Modification of the existing MRLs for emamectin benzoate in plums, apricots and citrus fruit 1

Transcription

1 REASNED PININ Modification of the existing MRLs for benzoate in plums, apricots and citrus fruit 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, The Netherlands, herewith referred to as the evaluating Member State (EMS), received an application from Syngenta Crop Protection AG to modify the existing MRLs for the active substance benzoate in citrus, apricots and plums. In order to accommodate for the intended uses of benzoate, it is proposed to raise the existing MRLs of 0.01* mg/kg for citrus fruit, apricots and plums to 0.01 mg/kg for citrus fruit and 0.02 mg/kg for apricots and plums. The Netherlands drafted an evaluation report according to Article 8 of that regulation, which was submitted to the European Commission and forwarded to EFSA on 16 August In the course of the assessment EFSA asked for further clarifications which were essential to finalise the risk assessment. The EMS provided the required information and submitted an updated evaluation report on 14 December EFSA bases its assessment on the evaluation report prepared by the EMS The Netherlands, the Draft Assessment Report (DAR), the addendum to the DAR prepared by The Netherlands also acting as rapporteur Member State (RMS) in support of the procedure to include the active substance in Annex I of Council Directive 91/414/EEC. The toxicological profile of benzoate was investigated by the EMS and the data were considered as sufficient to derive an ADI of mg/kg bw/day and an ARfD of 0.05 mg/kg bw. These toxicological reference values have to be considered as provisional pending a complete EU peer review of the toxicological data. The metabolism of benzoate was assessed in pears, lettuce, head cabbage and sweet corn. From these studies, the EMS proposed to set the risk assessment and enforcement residue definition as B1a benzoate expressed as (free base). The current residue definition in Regulation (EC) No 396/2005 is equivalent to this proposal. EFSA is of the opinion that on a provisional basis this residue definition should be maintained, pending the full review of the dossier of benzoate in the framework of Directive 91/414/EEC. 1 n request from the European Commission, Question No EFSA-Q , issued on 10 January Correspondence: praper.mrl@efsa.europa.eu Suggested citation: European Food Safety Authority; Modification of the existing MRLs for benzoate in plums, apricots and citrus fruit.. [37 pp.] doi: /j.efsa Available online: European Food Safety Authority, 2011

2 Emamectin benzoate residues can not be determined with multi-residue methods, but require a specific single method based on PLC involving a two column switching method and mass spectrometric detection. The method was sufficiently validated in matrices with high water content, high acid content, high oil content and dry matrices at a limit of quantification (LQ) of mg/kg. The number of supervised residue trials performed in accordance with the respective intended use on citrus fruit and plums was sufficient to derive MRL proposals for these crops. For apricots residue trials on peaches were used by extrapolation to derive a MRL. owever, data were only available and representative for the GAP in southern Europe. It must be noted that the acceptability of the trials in citrus is pending the submission of storage stability data in high acid content matrices. The effect of processing on the nature of B1a benzoate was investigated under the standard hydrolytic conditions representative for pasteurisation, baking/brewing/boiling and sterilisation. Results demonstrate that B1a benzoate undergoes limited hydrolysis (<20 % of the applied radioactivity) with the formation of minor degradation products. Data on the magnitude of the residues of B1a benzoate in processed commodities were not triggered as no significant residue levels (<0.1 mg/kg) occurred in plums, apricots and citrus (oranges/mandarins). The crops under consideration in this reasoned opinion are perennial crops and are not supposed to be rotated. Thus, the investigation of the nature and magnitude of benzoate residues in rotational crops is not required. Since citrus pomace can be used as a livestock feed, the potential livestock exposure to B1a benzoate residues was assessed. The calculated dietary burden did not trigger ruminants and poultry metabolism and livestock feeding studies. Consequently there is no need to revise the existing MRLs for B1a benzoate in food commodities of animal origin. The consumer dietary risk assessment was performed using revision 2 of EFSA PRIMo. For the calculation of the chronic exposure, EFSA used the STMR values derived for plums, apricots and citrus fruit. For the remaining commodities of plant and animal origin, the existing MRLs as established in Annex III of Regulation (EC) No 396/2005 were used as input values. To refine the calculation, EFSA used the STMR values reported in the previously issued EFSA reasoned opinion. The acute exposure assessment was carried out only with regard to plums, apricots and the individual citrus fruits applying the R value as derived from the supervised residue trials on these crops. No long-term consumer intake concern was identified for any of the European diets incorporated in the EFSA PRIMo. The total calculated chronic intake ranged from 3.1 to 26.1% of the ADI. Citrus fruit, plums and apricots contributed maximal 0.6%, 0.04% and 0.12% of the ADI, respectively. The acute intake, expressed in percent of the ARfD accounted for 1.1% for oranges, 0.9% for apricots, 0.7% for grapefruits, 0.6% for plums and 0.4% for mandarins. Thus, it is concluded that the residues resulting from the intended uses are not posing a consumer health risk and therefore EFSA concludes on the following MRL proposals. Code number Commodity Existing EC MRL (mg/kg) Proposed EC MRL (mg/kg) Justification for the proposal Enforcement residue definition: Emamectin B1a benzoate (expressed as, free base) 2

3 Code number Commodity Existing EC MRL (mg/kg) Proposed EC MRL (mg/kg) Justification for the proposal Citrus fruits 0.01* 0.01 The MRL proposals are Apricots 0.01* 0.02 supported by sufficient residue data and no consumer chronic Plums 0.01* 0.02 and acute intake concerns were identified. The MRL proposal on citrus fruits has to be regarded as provisional pending the submission of storage stability data in high acid content matrices. The MRL proposal on apricots is reflecting only the intended use in southern Europe. For the northern EU use no data were provided. (*): Indicates that the MRL is set at the limit of analytical quantification. Since the peer review under Directive 91/414/EEC has not yet been finalised, the conclusions reached in this reasoned opinion should be taken as provisional and might need to be reconsidered in the light of the outcome of the peer review. KEY WRDS Emamectin benzoate, citrus fruits, apricots, plums, MRL application, Regulation (EC) No 396/2005, consumer risk assessment,, avermectin insecticides. 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 a party requesting an authorisation for the use of a plant protection product in accordance with Directive 91/414/EEC, 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. The Netherlands, hereafter referred to as the Evaluating Member State (EMS), received an application from Syngenta Crop Protection AG 4 to set MRLs for the active substance benzoate in citrus fruits, apricots and plums. This application was notified to the European Commission and EFSA and subsequently evaluated by the EMS in accordance with Article 8 of the Regulation. After completion, the evaluation report of the EMS was submitted to the European Commission who forwarded the application and the evaluation report to EFSA on 16 August The application was included in the EFSA Register of Questions with the reference number EFSA-Q and the following subject: Emamectin benzoate Modification of the existing MRLs for benzoate in plums, apricots and citrus fruit. Both the applicant and the EMS (The Netherlands) proposed to raise the existing MRLs of 0.01* mg/kg for citrus fruit, apricots and plums to 0.01 mg/kg for citrus fruit and to 0.02 mg/kg for apricots and plums. EFSA then proceeded with the assessment of the application as required by Article 10 of the Regulation. In the course of the assessment EFSA asked for further clarifications which were essential to finalise the risk assessment. The EMS provided the required information and submitted an updated evaluation report on 14 December 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 16 November Regulation of the Council and Parliament (EC) No 396/2005 of 23 February J L 70, , p Syngenta Crop Protection AG, Schwarzwaldallee 215, C-4002 Basel, Switzerland 5

6 TE ACTIVE SUBSTANCE AND ITS USE PATTERN Emamectin benzoate is the IS common name for a mixture containing 90% of B1a benzoate (10E,14E,16E)-(1R,4S,5'S,6S,6'R,8R,12S,13S,20R,21R,24S)-6'-[(S)-sec-butyl]-21,24-dihydroxy- 5',11,13,22-tetramethyl-2-oxo-(3,7,19-trioxatetracyclo[ ,8.0 20,24 ]pentacosa-10,14,16,22- tetraene)-6-spiro-2'-(5',6'-dihydro-2'-pyran)-12-yl 2,6-dideoxy-3--methyl-4--(2,4,6-trideoxy-3-methyl-4-methylamino-α-L-lyxo-hexopyranosyl)-α-L-arabino-hexopyranoside benzoate and 10% of B1b benzoate (10E,14E,16E)-(1R,4S,5'S,6S,6'R,8R,12S,13S,20R,21R,24S)-21,24-dihydroxy-6'-isopropyl- 5',11,13,22-tetramethyl-2-oxo-(3,7,19-trioxatetracyclo[ ,8.0 20,24 ]pentacosa-10,14,16,22- tetraene)-6-spiro-2'-(5',6'-dihydro-2'-pyran)-12-yl 2,6-dideoxy-3--methyl-4--(2,4,6-trideoxy-3-methyl-4-methylamino-α-L-lyxo-hexopyranosyl)-α-L-arabino-hexopyranoside benzoate C 3 R C 3 C 3 C 3 C 3 C 2 C 3 C 3 C 3 N 2 C 3 B 1a R = C 3 C 2 - C 3 B 1b R = C 3 - Molecular weight of B1a benzoate: Molecular weight of B1b benzoate: Molecular weight of : (calculated for the 9:1 ratio of B1a: B1b ) Emamectin benzoate is an insecticide with translaminar or local systemic properties which provides residual activity against foliar feeding insects. It belongs to the group of avermectines. The active substance acts as a GABA (gamma-aminobutyric acid) and glutamate receptor site agonist blocking neurochemical transmission leading to insect muscle contraction, paralysis and death. It paralyses insects which stop feeding within hours of ingestion and die two to four days after treatment. 6

7 Emamectin benzoate is evaluated in the framework of Council Directive 91/414/EEC 5 as a new active substance with The Netherlands being the designated rapporteur Member State. The representative uses assessed under the peer review of Council Directive 91/414/EEC include foliar application (SG formulation) on grapes (outdoor covering northern and southern Europe), tomatoes (outdoor covering northern and southern Europe, indoor), cherry tomatoes (outdoor in southern Europe, indoor), peppers (outdoor southern Europe, indoor), cucumbers (indoor), melons (outdoor in southern Europe, indoor) and lettuce (outdoor covering northern and southern Europe, indoor). The EU peer review of this active substance is currently in an early stage. A Draft Assessment Report (DAR) (The Netherlands, 2008a) and an addendum to the DAR (The Netherlands, 2008b) are available and are currently under evaluation. Temporary MRLs are established for benzoate B1a expressed as in the Annex IIIA of Regulation (EC) No 396/2005. MRLs have been amended on pome fruit, peaches (nectarines), table and wine grapes, strawberries, tomatoes, aubergines, peppers, cucurbits (edible peel), cucurbits (inedible peel), cauliflower and broccoli, head cabbage, lettuce and other salad plants (except scarole), scarole, herbs, fresh beans (with pods), fresh peas (with pods) and artichokes by Commission Regulation (EU) No 1050/2009 6, following the recommendations provided in an EFSA opinion issued in response to a routine MRL application. The existing MRLs are summarized in Appendix C. Codex Alimentarius did not establish maximum residue limits (CXL) for benzoate. Since is also used as veterinary medicine as antiparasitic agent and against endoand ectoparacites, Regulation (EU) No 37/ contains provisions regarding the maximum residue levels in certain products of animal origin. The marker residue is defined as B1a, and the MRL for fin fish (muscle and skin in natural proportions) is 100 µg/kg. The GAPs on plums, apricots and citrus fruit for which authorizations are requested in Europe refer to 2 to 3 foliar spray applications of benzoate as a water soluble granules (SG) formulation at dose rates between 20 g and 37.5 g a.s./ha. The details of the intended GAPs are summarized in Appendix A; the information for which Member States the authorisations have been requested is not reported by the EMS. 5 Council Directive 91/414/EEC of 15 July 1991, J L 230, , p Commission Regulation (EC) No 1050/2009 of 28 ctober 2009, J L 290 of , p Commission Regulation (EC) No 37/2010 of 22 December 2009, J L 15, ,

8 ASSESSMENT EFSA bases its assessment on the evaluation report submitted by the EMS (The Netherlands, 2010), the Draft Assessment Report (The Netherlands, 2008a) prepared under Council Directive 91/414/EEC, the addendum to the DAR (The Netherlands, 2008b) as well as the previously issued EFSA reasoned opinion for setting of new MRLs for benzoate in various crops. 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). Since the peer review under Directive 91/414/EEC has not yet been finalised, the conclusions reached in this reasoned opinion should be taken as provisional and might need to be reconsidered in the light of the outcome of the peer review. 1. Methods of analysis 1.1. Methods for enforcement of residues in food of plant origin Analytical methods for the determination of the benzoate residues in plants matrices were reported in the DAR (The Netherlands, 2008a). Since the multi-residue analytical method DFG S 19 was not considered as suitable for the determination of benzoate residues in plant matrices due to unacceptable recoveries during the extraction and clean-up procedures, a single residue analytical method was developed for enforcement purposes in commodities of plant origin. The residues were extracted with methanol; the final determination of the analytes is done with PLC using a two column switching method with mass spectrometric detection. The method is applicable for the determination of B1a benzoate, B1b benzoate and several other avermectin-like photodegradates which were identified in plant metabolism studies. The method was validated for crops belonging to the groups of high water content (apple, lettuce, peas with pods, tomatoes, sweet pepper, cucumber, melons (peel and pulp), green beans with pods and potatoes), high acid content (grapes), high oil content (oil seed rape), dry crops (wheat grain) and in wheat straw. The validation demonstrated that for all crops a LQ of mg/kg can be achieved for B1a; a similar LQ is reported for the other components covered by the analytical method ( B1b and the degradation products MFB 1a (NA415692), AB 1a (NA438309), FAB 1a (NA415693) and 8,9-Z-MAB 1a (NA438376)). It is noted that for the photodegradate FAB 1a (NA415693) a specific clean-up and detection system (LC-MS/MS) is required. The CAS names and structures are reported in Appendix D. This method was also tested in an independent laboratory validation (ILV) for high water content commodities only and was considered as acceptable. 8

9 The RMS considered that this method was sufficiently validated for enforcement purposes in compliance with the residue definition for monitoring which is, according to Regulation (EC) No 396/2005, established as benzoate B1a expressed as. The results of B1a benzoate are recalculated to equivalent (free base) according to the residue definition set for monitoring, taking into account the ratio of B1a benzoate and B1b benzoate in benzoate (90:10) and the molecular weight (MW) of (884.7) and B1a benzoate (1008.3): 10 MW( ) = MW( B1a _benzoate ) The conversion factor of 0.97 is used to convert B1a benzoate to (free base) Methods for enforcement of residues in food of animal origin Analytical methods for the determination of the residues of B1a benzoate were reported in the DAR (the Netherlands, 2008a). These methods are also applicable to measure residues of B1b benzoate and the degradation products MFB 1a, FAB 1a, AB 1a and 8,9-Z-MAB 1a in animal tissues and milk. Since the intended uses assessed under this application will not have an impact on the residues in food of animal origin (see section 3.2), a complete assessment of these analytical methods according to the current guidelines (EC, 2004) should be performed in the framework of the MRL review under Article 12 or when the amendment of MRLs for animal commodities is necessary as a result of a new use on feed crops which lead to a significant dietary burden for livestock. 9

10 2. Mammalian toxicology The RMS derived toxicological reference values (Table 2-1) in the framework of the assessment of the active substance under Council Directive 91/414/EEC (The Netherlands, 2008a). For this application, EFSA bases the risk assessment on the proposal of the RMS. If the toxicological reference values are changed during the peer review process, the conclusions on consumer safety regarding the MRL proposals have to be reconsidered. Table 2-1. verview of the toxicological reference values Emamectin Source Year Value (mg/kg bw/d) Study relied upon ADI NL Dog, 14 weeks Dog, 1 year, Rat, 2 years Safety factor ARfD NL Rat, acute neurotoxicity Emamectin was originally developed as the hydrochloride salt but was subsequently changed to the benzoate and benzoate hydrate salts, respectively (The Netherlands, 2008a). There is no complete toxicity data set available for each salt and the available toxicity studies performed with the three salts were considered together since there were no indications for significant differences in toxicity between the three salts of. The studies reported, with the exception of those employing molar concentrations, were performed using dose levels calculated as free base to account for differences in the molecular weights of the different salts. 10

11 3. Residues 3.1. Nature and magnitude of residues in plant Primary crops Nature of residues The metabolism of benzoate in plants was assessed in the DAR in the framework of the peer review of this active substance (The Netherlands, 2008a). All studies were performed by using the B1a benzoate variant labelled as [23-14 C]- B1a benzoate (fruit crops) or [3, 7, 11, 13, C]- B1a benzoate (leafy crops and cereals); the design of the studies is summarised in Table 3-1. No data is available on the plant metabolism of B1b benzoate which may account for up to 10 % of the technical benzoate but due to the close structural similarity of both compounds, it is assumed that the B1b benzoate will behave similarly in plant commodities. Table 3-1. Summary of available metabolism studies in plants Group Crop Label position (F) or (G/I) Rate (kg a.s./ha) Application details No/ interval Sampling (DALA) Remarks Fruit Pears [23-14 C]- B1a benzoate F Foliar spray (0.5N) and (5N ) 3/ spray interval of 7 days 48 hours after 1 st application, 14, 28 days Critical PI is of 7 days in the representative uses. Non-ionic surfactant was added to spray solution. Leafy crops Lettuce [3, 7, 11, 13, C]- B1a benzoate F Foliar spray and / spray interval of 7 days 2 hours, 1, 3, 7, 10 days Foliar applications from the 2 leaf stage until maturity. Application without surfactant. ead cabbage [3, 7, 11, 13, C]- B1a benzoate F Foliar spray and / spray interval of 7 days 2 hours, 1, 3, 7, 10 days Foliar applications from the 2 leaf stage until maturity. Application without surfactant. 11

12 Group Crop Label position (F) or (G/I) Rate (kg a.s./ha) Application details No/ interval Sampling (DALA) Remarks Cereals Sweet corn [3, 7, 11, 13, C]- B1a benzoate F Foliar spray and / spray interval of 3-5 days 2 hours, 1, 3, 7 days Non-ionic surfactant was added to spray solution a. Pears The metabolism study on pears (fruit crops) showed that a non negligible fraction of the total radioactive residues (81-89% of TRR) was constituted of polar fractions and avermectin like compounds. The polar fractions were characterized mainly as simple sugars (xylose, fructose, glucose, sucrose and galactose) at levels of 12.7% and 38% of TRR at PIs of 14 and 28 days, respectively. The parent B1a benzoate was the only compound recovered in the avermectin like fraction at levels of 4% and 8% of TRR at PIs of 28 and 14 days, respectively and was subsequently extensively degraded into low molecular weight molecules, none of which co-chromatographed with reference standards of the degradation products of the parent compound (FAB 1a, MFB 1a, 8a-oxo MAB 1a, AB 1a, 8,9-Z-MAB 1a ). b. Lettuce, head cabbage In leafy crops (lettuce, head cabbage), the major part of the radioactivity (>85% of TRR) was located in the wrapper leaves at all PIs intervals with little translocation to the head leaves. The predominant compound of the extracted radioactive fraction was the parent compound (up to 34.5% of TRR just after last application). This level declined rapidly along with the PI interval (3% of TRR at PI of 10 days) while the polar fraction increased significantly (up to 58.5% of TRR at PI of 10 days) and consisted of unresolved minor compounds that were not conjugated with glucose or glucuronide. The remaining radioactivity was resolved into avermectin-like degradation compounds (FAB 1a, MFB 1a, 8a-oxo MAB 1a /8a-MAB 1a, AB 1a, 8,9-Z-MAB 1a, MSB 1a ) which occurred at very low levels (<5% of TRR, <0.05 mg equiv./kg) with further degradation to polar compounds. The major part of the radioactivity released from the post extraction solids fraction was incorporated into the natural products of the plants (glucose, protein). c. Sweet corn In cereals (sweet corn), no significant decline of the total radioactive residues along with the PI was observed in any plant part with maximum residue levels of 1.2 mg equiv./kg in leaf/stalk, mg equiv./kg in husk/silk, mg equiv./kg in kernels and mg equiv./kg in cobs. The total radioactive residues in leaves/stalks/husks, kernels and cobs were fractionated into a polar fraction and an avermectin-like fraction. The polar fraction was characterized as a complex mixture of sugars (up to 22% of TRR in leaves/stalks and husk, 21.5% of TRR in cobs and 26% of TRR in kernels). The predominant compound of the avermectin-like fraction was found to be the parent compound in leaves/stalks and husks (5.0% and 13.7% of TRR, respectively at PI of 7 days) along with minor metabolites accounting for less than 5% of TRR and similar to the primary degradation products identified in leafy crops. In kernels and cobs, the parent B1a benzoate was detected at a trace level (<0.008 mg/kg) and no primary degradation products were recovered. Enzymatic hydrolysis of the post extraction solids fraction of the different sweet corn plant parts indicated that radioactivity was also incorporated into natural plant products such as sugars, polysaccharides and proteins. 12

13 The metabolic profile in fruit crops differed from the degradation pathway depicted in lettuce, cabbage and sweet corn as the only compounds identified in fruit crops were the parent B1a benzoate and low molecular weight products that were subsequently incorporated into the natural products of the plant. No avermectin like degradation products of the parent compound were detected in fruits. Nevertheless, the metabolic pattern of B1a benzoate in fruit crops was investigated 2 days after the first application and at PI of 14 and 28 days respectively but no investigation on the potential occurrence of the B1a benzoate degradation products was attempted at a PI of 7 days representative for the intended uses in stone fruit and citrus fruit. In leafy crops (lettuce, head cabbage and foliage sweet corn plants), B1a benzoate undergoes an extensive degradation through a photodegradative process on the crop surface with the formation of primary degradation products (8,9-Z-MAB 1a, FAB 1a, MFB 1a, AB 1a ) and the major part of the radioactivity was characterized as a polar fraction (up to 58% TRR) without any further metabolites identification. It was noted that the absence of avermectin like compounds in the fruit metabolism study is not consistent with the results of the supervised residue trials. In the DAR (The Netherlands, 2008a) and in the addendum to the DAR (The Netherlands, 2008b), residue trials on leafy crops (lettuce) and fruit crops (peaches and nectarines) were reported where avermectin-like metabolites (8,9-Z-MAB 1a, FAB 1a, MFB 1a, AB 1a ) were analysed according to the validated analytical method. In the residue trials performed on lettuce at a PI of 3 days, residue levels of these metabolites were recovered above the LQ (0.001 mg/kg) while in peaches and nectarines, only the metabolite MFB 1a was recovered at non negligible levels ( mg/kg) both at PIs of 7 and 14 days. The difference observed seems mainly due to the fact that the metabolism study on fruits was performed at later PIs (14, 28 days) than the other metabolism studies in/on leafy crops and cereals. The identified metabolites indicated that the metabolic pathway of B1a benzoate proceeds initially through a re-arrangement of the parent structure to form the (8,9-Z)-isomer of the parent B1a benzoate followed by different routes of hydroxylation, oxidation and demethylation with an ultimate incorporation into natural constituents of the plants. A general residue definition for monitoring and risk assessment is proposed as B1a benzoate expressed as (free base) assuming that B1b benzoate degrades similarly as B1a benzoate. In the rat metabolism, B1a benzoate is not metabolised to a substantial extent and only one metabolite AB 1a was identified and resulted from demethylation of the parent compound. No toxicological data were provided to cover the other avermectin-like metabolites identified in leafy crops and cereals. The current residue definition in Regulation (EC) No 396/2005 is equivalent to the residue definition proposed by the EMS. EFSA is of the opinion that on a provisional basis this residue definition should be maintained, pending the full review of the dossier of benzoate in the framework of Directive 91/414/EEC Magnitude of residues a. Citrus fruits, southern Europe In total 16 residue trials on mandarins covering several growing seasons performed in southern Europe were submitted. The formulation in all crops was a 9.5 g/kg SG formulation. Eight trials were performed without addition of oil and 8 trials with oil (0.25% w/v). All trials were performed 13

14 according to the critical GAP. From all trials, the highest residues with a PI of 7 days were appropriate for setting of the MRL. Trials performed with oil generally resulted in higher levels of residues and were therefore used to derive the MRL proposal. In addition, 16 residue trials on oranges covering several growing seasons performed in southern Europe were submitted. The formulation in all crops was a 9.5 g/kg SG formulation. Eight trials were performed without addition of oil and 8 trials with oil (0.25% w/v). All trials were performed according to the critical GAP. From all trials, the highest residues with a PI of 7 days were appropriate to propose a MRL. Trials performed with oil generally resulted in higher levels of residues and were therefore used to derive the MRL proposal. The data on oranges and mandarins were pooled to derive a MRL proposal for the whole citrus fruit group. Such an extrapolation is in compliance with the EU guidance document (EC, 2008). The trials on oranges and mandarines demonstrated that no residues above the level of 0.01 mg/kg are expected and that the intended use on citrus will not require a modification of the existing MRL of 0.01 mg/kg. It must be noted that the acceptability of these residue trials is pending the submission of storage stability data in high acid content matrices covering the storage period of the samples from these trials. The results of the trials on oranges and mandarins are summarised in Table 3-2. b. Plums, northern Europe In total 16 residue trials covering several growing seasons performed in northern Europe were submitted. The formulation in all crops was a 9.5 g/kg SG formulation. Eight trials were performed without addition of oil and 8 trials with oil (0.25% w/v). These residue trials were not taken into consideration since there is no intended use on plums for northern Europe. c. Plums, southern Europe In total 16 residue trials covering several growing seasons performed in southern Europe were submitted. The formulation in all crops was a 9.5 g/kg SG formulation. Eight trials were performed without addition of oil and 8 trials with addition of oil (0.25% w/v). All trials were performed according to the critical GAP. From all trials, the highest residues with a PI of 7 days were appropriate to propose a MRL. Trials performed with oil generally resulted in higher levels of residues and were therefore used to derive the MRL proposal for southern EU. The results of the trials on plums are summarised in Table 3-2. d. Apricot, northern and southern Europe No residue trials were submitted for apricots but the EMS proposed to extrapolate from the trials performed on peaches since the GAPs are similar. These peaches trials were already evaluated in the previously issued reasoned opinion. An extrapolation from peaches to apricots is in line with the EU guidance document (EC, 2008). It is concluded that sufficient trials are available to derive a MRL proposal for the intended use covering southern Europe. owever, no residue trials were submitted to support the use on apricots in northern Europe. Thus, the derived MRL proposal is covering only the southern European use. 14

15 The results of the trials on peaches with extrapolation to apricots are summarised in Table 3-2. All the residue values were reported as B1a benzoate in the original report and were recalculated by EFSA to be in line with the residue definition for monitoring by using the conversion factor of 0.97 (See section 1.1.). The residue values reported in Table 3-2 are expressed as (free base). The storage stability data under frozen conditions of B1a benzoate residues reported in the DAR refer to tomatoes, potatoes and green beans with pods (The Netherlands, 2008a). The residues of the parent compound were demonstrated to be stable in matrices with high water content when stored at -18 C for 18 months. The samples of the supervised field trials for plums and peaches were stored for a maximum of 8 and 10 months, respectively and were therefore covered by the available storage stability data. The citrus samples were stored for 3 to 16 months at temperature of -18 C. No storage stability data were provided for this matrix. Since tomato is a crop with a relative low p value, it is assumed that the storage period of the samples from the residue trials on citrus are covered by the available storage stability data on tomato. owever, a confirmatory study is requested to confirm this assumption and to consider the submitted residue trials on citrus as acceptable. The analytical method used in the supervised residue trials on peaches, plums and citrus fruit was assessed in section 1.1 and was shown to be sufficiently validated for enforcement purposes (EC, 2004) in compliance with the residue definition for monitoring. 15

16 Table 3-2. verview of the available residues trials data Commodity Region (a) utdoor/indoo r Individual trial results (mg/kg) Enforcement Risk assessment STMR (mg/kg) (b) R (mg/kg) (c) Provisional residue definition enforcement and risk assessment: Emamectin B1a benzoate (expressed as, free base) ranges SEU utdoor 2x<0.001; 2x ; 4x Mandarins SEU utdoor <0.001; 2x ; ; 4x Plums SEU utdoor <0.001; 2x ; ; ; ; ; Peaches apricots 2x<0.001; 2x ; 4x <0.001; 2x ; ; 4x <0.001; 2x ; ; ; ; ; MRL proposal (mg/kg) Median CF (d) Comments Results of residue trials with addition of oil. ranges: Rmax= mg/kg Rber= mg/kg Mandarins: Rmax= mg/kg Rber= mg/kg Combined data (oranges and mandarins): Rmax= mg/kg Rber=0.006 mg/kg Results of residue trials with addition of oil. Rmax=0.011 mg/kg Rber=0.008 mg/kg NEU utdoor No data No residue trials submitted to support the use on apricot in Northern Europe 16

17 Commodity Region (a) utdoor/indoo r Individual trial results (mg/kg) Enforcement SEU utdoor ; ; ; ; 2x ; ; Risk assessment ; ; ; ; 2x ; ; STMR (mg/kg) (b) R (mg/kg) (c) MRL proposal (mg/kg) Median CF (d) Comments (1) 1 Results of residue trials with addition of oil. Extrapolation from peaches to apricots. R ber =0.019 mg/kg R max =0.02 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): ighest 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. (1) : MRL proposal for Southern Europe only. 17

18 Effect of industrial processing and/or household preparation The effect of processing on the nature of B1a benzoate residues was investigated in degradation studies as reported in the DAR simulating conditions of pasteurisation, baking/brewing/boiling and sterilisation (The Netherlands, 2008a). The results demonstrated that B1a benzoate undergoes limited hydrolysis which increases with temperature and p. Under sterilisation conditions, up to 20 % of B1a benzoate was degraded. The resulting degradation products were identified as the aglycone milbemectin B (1.4% of AR), the monosaccharide MSB 1a (up to 7.2% of AR) and AB 1a (1.8% of AR) (see Appendix D). Further minor unknown degradation products could not be identified. The toxicological properties of these metabolites, mainly the monosaccharide MSB 1a was not discussed in the DAR. It is assumed that B1b benzoate behaves in a comparable way. The parent compound remains a valid indicator of the total residues in the processed commodities. The proposed residue definitions for monitoring and risk assessment established for the primary crops are also valid for the processed commodities. Data on the magnitude of the residues of B1a benzoate in processed commodities were not triggered as no significant residue levels (<0.1 mg/kg) occurred in plums, apricots and citrus fruit (oranges/mandarins) (EC, 1997d; ECD, 2007a) Rotational crops Since the intended uses of benzoate refer to perennial crops, investigations of residues in rotational crops are not required (EC, 1997c; ECD, 2007b) Nature and magnitude of residues in livestock Since citrus by-products (pomace) can be fed to ruminants, the dietary burden for livestock was calculated according to the EC methodology, considering the livestock intake from citrus pomace and form other feed crops on which the use of is authorised. To refine the calculations, EFSA used the risk assessment values as reported in the framework of the previously issued EFSA reasoned opinion. For apple pomace and citrus pomace the default processing factor of 2.5 was applied to the STMR value. The summary of the input values is summarised in Table 3-3. Table 3-3. Input values for the dietary burden calculation Commodity Median dietary burden Maximum dietary burden Input value (mg/kg) Comment Input value (mg/kg) Comment Risk assessment residue definition: B1a benzoate (expressed as, free base) Citrus pomace STMR*PF (2.5) Apple pomace STMR*PF (2.5) STMR*PF (2.5) STMR*PF (2.5) ead cabbage STMR R The results of the dietary burden calculations are reported in the Table

19 Table 3-4. Results of the dietary burden calculation Maximum dietary burden (mg/kg bw/d) Median dietary burden (mg/kg bw/d) ighest contributing commodity Max dietary burden (mg/kg DM) Trigger exceeded? Risk assessment residue definition: B1a benzoate (expressed as, free base) Dairy ruminants Apple pomace No Meat ruminants Apple pomace No Poultry Cabbage No Pigs Cabbage No The calculated dietary burden did not trigger ruminants and poultry metabolism and livestock feeding studies (EC, 1996, 1997e). Consequently, there is no need to amend the existing MRLs for B1a benzoate in food commodities of animal origin. 4. Consumer risk assessment The consumer risk assessment was performed using revision 2 of the EFSA PRIMo (Pesticide Residues Intake Model) (EFSA, 2007). For the calculation of the chronic exposure, EFSA used the STMR values derived for plums, apricots and citrus fruit (see Table 3-2). For the remaining commodities of plant and animal origin, the existing MRLs as established in Annex III of Regulation (EC) No 396/2005 were used as input values. To refine the calculation, EFSA used the STMR values reported in the previously issued EFSA reasoned opinion. The acute exposure assessment was carried out only with regard to plums, apricots and citrus fruit applying the R value as derived from the supervised residue trials on these crops. The input values used for the dietary exposure calculations are summarised in Table 4-1. Table 4-1. Input values for the consumer risk assessment Commodity Chronic risk assessment Acute risk assessment Input value (mg/kg) Comment Emamectin B1a benzoate (expressed as, free base) Input value (mg/kg) Comment Citrus fruit STMR R Apricot STMR R Plums STMR R Pome fruit STMR Peaches STMR The acute risk assessment was performed only for the crops for which a MRL modification is requested. 19

20 Commodity Chronic risk assessment Acute risk assessment Input value (mg/kg) Comment Grapes STMR Strawberries STMR Tomatoes STMR Aubergines STMR Peppers STMR Cucurbits (edible peel) STMR Cucurbits (inedible peel) STMR Cauliflower, broccoli, head cabbage Lettuce and other salad plants (excluding scarole) STMR 0.27 STMR erbs 0.27 STMR Scarole 0.03 STMR Fresh beans and peas (with pods) STMR Artichokes STMR ther food commodities of plant and animal origin MRL See Appendix C Input value (mg/kg) Comment The estimated short term and long term exposure was compared with the ARfD and ADI, respectively. The results of these calculations are presented in Appendix B. No long-term consumer intake concern was identified for any of the European diets incorporated in the EFSA PRIMo. The total calculated chronic intake ranged from 3.1 to 26.1% of the ADI. Citrus fruit, plums and apricots contributed maximal 0.6%, 0.04% and 0.12%, respectively. The acute intake, expressed in percent of the ARfD, accounted for 1.1% for oranges, 0.9% for apricots, 0.7% for grapefruits, 0.6% for plums and 0.4% for mandarins. Thus, it is concluded, that the residues resulting from the intended uses are not posing a consumer health risk. 20

21 CNCLUSINS AND RECMMENDATINS CNCLUSINS The toxicological profile of benzoate was investigated by the EMS and the data were considered as sufficient to derive an ADI of mg/kg bw/day and an ARfD of 0.05 mg/kg bw. These toxicological reference values have to be considered as provisional pending a complete EU peer review of the toxicological data. The metabolism of benzoate was assessed in pears, lettuce, head cabbage and sweet corn. From these studies the EMS proposed to set the risk assessment and enforcement residue definition as B1a benzoate expressed as (free base). The current residue definition in Regulation (EC) No 395/2005 is equivalent to this proposal. EFSA is of the opinion that on a provisional basis this residue definition should be maintained, pending the full review of the dossier of benzoate in the framework of Directive 91/414/EEC. Emamectin benzoate residues can not be determined with multi-residue methods, but require a specific single method based on PLC involving a two column switching method and mass spectrometric detection. The method was sufficiently validated in matrices with high water content, high acid content, high oil content and dry matrices at a limit of quantification (LQ) of mg/kg. The number of supervised residue trials performed in accordance with the respective intended use on citrus fruit and plums was sufficient to derive MRL proposals for these crops. For apricots residue trials on peaches were used by extrapolation to derive a MRL. owever, data were only available and representative for the GAP in southern Europe. It must be noted that the acceptability of the trials in citrus is pending the submission of storage stability data in high acid content matrices. The effect of processing on the nature of B1a benzoate was investigated under the standard hydrolytic conditions representative for pasteurisation, baking/brewing/boiling and sterilisation. Results demonstrate that B1a benzoate undergoes limited hydrolysis (<20 % of the applied radioactivity) with the formation of minor degradation products. Data on the magnitude of the residues of B1a benzoate in processed commodities were not triggered as no significant residue levels (<0.1 mg/kg) occurred in plums, apricots and citrus (oranges/mandarins). The crops under consideration in this reasoned opinion are perennial crops and are not supposed to be rotated. Thus, the investigation of the nature and magnitude of benzoate residues in rotational crops is not required. Since citrus pomace can be used as a livestock feed, the potential livestock exposure to B1a benzoate residues was assessed. The calculated dietary burden did not trigger ruminants and poultry metabolism and livestock feeding studies. Consequently there is no need to revise the existing MRLs for B1a benzoate in food commodities of animal origin. The consumer dietary risk assessment was performed using revision 2 of EFSA PRIMo. For the calculation of the chronic exposure, EFSA used the STMR values derived for plums, apricots and citrus fruit. For the remaining commodities of plant and animal origin, the existing MRLs as established in Annex III of Regulation (EC) No 396/2005 were used as input values. To refine the calculation, EFSA used the STMR values reported in the previously issued EFSA reasoned opinion. The acute exposure assessment was carried out only with regard to plums, apricots and the individual citrus fruits applying the R value as derived from the supervised residue trials on these crops. 21

22 No long-term consumer intake concern was identified for any of the European diets incorporated in the EFSA PRIMo. The total calculated chronic intake ranged from 3.1% to 26.1% of the ADI. Citrus fruit, plums and apricots contributed maximal 0.6%, 0.04% and 0.12% of the ADI, respectively. The acute intake, expressed in percent of the ARfD accounted for 1.1% for oranges, 0.9% for apricots, 0.7% for grapefruits, 0.6% for plums and 0.4% for mandarins. Thus, it is concluded that the residues resulting from the intended uses are not posing a consumer health risk and therefore EFSA concludes on the following MRL proposals. Code number Commodity Existing EC MRL (mg/kg) Proposed EC MRL (mg/kg) Justification for the proposal Enforcement residue definition: Emamectin B1a benzoate (expressed as, free base) Citrus fruits 0.01* 0.01 The MRL proposals are Apricots 0.01* 0.02 supported by sufficient residue data and no consumer chronic Plums 0.01* 0.02 and acute intake concerns were identified. The MRL proposal on citrus fruits has to be regarded as provisional pending the submission of storage stability data in high acid content matrices. The MRL proposal on apricots is reflecting only the intended use in southern Europe. For the northern EU use no data were provided. 22

23 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. Classification 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. 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), 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), Classes 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 ealth 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 the setting of new MRLs for benzoate in various crops prepared by EFSA Pesticide Risk Assessment Peer Review (PRAPeR) Unit. EFSA Scientific Report (2009), 290,