteshim Agan International to modify the existing MRLs for the active substance propiconazole in table and wine grapes. In order to accommodate for the intended use of propiconazole, it is proposed to raise the current MRL from 0.05 mg/kg, equivalent to limit of quantification (LOQ), to 0.3 mg/kg. Finland drafted an evaluation report according to Article 8 of Commission Regulation (EC) No 396/2005, which was submitted to the European Commission and forwarded to EFSA on 3 May According to Article 6 of the Commission Regulation (EC) No 396/2005, Finland, herewith referred as the evaluating Member State (EMS), received a further application from Makhteshim Agan International to modify the existing MRL for the active substance propiconazole in apples. In order to accommodate for the intended use of propiconazole on apple, it is proposed to raise the current MRL from 0.05 mg/kg, equivalent to the LOQ, to 0.15 mg/kg. Additionally, Article 6 of that regulation lays down that where a Member State considers that the modification of an MRL is necessary, that Member State may compile and evaluate an application to modify the MRL in accordance with the provisions of Article 7 of the regulation. Finland therefore compiled an application to modify the existing MRL in apricots, peaches and nectarines after having re-assessed the data evaluated in the draft assessment report (DAR) and having considered not adequate to keep on with the current MRL of 0.2 mg/kg. It is proposed to lower the value to 0.15 mg/kg. Finland drafted a combined evaluation report according to Article 8 of Commission Regulation (EC) No 396/2005, which was submitted to the European Commission and forwarded to EFSA on 3 May Considering that both applications refer to modifications of existing MRLs for propiconazole, EFSA decided to address the MRL applications in a single reasoned opinion. EFSA bases its assessment on the above mentioned evaluation reports (ER), the review report for the active substance including the list of endpoints, the draft assessment report (DAR) and its addendum prepared by Finland under the framework of Directive 91/414/EEC Annex I inclusion and the Joint FAO/WHO meeting on pesticide residues (JMPR) evaluation report on propiconazole. 1 On request from European Commission, Question No EFSA and No EFSA , issued on 24 September Correspondence: praper.mrl@efsa.europa.eu Suggested citation: European Food Safety Authority; Modification of the existing MRLs for propiconazole in table and wine grapes, apples and stone fruits.. [32 pp.] doi: /j.efsa Available online: European Food Safety Authority,

2 The toxicological profile of propiconazole was assessed under the peer review and the data were sufficient to conclude on an ADI of 0.04 mg/kg bw/day and an ARfD of 0.3 mg/kg bw. The peer review concluded that the metabolism of propiconazole was sufficiently elucidated in primary crops and supported the residue definition for risk assessment and monitoring as parent compound. An analytical method for the enforcement of residues in the crops under assessment is available. However, as propiconazole, similarly to other active substances belonging to the triazole class, when applied to plant is known to produce the degradation/metabolism products named triazole derivative metabolites (TDMs), EFSA is of the opinion that the residue definition may require to be revised pending the decision on the risk assessment methodology for all substances of the triazole chemical group. Nevertheless, as TDMs were mainly detected in the metabolism studies conducted on oilseeds and cereals with the triazole labelled propiconazole, the occurrence of TDMs for the crops under assessment might be of minor relevance. The supervised field trials in support of the intended uses were sufficient to derive provisional MRLs according to the current residue definition of propiconazole. The following MRLs would be required to accommodate the intended uses of propiconazole: 0.15 for apples, 0.1 mg/kg for apricots, peaches, nectarines and 0.3 mg/kg for table and wine grapes. A hydrolysis study simulating conditions of pasteurisation baking/brewing/boiling and sterilisation was not performed with propiconazole. The peer review did not derive specific risk assessment and enforcement residue definitions for processed commodities. Although not necessary as the total theoretical maximum daily intake (TMDI) is less than 10 % of the ADI, specific studies investigating the effect of processing on the magnitude of propiconazole residues on grapes, apples and stone fruits were provided in the framework of these applications. Since the nature of propiconazole residues is not fully investigated and since the possible occurrence of TDMs in processed products should be reconsidered, EFSA does not recommend the derived processing factors. Further investigations, such as the performance of a hydrolysis study, with the compound are recommended prior to apply for additional crop uses. For apples, grapes and stone fruits (perennial crops) the crop rotation is not relevant and was therefore not evaluated in the framework of these MRL applications. The exposure of livestock to propiconazole residues form the intake of apple pomace, the only byproducts used as feed item, was assessed in ruminants. The other crops and livestock species are not relevant regarding the potential occurrence of residues in products of animal origin. The ruminant exposure to propiconazole residues was calculated considering the intake from apple pomace as well as from all commodities which are potential feeding items and for which the current EC MRLs are set above the LOQ (peanuts, oat and barley). The dietary burden of 0.1 mg/kg DM was exceeded but was mainly driven by the existing uses of propiconazole on feed crops. The contribution of apple pomace to the total ruminant dietary exposure was low. Thus, the existing EU MRLs for the food commodities of animal origin do not require to be amended in view of the intended use of propiconazole in apples. The consumer exposure assessment was performed with revision 2 of the EFSA PRIMo (Pesticide Residues Intake Model). For the chronic intake assessment, EFSA used the STMR value derived from the submitted supervised residue trials and the existing MRLs as established in Commission Regulation (EC) No 396/2005. The acute intake assessment was performed only with regard to the crops under consideration applying the HR/STMR values as derived from the supervised residue trials. The estimated long-tem and short-term exposures were compared with the toxicological reference values established for propiconazole. No long-term consumer risk was identified for any of the European diets incorporated in the EFSA PRIMo. The total calculated dietary intake ranged from 1 to 6 % of the ADI. For the crops under consideration, the contribution to the total propiconazole consumer exposure was low, not exceeding the 1.1 % for apple fruits, 0.02 % for apricots and 0.13 % for table grapes (DE child diet), the 0.03 % 2

3 for peaches and nectarines (IE adult) and the 0.4 % for wine grapes (FR all population), expressed as percentage of the ADI. No acute consumer risk was identified in relation to the MRL proposals for apples, grapes, peaches, nectarines and apricots. The calculated maximum exposure in children and adults was 3.5 % and 1.7 % for table grapes, 2.3 % and 0.5 % for apples, 1.4 % and 0.4 % for peaches, 0.7 % and 0.3 % for apricots and 0.1 % and 0.2 % for wine grapes, with respect to the ADI and ARfD, respectively. EFSA concludes that the intended uses of propiconazole on table and wine grapes, apples, apricots, peaches and nectarines are acceptable and provides the below recommendations. EFSA could not perform the risk assessment for TDMs. Commodity Existing EC MRL Proposed EC MRL Justification for the proposal Enforcement residue definition: propiconazole Apples 0.05* 0.15 The MRL proposals are sufficiently Table grapes 0.05* 0.3 supported by data and no consumer intake concerns were identified based on the Wine grapes 0.05* 0.3 current residue definition. The risk assessment for TDMs could not be performed Apricots Before the lowering of the MRLs is Peaches (Nectarines decided, it has to be clarified if more and similar hybrids) critical GAPs than those reported by the EMS are still authorized, which require to maintain the existing MRLs. (*): 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. KEY WORDS Propiconazole, apples, table and wine grapes, apricots, peaches, nectarines, MRL application, Commission Regulation (EC) No 396/2005, consumer risk assessment, triazole fungicide, triazole derivative metabolites (TDMs). 3

4 TABLE OF CONTENTS Summary... 1 Table of contents... 4 Background... 5 Terms of reference... 6 The active substance and its use pattern... 7 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 Nature and magnitude of residues in plant Primary crops Rotational crops Nature and magnitude of residues in livestock Dietary burden of livestock Consumer risk assessment Conclusions and recommendations References Appendices Appendix A. Good Agricultural Practices (GAPs) Appendix B. Pesticide Residues Intake Model (PRIMo) Appendix C. Existing EC maximum residue limits (MRLs) Appendix D. List of metabolites and related structural formula Abbreviations

5 BACKGROUND Commission Regulation (EC) No 396/ establishes the rules governing the setting of pesticide MRLs at Community level. Article 6 of that regulation lays down that a party requesting an authorisation for the use of a plant protection product in accordance with Council Directive 91/414/EEC 4, shall submit to a Member State, when appropriate, an application to set or modify an MRL in accordance with the provisions of Article 7 of that regulation. Finland, hereafter referred to as the evaluating Member State (EMS), received an application from the company Makhteshim Agan International 5 to modify the existing MRL for the active substance propiconazole in wine and table grapes. The EMS received a further application from the above cited applicant to modify the existing MRL for the active substance propiconazole in apples. Additionally, Article 6 of Commission Regulation (EC) No 396/2005 lays down that where a Member State considers that the modification of an MRL is necessary, that Member State may compile and evaluate an application to modify the MRL in accordance with the provisions of Article 7 of that regulation. Finland compiled an application to modify the existing MRLs for propiconazole in apricots and peaches, including nectarines, after having re-assessed the data evaluated in the draft assessment report (DAR). This application was combined with the company request on apples, notified to the European Commission and EFSA and subsequently evaluated in accordance with Article 8 of the regulation. After completion, the comprehensive evaluation report of the EMS was submitted to the European Commission who forwarded the applications, the evaluation report and the supporting dossier to EFSA on 3 May The applications were included in the EFSA Register of Questions with the reference EFSA-Q and Q with the following subjects: Propiconazole - Application to modify the existing MRLs in table and wine grapes. Propiconazole - Application to modify the existing MRLs in apples and stone fruits. Finland proposed to modify the existing MRLs of propiconazole in table and wine grapes from the limit of quantification (LOQ) value of 0.05 mg/kg to 0.3 mg/kg, in apples from the LOQ of 0.05 mg/kg to 0.15 mg/kg and in the stone fruits from 0.2 mg/kg to 0.15 mg/kg. Furthermore, they are requesting to revise the MRLs on edible tissues and eggs of animals which were set at the LOQ of 0.01 mg/kg. Considering that both applications refer to the modification of existing MRLs for propiconazole, EFSA decided to address the MRL applications in a single reasoned opinion. EFSA requested clarifications from the EMS regarding the GAP to which the MRL applications refer. These clarifications were provided and the corrected version of the evaluation report together with the modified application from the applicant were uploaded on 20 September EFSA then proceeded with the assessment of the applications as required by Article 10 of the regulation. 3 Commission Regulation (EC) No 396/2005 of 23 February OJ L 70, , p Council Directive 91/414/EEC of 15 July 1991, OJ L 230, , p Makhteshim Agan International. Coordination Center, Avenue Louise 283, Box No.7, 1050 Brussels, Belgium 5

6 TERMS OF REFERENCE According to Article 10 of Commission Regulation (EC) No 396/2005, EFSA shall, based on the evaluation report provided by the evaluating Member State, provide a reasoned opinion on the risks to the consumer associated with the application. According to Article 11 of that regulation, the reasoned opinion shall be provided as soon as possible and at the latest within three months from the date of receipt of the application. Where EFSA requests supplementary information, the time limit laid down shall be suspended until that information has been provided. In this particular case the calculated deadline for providing the reasoned opinion is 3 August

7 THE ACTIVE SUBSTANCE AND ITS USE PATTERN Propiconazole is the ISO common name for (±)-1-[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2- ylmethyl]-1h-1,2,4-triazole (IUPAC). Cl Cl O C CH 2 O N N N C 3 H 7 Molecular weight: Propiconazole is a systemic fungicide belonging to the class of triazoles. It is a mixture of cis-trans isomers, both exerting biological activity. The compound acts as an ergosterol biosynthesis inhibitor (EBI). The lack of normal sterol production slows or stops the growth of the fungus, effectively preventing further infection and/or invasion of host tissues. The active substance is used against several fungal pathogens in a of agricultural crops. Propiconazole is an active substance for which Finland was designated as rapporteur Member State (RMS). It has been peer reviewed under Council Directive 91/414/EEC and included in Annex I to this directive by the Commission Directive 2003/70/EC 6 for use as fungicide only. The representative uses assessed under the peer review of Council Directive 91/414/EEC include foliar applications to cereals, sugar beets, stone fruits and grass turf. Propiconazole was not peer reviewed by EFSA. Harmonised community MRLs for propiconazole were established by Council Directive 94/29/EC and 94/30/EC 7 on the fixing of maximum levels for pesticide residues in and on cereals and foodstuffs of animal origin and certain products of plant origin, including fruit and vegetables. MRLs have been further amended in 2000 and 2005 and then transferred to Annex II and IIIB of Commission Regulation (EC) No 396/2005 by Commission Regulation (EC) No 149/ The existing MRLs are reported in Appendix C. x Alimentarius has established maximum residue limits (CXLs) for propiconazole on various agricultural and livestock commodities but not on the crops associated with these two applications. The intended GAPs according to which a modification of the MRLs is requested are summarized in Appendix A. They concerns outdoor foliar applications of a 25 % emulsifiable concentrate (EC) formulation on grapes in the southern European region (SEU) and on apples in Poland. The GAP for stone fruits which, according to the EMS, justified the lowering of the MRLs for peaches, nectarines and apricots are also reported in Appendix A. 6 Commission Directive 2003/70/EC of 17 July OJ L 184, , p Council Directive 94/29/EC and 94/30/EC of 23 June 1994, L 189, p and Commission Regulation (EC) No 149/2008 of 29 January 2008, OJ L 58, , p

8 ASSESSMENT EFSA bases its assessment on the evaluation report submitted by the EMS (Finland, 2010), the Draft Assessment Report (DAR) and its addendum (AR) prepared under Directive 91/414/EEC (Finland, 1998, 2002), the Review Report on propiconazole including the list of endpoints (EC, 2003) and the Joint FAO/WHO Meeting on Pesticide Residues (JMPR) Evaluation report (FAO, 2007). The assessment is performed in accordance with the legal provisions of the Uniform Principles for the Evaluation of the Authorization of Plant Protection Products set out in Annex VI to Council Directive 91/414/EEC 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, 2008). 1. Methods of analysis 1.1. Methods for enforcement of residues in food of plant origin Analytical methods for the determination of propiconazole residues in foodstuffs of plant origin were assessed in the DAR (Finland, 1998). Basically, two groups of methods using capillary gas chromatography (GC) are available: one is determining parent propiconazole residues and the other is determining propiconazole as 2,4 dichlorobenzoic acid (DCBA) 9 moiety and express the amounts as propiconazole equivalents (eq) by using a conversion factor of 1.79 (total residue method). In addition, a revised version of the multi-residue method DFG S19 to quantify residues of propiconazole by liquid chromatography with tandem mass detection (LC-MS/MS) is proposed in the framework of these applications and considered acceptable by the EMS. The limit of quantification on the tested commodities (cherries, grapes, wheat and oilseed rapes) is 0.01 mg/kg (Finland, 2010). Propiconazole residues are also detectable by the mutli-residue method described in the European Standard EN 15662:2008 using QuEChERS preparation for sample extraction and LC-MS/MS for the analysis in acid, dry (cereals), water and sugar containing matrices with the LOQ of 0.01 mg/kg (CEN, 2009). In the samples of the supervised residue trials, propiconazole was determined by using the HPLC- MS/MS method, which was validated at the LOQ of 0.01 mg/kg and confirmed to fit the purpose (Finland, 2010). It is therefore concluded that suitable analytical methods are available to enforce, according to the current residue definition of parent compound, the proposed MRLs for propiconazole on apples, grapes and stone fruits, which belong to the group of high water and acid content commodities Methods for enforcement of residues in food of animal origin Analytical methods for the quantification of propiconazole residues in commodities of animal origin were provided and assessed in the DAR and its addendum (Finland, 1998, 2002) and in the evaluation report (Finland, 2010). The method for enforcement of the residues complying with the established residue definition of parent compound is based on LC-MS/MS with the LOQ of 0.01 mg/kg for milk, tissues, organs and eggs. The total residue method (GC) used in the feeding studies was validated at LOQ of 0.01 mg/kg in milk and 0.05 mg/kg in tissues, organs and eggs. 9 2,4-dichlorobenzoic acid (CGA ). See Appendix D. 8

9 2. Mammalian toxicology Modification of the existing MRLs for propiconazole in grapes, apples and stone fruits The toxicological profile of propiconazole was assessed under the peer review and the derived toxicological endpoints are compiled in Table 2-1 (EC, 2003). Metabolism studies in both mammalians and plants have shown that active substances belonging to the chemical class of triazoles are degraded/metabolized to common metabolites known as triazole derivative metabolites (TDMs), the major ones being the metabolites 1,2,4-triazole 10, triazole alanine 11, triazole lactic acid 12 and triazole acetic acid 13. These TDMs were initially considered of no toxicological concerns, but further evaluations indicated their toxicological relevance. The toxicological profile of TMDs was discussed by the EFSA Pesticide Risk Assessment Peer Review (PRAPeR) Expert Meeting on Toxicology and the agreed toxicological reference values are compiled in Table 2-1 (EFSA PRAPeR 14, 2007a). Table 2-1: Overview of the toxicological reference values Source Year Value Study relied upon Safety factor Propiconazole ADI EC mg/kg bw/d Rat, chronic toxicity study 100 ARfD EC mg/kg bw Rat, developmental study 100 Metabolites: 1,2,4-triazole and triazole acetic acid a ADI PRAPeR mg/kg bw/d Rat, multigenerational study 1000 ARfD PRAPeR mg/kg bw Rat, developmental study 500 Metabolite: triazole alanine ADI PRAPeR mg/kg bw/d Rat, developmental study 1000 ARfD PRAPeR mg/kg bw Rat, developmental study 1000 (a): EFSA PRAPeR Expert Meeting 14 concluded to apply the same value as for 1,2,4 triazole in absence of reproductive data. 3. Residues 3.1. Nature and magnitude of residues in plant Primary crops Nature of residues The metabolism of propiconazole in grapes, peanuts, wheat and rice was assessed by the RMS in the framework of the peer review of Council Directive 91/414/EEC (Finland, 1998, 2002) and on celery and carrots by the JMPR (FAO, 2007). In all trials the residues were measured as 2,4-DCBA and expressed as propiconazole equivalents. Overall, the following crop categories were evaluated: 10 1H-[1,2,4]triazole (CGA-71019). See Appendix D amino-3-[1,2,4]triazol-1-yl-propionic acid (CGA ). See Appendix D. 12 [1,2,4]triazol-1-yl-lactic acid (CGA ). See Appendix D. 13 [1,2,4]triazol-1-yl-acetic acid (CGA ). See Appendix D. 9

10 Table 3-1: Summary of available metabolism studies in plants Group Crop Label position Type/(F) or (G) or (I) a Application details Rate No Sampling Remarks Propiconazole. Studies evaluated by the peer review (Finland 1998, 2002) and by JMPR (2007) Leafy vegetables Pulses and oilseeds Cereals grape b (leaves) peanuts winter wheat spring wheat triazole- 14 C phenyl- 14 C triazole- 14 C phenyl- 14 C foliar, F kg a.s/hl foliar, G c 0.34 kg a.s./ha triazole- 14 C foliar, F 0.17 kg a.s./ha triazole- 14 C foliar, G d 2.5 kg a.s./ha triazole- 14 C overtop spraying, F kg a.s./ha 4 30, 63 DAT d- interval 3 14 DAT 8 14 DAT 14 d- interval 8 14 DAT 1-2 wkinterval 1 5 h, 11, 25, 49 DAT phenyl- 14 C 5 h, 11, 25, 41 DAT phenyl- 14 C foliar, G kg a.s./ha rice triazole- 14 C overtop spraying, G Propiconazole. Studies evaluated by JMPR (2007) Root and tuber vegetables carrots phenyl- 14 C foliar (4/5) soil (1/5), G kg a.s./ha 0.25 kg a.s./ha 0.12 kg a.s./ha up to 1.30 kg a.s./ha Leafy vegetables celery phenyl- 14 C foliar, G 0.56 kg a.s./ha 1.4 kg a.s./ha 1 12, 77 DAT (1x) 2 Just postapplications, 42 DAT BBCH 51 (5x) 15 d- interval 4 DAT 14 (1x) (10x) 1 7 DAT (1x) 2 61 DAT (5x), 16 d interval Metabolite: 1,2,4-triazole. Studies evaluated by the peer review (Finland 1998, 2002) and by JMPR (2007) Fruits and fruiting vegetable tomatoes triazole- 14 C injection mg/kg 1 n.a. (a): Outdoor or field use (F), glasshouse application (G) or indoor application (I).(b): As grape leaves were sampled and analysed, the study is classified in the group of leafy vegetables. (c): Exact application rate was 0.34, 0.31 and 0.34 kg a.s./ha at 5, 12, 17 weeks post-planting. (d): The compound was sprayed in the inner canopy at 7, 8, 9, 12, 14, 16, 17 and 19 weeks post-planting. In grape leaves at harvest (PHI 63 d), the amount of total residues was low: 1.32 and 0.67 mg/kg propiconazole equivalents, for the triazole and the phenyl label, respectively. The unchanged 10

11 compound accounted for the 16 % of the TRR. A of non-polar metabolites was identified, but only ketone 14 in significantly high concentrations (49.6 % of TRR). TDMs were not identified. In peanuts, the data indicate that the qualitative distribution of residues was comparable although metabolism was more extensive under outdoor conditions. At harvest (PHI 14 d), unchanged parent compound and non-polar metabolites conjugated with sugars represented up to 69 % of the TRR in stalks, 61 % of TRR in shells and 95 % of TRR in kernels. The polar fraction of the triazole label studies was mainly composed by products containing the triazole ring (the 73 % - 82% of the fraction in mature kernels). In winter wheat, the amounts of the parent compound in the upper plant parts of the triazole label study decreased over the time from 92.6 % at 5 hours to 9.8 % at 25 days after application, with a gradual increase in the formation of polar metabolites (70 % at 25 d after application), characterized as water soluble sugar conjugates. At harvest (PHI 49 d), the compound could not be determined in grain (< 0.01 mg/kg eq), whereas straw contained the 12.7 % of the TRR (0.18 mg/kg eq). Triazole alanine was identified in high amounts (54 %). In spring wheat, propiconazole represented 0.4 % of the TRR at harvest. Six organo-soluble metabolites were identified, which together did not exceed 4 % of the TRR. In rice, total residues decreased over the time up to harvest (PHI 42 d), where 5.2 mg/kg eq in stalks, 2.8 mg/kg eq in husks and 0.29 mg/kg eq in grains were found. Unchanged propiconazole represented the 27.6 %, 46.8 % and 27.7 % of the TRR in stalks, husks and grains, respectively. The two major metabolites in grains were identified as triazole acetic acid (35 % of TRR) and triazole alanine (15 % of TRR). In carrots at harvest (PHI 14 d), the residues in roots were lower than in leaves and reflected the different application rates (from 1x to 10x). At normal rate, propiconazole was the major identified component of the TRR (tuber: 56 %; leaf: 63.5 %). Other minor metabolites were identified, none of them at significant amounts. In celery at harvest, the amount of the radioactive residues was low (0.845 mg/kg eq at normal rate) and propiconazole was the major identified component of the TRR (97.6 %) with few other minor metabolites at very low levels. Besides, a metabolism study on tomatoes injected with mg/kg with the propiconazole metabolite 14 C-1,2,4-triazole was also conducted. No free triazole was found in any sample and the major identified metabolite was triazole alanine conjugate (80 % of TRR). Overall, the metabolism was qualitatively similar in all tested crops and proceeded along three basic pathways: Hydroxylation and oxidative decarboxylation of buthyl side-chain leading eventually to deketalization. The various hydroxylated metabolites are conjugated with sugars. Hydrolysis of the dioxolane ring to form the ketone followed by reduction to the alkanol 15 ; Cleavage of the phenyl-triazole bridge to form free triazole which is further conjugated with endogenous serine to form triazole alanine and triazole acetic acid. A significant formation of TDMs was observed only in the metabolism studies with cereals and oilseeds. The degradation of propiconazole was extensive. At harvest, the unchanged parent compound was present in all edible parts of the tested crops with the exception of winter wheat grains. Several nonpolar metabolites were present and in most of the studies at amounts below the 10 % of the TRR (2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (CGA-91304). See Appendix D (2,4-dichlorophenyl)-2-(1,2,4)triazol-1-yl-ethanol (CGA-91305). See Appendix D. 11

12 These metabolites were also observed in animal metabolism and were considered as not toxicologically relevant. TDMs were detected in significant amounts in the metabolism studies conducted on oilseeds and cereals with the triazole labelling. The peer review concluded that the metabolism of propiconazole was sufficiently elucidated in primary crops and supported the residue definition for risk assessment and monitoring as parent compound (Finland, 1998, 2002). Having regard to the conclusion of the EFSA PRAPeR meeting 14 on toxicology of January 2007 that proposed specific toxicological reference values for TDMs as the result of their reproduction and development effects, EFSA is of the opinion that the residue definition for propiconazole may need to be revised pending the decision on the risk assessment methodology for all substances of the triazole chemical group. Nevertheless, as the crops for which MRL modifications are requested do not belong to the pulse/oilseed and cereal groups, the occurrence of TDMs might be of minor relevance Magnitude of residues In support of the concerned applications the following supervised residue trials were submitted. Apples A total of eight outdoor supervised residue trials were submitted. The studies, which were performed in Germany, Poland, northern France and the Netherlands over two seasons (2005 and 2009), reflected the intended GAP (within the ± 25 % tolerance range). The two decline studies showed a progressive decline in propiconazole concentrations over the time. At the PHI of 14 days the residue levels of the compound ranged from 0.03 to 0.07 mg/kg. Grapes A total of eight outdoor supervised residue trials were submitted (two in table and six in wine grapes) according to the intended critical GAP of 5 x 0.05 kg a.s./ha, PHI 14 days. The studies were performed in Spain, Greece, Italy and southern France at the proposed dose rate but with four instead of five applications. This deviation is acceptable as within the tolerance interval of ± 25 % (EC, 2008). Although the applications occurred during a single growing season, the field studies were generated in different production areas with different climatic conditions and the residue data can be accepted to derive an MRL proposal and perform the consumer risk assessment. The four decline studies showed that there was a progressive decline in propiconazole residues over the time. At the PHI of 14 days (13 to 16 days), the residue levels of the compound ranged from 0.02 to 0.16 mg/kg. Peaches, including nectarine, and apricots A total of eight new outdoor supervised residue trials were submitted (four in peaches, two in nectarines and two in apricots). The studies were performed in Spain, Greece and Italy according to the GAP. Finland proposed to extrapolate the residue data generated on peaches to nectarines and apricots, which is acceptable as four trials in peaches are available (EC, 2008). These new studies were carried out during a single growing season (2005), however the results are in line with those generated with a comparable GAP previously evaluated in the framework of the peer review of Directive 91/414/EEC (Finland, 1998). The new studies, which were all decline studies, showed a progressive decline in propiconazole levels over the time. The residue concentrations of propiconazole were very similar among these three fruits and at harvest ranged from 0.02 to 0.07 mg/kg. EFSA considers that these data are sufficient to derive MRL proposals according to the current residue definition. The submitted supervised residue field trials indicate that the following MRLs would be 12

13 required to accommodate the intended uses of propiconazole: 0.1 mg/kg for apricots, peaches, nectarines, 0.15 mg/kg for apples and 0.3 mg/kg for table and wine grapes. The results of the residue trials, the related risk assessment input values (HR and STMR) and the MRL proposals are summarized in Table 3-2. The storage stability of propiconazole in analytical matrices belonging to the group of high water content commodities was evaluated in the framework of the peer review of Directive 91/414/EEC (Finland, 1998, 2002). The studies demonstrated a storage stability of the parent compound determined as 2,4-DCBA for up to 36 months when stored at or below 20 C. In the supervised residue trial, the samples were stored for up to 4 months (apples), 19 weeks (stone fruits) and 5 months (grapes) at < -18 C, thereby not exceeding the storage stability period of propiconazole residues. The residue data were generated using a HPLC-MS/MS analytical method which complies with the residue definition established for enforcement purpose (propiconazole). The evaluating Member State considered the analytical method applied as validated and fitting the purpose (see section 1.1). 13

14 Table 3-2: Overview of the available residues trials data Commodity Region (a) Outdoor /Indoor Enforcement residue definition: propiconazole Individual trial results Enforcement (propiconazole) Apples NEU Outdoor 0.03; 0.03 e ; 0.031; 0.033; 0.04; 0.05; 2 x 0.07 Table and wine grapes Apricots, peaches, nectarines Risk assessment (propiconazole) 0.03; 0.03 e ; 0.031; 0.033; 0.04; 0.05; 2 x 0.07 STMR (b) HR (c) MRL proposal Median CF (d) Comments R max : R ber : 0.13 SEU Outdoor 2 x 0.02 f ; 0.02; 0.03 e ; 2 x 0.02 f ; 0.02; 0.03 e ; 0.05; R max : ; 0.07 f ; 0.15 f ; 0.16 f 0.07 f ; 0.15 f ; 0.16 f R ber : 0.26 SEU Outdoor 5 x 0.02; 0.03; 0.06; 5 x 0.02; 0.03; 0.06; 0.07 f R max : f R ber : (a): NEU, SEU, EU or Import (country code). In the case of indoor uses there is no necessity to differentiate between NEU and SEU. (b): Median value of the individual trial results according to the enforcement residue definition. (c): Highest value of the individual trial results according to the enforcement residue definition. (d): The median conversion factor for enforcement to risk assessment is obtained by calculating the median of the individual conversion factors for each residues trial. (e): Residue data from samples collected 1 day before the proposed PHI of 14 days. (f). Residue data from samples collected 1 or 2 days after the proposed PHI of 14 days. (*): Indicates that the MRL is set at the limit of analytical quantification. 14

15 Effect of industrial processing and/or household preparation A hydrolysis study simulating conditions of pasteurisation baking/brewing/boiling and sterilisation was not performed with propiconazole. The peer review evaluated the nature of propiconazole residues in processed grape juice and presscake as part of the metabolism field study using radiolabel compound (see table 3-1). For both labels, total residues were < 0.05 mg/kg propiconazole equivalents. The amount of unchanged parent propiconazole did not exceed 0.01 mg/kg in any specimen. In grape juice the level of propiconazole residues was <0.001 mg/kg. In the study the occurrence of 1,2,4-triazole alanine in grape juice was recorded. No specific residue definition was proposed for processed products (Finland, 1998). Although not necessary as the total theoretical maximum daily intake (TMDI) is less than 10 % of the ADI, specific studies investigating the effect of processing on the magnitude of propiconazole residues on grapes, apples and stone fruits were provided. The samples were taken from the metabolism study on grapes (Finland, 1998) and from field and mass balance studies submitted in the framework of the request for the MRL modifications (Finland, 2010). The applicant analyzed the processed product samples for parent compound or for total 2,4-DCBA residues. Results indicated that in grapes the total residues decreased in processing to juice and no parent compound was observed, while remained almost at the same concentrations in presscake. (Finland, 1998). Reduction was recorded also in must and white and unheated red wine, whereas residues concentrated in raisins. In apples, the residues decreased in juice and concentrated in pomace. Processing of peach jam and canning resulted in a dilution of the propiconazole residues (Finland, 2010). The median processing factors for commodities intended for human consumption are summarised in table 3-3. Table 3-3. Overview of the available processing studies Processed commodity Number of studies Median PF (a) Median CF (b) Individual PF Enforcement residue definition: propiconazole c grape, juice 1-1 <0.05. Insufficient No of studies grapes, pressed cake Insufficient No of studies grapes, raisins ; 1.3. Insufficient No of studies grapes, must d ;0.13; 0.33 grapes, wine g d ; 0.06; <0.33 apples, juice ef ; <0.1 e ;<0.11 e apples, sauce ef, 0.6 e, 0.44 e apples, wet pomace ef. Insufficient No of studies apples, dry pomace ef. Insufficient No of studies peaches, jam ef ; 0.4 e ; 0.09 e peaches, canned ef ; 0.07 e ; 0.05 e (a): The median processing factor is obtained by calculating the median of the individual processing factors of each processing study. (b): The median conversion factor for enforcement to risk assessment is obtained by calculating the median of the individual conversion factors of each processing study. 15

16 (c): EFSA assumes that the same residue definition applies for RAC and processed commodities. (d). Bunches were sprayed once at the rate of approximately 1 mg propiconazole/kg grapes and processed the same day. (d): Residue from exaggerated application rate (approx 3N) for mass balance study. (e): Residue in RAC analysed at PHI 0 days. (f): PFs could not be derived separately for white and unheated red wine. The highest instead of the median PF is conservatively selected. Since the nature of propiconazole residues is not fully investigated and since the possible occurrence of TDMs in processed products should be reconsidered, EFSA does not recommend the derived processing factors. Further investigations, such as the performance of a hydrolysis study, with the compound are recommended prior to apply for additional crop uses Rotational crops For apples, grapes and stone fruits (perennial crops) the crop rotation is not relevant and was therefore not evaluated in the framework of these MRL applications (EC, 1997c) Nature and magnitude of residues in livestock Dietary burden of livestock Among the crops under assessment, only the by-products of apple fruit (pomace) is used as feed item in ruminants (EC, 1996). The other crops and livestock species are therefore not relevant regarding the potential occurrence of residues in products of animal origin. EFSA calculated the ruminant exposure according to the agreed European methodology (EC, 1996) considering the propiconazole intake from apple pomace as well as from all commodities which are potential feeding items and for which the current EC MRLs are set above the LOQ (peanuts, oats and barley). The STMR and HR values for peanuts, oats and barley were derived from previous evaluations (Finland, 2005) and for apple pomace from the residue studies performed in apples. The following default processing factors were used: 2.5 for pome fruit pomace and 2 for peanut meal. The input values for the livestock dietary burden calculation are compiled in the table below. Table 3-4: Input values for the dietary burden calculation Commodity Median dietary burden Maximum dietary burden Input value Comment Input value Comment Propiconazole (residues from the proposed use) Apple pomace (wet) (0.037*2.5) STMR*PF (2.5) STMR*PF (2.5) Propiconazole (residues from the existing uses) a Barley and oat, grain 0.03 STMR 0.03 STMR Barley and oat, straw 0.28 STMR 1.03 HR Peanuts 0.07 STMR 0.07 STMR Peanut meal 0.14 (0.07*2) STMR*CF (2) 0.14 STMR*CF (2) (a): STMR and HR values reported in Revised MRL Proposals for Propiconazole presented by the RMS at the SCoCAH and WGPR Meeting held on March

17 In order to assess whether the use of apple pomace in the ruminant diet has a significant contribution to the livestock exposure to residues and whether the existing MRLs for propiconazole in food commodities of animal origin need to be amended, EFSA performed 2 scenarios of ruminant dietary burden calculations. Scenario 1 was performed with all crops, including apple pomace (Table 3-5), while scenario 2 excluded the by-product from the calculation (Table 3-6). The results of the dietary burden calculation are reported in the following tables. Table 3-5: Results of the dietary burden calculation (scenario 1) Propiconazole Maximum dietary burden (mg/kg bw/d) Median dietary burden (mg/kg bw/d) Highest contributing commodity Max dietary burden (mg/kg DM) Trigger exceeded (Y/N) Dairy ruminants Barley straw 0.34 Y Meat ruminants Barley straw 0.75 Y Table 3-6: Results of the dietary burden calculation (scenario 2) Propiconazole Maximum dietary burden (mg/kg bw/d) Median dietary burden (mg/kg bw/d) Highest contributing commodity Max dietary burden (mg/kg DM) Trigger exceeded (Y/N) Dairy ruminants Barley straw 0.30 Y Meat ruminants Barley straw 0.65 Y In both scenarios the dietary burden of 0.1 mg/kg DM was exceeded, however it was mainly driven by the existing uses of propiconazole. Barley straw is expected to be the more relevant source of the compound residues. The calculations demonstrate that there is no need to amend the current MRLs in commodities of animal origin in view of the intended use on apples. It should be noted that the livestock exposure to triazole derivative metabolites (TDMs) which might be present in primary or processed crops treated with propiconazole or with other active substances belonging to the triazole class could not be assessed since any comprehensive data on the magnitude of these metabolites is available. The conclusions on the risk assessment for commodities of animal origin are therefore provisional. According to Commission Regulation (EC) No 396/2005, the EU MRLs for the food of animal origin, with the exception of bovine, ovine and caprine liver (0.1 mg/kg), were set at the LOQ (0.01 mg/kg) of the analytical method available for the enforcement of residues. The EMS is pointing out that as the samples of tissues, organs and eggs in the feeding studies evaluated under the peer review (Finland, 1998) were analysed using the total residue GC method with a LOQ of 0.05, current MRLs for edible commodities and eggs except ruminant liver should be raised to 0.05* mg/kg align with the LOQ of the analytical method applied in the studies. EFSA suggests postponing the discussion on the amendment of the LOQ for animal commodities. It should be evaluated in the framework of the comprehensive MRL revision according to Article 12(2) of Commission Regulation (EC) No 396/2005. An analytical method to enforce the existing MRLs is available. Noteworthy is that x MRLs for food commodities are set at 0.01* mg/kg. 17

18 4. Consumer risk assessment Modification of the existing MRLs for propiconazole in grapes, apples and stone fruits The consumer exposure assessment was performed with revision 2 of the EFSA PRIMo (Pesticide Residues Intake Model) (EFSA, 2007b). For the chronic intake assessment, EFSA used the STMR values derived from the submitted supervised residue trials. For the remaining crops, the existing MRLs as established in Annex II and IIIB of Commission Regulation (EC) No 396/2005 were used. The acute intake assessment was performed only with regard to the crops under consideration applying the HR/STMR value as derived from the supervised residue trials. Processing factors were not included in the intake calculations since the studies were insufficient. However it is noted that the conservative approach used in the risk assessment (MRL values instead of the processing factors) is likely to overestimate the consumer exposure. Table 4-1. Input values for the consumer risk assessment Commodity Chronic risk assessment Acute risk assessment Input value Risk assessment residue definition: propiconazole Comment Input value Comment Apples 0.04 STMR 0.07 HR Table grapes 0.04 STMR 0.16 HR Wine grapes 0.04 STMR 0.04 STMR Apricots 0.02 STMR 0.07 HR Peaches, nectarines 0.02 STMR 0.07 HR Barley 0.03 STMR (Finland, 2005) Acute exposure was assessed only Oats 0.03 STMR (Finland, 2005 with regard to the crops under consideration. Peanuts 0.07 STMR (Finland, 2005 Other commodities of food and animal origin MRL See Appendix C The estimated long-tem and short-term exposures were compared with propiconazole ADI and the ARfD, respectively. The results of the intake calculations are reported in Appendix B to this reasoned opinion. No long-term consumer risk was identified for any of the European diets incorporated in the EFSA PRIMo. The total calculated dietary intake ranged from 1 to 6 % of the ADI. For the crops under consideration, the contribution to the total propiconazole consumer exposure was low. As percentage of the ADI, a maximum of 1.1 % was recorded for apple fruits, 0.02 % for apricots and 0.13 % for table grapes (DE child diet), while a maximum of 0.03 % was recorded for peaches and nectarines (IE adult) and of 0.4 % for wine grapes (FR all population). No acute consumer risk was identified in relation to the MRL proposals for apples, grapes, peaches, nectarines and apricots. The calculated maximum exposure in children and adults was 3.5 % and 1.7% for table grapes, 2.3 % and 0.5 % for apples, 1.4 % and 0.4 % for peaches, 0.7 % and 0.3 % for apricots and 0.1 % and 0.2 % for wine grapes, with respect to the ADI and ARfD, respectively. The consumer exposure assessment indicates that the intended uses of propiconazole on table and wine grapes, apples, apricots, peaches and nectarines are acceptable. EFSA could not perform the risk assessment for TDMs. 18

19 CONCLUSIONS AND RECOMMENDATIONS CONCLUSIONS The toxicological profile of propiconazole was assessed under the peer review and the data were sufficient to conclude on an ADI of 0.04 mg/kg bw/day and an ARfD of 0.3 mg/kg bw. The peer review concluded that the metabolism of propiconazole was sufficiently elucidated in primary crops and supported the residue definition for risk assessment and monitoring as parent compound. An analytical method for the enforcement of residues in the crops under assessment is available. However, as propiconazole, similarly to other active substances belonging to the triazole class, when applied to plant is known to produce the degradation/metabolism products named triazole derivative metabolites (TDMs), EFSA is of the opinion that the residue definitions may require to be revised pending the decision on the risk assessment methodology for all substances of the triazole chemical group. Nevertheless, as TDMs were mainly detected in the metabolism studies conducted on oilseeds and cereals with the triazole labelled propiconazole, the occurrence of TDMs for the crops under assessment might be of minor relevance. The supervised field trials in support of the intended uses were sufficient to derive provisional MRLs according to the current residue definition of propiconazole. The following MRLs would be required to accommodate the intended uses of propiconazole: 0.15 for apples, 0.1 mg/kg for apricots, peaches, nectarines and 0.3 mg/kg for table and wine grapes. A hydrolysis study simulating conditions of pasteurisation baking/brewing/boiling and sterilisation was not performed with propiconazole. The peer review did not derive specific risk assessment and enforcement residue definitions for processed commodities. Although not necessary as the total theoretical maximum daily intake (TMDI) is less than 10 % of the ADI, specific studies investigating the effect of processing on the magnitude of propiconazole residues on grapes, apples and stone fruits were provided in the framework of these applications. Since the nature of propiconazole residues is not fully investigated and since the possible occurrence of TDMs in processed products should be reconsidered, EFSA does not recommend the derived processing factors. Further investigations, such as the performance of a hydrolysis study, with the compound are recommended prior to apply for additional crop uses. For apples, grapes and stone fruits (perennial crops) the crop rotation is not relevant and was therefore not evaluated in the framework of these MRL applications. The exposure of livestock to propiconazole residues form the intake of apple pomace, the only byproducts used as feed item, was assessed in ruminants. The other crops and livestock species are not relevant regarding the potential occurrence of residues in products of animal origin. The ruminant exposure to propiconazole residues was calculated considering the intake from apple pomace as well as from all commodities which are potential feeding items and for which the current EC MRLs are set above the LOQ (peanuts, oat and barley). The dietary burden of 0.1 mg/kg DM was exceeded but was mainly driven by the existing uses of propiconazole on feed crops. The contribution of apple pomace to the total ruminant dietary exposure was low. Thus, the existing EU MRLs for the food commodities of animal origin do not require to be amended in view of the intended use of propiconazole in apples. The consumer exposure assessment was performed with revision 2 of the EFSA PRIMo (Pesticide Residues Intake Model). For the chronic intake assessment, EFSA used the STMR value derived from the submitted supervised residue trials and the existing MRLs as established in Commission Regulation (EC) No 396/2005. The acute intake assessment was performed only with regard to the crops under consideration applying the HR/STMR values as derived from the supervised residue trials. The estimated long-tem and short-term exposures were compared with the toxicological reference values established for propiconazole. 19