Modification of the existing MRL for procymidone in soybean 1

Transcription

1 REASNED PININ Modification of the existing MRL for procymidone in soybean 1 European Food Safety Authority 2 European Food Safety Authority (EFSA), Parma, Italy SUMMARY According to Article 6 of the Regulation (EC) No 396/2005, France, herewith referred as the evaluating Member State (EMS), received an application from Sumitomo Chemical Co., Ltd. to amend the existing MRL on soybean for the active substance procymidone. In order to accommodate the use of procymidone on soybean in Brazil, it is proposed to raise the existing MRL of 0.05 mg/kg to 0.5 mg/kg. France drafted an evaluation report according to Article 8 of that regulation, which was submitted to the European Commission and forwarded to EFSA on 13 September EFSA bases its assessment on the evaluation report prepared by the EMS France, the draft assessment report (DAR), the addenda to the DAR, the reports of the expert meetings organised in support of the procedure to include the active substance in Annex I of Council Directive 91/414/EEC and previously issued EFSA reasoned opinions. The toxicological profile of procymidone was investigated by the rapporteur Member State France in the framework of the peer review under Directive 91/414/EEC and again in 2007 in view of the extension of the Annex I inclusion. Taking into account the new data provided by the manufacturer for the Annex I prolongation, France proposed to set lower ADI and ARfD values (ADI mg/kg bw/d, ARfD mg/kg bw) compared with the values derived in the first peer review. Member States and the European Commission confirmed that these toxicological reference values should be used for the risk assessment of MRLs although there was no formal adoption of these values by the Standing Committee on Food Chain and Animal Health. The metabolism of procymidone was investigated in cucumber, grape vines, kidney beans and in lettuce, representing crops belonging to the group of fruits and fruiting vegetables, pulses and oilseeds and leafy vegetables. The metabolism pattern was similar in all crops with procymidone as the predominant compound of the total residues. The EMS proposed to define both the monitoring and risk assessment residue definitions as the parent compound alone. This is in line with the current residue definition for enforcement purposes in Regulation (EC) No 396/2005. The multi-residue analytical method DFG S19 is sufficiently validated at the limit of quantification of 0.02 mg/kg and is suitable for enforcement purposes in all categories of crops, including soybeans. 1 n request from the European Commission, Question No EFSA-Q , issued on 18 April Correspondence: praper.mrl@efsa.europa.eu Suggested citation: European Food Safety Authority; Modification of the existing MRL for procymidone in soya bean.. [34 pp.] doi: /j.efsa Available online: European Food Safety Authority, 2011

2 The number of supervised residue trials performed in accordance with the intended GAP was sufficient to derive an MRL proposal of 0.5 mg/kg for procymidone in soybeans. A new hydrolysis study has been provided in the framework of this MRL application. Procymidone was shown to be stable under pasteurisation conditions, but degraded significantly under baking/boiling/brewing and sterilisation processing conditions into procymidone-nh-ch, 1,2- dimethylcyclopropane-1,2-dicarboxylic acid (CCA) and 3,5-dichloroaniline (3,5-DCA). Since the refining of oil or the production of other processed soybean products (e.g. soybean milk, soybean sauce, tofu) involves steps where hydrolytic processes may be relevant, the formation of these degradation products cannot be excluded in processed soybean products. The toxicological relevance of the degradation products identified in the hydrolysis studies and their magnitude in the processed commodities were not addressed by the EMS. Processing studies were submitted for rape seed and sunflower seed where the procymidone concentration was measured in rape seed cake and in rape seed and sunflower oil (crude oil and refined oil). The studies demonstrate that procymidone residues accumulate in the crude and unrefined oil as a result of its fat solubility (LogP ow : 3.3). In deodorised rape seed oil, however, the residue concentrations were significantly lower. In refined sunflower oil only a slight reduction was observed. No information on the concentration of the degradation products identified in the hydrolysis studies was reported. The occurrence of procymidone residues in rotational and/or succeeding crops was not investigated as the crop rotation is not relevant for the import tolerance applications. Soybean is an important feed item and therefore the possible carry-over of procymidone residues in food of animal origin has to be considered. However, it is noted that the current residue definition for enforcement purposes for animal commodities was established in Regulation (EC) No. 396/2005 as vinclozolin, iprodione, procymidone, sum of compounds and all metabolites containing the 3,5- dichloroaniline moiety expressed as 3,5-dichloroaniline. Thus, for estimating the dietary exposure of livestock and the transfer into food of animal origin the total exposure resulting from feed containing residues of all three active substances has to be included. When performing these calculations, EFSA identified soybeans containing procymidone residues being an insignificant contributor to the overall dietary burden. It is therefore concluded the import of soybeans from Brazil containing residues at 0.5 mg/kg will not have an impact on the procymidone MRLs for animal commodities established in the Regulation (EC) No.396/2005. The consumer dietary risk assessment for procymidone was performed with revision 2 of the EFSA PRIMo. For the calculation of the chronic exposure, EFSA used the median residue value as derived from the residue trials on soybean. For the remaining commodities of plant and animal origin, the existing MRLs as established in Annex II of Regulation (EC) No 396/2005 were used as input values. The acute dietary intake risk assessment was carried out only with regard to soybean applying the STMR value as derived from the supervised residue trials on this crop. No chronic intake concerns were identified for any of the European diets and the total intake values accounted for a maximum of 93.2% of the ADI. The contribution of soybean to the total dietary intake was low (2.1 % ADI WH cluster diet F). No acute intake concerns were identified in relation to the MRL proposal for soybean (1.7 % of the ARfD). However, since no data are available to conclude on the toxicological relevance of the degradation products identified in the hydrolysis studies and the expected concentration of these metabolites in oil or other processed products derived from soybeans (e.g. soybean milk, soybean sauce, etc...), the consumer risk assessment for this application cannot be finalised. Since EFSA cannot exclude a 2

3 potential consumer health risk resulting from the procymidone degradation products procymidone- NH-CH, 1,2-dimethylcyclopropane-1,2-dicarboxylic acid and 3,5-dichloroaniline, EFSA does not recommend to amend the existing MRL for soybeans. EFSA also recommends to review the existing MRLs for procymidone with view to the possible formation of the degradation products identified in the new hydrolysis study and the related consumer health risks. Therefore EFSA does not derive a final MRL proposal for the import tolerance request for soybeans. Code number Commodity Existing EC MRL Enforcement residue definition: Procymidone Proposed EC MRL Justification for the proposal Soybean The MRL application is supported by data to derive a MRL proposal for procymidone. However, data gaps were identified regarding the toxicological relevance and the magnitude of degradation products that may be formed during the processing of soybeans. Therefore EFSA does not recommend to amend the existing MRL. KEY WRDS Procymidone, fungicide, soybean, MRL application, Regulation (EC) No 396/2005, consumer risk assessment. 3

4 TABLE F CNTENTS Summary... 1 Table of contents... 4 Background... 5 Terms of reference... 5 The active substance and its use pattern... 6 Assessment Methods of analysis Methods for enforcement of residues in food of plant origin Methods for enforcement of residues in food of animal origin Mammalian toxicology Residues Nature and magnitude of residues in plant Primary crops Rotational crops Nature and magnitude of residues in livestock Consumer risk assessment Conclusions and recommendations References Appendix A Good Agricultural Practices (GAPs) Appendix B Pesticide Residues Intake Model (PRIMo) Appendix C Existing EC MRLs Appendix D List of metabolites and related structural formula Abbreviations

5 BACKGRUND Regulation (EC) No 396/ establishes the rules governing the setting of pesticide MRLs at Community level. Article 6 of that regulation lays down that any party having a legitimate commercial interest may submit to the rapporteur Member State designated pursuant to Council Directive 91/414/EEC 4 an application to set an import tolerance in accordance with the provisions of Article 7 of that regulation. France which acted as the rapporteur Member State for the European peer review of procymidone and hereafter referred to as the evaluating Member State (EMS), received from the company Sumitomo Chemical Co., Ltd. 5, an application to modify the existing MRL for the active substance procymidone in soybean, in the frame of an import tolerance. This application was notified to the European Commission and EFSA and subsequently evaluated by the EMS in accordance with Article 8 of the Regulation. The evaluation report of the EMS was submitted to the European Commission who forwarded the application and the evaluation report to EFSA on 13 September The application was included in the EFSA Register of Questions with the reference number EFSA-Q and the following subject: Procymidone Modification of the existing MRL for procymidone in soybean. To accommodate the use on soybean in Brazil, the EMS proposed to set the import tolerance at 0.5 mg/kg. EFSA proceeded with the assessment of the application as required by Article 10 of the Regulation. TERMS F REFERENCE According to Article 10 of Regulation (EC) No 396/2005, EFSA shall, based on the evaluation report provided by the evaluating Member State, provide a reasoned opinion on the risks to the consumer associated with the application. According to Article 11 of that Regulation, the reasoned opinion shall be provided as soon as possible and at the latest within 3 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 13 December Regulation of the Council and Parliament (EC) No 396/2005 of 23 February J L 70, , p Council Directive 91/414/EEC of 15 July 1991, J L 230, , p Sumitimo Chemical Co., Ltd. 27-1, Shinkawa 2-chome chuo-ku, Tokyo (Japan) 5

6 THE ACTIVE SUBSTANCE AND ITS USE PATTERN Procymidone is the IS common name for N-(3,5-dichlorophenyl)-1,2-dimethylcyclopropane-1,2- dicarboximide (IUPAC). N CH 3 CH 3 Molecular weight: Procymidone belongs to the class of dicarboximide fungicides. It is moderately systemic and acts as an inhibitor of triglyceride synthesis in fungi. Procymidone has been assessed in the framework of Directive 91/414/EEC in the first stage with France being the designated Rapporteur Member State. The resulting decision on inclusion in Annex I to Directive 91/414/EEC, which was published in Directive 2006/132/EC 6 and entered into force on 1 January 2007, was linked to specific risk mitigation measures. The Annex I inclusion was restricted to the use as fungicide only on: cucumbers in greenhouses (closed hydroponic systems), plums (for processing), at application rates not exceeding 0.75 kg a.s./ha per application. In accordance with the provisions of Directive 91/414/EEC, the manufacturer of procymidone submitted further data in order to renew the Annex I inclusion beyond June These data were evaluated by the Rapporteur Member State in an addendum to the Draft Assessment Report (DAR) (France 2007). EFSA was not requested by the European Commission to organise a peer review of the new submitted data. The Annex I inclusion expired on 30 June 2008 because no proposal regarding the renewal of the Annex I inclusion or a specific non-inclusion decision was prepared by the European Commission on this active substance. As a consequence, the above mentioned uses had to be revoked by 1 July Member States and the European Commission agreed that the toxicological reference values proposed by the Rapporteur Member State France in the addendum to the DAR (France, 2007) should be used at European level. These updated ADI and ARfD were also included in the EU Pesticides database on the European Commission Website: ( Following the revocation of the authorisations at EU level and the lowering of the toxicological reference values, the EU MRLs for procymidone were revised by Commission Regulation (EC) No 1097/ Codex Alimentarius adopted CXLs on plant commodities in 1995 and At the 42 nd session of the CCPR, the Committee noted that there was no support by the manufacturers and agreed to consider 6 Commission Directive 2006/132/EC of 11 December J L 349, , p Commission Regulation (EC) No 1097/2009 of 16 November J L 301, , p

7 revocation of all these CXLs at the next session. It is noted that currently there is still a CXL of 1 mg/kg for pulses in the Codex system which is also applicable for soybeans. Sumitomo Chemical Co., Ltd has submitted an application for an import tolerance to modify the existing MRL for the active substance procymidone in soybean grown in Brazil. The current MRL on soybean is set at 0.05 mg/kg and the MRL proposal in this application is 0.5 mg/kg. The Brazilian GAP on soybean refers to 2 foliar spray applications of procymidone (interval between applications: days) as a wettable powder (WP) formulation at a dose rate of 0.5 kg a.s./ha at BBCH growth stage 66 (about 60% of flowers open) and a minimum PHI of 60 days. The details of the intended GAP are summarized in Appendix A. 7

8 ASSESSMENT EFSA bases its assessment on the evaluation report submitted by the EMS (France, 2010), the Draft Assessment Report (France, 2000) prepared under Council Directive 91/414/EEC, a first addendum to the DAR (France, 2002), a second addendum to the DAR (France, 2007) as well as the previously issued EFSA reasoned opinions (EFSA, 2008, 2009). EFSA also refers to the expert meetings on mammalian toxicology (ECC 123) and on residues (ECC 125) organised in support of the procedure to include procymidone in Annex I to Directive 91/414/EEC (EC, 2002a; 2002b) and to the Review Report for the active substance procymidone finalised at the Standing Committee on the Food Chain and Animal Health in view of the inclusion of the active substance in Annex I of Directive 91/414/EEC (EC, 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, 2010). 1. Methods of analysis 1.1. Methods for enforcement of residues in food of plant origin A multi-residue analytical method DFG S19 has been assessed for the determination of residues of procymidone in plant commodities in the Addendum to the DAR (2002) and reassessed in the addendum to the DAR (2007). The residues were extracted with acetone followed by partitioning against ethyl acetate/cyclohexane with subsequent clean-up steps. The final determination of the residues of procymidone was carried out by GC/MSD analysis. The method was validated for crops belonging to the groups of: high water content (white cabbage), high acid content (currant), high oil content (oilseed rape), dry crops (barley grain) and in barley straw. The validation data package demonstrated that for each crop a limit of quantification (LQ) of 0.02 mg/kg can be achieved for procymidone. The EMS considered that the DFG S19 multiresidue method was fully validated at the limit of quantification of 0.02 mg/kg and suitable for enforcement purposes in compliance with the residue definition for monitoring established under Regulation (EC) No 396/2005. A confirmatory method was not required since this method is considered as highly specific. No ILV was reported as the multiresidue DFG S19 method is an official analytical method Methods for enforcement of residues in food of animal origin Not required in the framework of this MRL application. 8

9 2. Mammalian toxicology In the peer review under Directive 91/414/EEC, an ADI of mg/kg bw/day and an ARfD of mg/kg bw was assigned to procymidone (EC, 2007). In the framework of the prolongation of the Annex I inclusion, the applicant submitted additional data which were assessed by the RMS France in an addendum to the Draft Assessment Report (France, 2007) where France proposed significantly lower ADI and ARfD values. Member States and the European Commission confirmed that these lower toxicological reference values should be used for the risk assessment of MRLs although there was no formal adoption of these values by the Standing Committee on Food Chain and Animal Health. In Table 2-1 the results of the two evaluations are summarised. Table 2-1. verview of the toxicological reference values Source Procymidone (EC, 2007) Year Value (mg/kg bw/d) Study relied upon Safety factor ADI EC Multi-generation study in rats 100 ARfD EC Developmental toxicity study in rats 100 Procymidone (France, 2007) ADI FR Two generation study in rats 900 ARfD FR Rat developmental study 300 9

10 3. Residues 3.1. Nature and magnitude of residues in plant Primary crops Nature of residues The metabolism of procymidone was investigated in fruits and fruiting vegetables (grapes, cucumber), leafy vegetables (lettuce) and pulses and oilseeds (kidney beans) using procymidone as the test substance [ 14 C] labelled either on the carbonyl moiety (cucumber, kidney bean) or on the phenyl ring (lettuce) or on both the carbonyl moiety and the phenyl ring (grapevines). Table 3-1. Summary of the experimental design of the available metabolism studies in plants Group Crop Label position (F) r (G/I) (a) Rate (kg a.s./ha) Application details No/ interval Samplin g (DALA) (b) Remark Fruits and fruiting vegetables Grapevines Phenyl-(U)- 14 C; Carbonyl-(U)- 14 C Foliar, F 1500 g a.s./ha Fruits and fruiting vegetables Leafy vegetables Pulses and oilseeds Cucumber Carbonyl-(U)- 14 C Foliar, F Fruit, F Root, F Lettuce Phenyl-(U)- 14 C Foliar, F Kidney beans Carbonyl-(U)- 14 C Foliar, F Soil, F 250 µg a.s./leaf 300 µg a.s./fruit 4 ppm in aqueous solution 809 g a.s./ha 250 µg a.s./leaf Soil treated at a rate of 10 mg a.s./kg (dw basis) (a): utdoor/field use (F) or glasshouse/protected crops/indoor application (G) (b): Days after last application These studies demonstrated that metabolism of procymidone in the crops investigated is comparable, with the parent procymidone recovered as the predominant compound of the total residues. Procymidone accounted for 36% and 58% of the applied radioactivity in kidney beans leaves and cucumber, respectively, 91% TRR in grapes and 97% TRR in lettuce. Minor metabolites were also identified as 4 -H-procymidone 8, procymidone-nh-ch 9 and procymidone-ch 2 -H 10 at a very 8 4 H-procymidone: see Appendix D 9 Procymidone-NH-CH: see Appendix D 10 Procymidone-CH 2 -H: see Appendix D 10

11 low level in cucumber, kidney beans leaves and lettuce (<1.4% of AR) whilst in grapes, additional metabolites were detected as the 3,5-dichloroaniline 11 (3,5-DCA, 2.1% TRR), cyclopropanedicarboxylic acid 12 (CCA, 0.5% TRR) and the glucoside conjugate of the metabolite procymidone-ch 2 -H (3.3% TRR). The unidentified radioactive residues in cucumber and kidney beans leaves were not further characterized. It should be highlighted that after foliar application on kidney beans, the total radioactive residues in pods and seeds accounted for mg/kg and mg/kg, respectively and therefore no further investigation of the metabolites in the seeds was attempted. The metabolites 4 -H-procymidone, procymidone-ch 2 -H, procymidone-ch 2 -H-glucuronide and 3,5-DCA (3,5-dichloroaniline) were recovered in the rat faeces and urine. During the Peer Review, further information was requested on the toxicological relevance of the 3,5-DCA metabolite. Although additional data (Addendum, 2007) that were not peer reviewed demonstrated that procymidone was transformed to procymidone-nh-ch in relation to the ph conditions in vitro, the metabolite procymidone-nh-ch was not detected in the rat metabolism. It was also unclear whether the metabolite CCA was formed in the rat metabolism. Nevertheless, based on the available metabolism studies in primary crops, these metabolites are not expected to be found in significant concentrations in the edible parts of the crops and were therefore not included in the residue definition for risk assessment (France, 2000). The EMS proposed to define both the monitoring and risk assessment residue definition as the parent compound alone for all the categories of crops. The current residue definition in Regulation (EC) No 396/2005 is similar to the residue definition for enforcement purposes proposed by the EMS Magnitude of residues During the growing seasons, 8 supervised residue trials were performed on non-genetically modified soybean varieties in compliance with the critical GAP and were carried out in 6 representative soybean field growing areas in Brazil. For each trial site, one trial plot was untreated while the treated plot received two applications at a dose of 0.5 kg a.s./ha with day interval between the 2 applications, the first one occurring at flowering. The PHI values ranged between 45 and 75 days. The samples from the supervised residue trials were stored under frozen conditions for a maximum of 28 days and were therefore covered by the available storage stability data for high oil content matrices. An analytical method using LC-MS/MS was submitted for the determination of the procymidone residues in soybean in the supervised residue trials. This method was considered as sufficiently validated according to the current guidance document (EC, 2000) at the limit of quantification of 0.01 mg/kg. Storage stability data on procymidone residues in high water matrices (tomato, cucumber, lettuce, shallots, haricot beans, sour cherries, egg plant), in high acid matrices (strawberries, grapes) and in high oil content (sunflower seed) were reported in the original DAR (France, 2000) and showed that the residues of procymidone can be considered as stable for up to 12 months. A new storage stability study on oilseed rape was reported in the addendum to the DAR (France, 2007) and confirmed the frozen storage stability of the procymidone residues over the same period. 11 3,5-DCA: see Appendix D 12 CCA: see Appendix D 11

12 The results of the supervised residue trials, the related risk assessment input values (STMR, HR) and the MRL proposal on soybean are summarized in Table 3-2. EFSA considers that the data are sufficient to derive a MRL proposal of 0.5 mg/kg to accommodate the use of procymidone on soybean in Brazil. 12

13 Table 3-2. verview of the available residue trials data Commodity Region (a) utdoor /Indoor Individual trial results Enforcement Risk assessment STMR (b) HR (c) MRL proposal Median CF (d) Comments Residue definition for enforcement and risk assessment: Procymidone Soybean Import (Brazil) utdoor 0.028; 0.032; 0.053; 0.076; 0.103; 0.228; 0.229; ; 0.032; 0.053; 0.076; 0.103; 0.228; 0.229; Rmax=0.456 mg/kg Rber=0.457 mg/kg (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. (*): Indicates that the MRL is set at the limit of analytical quantification. 13

14 Effect of industrial processing and/or household preparation A hydrolysis study addressing the effect of processing on the nature of the residues was reported in the addendum to the DAR (France, 2007). The hydrolysis of Carbonyl-(U)-[ 14 C] and Phenyl-(U)- [ 14 C]- procymidone was conducted in buffered aqueous solutions at temperatures, times and phs representative of the processes of pasteurisation, baking/brewing/boiling and sterilisation. Procymidone was shown to be stable under pasteurisation and degraded significantly under baking/boiling/brewing and sterilisation processing conditions into procymidone-nh-ch (up to 8.8 % AR) and cyclopropanedicarboxylic acid (CCA) (15.5 % AR) for the Carbonyl-(U)-[ 14 C] labelling form and into procymidone-nh-ch (up to 8.9 % AR) and 3,5-dichloroaniline (3,5-DCA) (16.4 % AR) for the Phenyl-(U)-[ 14 C] labelling form. No information is available regarding the toxicological relevance of the degradation products identified. It is noted that in the framework of the peer review specifically data to characterise the toxicological properties of the metabolite 3,5-dichloroaniline (3,5-DCA) were requested. Since the refining of oil or the production of other processed soybean products (e.g. soybean milk, soybean sauce, tofu) involves steps where hydrolytic processes may be relevant, the formation of these degradation products cannot be excluded in processed soybean products. Due to the outstanding data on the toxicological relevance of these metabolites and their magnitude in the processed commodities, no final conclusion on a risk assessment residue definition can be taken at the moment. The applicant also submitted studies investigating the effect of processing on the magnitude of procymidone residue concentration in rape seed oil and sunflower seed oil and the relevant byproducts. The key findings of the studies are summarised in Table 3-3 and 3-4. Table 3-3. verview of the available processing studies ilseed rape (oil content: circa 40%) Processed commodity Number of studies Median PF (a) Enforcement residue definition: Procymidone Median CF (b) Pressed oil Extracted oil Whitened oil Comments Deodorised oil The procymidone residue level recovered in the deodorised oil was <0.05 mg/kg. Cake (c) - The procymidone residue level recovered in cattle cake was <0.05 mg/kg. (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. (c): The processing factor for cake was derived from only one residue trial and can therefore not be considered as reliable. The default processing factor of 1.3 was used to perform the livestock dietary burden calculation 14

15 Table 3-4. verview of the available processing studies Sunflower (oil content: circa 25-30%) Processed commodity Number of studies Enforcement residue definition: Procymidone Individual PF Median CF (a) Crude oil 2 2.4; Refined oil 2 2.0; Comments (a): The median conversion factor for enforcement to risk assessment is obtained by calculating the median of the individual conversion factors of each processing study. The processing factors reported in Tables 3-3 and 3-4 were derived from the residue levels of procymidone determined in oilseed rape and sunflower seed, rape seed cake and in oil at various stages (crude oil and refined oil). The results demonstrated that residues of procymidone concentrated mainly in rape seed and sunflower crude oil as procymidone is considered as fat soluble (log Pow=3.3). EFSA does not recommend including these processing factors in Annex VI of Regulation (EC) No 396/2005 because the values are based on insufficient number of trials and because of the open questions on the residue definition for processed commodities. Since the formation of the degradation products identified in the hydrolysis study may be of relevance also for other commodities on which procymidone is used, EFSA recommends to review the existing MRLs for procymidone with view to the possible formation of the degradation products identified in the new hydrolysis study and the related consumer health risks Rotational crops Not relevant for the requested import tolerance Nature and magnitude of residues in livestock Soybean and/or its by-products can be used as livestock feed according to EU guidance documents (EC, 1996) and therefore the potential livestock exposure to procymidone residues and the possible carry-over of residues to food commodities of animal origin has to be assessed. Since the residue definition for enforcement purposes for animal commodities was established as vinclozolin, iprodione, procymidone, sum of compounds and all metabolites containing the 3,5- dichloroaniline moiety expressed as 3,5-dichloroaniline, the contribution of the residues of iprodione and vinclozoline in feed items to the livestock exposure has also to be assessed. EFSA calculated the median and maximum dietary burdens for the different types of livestock using the agreed European methodology (EC, 1996) in three scenarios, estimating the contribution of soybeans to the total dietary burden of livestock, taking into account also the exposure to residues for procymidone, vinclozolin and iprodione. In Scenario 1 the exposure was calculated for procymidone, including feed items derived from commodities for which currently EU MRLs are set above the LQ, i.e. peas, sunflower seed and rape seed. In addition, the residue concentrations expected on imported soybeans from Brazil were included in the calculation. For soybean meal the default processing factor of 1.3 was applied. The input values for the dietary burden calculation are summarised in Table 3-5. Table 3-5. Input values for the dietary burden calculation - procymidone (scenario 1) 15

16 Commodity Median dietary burden Maximum dietary burden Input value Risk assessment residue definition: Procymidone Comment Input value Comment Soybean 0.09 STMR 0.09 STMR Soybean meal cake STMR-P (PF = 1.3) STMR-P Sunflower seed 0.2 EU MRL 0.2 EU MRL Sunflower seed meal 0.26 MRL-P (PF = 1.3) 0.26 MRL-P (PF = 1.3) Peas, dry 0.2 EU MRL 0.2 EU MRL The resulting dietary burden for procymidone did not exceed the trigger value of 0.1 mg/kg except for pigs, where the maximum dietary burden slightly exceeds the trigger (Table 3-6). Peas were identified as the main contributor to the overall dietary burden under this scenario. Table 3-6. Results of the dietary burden calculation procymidone (scenario 1) Maximum dietary burden (mg/kg bw/d) Median dietary burden (mg/kg bw/d) Risk assessment residue definition: Procymidone Highest contributing commodity Max dietary burden (mg/kg DM) Trigger exceeded Dairy ruminants Peas, dry No Meat ruminants Peas, dry No Poultry Peas, dry No Pigs Peas, dry Yes In Scenario 2 EFSA calculated the dietary burden for vinclozoline. In this scenario the MRLs for beans and root and tuber vegetables were included in the calculation, the only feed crops for which MRLs are established above the LQ. The input values are presented in Table 3-7. Table 3-7. Input values for the dietary burden calculation vinclozolin (scenario 2) Commodity Median dietary burden Input value Comment Maximum dietary burden Input value Comment Root and tuber vegetables 0.05 EU MRL 0.05 EU MRL Beans, dry 0.5 EU MRL 0.5 EU MRL 16

17 Table 3-8. Results of the dietary burden calculation vinclozolin (scenario 2) Maximum dietary burden (mg/kg bw/d) Median dietary burden (mg/kg bw/d) Highest contributing commodity Max dietary burden (mg/kg DM) Trigger exceeded Dairy ruminants turnips Yes Meat ruminants turnips Yes Poultry beans (dry) Yes Pigs turnips Yes In this scenario the dietary burden exceeds the trigger value for all species (Table 3-8). In scenario 3 finally, the dietary exposure is calculated for iprodione, including feed commodities and by-products derived thereof for which the MRLs for iprodione are set at levels above the LQ. The input values for this scenario are summarised in Table 3-9. Table 3-9. Input values for the dietary burden calculation iprodione (scenario 3) Commodity Median dietary burden Maximum dietary burden Input value Comment Input value Comment Cabbage 5 EU MRL 5 EU MRL Apple pomace 12.5 EU MRL* PF (2.5) 12.5 EU MRL* PF (2.5) Lemon pomace 12.5 EU MRL *PF (2.5) 12.5 EU MRL *PF (2.5) Peas, beans, lupins 0.2 EU MRL 0.2 EU MRL Rape seed 0.5 EU MRL 0.5 EU MRL Rape seed meal 0.8 EU MRL*PF 0.8 EU MRL*PF Sunflower seed 0.5 EU MRL 0.5 EU MRL Sunflower seed meal 0.7 EU MRL*PF 0.7 EU MRL*PF Wheat grain 0.5 EU MRL 0.5 EU MRL Wheat bran 4 EU MRL*PF 4 EU MRL*PF Sugar beet root 0.2 EU MRL 0.2 EU MRL Table Results of the dietary burden calculation iprodione (scenario 3) 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 Dairy ruminants Cabbage 13.9 Yes Meat ruminants Lemon pomace 17.7 Yes Poultry Cabbage 2.83 Yes Pigs Cabbage 6.94 Yes 17

18 Based on the different scenarios of livestock exposure presented here above, the main contributors to the livestock dietary intake are the residues of iprodione and vinclozolin in the feed items. From scenario 1, it can be concluded that the residues of procymidone in soybean meal cake will not contribute significantly to the slightly exceedance of the trigger value of 0.1 mg/kg DM for the dietary burden for pigs and therefore, EFSA is of the opinion that the presence of procymidone on soybeans imported from Brazil will not alter the overall dietary exposure of livestock. It is therefore not necessary to revise the existing MRLs for animal commodities established in Regulation (EC) No 396/ Consumer risk assessment The consumer risk assessment for procymidone was performed with revision 2 of the EFSA Pesticide Residues Intake Model (PRIMo). This exposure assessment model contains the relevant European food consumption data for different sub-groups of the EU population 13 (EFSA, 2007). For the calculation of the chronic exposure, EFSA used the median residue value as derived from the residue trials on soya bean (see Table 3-2). For the remaining commodities of plant and animal origin, the existing MRLs as established in Annex II of Regulation (EC) No 396/2005 were used as input values. The model assumptions for the long-term exposure assessment are considered to be rather conservative, assuming that all food items consumed have been treated with the active substance under consideration. In reality, it is not likely that all food consumed will contain residues at the MRL or at levels of the median residue values identified in supervised field trials. However, if this first tier exposure assessment, does not exceed the toxicological reference value for long-term exposure (i.e. the ADI), a consumer health risk can be excluded with a high probability. The acute exposure assessment was performed only with regard to the commodity under consideration assuming the consumption of a large portion of the food item as reported in the national food surveys containing residues at the highest level as observed in supervised field trials. Table 4-1. Commodity Input values for the consumer exposure assessment Chronic exposure assessment Input value Risk assessment residue definition: Procymidone Comment Acute exposure assessment Input value Comment Soybean 0.09 STMR 0.09 STMR ther food commodities of plant and animal origin (1) EU MRL See Appendix C Not relevant (1) : The MRLs for food commodities of animal origin were established in compliance with the enforcement residue definition for animal commodities, i.e. vinclozolin, iprodione, procymidone, sum of compounds and all metabolites containing the 3,5-dichloroaniline moiety expressed as 3,5-dichloroaniline and are therefore expressed as 3,5-dichloroaniline equivalents. No conversion into procymidone equivalent was applied as the current procymidone MRLs are at the LQ. 13 The calculation of the long-term exposure (chronic exposure) is based on the mean consumption data representative for 22 national diets collected from MS surveys plus 1 regional and 4 cluster diets from the WH GEMS Food database; for the acute exposure assessment the most critical large portion consumption data from 19 national diets collected from MS surveys is used. The complete list of diets incorporated in EFSA PRIMo is given in its reference section (EFSA, 2007). 18

19 The estimated exposure was compared with the toxicological reference value derived for procymidone (see Table 2-1). The results of the intake calculation are presented in Appendix B of this reasoned opinion. No chronic intake concerns were identified for any of the European diets and the total intake values accounted for a maximum of 93.2% of the ADI. The contribution of soybean to the total dietary intake was low (2.1% ADI WH cluster diet F). No acute intake concerns were identified in relation to the MRL proposal for soybean (1.7% of the ARfD). EFSA could not perform a consumer risk assessment for the degradation products formed during processing of soybeans. Therefore the consumer risk assessment is considered as incomplete. Further information regarding the toxicological relevance of the degradation products and their magnitude in the processed commodities needs to be provided. 19

20 CNCLUSINS AND RECMMENDATINS CNCLUSINS The toxicological profile of procymidone was investigated by the rapporteur Member State France in the framework of the peer review under Directive 91/414/EEC and again in 2007 in view of the extension of the Annex I inclusion. Taking into account the new data provided by the manufacturer or the Annex I prolongation, France proposed to set lower ADI and ARfD values (ADI mg/kg bw/d, ARfD mg/kg bw) compared with the values derived in the first peer review. Member States and the European Commission confirmed that these toxicological reference values should be used for the risk assessment of MRLs although there was no formal adoption of these values by the Standing Committee on Food Chain and Animal Health. The metabolism of procymidone was investigated in cucumber, grape vines, kidney beans and in lettuce, representing crops belonging to the group of fruits and fruiting vegetables, pulses and oilseeds and leafy vegetables. The metabolism pattern was similar in all crops with procymidone as the predominant compound of the total residues. The EMS proposed to define both the monitoring and risk assessment residue definitions as the parent compound alone. This is in line with the current residue definition for enforcement purposes in Regulation (EC) No 396/2005. The multi-residue analytical method DFG S19 is sufficiently validated at the limit of quantification of 0.02 mg/kg and is suitable for enforcement purposes in all categories of crops, including soya beans. The number of supervised residue trials performed in accordance with the intended GAP was sufficient to propose an MRL of 0.5 mg/kg for procymidone in soybeans. A new hydrolysis study has been provided in the framework of this MRL application. Procymidone was shown to be stable under pasteurisation conditions, but degraded significantly under baking/boiling/brewing and sterilisation processing conditions into procymidone-nh-ch, 1,2- dimethylcyclopropane-1,2-dicarboxylic acid (CCA) and 3,5-dichloroaniline (3,5-DCA). Since the raffination of oil or the production of other processed soybean products (e.g. soybean milk, soybean sauce, tofu) involves steps where hydrolytic processes may be relevant, the formation of these degradation products cannot be excluded in processed soybean products. The toxicological relevance of the degradation products identified in the hydrolysis studies and their magnitude in the processed commodities were not addressed by the EMS. Processing studies were submitted for rape seed and sunflower seed where the procymidone concentration was measured in rape seed cake and in rape seed and sunflower oil (crude oil and refined oil). The studies demonstrated that procymidone residues accumulate in the crude, unrefined oil which is a result of its fat solubility. In deodorised rape seed oil, however, the residue concentrations were significantly lower. In refined sunflower oil only a slight reduction was observed. No information on the concentration of the degradation products identified in the hydrolysis studies was reported. The occurrence of procymidone residues in rotational and/or succeeding crops was not investigated as the crop rotation is not relevant for the import tolerance applications. Soybean is an important feed item and therefore the possible carry-over of procymidone residues in food of animal origin has to be considered. However, it is noted that the current residue definition for enforcement purposes for animal commodities was established in Regulation (EC) No. 396/2005 as vinclozolin, iprodione, procymidone, sum of compounds and all metabolites containing the 3,5-20

21 dichloroaniline moiety expressed as 3,5-dichloroaniline. Thus, for estimating the dietary exposure of livestock and the transfer into food of animal origin the total exposure resulting from feed containing residues of all three active substances has to be included. When performing these calculations, EFSA identified soybeans containing procymidone residues being an insignificant contributor to the overall dietary burden. It is therefore concluded the import of soybeans from Brazil containing residues at 0.5 mg/kg will not have an impact on the procymidone MRLs for animal commodities established in the Regulation (EC) No.396/2005. No chronic intake concerns were identified for any of the European diets and the total intake values accounted for a maximum of 93.2% of the ADI. The contribution of soybean to the total dietary intake was low (2.1 % ADI WH cluster diet F). No acute intake concerns were identified in relation to the MRL proposal for soybean (1.7 % of the ARfD). However, since no data are available to conclude on the toxicological relevance of the degradation products identified in the hydrolysis studies and the expected concentration of these metabolites in oil or other processed products derived from soybeans (e.g. soybean milk, soybean sauce, etc...), the consumer risk assessment for this application cannot be finalised. RECMMENDATINS Since EFSA cannot exclude a potential consumer health risk resulting from the procymidone degradation products procymidone-nh-ch, 1,2-dimethylcyclopropane-1,2-dicarboxylic acid and 3,5-dichloroaniline, EFSA does not recommend to amend the existing MRL for soybeans. EFSA also recommends to review the existing MRLs for procymidone with view to the possible formation of the degradation products identified in the new hydrolysis study and the related consumer health risks. Code number Commodity Existing EC MRL Enforcement residue definition: Procymidone Proposed EC MRL Justification for the proposal Soybean The MRL application is supported by data to derive a MRL proposal for procymidone. However, data gaps were identified regarding the toxicological relevance and the magnitude of degradation products that may be formed during the processing of soybeans. Therefore EFSA does not recommend to amend the existing MRL. 21

22 REFERENCES EC (European Commission), Appendix G. Livestock Feeding Studies. 7031/VI/95 rev.4. Available from: EC (European Commission), 1997a. Appendix A. Metabolism and distribution in plants. 7028/IV/95- rev.3. Available from: EC (European Commission), 1997b. Appendix B. General recommendations for the design, preparation and realization of residue trials. Annex 2. assification of (minor) crops not listed in the Appendix of Council Directive 90/642/EEC. 7029/VI/95-rev.6. Available from: EC (European Commission), 1997c. Appendix C. Testing of plant protection products in rotational crops. 7524/VI/95-rev.2. Available from: EC (European Commission), 1997d. Appendix E. Processing studies. 7035/VI/95-rev.5. Available from: EC (European Commission), 1997e. Appendix F. Metabolism and distribution in domestic animals. 7030/VI/95-rev. 3. Available from: EC (European Commission), 1997f. Appendix H. Storage stability of residue samples. 7032/VI/95- rev.5. Available from: EC (European Commission), 1997g. Appendix I. Calculation of maximum residue level and safety intervals. 7039/VI/95. As amended by the document: classes to be used for the setting of EU pesticide maximum residue levels (MRLs). SANC 10634/2010. Available from: EC (European Commission), Residue analytical methods. For pre-registration data requirement for Annex II (part A, section 4) and Annex III (part A, section 5 of Directive 91/414. SANC/3029/99-rev.4. Available from: EC (European Commission), 2004a. Residue analytical methods. For post-registration control. SANC/825/00-rev.7. Available from: EC (European Commission), Appendix D. Guidelines on comparability, extrapolation, group tolerances and data requirements for setting MRLs. 7525/VI/95-rev.8. Available from: EC (European Commission), asses to be used for the setting of EU pesticide Maximum Residue Levels (MRLs). SANC 10634/2010 Rev. 0, finalized in the Standing Committee on the Food Chain and Animal Health at its meeting of March Available from: pdf EFSA (European Food Safety Authority), Pesticide Residues Intake Model for assessment of acute and chronic consumer exposure to pesticide residues-rev.2. Available from EFSA (European Food Safety Authority), Reasoned opinion on MRLs of concern for the active substance procymidone, prepared by EFSA Pesticide Risk Assessment Peer Review (PRAPeR) Unit. EFSA Scientific Report (2008), 165,

23 EFSA (European Food Safety Authority), Reasoned opinion on MRLs of concern for the active substance procymidone, taking into account revised toxicological reference values, prepared by EFSA Pesticide Risk Assessment Peer Review (PRAPeR) Unit. EFSA Scientific Report (2009), 227, France, Draft Assessment Report (DAR) on the active substance procymidone prepared by the rapporteur Member State France in the framework of Council Directive 91/414/EEC, November France, Addendum to the Draft Assessment Report (DAR) on the active substance procymidone prepared by the rapporteur Member State France in the framework of Council Directive 91/414/EEC, February France, Addendum to the Draft Assessment Report (DAR) on the active substance procymidone prepared by the rapporteur Member State France in the framework of Council Directive 91/414/EEC, August EC (European Commission), 2004b. Recommendations of the ECC-verview Meeting/Conclusions of the evaluation group (SANC/4086/2001 rev.3-1 ( )). EC (European Commission), 2002a. Report of ECC123 Peer Review Meeting (7032/ECC/PSD/02 11 March 2002). EC (European Commission), 2002b. Report of ECC125 Peer Review Meeting (7037/ECC/PSD/02 26 June 2002). EC (European Commission), Review Report for the active substance procymidone finalised in the Standing Committee on the Food Chain and Animal Health at its meeting on 3 March 2006 in view of the inclusion of procymidone in Annex I of Directive 91/414/EEC (SANC/4064/2001 Final 5 January 2007). Commission Directive 2006/132/EC of 11 December 2006 amending Council Directive 91/414/EEC to include procymidone as active substance. Report of the forty-second session of the Codex Committee on Pesticide Residues (Xian, China, April 2010) 23