Outcome of the consultation with Member States, the applicant and EFSA on the pesticide risk assessment for eugenol in light of confirmatory data

TECHNICAL REPORT APPROVED: 12 January 2017 doi:10.2903/sp.efsa.2017.en-1165 Outcome of the consultation with Member States, the applicant and EFSA on the pesticide risk assessment for eugenol in light of confirmatory data Abstract European Food Safety Authority (EFSA) The European Food Safety Authority (EFSA) was asked by the European Commission to provide scientific assistance with respect to the risk assessment for an active substance in light of confirmatory data requested following approval in accordance with Article 6(1) of Directive 91/414/EEC and Article 6(f) of Regulation (EC) No 1107/2009. In this context EFSA s scientific views on the specific points raised during the commenting phase conducted with Member States, the applicant and EFSA on the confirmatory data and their use in the risk assessment for eugenol are presented. The current report summarises the outcome of the consultation process organised by the rapporteur Member State the United Kingdom and presents EFSA s scientific views and conclusions on the individual comments received. European Food Safety Authority, 2017 Keywords: eugenol, peer review, confirmatory data, risk assessment, pesticide, fungicide Requestor: European Commission Question number: EFSA-Q-2016-00853 Correspondence: pesticides.peerreview@efsa.europa.eu www.efsa.europa.eu/publications EFSA Supporting publication 2017:EN-1165

Suggested citation: EFSA (European Food Safety Authority), 2017. Technical report on the outcome of the consultation with Member States, the applicant and EFSA on the pesticide risk assessment for eugenol in light of confirmatory data. EFSA supporting publication 2017:EN-1165. 56 pp. European Food Safety Authority, 2017 Reproduction is authorised provided the source is acknowledged. www.efsa.europa.eu/publications 2 EFSA Supporting publication 2017:EN-1165

Summary Eugenol was approved on 1 December 2013 under Regulation (EC) No 1107/2009 by Commission Implementing Regulation (EU) 546/2013. It was a specific provision of the approval that the applicant was required to submit to the European Commission further studies by 30 November 2015 on: (a) the storage stability (2 years) at ambient temperature on the formulated product; (b) data comparing natural background exposure situations of eugenol and methyl eugenol in relation to exposure from the use of eugenol as a plant protection product. This data shall cover human exposure as well as exposure of birds and aquatic organisms; (c) the groundwater exposure assessment for potential metabolites of eugenol, in particular for methyl eugenol. In accordance with the specific provision, the applicant, Eden Research PLC, submitted an updated dossier in November 2015, which was evaluated by the designated rapporteur Member State (RMS), the United Kingdom, in the form of an addendum to the draft assessment report. In compliance with guidance document SANCO 5634/2009-rev.6.1, the RMS distributed the addendum to Member States, the applicant and EFSA for comments on 30 September 2016. The RMS collated all comments in the format of a reporting table, which was submitted to EFSA on 15 December 2016. EFSA added its scientific views on the specific points raised during the commenting phase in column 4 of the reporting table. The current report summarises the outcome of the consultation process organised by the RMS, the United Kingdom, and presents EFSA s scientific views and conclusions on the individual comments received. Eugenol is the given name for 4-allyl-2-methoxyphenol (IUPAC). The representative formulated product for the evaluation was Mevalone 3AEY, a capsule suspension (CS) containing 3.2 % eugenol, 6.4 % geraniol and 6.4% thymol. The representative use evaluated comprised outdoor foliar spraying against Botrytis on table and wine grapes. It was confirmed that the methyl eugenol content is not increasing during storage, however the levels found still cannot be explained if the proposed specification of the technical material is 0.05 g/kg. The confirmatory data requirement to compare the natural background exposure situations of eugenol and methyl eugenol in relation to dietary exposure from the use of eugenol as a plant protection product cannot be considered as fulfilled. The natural dietary background exposure levels of eugenol and methyl eugenol were not supported by reliable and robust validated average daily consumption data for the European consumers. Furthermore the consumer exposure assessment resulting from the use of eugenol as a plant protection product could not be concluded on in view of the identified data gaps for eugenol residues storage stability data and the occurrence of methyl eugenol as a residue in grapes. Overall and based on the available data the comparison of natural background exposure levels of eugenol/methyl eugenol to the dietary exposure to eugenol/methyl eugenol residues resulting from the use of eugenol as a plant protection product is not addressed. RMS considers this confirmatory data requirement as addressed. To address the confirmatory data requirement on the groundwater exposure assessment for potential metabolites of eugenol, in particular for methyl eugenol, the following environmental fate studies were submitted by the applicant: an aerobic laboratory route and rate of degradation dosed with eugenol, a batch adsorption/desorption study with eugenol, and new FOCUS groundwater modelling for eugenol. The RMS s assessment of this confirmatory information was essentially agreed by the Member States and EFSA experts. Methyl eugenol was not identified as a metabolite in the aerobic degradation study and was therefore not considered relevant with regards its groundwater exposure. Using the available information the potential for groundwater exposure from the representative uses by eugenol above the parametric drinking water limit of 0.1 µg/l was concluded to be low in geoclimatic situations that are presented by all the relevant FOCUS groundwater scenarios. In the section of ecotoxicology, it was concluded that the submitted information was not sufficient to enable a comparison, for birds and aquatic organisms, between the natural background exposure of www.efsa.europa.eu/publications 3 EFSA Supporting publication 2017:EN-1165

eugenol and methyl eugenol and the exposure due to the use of eugenol as a plant protection product. Overall, the ecotoxicological confirmatory data requirements are not considered addressed. www.efsa.europa.eu/publications 4 EFSA Supporting publication 2017:EN-1165

Table of contents Abstract... 1 Summary... 3 1. Introduction... 6 1.1. Background and Terms of Reference as provided by the requestor... 6 1.2. Interpretation of the Terms of Reference... 6 2. Assessment... 7 Documentation provided to EFSA... 7 References... 7 Abbreviations... 8 Appendix A Collation of comments from Member States, applicant and EFSA on the pesticide risk assessment for the active substance eugenol in light of confirmatory data and the conclusions drawn by EFSA on the specific points raised... 9 Appendix B Used compound codes... 56 www.efsa.europa.eu/publications 5 EFSA Supporting publication 2017:EN-1165

1. Introduction 1.1. Background and Terms of Reference as provided by the requestor Eugenol was approved on 1 December 2013 under Regulation (EC) No 1107/2009 1 by Commission Implementing Regulation (EU) 546/2013 2. EFSA previously finalised a Conclusion on this active substance on 5 November 2012 (EFSA, 2012). It was a specific provision of the approval that the applicant was required to submit to the European Commission further studies by 30 November 2015 on: (a) the storage stability (2 years) at ambient temperature on the formulated product; (b) data comparing natural background exposure situations of eugenol and methyl eugenol in relation to exposure from the use of eugenol as a plant protection product. This data shall cover human exposure as well as exposure of birds and aquatic organisms; (c) the groundwater exposure assessment for potential metabolites of eugenol, in particular for methyl eugenol. In accordance with the specific provision, the applicant, Eden Research PLC, submitted an updated dossier in November 2015, which was evaluated by the designated rapporteur Member State (RMS), the United Kingdom, in the form of an addendum to the draft assessment report (United Kingdom, 2016a). In compliance with guidance document SANCO 5634/2009-rev.6.1 (European Commission, 2013), the RMS distributed the addendum to Member States, the applicant and EFSA for comments on 30 September 2016. The RMS collated all comments in the format of a reporting table, which was submitted to EFSA on 15 December 2016 (United Kingdom, 2016b). EFSA added its scientific views on the specific points raised during the commenting phase in column 4 of the reporting table. The current report summarises the outcome of the consultation process organised by the RMS, the United Kingdom and presents EFSA s scientific views and conclusions on the individual comments received. 1.2. Interpretation of the Terms of Reference On 22 December 2014 the European Commission requested EFSA to provide scientific assistance with respect to the risk assessment of confirmatory data following approval of an active substance in accordance with Article 6(1) of Directive 91/414/EEC and Article 6(f) of Regulation (EC) No 1107/2009. EFSA s scientific views on the specific points raised during the commenting phase conducted with Member States, the applicant and EFSA on the risk assessment of confirmatory data for eugenol are presented. To this end, a technical report containing the finalised reporting table is being prepared by EFSA. The deadline for providing the finalised report is 13 January 2017. On the basis of the reporting table, the European Commission may decide to further consult EFSA to conduct a full or focused peer review and to provide its conclusions on certain specific points. 1 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, 24.11.2009, p. 1-50. 2 Commission Implementing Regulation (EU) No 546/2013 of 14 June 2016 approving the active substance eugenol, in accordance with Regulation (EC) No 1107/2009 of the European Parliament and of the Council concerning the placing of plant protection products on the market, and amending the Annex to Commission Implementing Regulation (EU) No 540/2011. OJ L 163, 15.6.2013, p. 17-20. www.efsa.europa.eu/publications 6 EFSA Supporting publication 2017:EN-1165

2. Assessment The comments received on the pesticide risk assessment for the active substance eugenol in light of confirmatory data and the conclusions drawn by EFSA are presented in the format of a reporting table. The comments received are summarised in column 2 of the reporting table. The RMS considerations of the comments are provided in column 3, while EFSA s scientific views and conclusions are outlined in column 4 of the table. The finalised reporting table is provided in Appendix A of this report. Documentation provided to EFSA 1. United Kingdom, 2016a. Addendum to the assessment report on eugenol, confirmatory data, August 2016. Available online: www.efsa.europa.eu. 2. United Kingdom, 2016b. Reporting table, comments on the pesticide risk assessment for eugenol in light of confirmatory data, December 2016. References EFSA (European Food Safety Authority), 2012. Conclusion on the peer review of the pesticide risk assessment of the active substance eugenol. EFSA Journal 2012;10(11):2914, 46 pp. doi:102903/j.efsa.2012.2914 European Commission, 2013. Guidance document on the procedures for submission and assessment of confirmatory information following approval of an active substance in accordance with Regulation (EC) No 1107/2009. SANCO 5634/2009-rev. 6.1 www.efsa.europa.eu/publications 7 EFSA Supporting publication 2017:EN-1165

Abbreviations a.s. ADI AOEL AR ARfD CS DAR DG SANCO DT 50 DT 90 EU GAP GLP HPLC HR IUPAC KF oc K oc LOQ LSC MCP MRL MS NOEC OECD PEC PEC air PEC soil PEC sw PPP PRIMo RIVM RMS SMILES TTC USDA active substance acceptable daily intake acceptable operator exposure level applied radioactivity acute reference dose capsule suspension draft assessment report European Commission Directorate General Health and Consumers period required for 50% dissipation period required for 90% dissipation European Union good agricultural practice good laboratory practice high-pressure liquid chromatography highest residue International Union of Pure and Applied Chemistry Freundlich organic carbon adsorption coefficient soil organic carbon-water partitioning coefficient limit of quantification liquid-solid chromatography maximum permissible concentration maximum residue level Member State no observed adverse effect concentration Organisation for Economic Cooperation and Development predicted environmental concentration predicted environmental concentration in air predicted environmental concentration in soil predicted environmental concentration in surface water plant protection product Pesticide Residue Intake Model Dutch National Institute for Public Health and the Environment rapporteur Member State simplified molecular-input line-entry system Threshold of Toxicological Concern United States Department of Agriculture www.efsa.europa.eu/publications 8 EFSA Supporting publication 2017:EN-1165

Appendix A Collation of comments from Member States, applicant and EFSA on the pesticide risk assessment for the active substance eugenol in light of confirmatory data and the conclusions drawn by EFSA on the specific points raised 1. Physical/Chemical Properties; Details of Uses and Further Information; Methods of Analysis Methods of analysis (B.5) No. Column 1 Reference to addendum to assessment report 1(1) B.5 Methods of analysis, page 9 1(2) Conf. data, B.2, Table B.2.1, p.7 Column 2 Comments from Member States / applicant / EFSA Applicant: For the avoidance of doubt, this method (Bates, 2012) was already evaluated and found to be acceptable in the EU review (Eugenol revised volume 3, B5 methods, April 2012). EFSA: it is confirmed that the methyl eugenol content is not increasing during storage, however the levels found still cannot be explained if the proposed specification of the technical material is 0.05 g/kg. This would lead to a maximum 1.6 mg/kg in the formulation, while the storage stability study shows values around 8 mg/kg.. If the specification is not changed, these formulations are not meeting the admissible maximum methyl eugenol content requirements. Column 3 Evaluation by rapporteur Member State RMS: Noted thank you for clarifying. Adressed. RMS: The RMS highlights that the confirmatory data requirement set was to confirm the storage stability (2 years) at ambient temperature on the formulated product as noted in the EFSA comment, this point has been addressed. It was not considered necessary to reopen the underlying data / evaluation supporting the specification, in order to address this confirmatory data requirement. This point is considered by the RMS to be a separate issue to the confirmatory data assessment. Column 4 EFSA s scientific views on the specific points raised in the commenting phase conducted on the RMS s assessment of confirmatory data The confirmatory data requirement set was fulfilled. However, it should be noted that the levels found still cannot be explained if the proposed specification of methyl eugenol in the technical material is 0.05 g/kg. www.efsa.europa.eu/publications 9 EFSA Supporting publication 2017:EN-1165

Nonetheless, the RMS will provide the following response: EFSA will note that in the initial draft of the Eugenol Volume 4 (May 2011), which was sent for EU MS commenting, the recommended methyl eugenol content within the specification was 1 g/kg. This was amended in the revised Volume 4 (April 2012) to 0.05 g/kg based on Member State comments. The revised value of 0.05 g/kg is out of step with the maximum level of 0.1% set for methyl-eugenol within the Commission Implementing Regulation (EU) No 546/2013. The level of 0.1% was set as a result of other substance evaluations. The Notifier s justification has been presented within Appendix 1 of the report (provided here for illustrative purposes only, does not form part of the UK assessment). Due to the lack of variability in the 5 batch dataset submitted appropriate tolerances could not be set using the mean±3sd rule of thumb. Due to the natural origins of the precursor material, such variation is to be expected. As the Notifier has stated, all material produced by this source is screened to ensure compliance with the 0.1% limit. www.efsa.europa.eu/publications 10 EFSA Supporting publication 2017:EN-1165

The RMS would recommend that the level of 0.05 g/kg be reconsidered and that a level of 0.1 g/kg would be more appropriate. This would also ensure consistency with other active substances containing methyl-eugenol as a relevant impurity (tea tree extract, citronella oil and clove oil). Should further information be deemed necessary to support the amendment of this level, then the provision of quality assurance data from the past 5 years, may be beneficial. Addressed (w.r.t. the original confirmatory data requirement). 1(3) Conf. data, B.2, Method of analysis for the relevant impurity, p.10 EFSA: the LOQ of 1 mg/kg is allowing for a proper quantification of the specified levels of methyl eugenol in the formulation and also in the technical material. RMS: Agreed. 2. Mammalian toxicology Exposure data (B.6.14) No. Column 1 Reference to addendum to assessment report Column 2 Comments from Member States / applicant / EFSA Column 3 Evaluation by rapporteur Member State Column 4 EFSA s scientific views on the specific points raised in the commenting phase conducted on the RMS s assessment of confirmatory data 2(1) Page 15, B6.14 Operator Exposure Applicant: Although it is agreed that massage, cigarettes and candles do not constitute natural UK RMS Noted. Other sources of (non dietary) exposure, to be relied upon, should contain sufficiently robust and www.efsa.europa.eu/publications 11 EFSA Supporting publication 2017:EN-1165

exposure, it is still considered that the assessment has some value in demonstrating that exposure due to plant protection product use is within existing exposure from other sources and therefore provides some reassurance that the risk to humans is acceptable from potential exposure due to the proposed use. validated data. 2(2) B.6.14, Operator exposure, p.11-16, eugenol EFSA: For eugenol, the risk assessment could be concluded for the operator/workers/bystanders, since an AOEL had been derived for the compound, exposure estimates had been provided and shown to be below the AOEL value. UK RMS Agreed. Natural background exposure to eugenol, to be relied upon, should be underpinned by sufficiently robust and validated data. See also comment 3(2). In any case, if natural background exposure levels are used, these levels have to be agreed by the residues section. 2(3) B.6.14, Operator exposure, p.11-16, methyl eugenol EFSA: The impurity methyl eugenol has been identified as a genotoxic carcinogen. For methyl eugenol, EFSA supports the use of the TTC approach (with the TTC value for genotoxic compounds), provided it is supported by well determined exposure estimates (agreed by the residue section for the consumers). By using this approach for UK RMS: The confirmatory data requirement is to compare natural background exposure to methyl eugenol in relation to exposure to methyl eugenol from the use plant protection product. The confirmatory data requirement is not to assess estimated exposures using the TTC approach. As a result a comparison between background exposures and exposure from the use plant protection product (worst case Natural background exposure to methyl eugenol, to be relied upon, should be underpinned by sufficiently robust and validated data. See also comments 3(2) and 3(5). www.efsa.europa.eu/publications 12 EFSA Supporting publication 2017:EN-1165

operators/workers/bystanders, there is no need to consider the natural background exposure levels (if safe exposure estimates are shown by the models). In any case, if natural background exposure levels are used, these levels have to be agreed by the residues section. For methyl eugenol, as carcinogenic data are available, the use of the margin of exposure could also be considered (EFSA Scientific Opinion, EFSA Journal 2012;10(3):2578). exposure scenario) has been presented within the assessment. Exposures are estimated to be within background dietary intake estimates (as presented within the Residues assessment). Please note that there is a typographical error within the UK POEM assessment on pg 13. Eugenol within the active substance section should read methyl eugenol. 3. Residues Metabolism in plants (B.7.1) No. Column 1 Reference to addendum to assessment report Column 2 Comments from Member States / applicant / EFSA Column 3 Evaluation by rapporteur Member State Column 4 EFSA s scientific views on the specific points raised in the commenting phase conducted on the RMS s assessment of confirmatory data 3(1) B.7.1. Eugenol, Table B.7.1.2. Concentration of methyleugenol in vegetables, herbs and spices EFSA: Please specify the sources/references of the reported concentrations of methyl eugenol in the plant commodities. RMS: Reference has been updated. Confirmatory data (August, 2016) www.efsa.europa.eu/publications 13 EFSA Supporting publication 2017:EN-1165

MRLs related issues and Consumer Risk Assessment (B.7.10 to B.7.15) No. Column 1 Reference to addendum to assessment report 3(2) B.7 Residues Confirmatory data (August, 2016) Column 2 Comments from Member States / applicant / EFSA EFSA: It is noted that a comparison of the chronic consumer exposures to eugenol from natural sources and from the use of plant protection product 3AEY has been carried out. What is the relevance of this calculation since an ADI of 1 mg/kg bw per day was agreed on (no ARfD was allocated) (see section 2 in EFSA Journal 2012; 10(11):2914) to carry out the consumer exposure assessment to eugenol residues from the use of eugenol as a PPP? Column 3 Evaluation by rapporteur Member State RMS: EFSA will note that a consumer risk assessment was made during the original DAR assessment, which considered chronic consumer exposures within the context of the ADI (1 mg/kg bw/day). This was not sufficient to preclude the inclusion of the confirmatory data requirement (within Commission Implementing Regulation (EU) No 546/2013). In line with this requirement, a comparison of the natural exposure scenario for both eugenol and methyl eugenol has been provided by the Notifier and this has been assessed by the UK RMS. As highlighted within the conclusion to the confirmatory data assessment, the calculated exposure for the use of 3AEY on grapes is within the anticipated natural background exposure for consumers based on the cited literature. Column 4 EFSA s scientific views on the specific points raised in the commenting phase conducted on the RMS s assessment of confirmatory data It is noted that the consumer dietary risk assessment with regard to eugenol residues will need to be reconsidered pending the acceptability of the residue trials for the determination of eugenol residues in grapes in compliance with the representative use. See also point 3(3). Furthermore EFSA is of the opinion that the natural dietary background exposure estimates respectively for eugenol and methyl eugenol residues should be based on robust and validated average daily consumption data related to these compounds. See also point 3(5). The assessment of the chronic exposure was included to provide clarity and allow for the direct comparison of the two scenarios www.efsa.europa.eu/publications 14 EFSA Supporting publication 2017:EN-1165

within the confirmatory assessment document. 3(3) B.7 Residues, Table B.7.1.5: Input values for the consumer risk assessment of eugenol following application of 3AEY Confirmatory data (August, 2016) EFSA: The acceptability of the HR value of 0.05 mg/kg from the residue trials on grapes is pending upon the outcome of the requested storage stability data to cover the maximum storage time interval of eugenol in the samples from the residue trials. RMS: The lack of clear storage stability data is noted, however data to address this EFSA data gap were not indicated as a condition for this confirmatory data assessment (as defined in the Commission Implementing Regulation (EU) No 546/2013). In lieu of this additional information, the RMS considers the use of this HR value to remain appropriate. When further information is provided to address this point (as part of a product assessment or as part of the renewal review), further consideration should be made. EFSA disagrees. Acceptable residue trials compliant with the representative use on grapes and analysing for eugenol residues are part of the confirmatory data to compare the natural background exposures of eugenol to exposure to eugenol from the use of this compound as a plant protection product. These residue trials should therefore be supported by valid storage stability data identified as a data gap during the initial peer review (EFSA, 2012). EFSA considers that the current assessment of the confirmatory data cannot be finalised without these data. 3(4) B.7.2. Methyl eugenol, Table B.7.2.1 Input values for the consumer risk assessment of methyl eugenol following application of 3AEY Confirmatory data (August, 2016) EFSA: EFSA is quite reluctant regarding the approach used to estimate the exposure assessment to methyl eugenol residues arisen from the use of eugenol as the PPP 3AEY as it is assumed that methyl eugenol is not formed when eugenol is applied to the plants. This cannot be supported as metabolism data were not provided. EFSA also refers to the identified data gap to determine the occurrence of methyl eugenol as a residue in grapes in accordance with the RMS: The RMS would point out that eugenol is considered to be thermally stable (based on the accelerated storage stability study) and does not absorb significantly at wavelengths above 290 nm (only a minor absorbance observed at 297nm). These points suggest that eugenol would remain stable on foliar surfaces. As noted by EFSA, the lack of a plant metabolism study means that conversion of eugenol to methyl EFSA disagrees. The occurrence of methyl eugenol as a residue in grapes when eugenol is applied as a pesticide active substance according to the representative use on grapes was identified as a data gap during the initial peer review (EFSA, 2012) and is part of the confirmatory data to compare the natural dietary background exposures of methyl eugenol to exposure to methyl eugenol from the use of eugenol as a plant protection product. EFSA considers that the current assessment of the www.efsa.europa.eu/publications 15 EFSA Supporting publication 2017:EN-1165

representative use (See section 3 in EFSA Journal 2012; 10(11):2914). eugenol cannot be categorically dismissed. Nonetheless, it should be noted that for all samples analysed directly following application and up until harvest, the residues of eugenol were all below the LOQ of 0.05 mg/kg. A supplementary consumer risk assessment has been conducted (see page Error! Bookmark not defined. of this document) which assumes (at a worst case) that all residues of eugenol are instead methyl eugenol. While it is noted that a number of EU diets exceed the ADI at these excessive intake levels, the intakes are still within those considered for natural sources (Table B.7.2.4 of the confirmatory assessment document). Even using these incredibly worst case assumptions, the conclusion holds that the use of 3AEY on grapes does not pose a greater risk scenario when compared to naturally occurring dietary sources of methyl eugenol. confirmatory data cannot be finalised without these data. It is noted that the EFSA defined data gap for information concerning the residue levels of methyl eugenol within grapes has not been addressed, but this was not a condition set for this confirmatory data assessment (as defined in the Commission Implementing www.efsa.europa.eu/publications 16 EFSA Supporting publication 2017:EN-1165

Regulation (EU) No 546/2013). 3(5) B.7 Residues, Table B.7.2.2: Input values for the consumer risk assessment of methyl eugenol from natural sources Confirmatory data (August, 2016) EFSA: It is not appropriate to address the confirmatory data considering the chronic and acute dietary intake calculations from natural sources of methyl eugenol using the highest concentrations of this compound in clove and in herbs. The average daily consumption data for methyl eugenol and underpinned by sufficient and robust background data should be provided with a detailed explanation. When further information is provided to address this point (as part of a product assessment or as part of the renewal review), further consideration should be made. However, with respect to the scope of the confirmatory data assessment to assess data comparing natural background exposure situations of eugenol and methyl eugenol in relation to exposure from the use of eugenol as a plant protection product, the point is considered to have been addressed. Addressed (w.r.t. the original confirmatory data requirement). RMS: While the RMS would agree that robust data to support average daily consumption of methyl-eugenol from background sources would be ideal. However, it is considered that requesting such data would be too onerous for the Notifier to undertake, particularly in the context of the confirmatory data requirement as defined. A comprehensive assessment would require an analysis to be made of all crops listed within PRIMo model and for analytical methods to be validated for each crop type. Such a survey of the background exposure EFSA disagrees. The natural dietary background exposure estimates for methyl eugenol should be based on robust and validated average daily consumption data of methyl eugenol. See also points 3(4) and 2(3). www.efsa.europa.eu/publications 17 EFSA Supporting publication 2017:EN-1165

situation has not been requested / undertaken previously. Given the lack of guidance available for such a study, the RMS would be disinclined to request the provision of such information. Particularly as such information would not be anticipated to significantly alter the conclusions reached (which were based on the data gathered from the literature review). While it is noted that for the chronic exposure the use of the HR will lead to an overestimation of the risk, the margin between the two scenarios is considered to be such that even if data at the average (median level) were to be used, then the conclusions would still remain unchanged. As for the acute assessment risk, it has always been appropriate to use the highest observed residue level - the RMS does not consider this situation to be different. The RMS supports the evaluation the natural and PPP exposure scenarios have been compared. The confirmatory data evaluation is considered to have been fulfilled. Should the Commission deem a full review to be necessary, then the RMS would recommend that this be www.efsa.europa.eu/publications 18 EFSA Supporting publication 2017:EN-1165

undertaken as part of a separate review (similar to how the triazole derivative metabolites review was handled). This would allow the concerned Notifiers time to generate the required data / allow these Notifiers the opportunity to form a Task Force, to share the burden that such a review would require. While the RMS would not agree with this request - if this is the option is chosen, then the Commission / EFSA should endeavour to clearly define the requirements (in lieu of any relevant guidance concerning reviews of this type). Addressed (w.r.t. the original confirmatory data requirement). 3(6) B.7.2 calculated natural exposure to methyl eugenol FR: The theoretical maximum daily intake for all consumer groups was 668.7 % of the ADI should be replaced by The theoretical maximum daily intake for all consumer groups was 39 248 001 % of the ADI RMS: Noted text has been amended. See also points 3(4), 3(5) and 2(3). 4. Environmental fate and behaviour Route and rate of degradation in soil (B.8.1) No. Column 1 Reference to addendum to assessment report Column 2 Comments from Member States / applicant / EFSA Column 3 Evaluation by rapporteur Member State 4(1) Addendum EFSA: it is acknowledged that the RMS: Noted. RMS considers that for 2 Column 4 EFSA s scientific views on the specific points raised in the commenting phase conducted on the RMS s assessment of confirmatory data www.efsa.europa.eu/publications 19 EFSA Supporting publication 2017:EN-1165

Confirmatory data, B.8.1.1.1 Aerobic studies, Jones (2015a), rate of degradation eugenol degradation is very rapid such that using a conservative modelling soil DT50 of 1 day is acceptable. However, it should be noted that the original data gap on the rate of degradation study of eugenol in four different soils under aerobic conditions is needed to refine the soil and groundwater exposure assessment cannot be considered addressed as only two soil DT50 values are available. 4(2) AT: No metabolites of >5% AR could be found, in particular the cancerogenic methyl-eugenol could not be detecetd in aerobic soil degradation studies AT agrees. 4(3) Addendum, Confirmatory data, August 2016, B.8.1.1.1. FR: Deviations are observed regarding the soil selection for this study. The organic carbon content for Brierlow, Empingham, and Calke soils exceed the limit value of 2.5% (OCDE 307). In addition, the microbial biomass content of soils Brierlow, Empingham, and Calke soils was lower than the limit value of 1% OC (OCDE 307). These soils could be considered as not active enough. However even if the soil activities was low, a rapid dissipation of the active was observed maybe not attributed to biotic degradation. of 4 soils tested, the eugenol degraded very rapidly such that whilst an absolute rate of degradation could not be confirmed, the data, nonetheless confirm that the 1day soil DT50 used is still a conservative value. RMS considered the soil DT50 of 1 day is sufficient to confirm an acceptable soil and groundwater exposure assessment. Additional rate of degradation data would not signficantly alter the soil and groundwater exposure assessment. The RMS considers the point is addressed. RMS: Acknowledged. The RMS considers the point is addressed RMS: Noted, however, the RMS agrees that the soil degradation was very rapid in all four soils which strongly indicates the organic carbon and microbial biomass values did not signficiacntly influence degradation as high and low values were similar to other values respectively. See also 4(1) above, the RMS considers the point addressed. An aerobic route and rate of degradation study in four soils was submitted. Although only two soil DT 50 values are available from this study, the information provided is sufficient to conclude that eugenol degraded very rapidly in soil and that the use of a conservative modelling soil DT 50 of 1 day is acceptable. Methyl eugenol could not be detected in aerobic soil degradation studies and therefore no further assessment is considered necessary. See 4(1). www.efsa.europa.eu/publications 20 EFSA Supporting publication 2017:EN-1165

Formally based on the previous deviations, the reliability of results obtained from the soils could be seen as questionable. Please clarify. 4(4) Addendum, Confirmatory data, August 2016, B.8.1.1.1. FR: The soil texture should be also provided according to the USDA classification. RMS: USDA soil textures based on sand, silt and clay values are: Brierlow Silt loam Ingleby Loamy sand Empingham Silt clay loam Calke Sandy loam The USDA classification of the soils investigated in the aerobic degradation study has been provided by the RMS in column 3. The RMS considers the point addressed 4(5) Confirmatory data, August 2016, B.8.1.1.1 FR: has some remarks on the metabolites observed in soils. In Calke and Ingleby soils, metabolite higher than 5 % could be observed at day 0 in the part others, but in the next sampling, radioactivity is lower than 3%. Therefore even if minor metabolites are in the part others at day 0, they should be considered as minor and transient. At day 0, two unknown metabolites (A and B) at a level higher than 5 % are observed in Brierlow soil, but no further sampling is available. It cannot be excluded that the threshold value of 5 % is exceeded in the next sampling (day 3; but not sampled). These metabolites could be considered as potentially minor non-transient. Thus, a risk RMS for Calke and Ingleby soils, the comment is acknowledged RMS: Taking the four soils, the RMS notes that in the study, sampling has occurred for the most part only where extractable residues exceed 10% (see Calke and Ingleby soils). In addition, Unknown A in all soils, was investigated further in the Ingelby soils and shown to comprise at least seven minor components. In Calke and Ingleby soils, where samples were taken and analysed beyond day 0, the total extracted residues was made up of eugenol, Unknowns A, B, C and D as well as an others (itself multiple minor components). Therefore,based on overall weight of evidence the unknowns A and B Satisfactory clarifications on the unknown individual metabolites measured in the observed in soils investigated in the aerobic degradation study have been provided by the RMS in column 3. www.efsa.europa.eu/publications 21 EFSA Supporting publication 2017:EN-1165

assessment is needed for these metabolites. Please clarify. In Ingleby soils, unknown metabolite A is observed at a level higher than 5 % until 120 days (for 2 consecutive points at least). Formally, identification and further risk assessment should be needed for this unknown metabolite A. Please clarify. 4(6) Continued from above FR: At day 0, unknown metabolite B at a level higher than 5 % is observed in Empingham soil, but no further sampling is available. It cannot be excluded that the threshold value of 5 % is exceeded in the next sampling (day 3, but not sampled). This metabolite could be considered as potentially minor non-transient. Based on the available information, a risk assessment is needed for this metabolite. Please clarify. Please check the RMS conclusion which indicated that the study does not report any metabolites > 10%, >5% at 2 consecutive time points or increasing until the study end. The definition of residues for the risk assessment may need to be updated accordingly. 4(7) Addendum, Confirmatory data, FR: While a very fast dissipation of thymol in soil is observed (< 3 in the Brierlow soil, would likely be present but at very low levels as overall extractable residues at day 3 were 9.2 and likely to comprise parent, unkowns A, B, C and D as well as other multiple components. For Unknown A in the Ignleby soil, the footnote to Table IIA 7.1.1.1/01.10 indicates that isolation and further TLC analysis confirms Unknown A comprised at least 7 components all 3.3% AR. RMS: For Unknown B in Empingham soil, see above comments regarding weight of evidence as for brierlow soil. The RMS conclusion that the study does not report any metabolites >10%, >5% at 2 consecutive time points or increasing until the study end is correct, but could be enhanced by including the weight of evidence from above and that this is accepted by the RMS for individual metabolites. Overall, the RMS considers the residues definition as stated is sufficient. The RMS considers the point addressed. RMS: Noted, however, RMS is unclear as this comment refers to fast Satisfactory clarifications on the unknown individual metabolites measured in the observed in soils investigated in the aerobic degradation study have been provided by the RMS in column 3. See point 4(1). www.efsa.europa.eu/publications 22 EFSA Supporting publication 2017:EN-1165

August 2016, B.8.1.1.1. days), more details should be provided on the stability of residues level of geraniol from 3 to 120 days. Since the kinetic fittings are visually poor, bi-phasic model should have been proposed by the notifier. The low microbial content of these soils could explain this behaviour in soils, please clarify. dissipation of thymol and stability of residues of geraniol. RMS suspects visually poor fitting is due to the very rapid degradation and incorporation of the compounds and as such the OC and microbial content is less signficiant than the interval between sampling times. Overall, the selection of a modelling DT50 of 1 day is still suitably conservative (see point 4(1) above). The RMS conmsiders the point addressed Adsorption, desorption and mobility in soil (B.8.2) No. Column 1 Reference to addendum to assessment report 4(8) Page 41, Paragraph 5, B.8, B.8.2.1 Column 2 Comments from Member States / applicant / EFSA Applicant: The RMS raised concerns that not concluding on mass balance during preliminary tests affected the integrity of the study results. The Applicant disagrees; mass balance was concluded during the main isotherm test in 1 replicate from each of the soil groups. Mass balance values were within the acceptable limits of 90-110 % AR therefore concluding that all radioactivity applied had been accounted for in the main test where Koc values are derived. Column 3 Evaluation by rapporteur Member State RMS: The RMS considers that mass balance for eugenol determined during initial studies would have identified the stability issues with eugenol and suggested more frequent and shorter sampling intervals employed. The mass balance of AR in the main isotherm experiment, determined by LSC, was in the range 90-110%. However, analysis of eugenol showed results from 28.9% to 124.9% for the 5.0mg/l concentration and was not determined at other concentrations. Column 4 EFSA s scientific views on the specific points raised in the commenting phase conducted on the RMS s assessment of confirmatory data www.efsa.europa.eu/publications 23 EFSA Supporting publication 2017:EN-1165

The RMS considers the point addressed 4(9) Page 41, Paragraph 5, B.8, B.8.2.1 Applicant: The RMS raised concerns that study results are not reliable since test item stability was not determined during preliminary tests.the applicant disagrees that, by not confirming stability tests in preliminary tests, the main isotherm test results would not be affected. RMS: See above and also, generally determinations were based largely on LSC. Where eugenol was determined, the results were not robust in confirming stability. In addition, the study states Equilibration was generally not reached due to degradation in most soils however an equilibrium time of 24 hours was used for all soils. The RMS considers the point addressed 4(10) Page 44, Paragraph 1, B.8, B.8.2.1 Applicant: The RMS suggests that soils were only analysed by combustion followed by LSC. The applicant disagrees; soil residues were extracted prior to combustion and LSC to allow profiling of parent and degradates by HPLC. This allowed determination of Koc values using the direct method- as prescribed for unstable test items in the OECD 106 guideline. RMS: Noted, however, the lack of stability of eugenol, and summed values for the eugenol and other radioactivity in supernatant and soil undermine any sorption calculated for the single compound: eugenol. Table 3 presents eugenol as % solution radioactivity in supernatatnt and % extractable radioactivity in soil, rather than eugenol. The RMS considers the point addressed. 4(11) Page 44, Paragraph 1, B.8, B.8.2.1 Applicant: The RMS suggests that Koc calculations were determined using the indirect method. The Applicant disagrees; Koc values RMS: Noted, suprnatant eugenol was expressesd as % solution radioactivity and soil eugenol expressed as % extracted www.efsa.europa.eu/publications 24 EFSA Supporting publication 2017:EN-1165

were determined using the direct method where the amount of parent present in the adsorption supernantants and soil residues (profiled from soil extracts) was corrected for degradation. This method is described in OECD 106 guideline for test items which are unstable in the test system. radioactivity. However, it is established that eugenol is not stable therefore radioactivity in supernatant may comprise polar breakdown products and soil highly sorbed in incorprated radioactivity. Therefore, the values do not indicate soprtion of eugenol but rather a range of compounds and cannot be attributed to eugenol. 4(12) Page 44, Paragraph 2, B.8, B.8.2.1 4(13) Page 44, Paragraph 3, B.8, B.8.2.1 Applicant: The RMS suggested that a correlation between ph and adsorption cannot be determined in the main test as test system ph s were not measured. The Applicant disagrees; the ph of each test system was measured during the soil-solution ratio test where the incubation conditions were exactly the same as the main test. Therefore a correlation between ph and adsorption could be concluded. Applicant: The RMS was concerned that strong enough extraction methods had not been utilised when extracting soil pellets. The applicant disagrees; a range of extraction solvents and techniques were investigated as part of the eugenol aerobic soil metabolism study (P.30, Table IIA 7.1.1.1/01.2) which was The RMS considers the point addressed RMS: See above, as the sorption of eugenol has not been established, any correlation or otherwise with ph is based on a behaviour of a number of compounds which contain radioactivity. The RMS considers the point addressed RMS: Noted. The RMS considers the point addressed. www.efsa.europa.eu/publications 25 EFSA Supporting publication 2017:EN-1165

conducted concurrently with the adsorption/desorption study. 4(14) Page 44, Paragraph 4, B.8, B.8.2.1 Applicant: The RMS state that the indirect method was utilised to conclude on Koc. The Applicant disagrees; see point (3) above. RMS: Noted, however, see points above. The RMS considers the point addressed. 4(15) Page 44, Paragraph 4, B.8, B.8.2.1 Applicant: The RMS do not believe a blanket correction factor should be utilised when determining test item stability at concentrations below 5 mg/l. The applicant believes that using a blanket correction factor was a robust correction method. RMS: Noted. See also 4(18) and 4(19) below The RMS considers the point addressed. 4(16) Page 44, Paragraph 5, B.8, B.8.2.1 Applicant: The RMS state that the results generated in this test are unreliable as test item stability has not been concluded. The Applicant disagrees; the direct method was utilised, as prescribed in the OECD 106 guideline, which allowed the amount of parent present in the aqueous and soil phases to be corrected for degradation therefore negating the requirement for test item to be stable in the test system. RMS: Noted see also 4(18) and 4(19) below. The RMS considers the point addressed. 4(17) Page 45, Paragraph 2, B.8, B.8.2.1 Applicant: The RMS states that the results generated in this test are unreliable as test item stability has not been concluded. The applicant disagrees; see point (9) above and adjacent further explanations. RMS: Noted see also 4(18) and 4(19) below. The RMS considers the point addressed. 4(18) Addendum Confirmatory data, EFSA: we agree with the RMS that the data provided in the batch RMS: Acknowledged by RMS The RMS considers the point A batch equilibrium www.efsa.europa.eu/publications 26 EFSA Supporting publication 2017:EN-1165

B.8.2.1, Adsorption and desorption, Jones (2015b) equilibrium adsorption/desorption study are not robust enough to be used to derive the sorption endpoint for eugenol and that default values will be relied upon. addressed. adsorption/desorption study for eugenol according to OECD 106 and to GLP was submitted and evaluated in the Addendum (United Kingdom, 2016a). Major deviations were identified in the study leading to results not robust enough to be used to derive the sorption endpoints for eugenol. Therefore, the peer review considered that default values (KFoc of 10 mg/l and 1/n of 0.9) need to be used as modelling endpoints for risk assessment. 4(19) Addendum, Confirmatory data, August 2016, B.8.2.1. FR: FR agrees with the RMS conclusion on the adsorption study numbered IIA 7.4.1/01. As proposed by the RMS, major deviations were identified leading to results not robust enough. Default values should have kept as modelling endpoints for the risk assessment. RMS: RMS acknowledges MS comment. The RMS considers the point addressed. See 4(18). PEC in soil (B.8.3) No. Column 1 Reference to addendum to assessment report Column 2 Comments from Member States / applicant / EFSA Column 3 Evaluation by rapporteur Member State 4(20) AT: No PEC soil calculated. RMS:RMS confirms new PECsoil values have not been calculated as the evaluation considered groundwater exposure only. Refer to original assessment for PECsoil values. Column 4 EFSA s scientific views on the specific points raised in the commenting phase conducted on the RMS s assessment of confirmatory data www.efsa.europa.eu/publications 27 EFSA Supporting publication 2017:EN-1165

The RMS considers the point addressed PEC in surface water and in ground water (B.8.6) No. Column 1 Reference to addendum to assessment report Column 2 Comments from Member States / applicant / EFSA Column 3 Evaluation by rapporteur Member State 4(21) AT: No PEC sw calculated. RMS: RMS confirms new PECsw values have not been calculated as the evaluation considered groundwater exposure only. Refer to original assessment for PECsw values. Column 4 EFSA s scientific views on the specific points raised in the commenting phase conducted on the RMS s assessment of confirmatory data 4(22) Vol. 3, B.8.5.2 DE: We thank the RMS for the good summary. The additional studies and information provided by the applicant seem not totally satisfying, but enough to complete the groundwater assessment. We agree with the assumptions of the RMS and think that the confirmatory data requirements have been sufficiently addressed. The RMS considers the point addressed. RMS: The RMS acknowledges the positive feedback from the MS. The RMS considers the point addressed. www.efsa.europa.eu/publications 28 EFSA Supporting publication 2017:EN-1165