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

Transcription

1 EFSA Journal 2015;13(1):3946 REASONED OPINION Reasoned opinion on the review of the existing maximum residue levels (MRLs) for dodine according to Article 12 of Regulation (EC) No 396/ European Food Safety Authority 2,3 European Food Safety Authority (EFSA), Parma, Italy ABSTRACT According to Article 12 of Regulation (EC) No 396/2005, the European Food Safety Authority (EFSA) has reviewed the Maximum Residue Levels (MRLs) currently established at European level for the pesticide active substance dodine. In order to assess the occurrence of dodine residues in plants, processed commodities, rotational crops and livestock, EFSA considered the conclusions derived in the framework of Directive 91/414/EEC, the MRLs established by the Codex Alimentarius Commission as well as the import tolerances and European authorisations reported by Member States (incl. the supporting residues data). Based on the assessment of the available data, MRL proposals were derived and a consumer risk assessment was carried out. Some information required by the regulatory framework was found to be missing and a possible acute risk to consumers was identified. Hence, the consumer risk assessment is considered indicative only, some MRL proposals derived by EFSA still require further consideration by risk managers and measures for reduction of the consumer exposure should also be considered. European Food Safety Authority, 2015 KEY WORDS dodine, MRL review, Regulation (EC) No 396/2005, consumer risk assessment, guanidine, fungicide 1 On request from EFSA, Question No EFSA-Q , approved on 05 December Correspondence: pesticides.mrl@efsa.europa.eu 3 Acknowledgement: EFSA wishes to thank the rapporteur Member State Portugal for the preparatory work on this scientific output. Suggested citation: European Food Safety Authority, Reasoned opinion on the review of the existing maximum residue levels (MRLs) for dodine according to Article 12 of Regulation (EC) No 396/2005. EFSA Journal 2015;13(1):3946, 48 pp. doi: /j.efsa Available online: European Food Safety Authority, 2015

2 SUMMARY Dodine was included in Annex I to Directive 91/414/EEC on 01 June 2011, which is after the entry into force of Regulation (EC) No 396/2005 on 02 September EFSA is therefore required to provide a reasoned opinion on the review of the existing MRLs for that active substance in compliance with Article 12(1) of the aforementioned regulation. In order to collect the relevant pesticide residues data, EFSA asked Portugal, as the designated rapporteur Member State (RMS), to complete the Pesticide Residues Overview File (PROFile) and to prepare a supporting evaluation report. The requested information was submitted to EFSA on 02 May 2012 and, after having considered several comments made by EFSA, the RMS provided on 22 April 2013 a revised PROFile. Based on the conclusions derived by EFSA in the framework of Directive 91/414/EEC, the MRLs established by the Codex Alimentarius Commission and the additional information provided by the RMS, EFSA issued on 06 June 2014 a draft reasoned opinion that was circulated to Member States experts for consultation. Comments received by 15 August 2014 were considered in the finalisation of this reasoned opinion. The following conclusions are derived. The toxicological profile of dodine was evaluated in the framework of Directive 91/414/EEC, which resulted in an ADI and an ARfD being established at 0.1 mg/kg bw per d and 0.1 mg/kg bw, respectively. Metabolism of dodine in primary crops was investigated for foliar applications on fruits and fruiting vegetables (apples, strawberries, pecans) using 14 C-labelled dodine. The metabolic pattern of dodine was shown to be similar in all fruit crops investigated. Parent compound dodine was predominant in apples and strawberries, while in nutmeat, metabolite guanidine was the major compound recovered. The residue for enforcement and risk assessment in fruits and fruiting vegetables following foliar application is defined as dodine only. Dodine is also authorised for foliar application on celery: in order to extend the proposed residue definition to leafy vegetables, a representative metabolism study for this crop group is required. Meanwhile, it is proposed, on a tentative basis, to also define the residue for enforcement and risk assessment in leafy vegetables as dodine only. Validated analytical methods for enforcement of the proposed residue definition are available, except for acidic matrices, where additional data are still required. Sufficient residue trials were available to derive MRL proposals and risk assessment values for all commodities under evaluation except for blueberries (aronia), cranberries, currants, gooseberries and celery where the available data were insufficient to derive tentative MRLs. Based on the available data for processed commodities, the residue definition for enforcement and risk assessment in primary crops can also apply to the processed commodities. Studies investigating the magnitude of residues in processed commodities of olives, apples and in peeled bananas were also reported and allowed the calculation of robust processing factors for enforcement and risk assessment. Further processing studies are not required as they are not expected to affect the outcome of the risk assessment. However, if more robust processing factors were to be required by risk managers, in particular for enforcement purposes, additional processing studies would be needed. Among the crops under consideration, celery may be grown in rotation. According to the laboratory degradation studies evaluated in the framework of the peer review, DT 90 values of dodine ranges between days, which is far below the trigger value of 100 days. Moreover, no relevant soil metabolites were identified. Therefore, further investigation of residues in rotational crops is not required and relevant residues in rotational crops are not expected. The calculated livestock dietary burden exceeded the trigger value of 0.1 mg/kg DM for dairy and meat ruminants. The results of the metabolism study on goat showed that, at the calculated maximum ruminant dietary burden, no residues above 0.01 mg/kg are expected in ruminant tissues and in milk. Consequently, the residue for enforcement and risk assessment in ruminant commodities is defined by EFSA Journal 2015;13(1):3946 2

3 default as dodine only and MRLs and risk assessment values for ruminant tissues and milk can be established at the default LOQ level of 0.01 mg/kg. These MRLs can only be tentatively derived, due to the data gap identified on the analytical methods in livestock commodities. The metabolic fate of dodine in goat and rat are considered to be similar; the findings in ruminants can therefore be extrapolated to pigs. In pigs and poultry matrices, no residue definition and no MRLs are necessary. Chronic and acute consumer exposure resulting from the authorised uses reported in the framework of this review was calculated using revision 2 of the EFSA PRIMo. For those commodities where data were insufficient to derive an MRL, EFSA considered the existing EU MRL for an indicative calculation. For apple and pear, an exceedance of the ARfD was identified representing 127 and 118 % of the ArfD, respectively. A second calculation was therefore performed considering a fall-back MRL for these two crops. According to this second calculation, the highest chronic exposure represented 13.5 % of the ADI (WHO Cluster diet B) and the highest acute exposure amounted to 47 % of the ARfD (apples). Apart from the MRLs evaluated in the framework of this review, internationally recommended CXLs have also been established for dodine. Additional calculations of the consumer exposure, considering these CXLs, were therefore carried out and exceedences of the ARfD were identified for the existing CXLs in apples (238 %), pears (221 %) and peaches (220 %). Excluding these CXLs from the calculation, the highest chronic exposure represented 13.5 % of the ADI (WHO Cluster diet B) and the highest acute exposure amounted to 47 % of the ARfD (apples). Based on the above assessment, EFSA does not recommend inclusion of this active substance in Annex IV to Regulation (EC) No 396/2005. MRL recommendations were derived in compliance with the decision tree reported in Appendix D of the reasoned opinion (see summary table). All MRL values listed as Recommended in the table are sufficiently supported by data and are therefore proposed for inclusion in Annex II to the Regulation. The remaining MRL values listed in the table are not recommended for inclusion in Annex II because they require further consideration by risk managers (see summary table footnotes for details). In particular, some tentative MRLs and existing EU MRLs need to be confirmed by the following data: a fully validated analytical method for the determination of dodine in acidic commodities; an ILV of the available analytical method for the determination of dodine in liver and kidney; a fully validated analytical method for the determination of dodine in milk, fat and muscle; a representative metabolism study in the leafy vegetables crop group; additional residue trials supporting the authorisations on currants, gooseberries, blueberries, cranberries and celery. If the above reported data gaps are not addressed in the future, Member States are recommended to withdraw or modify the relevant authorisations at national level. Members States are in any case recommended to withdraw or modify their authorisations on apples and pears in order to ensure acceptable consumer exposure and compliance with the recommended MRL. Minor deficiencies were also identified in the assessment but these deficiencies are not expected to impact either on the validity of the MRLs derived or on the national authorisations. The following data are therefore considered desirable but not essential: additional residue trials supporting the authorisations on pome fruit, peaches, apricots, and cherries; a storage stability study in acidic commodities. EFSA Journal 2015;13(1):3946 3

4 SUMMARY TABLE Code number Commodity Enforcement residue definition: dodine Existing EU MRL Existing CXL MRL Outcome of the review Comment Apples Recommended (a) Pears Recommended (a) Quinces Recommended (b) Medlar Recommended (b) Loquat Recommended (b) Apricots Recommended (c) Cherries Recommended (d) Peaches Recommended (a) Blueberries 0.05* Further consideration needed (e) Cranberries 0.05* Further consideration needed (e) Currants (red, black and white) 0.05* Further consideration needed (e) Gooseberries 0.05* Further consideration needed (e) Table olives Recommended (c) Bananas Recommended (c) Celery 0.05* Further consideration needed (e) Olives for oil production Recommended (c) Bovine muscle 0.05* * Further consideration needed (f) Bovine fat 0.05* * Further consideration needed (f) Bovine liver 0.05* * Further consideration needed (f) Bovine kidney 0.05* * Further consideration needed (f) Sheep muscle 0.05* * Further consideration needed (f) Sheep fat 0.05* * Further consideration needed (f) Sheep liver 0.05* * Further consideration needed (f) Sheep kidney 0.05* * Further consideration needed (f) Goat muscle 0.05* * Further consideration needed (f) Goat fat 0.05* * Further consideration needed (f) Goat liver 0.05* * Further consideration needed (f) Goat kidney 0.05* * Further consideration needed (f) Cattle milk 0.05* * Further consideration needed (f) Sheep milk 0.05* * Further consideration needed (f) Goat milk 0.05* * Further consideration needed (f) - Other products of plant and animal origin See App C1 (*): Indicates that the MRL is set at the limit of analytical quantification. - - Further consideration needed (g) EFSA Journal 2015;13(1):3946 4

5 (a): MRL is derived from a GAP evaluated at EU level, which is fully supported by data and for which no risk to consumers is identified; CXL is higher, supported by data but a risk to consumers cannot be excluded (combination G-VI in Appendix D). (b): MRL is derived from the existing CXL, which is supported by data and for which no risk to consumers is identified; GAP evaluated at EU level, which is also fully supported by data, leads to a lower MRL (combination G-VII in Appendix D). (c): MRL is derived from a GAP evaluated at EU level, which is fully supported by data and for which no risk to consumers is identified; no CXL is available (combination G-I in Appendix D). (d): MRL is derived from a GAP evaluated at EU level, which is fully supported by data and for which no risk to consumers is identified; existing CXL is covered by the recommended MRL (combination G-III in Appendix D). (e): GAP evaluated at EU level is not supported by data but no risk to consumers was identified for the existing EU MRL; no CXL is available (combination C-I in Appendix D). (f): Tentative MRL is derived from a GAP evaluated at EU level, which is not fully supported by data but for which no risk to consumers was identified; no CXL is available (combination E-I in Appendix D). (g): There are no relevant authorisations or import tolerances reported at EU level; no CXL is available. Either a specific LOQ or the default MRL of 0.01 mg/kg may be considered (combination A-I in Appendix D). EFSA Journal 2015;13(1):3946 5

6 TABLE OF CONTENTS Abstract... 1 Summary... 2 Background... 7 Terms of reference... 8 The active substance and its use pattern... 8 Assessment Methods of analysis Methods for enforcement of residues in food of plant origin Methods for enforcement of residues in food of animal origin Mammalian toxicology Residues Nature and magnitude of residues in plant Primary crops Rotational crops Nature and magnitude of residues in livestock Dietary burden of livestock Nature and magnitude of residues Consumer risk assessment Consumer risk assessment without consideration of the existing CXLs Consumer risk assessment with consideration of the existing CXLs Conclusions and recommendations Documentation provided to EFSA References Appendix A Good Agricultural Practices (GAPs) Appendix B Pesticide Residues Intake Model (PRIMo) Appendix C Existing EU maximum residue limits (MRLs) and Codex Limits (CXLs) Appendix D Decision tree for deriving MRL recommendations Appendix E List of metabolites and related structural formula Abbreviations EFSA Journal 2015;13(1):3946 6

7 BACKGROUND Regulation (EC) No 396/ establishes the rules governing the setting and the review of pesticide MRLs at European level. Article 12(1) of that regulation stipulates that EFSA shall provide within 12 months from the date of the inclusion or non-inclusion of an active substance in Annex I to Directive 91/414/EEC 5 a reasoned opinion on the review of the existing MRLs for that active substance. As dodine was included in Annex I to the above mentioned directive on 01 June 2011, EFSA initiated the review of all existing MRLs for that active substance and a task with the reference number EFSA-Q was included in the EFSA Register of Questions. According to the legal provisions, EFSA shall base its reasoned opinion in particular on the relevant assessment report prepared under Directive 91/414/EEC. It should be noted, however, that in the framework of Directive 91/414/EEC only a few representative uses are evaluated, while MRLs set out in Regulation (EC) No 396/2005 should accommodate all uses authorised within the EU, and uses authorised in third countries that have a significant impact on international trade. The information included in the assessment report prepared under Directive 91/414/EEC is therefore insufficient for the assessment of all existing MRLs for a given active substance. In order to gain an overview of the pesticide residues data that have been considered for the setting of the existing MRLs, EFSA developed the Pesticide Residues Overview File (PROFile). The PROFile is an inventory of all pesticide residues data relevant to the risk assessment and MRL setting for a given active substance. This includes data on: the nature and magnitude of residues in primary crops; the nature and magnitude of residues in processed commodities; the nature and magnitude of residues in rotational crops; the nature and magnitude of residues in livestock commodities and; the analytical methods for enforcement of the proposed MRLs. Portugal, the designated rapporteur Member State (RMS) in the framework of Directive 91/414/EEC, was asked to complete the PROFile for dodine and to prepare a supporting evaluation report. The requested information was submitted to EFSA on 02 May 2012 and subsequently checked for completeness. On 22 April 2013, after having clarified some issues with EFSA, the RMS provided a revised PROFile. A draft reasoned opinion was issued by EFSA on 06 June 2014 and submitted to Member States (MS) for commenting. All MS comments received by 15 August 2014 were considered by EFSA in the finalisation of the reasoned opinion. 4 Regulation (EC) No 396/2005 of the European Parliament and of the Council of 23 February 2005 on maximum residue levels of pesticides in or on food and feed of plant and animal origin and amending Council Directive 91/414/EEC. OJ L 70, , p Council Directive 91/414/EEC of 15 July 1991 concerning the placing of plant protection products on the market. OJ L 230, , p EFSA Journal 2015;13(1):3946 7

8 TERMS OF REFERENCE According to Article 12 of Regulation (EC) No 396/2005, EFSA shall provide a reasoned opinion on: the inclusion of the active substance in Annex IV to the Regulation, when appropriate; the necessity of setting new MRLs for the active substance or deleting/modifying existing MRLs set out in Annex II or III of the Regulation; the inclusion of the recommended MRLs in Annex II or III to the Regulation; the setting of specific processing factors as referred to in Article 20(2) of the Regulation. THE ACTIVE SUBSTANCE AND ITS USE PATTERN Dodine is the ISO common name for 1-dodecylguanidinium acetate (IUPAC). Figure 1: Structure of dodine Dodine belongs to the group of guanidine compounds and it is a fungicide with protective and curative actions. This compound is not systemic but has a translaminar action. It is a multisite inhibitor acting mainly on the fungus membranes. Dodine is used by foliar treatment against various fungal diseases of fruit and vegetable crops (e.g. scab, leaf spots, leaf curl). Dodine was evaluated in the framework of Directive 91/414/EEC with Portugal being the designated rapporteur Member State (RMS). The representative uses initially supported for the peer review process were northern and southern outdoor foliar spraying treatments of fruit crops (apple, pear, peach and cherry), up to 5 times at 900 g a.s./ha with a PHI ranging from 14 to 60 days. However, the applicant voluntarily withdrew, in accordance with Article 11e of Regulation (EC) No 1490/2002 6, the support for the inclusion of dodine in Annex I to Directive 91/414/EEC. Consequently, a first decision on non-inclusion of the active substance was published by means of Commission Decision 2008/934/EC 7, which entered into force on 31 December In accordance with the provisions laid down in Chapter III of Regulation (EC) No 33/2008 8, dodine was subject to an accelerated resubmission procedure. The representative uses supported were the same but restricted to a maximum of 4 applications and to longer PHIs (up to 75 d for peaches). Following the peer review, which was carried out by EFSA, a decision on inclusion of the active substance in Annex I to Directive 91/414/EEC was published by means of Commission Directive 2011/09/EU 9, which entered into force 6 Commission Regulation (EC) No 1490/2002 of 14 August 2002 laying down further detailed rules for the implementation of the third stage of the programme of work referred to in Article 8(2) of Council Directive 91/414/EEC and amending Regulation (EC) No 451/2000. OJ L 224, , p Commission Decision 2008/934/EC of 5 December 2008 concerning the non-inclusion of certain active substances in Annex I to Council Directive 91/414/EEC and the withdrawal of authorisations for plant protection products containing these substances. OJ L 333, , p Commission Regulation (EC) No 33/2008 of 17 January 2008 laying down detailed rules for the application of Council Directive 91/414/EEC as regards a regular and an accelerated procedure for the assessment of active substances which were part of the programme of work referred to in Article 8(2) of that Directive but have not been included into its Annex I. OJ L 15, , p Commission Directive 2011/09/EU of 1 February 2011 amending Council Directive 91/414/EEC to include dodine as active substance and amending Decision 2008/934/EC. OJ L 28, , p EFSA Journal 2015;13(1):3946 8

9 on 01 June According to Regulation (EU) No 540/ , dodine is deemed to have been approved under Regulation (EC) No 1107/ This approval is restricted to uses as fungicide only. The EU MRLs for dodine are established in Annex IIIA of Regulation (EC) No 396/2005. Since the entry into force of that regulation, EFSA recommended the modification of the existing MRLs for pome fruits, apricots, cherries, peaches, olives (table and for oil production) and bananas (EFSA, 2013a, 2013b) which were legally implemented in Regulation (EU) No 1138/2013/EU 12. All existing EU MRLs, which are established for the parent compound only, are summarised in Appendix C.1 to this document. CXLs for dodine were also established by the Codex Alimentarius Commission and are reported in Appendix C.2 to this reasoned opinion. These CXLs also refer to parent compound only. For the purpose of this MRL review, the uses of dodine currently authorised within the EU as well as uses authorised in third countries that might have a significant impact on international trade have been collected by the RMS and reported in the PROFile. The additional GAPs reported during the consultation of Member States were also considered (see Appendix A). These GAPs include up to 5 foliar spray applications on fruits, fruiting vegetables and celery, at dose rates ranging from 60 g a.s./ha to 900 g a.s./ha and PHIs ranging between 7 and 75 days, in Northern and Southern Europe, under outdoor and indoor conditions. An import tolerance use on bananas was also reported, consisting in up to 5 foliar spray applications at 800 g a.s./ha, until BBCH 98 (harvest). 10 Commission Implementing Regulation (EU) No 540/2011 of 25 May 2011 implementing Regulation (EC) No 1107/2009 of the European Parliament and of the Council as regards the list of approved active substances. OJ L 153, , p Regulation (EC) No 1107/2009 of the European Parliament and of the Council of 21 October 2009 concerning the placing of plant protection products on the market and repealing Council Directives 79/117/EEC and 91/414/EEC. OJ L 309, , p Commission Regulation (EU) No 1138/2013 of 8 November 2013 amending Annexes II, III and V to Regulation (EC) No 396/2005 of the European Parliament and of the Council as regards maximum residue levels for bitertanol, chlorfenvinphos, dodine and vinclozolin in or on certain products. OJ L 307, , p EFSA Journal 2015;13(1):3946 9

10 ASSESSMENT EFSA bases its assessment on the PROFile submitted by the RMS, the evaluation report accompanying the PROFile (Portugal, 2012), the Draft Assessment Report (DAR) and the additional report (AR) prepared under Council Directive 91/414/EEC (Portugal, 2006, 2009), the conclusion on the peer review of the pesticide risk assessment of the active substance dodine (EFSA, 2010), the JMPR Evaluation report (FAO, 2003), the previous reasoned opinions on dodine (EFSA 2013a, 2013b) as well as the evaluation reports submitted during the consultation of Member States (Germany, 2014; Italy, 2014; Netherlands, 2014; United Kingdom, 2014). The assessment is performed in accordance with the legal provisions of the Uniform Principles for Evaluation and Authorisation of Plant Protection Products adopted by Commission Regulation (EU) No 546/ and the currently applicable guidance documents relevant for the consumer risk assessment of pesticide residues (EC, 1996, 1997a, 1997b, 1997c, 1997d, 1997e, 1997f, 1997g, 2000, 2010a, 2010b, 2011 and OECD, 2011). 1. Methods of analysis 1.1. Methods for enforcement of residues in food of plant origin During the peer review under Directive 91/414/EEC, an analytical method using GC-MS, confirmed by LC-MS/MS and its ILV were evaluated and validated for the determination of dodine in plant matrices with an LOQ of 0.05 mg/kg in high water commodities. In addition, after Annex I inclusion, the RMS also evaluated an LC-MS/MS method and its ILV which was fully validated for the determination of dodine with an LOQ of 0.01 mg/kg in high oil content and high water content commodities (EFSA, 2013a). The multi-residue QuEChERS method in combination with LC-MS/MS, as described by CEN (2008), is also reported for analysis of dodine in acidic commodities. Nevertheless, the validation data reported are too limited to conclude on the validity of this analytical method (Table 1-1). Table 1-1: Recovery data for the analysis of dodine in high acidic commodities using the QuEChERS method in combination with LC-MS/MS (EURL, 2014) Commodity group Spiking levels Recoveries Mean (%) RSD (%) n No of labs Acidic Hence it is concluded that dodine can be enforced in food of plant origin with an LOQ of 0.01 mg/kg in high water content and high oil content commodities. There are indications that dodine can be enforced in acidic commodities and, according to the EURLs, the LOQ of 0.01 mg/kg is achievable also in this matrix. Nevertheless, a fully validated analytical method for the determination of dodine in acidic commodities is still required Methods for enforcement of residues in food of animal origin During the peer review under Directive 91/414/EEC, an analytical method using LC-MS/MS was evaluated and validated for the determination of dodine in food of animal origin with an LOQ of 0.01 mg/kg in kidney and liver. As validation data were provided for two mass transitions, the method 13 Commission Regulation (EU) No 546/2011 of 10 June 2011 implementing Regulation (EC) No 1107/2009 of the European Parliament and of the Council as regards uniform principles for evaluation and authorisation of plant protection products. OJ L 155, , p EFSA Journal 2015;13(1):

11 is considered highly specific. Nevertheless, an ILV is missing and is required. An analytical method for enforcement in milk, fat and muscle is not available but, according to the EURLs, the LOQ of 0.01 mg/kg is achievable in all animal commodities. Hence there are indications that dodine can be enforced in food of animal origin with an LOQ of 0.01 mg/kg. However, an ILV in liver and kidney and a fully validated analytical method for the determination of dodine in milk, fat and muscle, are still required. 2. Mammalian toxicology The toxicological assessment of dodine was peer reviewed under Directive 91/414/EEC and toxicological reference values were established by EFSA (2010). These toxicological reference values are summarised in Table 2-1. Table 2-1: Overview of the toxicological reference values Dodine Source Year Value Study relied upon Safety factor ADI EFSA mg/kg bw per d Dog, 1 year and 90 day studies 100 ARfD EFSA mg/kg bw Rat, developmental study Residues 3.1. Nature and magnitude of residues in plant Primary crops Nature of residues Metabolism of dodine was investigated for foliar application on fruits and fruiting vegetables (apples, strawberries, pecans), using 14 C-labelled dodine (EFSA, 2010; FAO, 2003). The characteristics of these studies are summarised in Table 3-1. Table 3-1: Summary of available metabolism studies in plants Group Crop Label position Fruits and fruiting vegetables Apples 14 C- guanidine Method, F or G (a) Foliar spray (until run-off), F Application and sampling details Rate (kg a.s./ha) 0.96, 0.93 and 0.90 No Samplin g (DAT) Remarks 3 7 (b) EFSA, 2010, FAO, 2003 Strawberries (c) EFSA, 2010, FAO, 2003 Pecans (d) EFSA, 2010, FAO, 2003 (a): Outdoor/field application (F) or glasshouse/protected/indoor application (G) (b): Only fruits were sampled. Samplings were also performed prior to the 2 nd and the 3 rd application. (c): Only fruits were sampled. Samplings were also performed prior to the 2 nd, the 3 rd and the 4 th application. (d): At maturity, only fruits (nuts) were sampled. Samplings of immature fruits and leaves were also performed prior to the 2 nd and the 3 rd application. EFSA Journal 2015;13(1):

12 In mature apples, total radioactive residues accounted for 1.51 mg eq./kg: 82 % of the TRR was in the apple peel, 5.7 % in the pulp and 12 % in the water rinses. More than 95 % of the TRR was extracted from each matrix (peel, pulp). In pulp, dodine was the major component of the residue, representing 80.6 % of the TRR (0.068 mg/kg). The remaining radioactivity was distributed between four minor components, none of them representing more than 0.01 mg eq./kg. In peel, where the highest residue levels were found, 25 components were recovered together with the parent compound, which accounted for 89.2 % of the TRR (1.06 mg/kg). One of these metabolites, tentatively identified as guanidine 14, amounted to mg eq./kg; the other metabolites were all below 0.01 mg eq./kg. In mature strawberries, total radioactive residues accounted for 4.28 mg eq./kg, with 97.5 % of the TRR found in the rinsed strawberries and 2.5 % of the TRR found in the water rinses. The extraction efficiencies for mature fruits were greater than 97 % of the TRR. Dodine accounted for 86.5 % of the TRR (3.6 mg/kg). Together with parent compound, several minor components were recovered: 9 of them were present at levels between 0.01 and 0.05 mg eq./kg and 2 of them were above 0.05 mg eq./kg. Among the minor recovered compounds, two could be identified as urea 15 and guanidine. In mature nuts (nutmeat only), total radioactive residues accounted for 0.11 mg eq./kg. The extraction efficiencies for mature nuts were satisfactory (around 100 % TRR). The major compound recovered was guanidine (0.041 mg eq./kg, 36 % TRR), while residues of dodine occurred at smaller amounts (0.015 mg eq./kg, 13.2 % TRR). Radiolabel was associated predominantly with the free fatty acid fraction (0.023 mg eq./kg, 20.2 % TRR). Therefore, according to the available studies, it can be concluded that the metabolic pathway of dodine is similar in all fruit crops investigated. It appears that dodine degrades in fruits relatively slowly. Nevertheless, in pecans, the degradation process occurs at a higher extent. Three possibilities for the degradation of dodine in plants can be proposed: - Oxidation of the dodecyl chain (without cleavage) giving rise to discrete metabolites. - Oxidation with cleavage of the dodecyl chain from the guanidine moiety. The radiolabelled carbon in that moiety would enter the carbon pool in the plant and would therefore appear in natural products. - Oxidation in the dodecyl substituent, in particular at C-1 of this chain, leading to an unstable derivative which would spontaneously decompose to liberate guanidine. N-oxidation of guanidine would produce urea which can be considered a detoxification mechanism. Subsequently, urea breaks down to ammonia and carbon dioxide and some of the radiolabelled carbon is, in turn, assimilated by the plant and incorporated in natural products. The occurrence of many minor peaks in the metabolism studies must be a result of this incorporation of the radiolabelled carbon. EFSA notes that parent compound dodine was predominant in apples and strawberries, while in nutmeat, metabolite guanidine was the major compound recovered. This result is consistent with the more extensive metabolism observed in pecans. Considering that the GAPs evaluated in this review do not include uses on nuts, the residue for enforcement and risk assessment in fruits and fruiting vegetables following foliar applications is defined as dodine only. However, the inclusion of metabolite guanidine in the residue definition should be evaluated in case authorizations for use on nuts would be granted in the future. Validated analytical methods for enforcement of the proposed residue definition are available, except for acidic matrices, where additional data are still required (see also section 1.1). This residue definition is limited to the foliar treatment on fruits and fruiting vegetables at the authorised application rates. Nevertheless, dodine is also authorised for foliar application on celery 14 guanidine: see Appendix E. 15 urea: see Appendix E. EFSA Journal 2015;13(1):

13 (leafy vegetables), for which no representative metabolism study is available. In order to extend the proposed residue definition to leafy vegetables, a representative metabolism study for this crop group is required. Meanwhile, it is proposed, on a tentative basis, to also define the residue for enforcement and risk assessment in leafy vegetables as dodine only. The conclusions reached by EFSA reflect the views of the RMS and are also in line with those of the JMPR (FAO, 2003) Magnitude of residues According to the RMS, the active substance dodine is authorised in northern and southern Europe for foliar treatment of fruits, fruiting vegetables and celery, both under outdoor and indoor conditions (see Appendix A). To assess the magnitude of dodine residues resulting from these GAPs, EFSA considered all residue trials reported in the PROFile or by the RMS in its evaluation report (Portugal, 2012), including residue trials evaluated in the framework of the peer review (EFSA, 2010) or in the framework of previous MRL applications (EFSA, 2013a, 2013b) and additional data submitted during the consultation of Member States (Germany, 2014, Italy, 2014; Netherlands, 2014). All available residue trials that, according to the RMS, comply with the authorised GAPs, are summarised in Table 3-2. The number of residue trials and extrapolations were evaluated in accordance with the European guidelines on comparability, extrapolation, group tolerances and data requirements for setting MRLs (EC, 2011). A sufficient number of trials compliant with the GAP was reported by the RMS for olives and bananas. For the other crops, the following considerations were made by EFSA: Pome fruit: 2 trials on apples supporting the southern outdoor use were conducted with a more critical GAP (PHI of 28 days instead of 40, Italy, 2014); nevertheless, as the residue levels in these trials are in the same range as in the compliant GAP trials, they are considered acceptable. Therefore, 1 additional trials compliant with the southern GAP is considered desirable only. Apricots, peaches: according to the EU guidance document, the available data package on peaches and apples would be acceptable to support the southern outdoor GAPs on peaches and apricots (last application at the growth stage BBCH 69 (end of flowering), i.e. where the consumable part of the crop has not yet started to form). Nevertheless, EFSA notes that the EU guidance document does not clearly define the growth stage up to which such an extrapolation would be acceptable: the use of an active substance at the end of flowering would probably be the boarder line. Moreover, trials on apples were performed with a less critical PHI ( d instead of 75 d) (EFSA, 2013b). Therefore, although appropriate MRL and risk assessment values can be derived, additional trials on apricots compliant with the southern outdoor GAP would be desirable. Cherries: considering that cherries are a major crop in northern Europe, the number of residue trials supporting the northern outdoor GAP is not compliant with the data requirements for this crop (7 trials instead of 8). Moreover, 3 northern trials and 4 southern trials were performed with 3 applications instead of 2; nevertheless, as the residue levels in overdosed trials are in the same range as in the compliant trials, overdosed trials are considered acceptable (EFSA, 2013a). Therefore, although appropriate MRL and risk assessment values can be derived from the southern data, 1 additional trial compliant with the northern GAP would still be desirable. Blueberries (aronia): no residue trials are available to support the northern outdoor use. Considering that this crop is minor in Europe, 4 residue trials compliant with the northern outdoor GAP are required. Meanwhile, neither MRLs nor risk assessment values can be derived. EFSA Journal 2015;13(1):

14 Cranberries: during the Member Sates Consultation, the United Kingdom submitted a northern outdoor GAP on cranberries, for which neither PHI nor maximal growth stage at application were specified. Moreover there are no residue trials available to support this GAP. Therefore, considering that this crop is minor in Europe, 4 residue trials on cranberries together with a clarification on the northern outdoor GAP are required. Meanwhile, neither MRLs nor risk assessment values can be derived. Currants, gooseberries: no residue trials are available to support the indoor uses. Considering that these crops are minor in Europe, 4 residue trials compliant with the indoor GAPs are required for each crop. Meanwhile, neither MRLs nor risk assessment values can be derived. Celery: no residue trials are available to support the southern outdoor and indoor uses. Therefore, complete residue data packages compliant with the southern outdoor and indoor GAPs are required. Meanwhile, neither MRLs nor risk assessment values can be derived. The potential degradation of residues during storage of the residue trials samples was also assessed. In the framework of the peer review, storage stability of dodine was demonstrated for a period of 18 months at -18 C in commodities with high water content (apple, peach, cherry) (Portugal, 2009). Moreover, storage stability of dodine was demonstrated for a period of 9 months at -20 C in high oil content commodities (peanut) (EFSA, 2013b). According to the RMS, all residue trial samples reported in the PROFile were stored in compliance with the storage conditions reported above. Degradation of residues during storage of the trial samples is therefore not expected. No storage stability data in high acid content commodities are available; however considering that the storage stability in plant commodities has been demonstrated for at least 9 months, a storage stability study in acidic commodities would only be desirable. Consequently, the available residues data are considered sufficient to derive MRL proposals as well as risk assessment values for all commodities under evaluation except for blueberries (aronia), cranberries, currants, gooseberries and celery where the available data were insufficient to derive tentative MRLs (see also Table 3-2). Where several uses are authorised for one commodity, the final MRL proposal was derived from the most critical use and indicated in bold in Table 3-2. EFSA Journal 2015;13(1):

15 Table 3-2: Overview of the available residue trials data Commodity Residue region (a) Outdoor /Indoor Individual trial results Enforcement Enforcement and risk assessment residue definition: dodine Apples, Pears NEU Outdoor 0.18; 0.37; 0.37; 0.45; 0.54; 0.61; 0.61;1.30 NEU (fallback) Outdoor 0.035; 0.052; 0.063; 0.070; 0.15; 0.16; 0.19; 0.37 SEU Outdoor Apples: 0.31; 0.48; 0.42 (e) ; 0.36 (e) Pears: 0.12; 0.13; 0.25; 0.18; 0.11 Risk assessment 0.18; 0.37; 0.37; 0.45; 0.54; 0.61; 0.61; ; 0.052; 0.063; 0.070; 0.15; 0.16; 0.19; 0.37 Apples: 0.31; 0.48; 0.42 (e) ; 0.36 (e) Pears: 0.12; 0.13; 0.25; 0.18; 0.11 Median residue (b) Highest residue (c) MRL proposal Median CF (d) Comments Trials on apples compliant with GAP on pome fruits (EFSA, 2010; Netherlands, 2014). R ber = 1.22 R max = 1.62 MRL OECD = Trials on apples compliant with GAP on pome fruits (Germany, 2014). R ber = 0.37 R max = 0.49 MRL OECD = Trials on apples and pears compliant with GAP on pome fruits (Italy, 2014). R ber = 0.68 R max = 0.78 MRL OECD = 0.81 EFSA Journal 2015;13(1):

16 Commodity Quinces, Medlar, Loquat Peaches, Apricots Residue region (a) Outdoor /Indoor Individual trial results Enforcement NEU Outdoor 0.035; 0.052; 0.063; 0.070; 0.15; 0.16; 0.19; 0.37 SEU Outdoor Apples: 0.31; 0.48; 0.42 (e) ; 0.36 (e) Pears: 0.12; 0.13; 0.25; 0.18; 0.11 SEU Outdoor 9 <0.05; 0.053; Cherries NEU Outdoor ; 0.14 (f) ; 0.17; 0.27 (f) ; (f) Blueberries (aronia) SEU Outdoor 0.096; 0.14 (f) ; 0.36; 0.46 (f) ; 0.56 (f) ; 0.77 (f) ; 1.25 Risk assessment 0.035; 0.052; 0.063; 0.070; 0.15; 0.16; 0.19; 0.37 Apples: 0.31; 0.48; 0.42 (e) ; 0.36 (e) Pears: 0.12; 0.13; 0.25; 0.18; <0.05; 0.053; ; 0.14 (f) ; 0.17; 0.27 (f) ; (f) 0.096; 0.14 (f) ; 0.36; 0.46 (f) ; 0.56 (f) ; 0.77 (f) ; 1.25 Median residue (b) Highest residue (c) MRL proposal Median CF (d) Comments Trials on apples compliant with GAP on pome fruits (Germany, 2014). R ber = 0.37 R max = 0.49 MRL OECD = Direct extrapolation from apples and pears Trials on peaches (7) and apples (4) compliant with GAP on peaches and apricots (EFSA, 2013b). R ber = 0.10 R max = 0.07 MRL OECD = Trials on cherries (EFSA, 2013a). R ber = 1.40 R max = 1.21 MRL OECD = Trials on cherries (EFSA, 2013a). R ber = 1.54 R max = 1.87 MRL OECD = 2.11 NEU Outdoor No trials available. EFSA Journal 2015;13(1):

17 Commodity Residue region (a) Outdoor /Indoor Individual trial results Enforcement Risk assessment Median residue (b) Highest residue (c) MRL proposal Median CF (d) Comments Cranberries NEU Outdoor No trials available. Currants (red, black and white) EU Indoor No trials available. Gooseberries EU Indoor No trials available. Table olives, Olives for oil production Bananas SEU Outdoor 3.7; 4.1; 4.6; 6.1; 6.9; 8.6; 10; 11.2 Import (USA, Central and South America) Outdoor 0.130; 0.132; 0.133; 0.142; 0.146; 0.155; 0.159; 0.160; 0.194; ; ; 4.1; 4.6; 6.1; 6.9; 8.6; 10; ; 0.132; 0.133; 0.142; 0.146; 0.155; 0.159; 0.160; 0.194; ; Trials on olives performed with a PHI of 21d instead of 7d considered acceptable (EFSA, 2013a). R ber = 19.3 R max = MRL OECD = Trials on un-bagged bananas (worst-case) compliant with GAP (EFSA, 2013a). R ber = 0.42 R max = 0.28 MRL OECD = 0.51 Celery SEU Outdoor No trials available. EU Indoor No trials available. (a): NEU (Northern and Central Europe), SEU (Southern Europe and Mediterranean), EU (i.e outdoor use) or Import (country code) (EC, 2011). (b): Median value of the individual trial results according to the enforcement residue definition. (c): Highest value of the individual trial results according to the enforcement residue definition. (d): The median conversion factor for enforcement to risk assessment is obtained by calculating the median of the individual conversion factors for each residues trial. (e): Residue trials performed with a PHI of 28 days instead of 40 considered acceptable (see body text). (f): Residue trials performed with 3 applications instead of 2 considered acceptable (see body text). EFSA Journal 2015;13(1):

18 Effect of industrial processing and/or household preparation The effect of processing on the nature of dodine was investigated in the framework of the peer review. Studies were conducted simulating representative hydrolytic conditions for pasteurisation (20 minutes at 90 C, ph 4), boiling/brewing/baking (60 minutes at 100 C, ph 5) and sterilisation (20 minutes at 120 C, ph 6). From these studies, it was concluded that processing by pasteurisation, baking/brewing/boiling and sterilisation is not expected to have a significant impact on the composition of residues in matrices of plant origin (EFSA, 2010). The relevant residue for enforcement and risk assessment in processed commodities is therefore expected to be the same as for primary crops. Studies investigating the magnitude of residues in processed commodities of olives, apples and in peeled bananas were also reported in the framework of the peer review (EFSA, 2010 ; Portugal, 2009) and in a previous MRL application (EFSA, 2013a). An overview of all available processing studies is available in Table 3-3. Robust processing factors for enforcement and risk assessment were derived for all processed commodities investigated. Further processing studies are not required as they are not expected to affect the outcome of the risk assessment. However, if more robust processing factors were to be required by risk managers, in particular for enforcement purposes, additional processing studies would be needed. Table 3-3: Overview of the available processing studies Processed commodity Number of studies Median PF (a) Median CF (b) Comments Enforcement residue definition: dodine Processing factors recommended (sufficiently supported by data) Apples, juice EFSA, 2010; Portugal, 2009 Apples, wet pomace EFSA, 2010; Portugal, 2009 Bananas, peeled Residues in pulp were below the LOQ of 0.01 mg/kg (EFSA, 2013a) Olives, virgin oil after cold press EFSA, 2013a Olives, press cake EFSA, 2013a (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 Rotational crops Among the crops under consideration, celery may be grown in rotation. According to the laboratory degradation studies evaluated in the framework of the peer review, DT 90 values of dodine ranges between days. These results are far below the trigger value of 100 days (EFSA, 2010). Moreover, no relevant soil metabolites were identified. According to the European guidelines on rotational crops (EC, 1997c), further investigation of residues in rotational crops is not required and relevant residues in rotational crops are not expected. EFSA Journal 2015;13(1):

19 3.2. Nature and magnitude of residues in livestock Dietary burden of livestock Dodine is authorised for use on a commodity that might be fed to livestock: apple. The median and maximum dietary burdens were therefore calculated for different groups of livestock using the agreed European methodology (EC, 1996). The input values for apple have been selected according to the recommendations of JMPR (FAO, 2009) and are reported in Table 3-4. Moreover, the processing factor derived for apple pomace under section has been included in the calculation. Table 3-4: Input values for the dietary burden calculation Commodity Median dietary burden Maximum dietary burden Input value Risk assessment residue definition: dodine Comment Input value Comment Apple pomace 1.30 Median residue PF 1.30 Median residue PF The results of the calculations are reported in Table 3-5. The calculated dietary burdens for dairy and meat ruminants were found to exceed the trigger value of 0.1 mg/kg DM. Further investigation of residues is therefore only required in these groups of livestock. Table 3-5: Results of the dietary burden calculation Median dietary burden (mg/kg bw per d) Risk assessment residue definition: dodine Maximum dietary burden (mg/kg bw per d) Highest contributing commodity Max dietary burden (mg/kg DM) Trigger exceeded (Y/N) Dairy ruminants Apple pomace 0.57 Y Meat ruminants Apple pomace 1.70 Y Poultry - - Not relevant - N Pigs - - Not relevant - N Nature and magnitude of residues The nature of dodine residues in commodities of animal origin was investigated in the framework of Directive 91/414/EEC (EFSA, 2010) and by the JMPR (FAO, 2003). One metabolism study performed on lactating goats and using 14 C labelled dodine has been reported. The characteristics of this study are summarised in Table 3-6. Lactating goat was dosed with 0.4 mg/kg bw per d of dodine, corresponding to approximately 6 times the exposure of meat ruminant. The overall recovered radioactivity was 86 % of the administered dose. Radioactivity was poorly absorbed: during the testing period, 38 % and 30 % of the administered dose were excreted in urine and faeces, respectively. Transfer of radioactivity into milk was low and accounted for 0.05 % of the administered dose, with total radioactive residues reaching a plateau of 0.01 mg eq./kg, 3-5 days after administration. Less than 1 % of the total dose administered remained in tissues. Indeed, radioactivity in liver and kidney accounted for 0.2 % (0.17 mg eq./kg) and 0.02 % (0.11 mg eq./kg) of the administered dose, respectively. Concentrations in muscle and fat were very low, accounting for 0.02 mg eq./kg and mg eq./kg, respectively. EFSA Journal 2015;13(1):