Peer review of the pesticide risk assessment of the active substance propyzamide

Transcription

1 CNCLUSIN N PESTICIDES PEER REVIEW APPRVED: 8 July 2016 doi: /j.efsa Peer review of the pesticide risk assessment of the active substance propyzamide Abstract European Food Safety Authority (EFSA) The conclusions of EFSA following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State, Sweden, and co-rapporteur Member State, the United Kingdom, for the pesticide active substance propyzamide are reported. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012. The conclusions were reached on the basis of the evaluation of the representative uses of propyzamide as a herbicide on lettuce and winter oilseed rape. The reliable end points, appropriate for use in regulatory risk assessment are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are identified European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority. Keywords: propyzamide, peer review, risk assessment, pesticide, herbicide Requestor: European Commission Question number: EFSA-Q Correspondence: pesticides.peerreview@efsa.europa.eu EFSA Journal 2016;14(8):4554

2 Suggested citation: EFSA (European Food Safety Authority), Conclusion on the peer review of the pesticide risk assessment of the active substance propyzamide. EFSA Journal 2016;14(8):4554, 25 pp. doi: /j.efsa ISSN: European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority. This is an open access article under the terms of the Creative Commons Attribution-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited and no modifications or adaptations are made. The EFSA Journal is a publication of the European Food Safety Authority, an agency of the European Union. 2 EFSA Journal 2016;14(8):4554

3 Summary Commission Implementing Regulation (EU) No 844/2012 (hereinafter referred to as the Regulation ) lays down the procedure for the renewal of the approval of active substances submitted under Article 14 of Regulation (EC) No 1107/2009. The list of those substances is established in Commission Implementing Regulation (EU) No 686/2012. Propyzamide is one of the active substances listed in Regulation (EU) No 686/2012. In accordance with Article 1 of the Regulation, the rapporteur Member State (RMS), Sweden, and co-rapporteur Member State (co-rms), the United Kingdom, received an application from Dow AgroSciences for the renewal of approval of the active substance propyzamide. Complying with Article 8 of the Regulation, the RMS checked the completeness of the dossier and informed the applicant, the co-rms (the United Kingdom), the European Commission and the European Food Safety Authority (EFSA) about the admissibility. The RMS provided its initial evaluation of the dossier on propyzamide in the renewal assessment report (RAR), which was received by EFSA on 31 July In accordance with Article 12 of the Regulation, EFSA distributed the RAR to the Member States and the applicant, Dow AgroSciences, for comments on 7 September EFSA also provided comments. In addition, EFSA conducted a public consultation on the RAR. EFSA collated and forwarded all comments received to the European Commission on 9 November Following consideration of the comments received on the RAR, it was concluded that additional information should be requested from the applicant, and that EFSA should conduct an expert consultation in the areas of mammalian toxicology, residues, environmental fate and behaviour, and ecotoxicology. In accordance with Article 13(1) of the Regulation, EFSA should adopt a conclusion on whether propyzamide can be expected to meet the approval criteria provided for in Article 4 of Regulation (EC) No 1107/2009 of the European Parliament and of the Council. The conclusions laid down in this report were reached on the basis of the evaluation of the representative uses of propyzamide as a herbicide on lettuce and winter oilseed rape, as proposed by the applicant. Full details of the representative uses can be found in Appendix A of this report. Data were submitted to conclude that the use of propyzamide according to the representative uses proposed at the European Union (EU) level results in a sufficient herbicidal efficacy against the target weeds. A data gap was identified for a more detailed assessment of the literature review for the active substance and its relevant metabolites. In the Section identity and analytical methods, data gaps were identified for additional validation data for the determination of two impurities in the technical material. In the Section mammalian toxicology, a data gap was identified related to an assessment of the toxicological relevance of the impurities. Information on the batches used in the toxicity studies was missing in order to conclude that they were representative of the technical specification (critical area of concern). A second data gap was related to comparative in vitro metabolism data, addressing differences between species and humans. Furthermore, the need for additional investigations of the toxicity profile of significant plant metabolites in primary and rotational crops is also highlighted (data gap). In the residue area, data gaps were identified for residue field trials, respectively, on lettuce and rapeseed, and analysing the magnitude of residues of all metabolites included in the residue definition for risk assessment, rotational crops field trials on leafy crops, root crops and small grain crops for the determination of propyzamide, mannoside conjugate of RH and glucoside of RH residues at 30 days plant back interval (PBI) and for the determination of the residues in pollen and bee products for human consumption resulting from residues taken up by honeybees from crops at blossom. The consumer dietary risk assessment cannot be concluded on considering the identified data gaps, the outstanding data on the toxicity profile of the metabolites relevant in primary and rotational crops and the finalisation of the residue definition for risk assessment in plants. The consumer risk assessment through drinking water with regard to metabolite RH is also not finalised. With respect to the fate and behaviour into the environment, data gaps have been identified for investigation of degradation of metabolite RH in one additional soil and dark aerobic conditions and to address the effect of water treatment processes on the nature of residues present in ground water and surface water when water is abstracted for drinking water. A critical area of concern has 3 EFSA Journal 2016;14(8):4554

4 been identified for potential groundwater contamination by soil metabolite RH and lysimeter leachate metabolites U1 (two components), U3, U4 (two components), U5, U6 and U7. In the ecotoxicology area, a data gap was identified for the assessment of the ecotoxicological relevance of the impurities and a critical area of concern was identified for the composition of some batches. A data gap was identified for a suitable reproductive avian endpoint leading to avian risk assessment not being finalised. Data gaps were also identified for addressing the long-term risk to wild mammals due to exposure to propyzamide and for addressing the risk of secondary poisoning due to exposure to the major soil metabolites. Data gaps were identified to address the risk to aquatic organisms, particularly macrophytes. Several data gaps were identified for bees. Finally, data gaps were identified for addressing the risk to soil organisms and to non-target terrestrial plants. A critical area of concern was identified for the risk to collembolans (Folsomia). 4 EFSA Journal 2016;14(8):4554

5 Table of contents Abstract... 1 Summary... 3 Background... 6 The active substance and the formulated product... 7 Conclusions of the evaluation Identity, physical/chemical/technical properties and methods of analysis Mammalian toxicity Residues Environmental fate and behaviour Ecotoxicology verview of the risk assessment of compounds listed in residue definitions triggering assessment of effects data for the environmental compartments Data gaps Particular conditions proposed to be taken into account to manage the risk(s) identified Concerns Issues that could not be finalised Critical areas of concern verview of the concerns identified for each representative use considered References Abbreviations Appendix A List of end points for the active substance and the representative formulation Appendix B Used compound codes EFSA Journal 2016;14(8):4554

6 Background Commission Implementing Regulation (EU) No 844/ (hereinafter referred to as the Regulation ) lays down the provisions for the procedure of the renewal of the approval of active substances, submitted under Article 14 of Regulation (EC) No 1107/ This regulates for the European Food Safety Authority (EFSA) the procedure for organising the consultation of Member States, the applicant(s) and the public on the initial evaluation provided by the rapporteur Member State (RMS) and/or co-rapporteur Member State (co-rms) in the renewal assessment report (RAR), and the organisation of an expert consultation where appropriate. In accordance with Article 13 of the Regulation, unless formally informed by the European Commission that a conclusion is not necessary, EFSA is required to adopt a conclusion on whether the active substance can be expected to meet the approval criteria provided for in Article 4 of Regulation (EC) No 1107/2009 within 5 months from the end of the period provided for the submission of written comments, subject to an extension of up to 8 months where additional information is required to be submitted by the applicant(s) in accordance with Article 13(3). In accordance with Article 1 of the Regulation, the RMS, Sweden, and the co-rms, the United Kingdom, received an application from Dow AgroSciences for the renewal of approval of the active substance propyzamide. Complying with Article 8 of the Regulation, the RMS checked the completeness of the dossier and informed the applicant, the co-rms (the United Kingdom), the European Commission and EFSA about the admissibility. The RMS provided its initial evaluation of the dossier on propyzamide in the RAR, which was received by EFSA on 31 July 2015 (Sweden, 2015). In accordance with Article 12 of the Regulation, EFSA distributed the RAR to the Member States and the applicant, Dow AgroSciences, for consultation and comments on 7 September EFSA also provided comments. In addition, EFSA conducted a public consultation on the RAR. EFSA collated and forwarded all comments received to the European Commission on 9 November At the same time, the collated comments were forwarded to the RMS for compilation and evaluation in the format of a reporting table. The applicant was invited to respond to the comments in column 3 of the reporting table. The comments and the applicant s response were evaluated by the RMS in column 3. The need for expert consultation and the necessity for additional information to be submitted by the applicant in accordance with Article 13(3) of the Regulation were considered in a telephone conference between EFSA and the RMS on 17 December n the basis of the comments received, the applicant s response to the comments and the RMS s evaluation thereof, it was concluded that additional information should be requested from the applicant, and that EFSA should conduct an expert consultation in the areas of mammalian toxicology, residues, environmental fate and behaviour, and ecotoxicology. The outcome of the telephone conference, together with EFSA s further consideration of the comments, is reflected in the conclusions set out in column 4 of the reporting table. All points that were identified as unresolved at the end of the comment evaluation phase and which required further consideration, including those issues to be considered in an expert consultation, were compiled by EFSA in the format of an evaluation table. The conclusions arising from the consideration by EFSA, and as appropriate by the RMS, of the points identified in the evaluation table, together with the outcome of the expert consultation and the written consultation on the assessment of additional information, where these took place, were reported in the final column of the evaluation table. A final consultation on the conclusions arising from the peer review of the risk assessment took place with Member States via a written procedure in June This conclusion report summarises the outcome of the peer review of the risk assessment of the active substance and the representative formulation, evaluated on the basis of the representative uses of propyzamide as a herbicide on lettuce and winter oilseed rape, as proposed by the applicant. A list of the relevant end points for the active substance and the formulation is provided in Appendix A. 1 Commission Implementing Regulation (EU) No 844/2012 of 18 September 2012 setting out the provisions necessary for the implementation of the renewal procedure for active substances, as provided for in Regulation (EC) No 1107/2009 of the European Parliament and of the Council concerning the placing of plant protection products on the market. J L 252, , p Regulation (EC) No 1107/2009 of 21 ctober 2009 of the European Parliament and of the Council concerning the placing of plant protection products on the market and repealing Council Directives 79/117/European Economic Community (EEC) and 91/414/EEC. J L 309, , p EFSA Journal 2016;14(8):4554

7 In addition, a key supporting document to this conclusion is the peer review report (EFSA, 2016), which is a compilation of the documentation developed to evaluate and address all issues raised in the peer review, from the initial commenting phase to the conclusion. The peer review report comprises the following documents, in which all views expressed during the course of the peer review, including minority views, where applicable, can be found: the comments received on the RAR; the reporting table (17 December 2015); the evaluation table (4 July 2016); the reports of the scientific consultation with Member State experts (where relevant); the comments received on the assessment of the additional information (where relevant); the comments received on the draft EFSA conclusion. Given the importance of the RAR, including its revisions (Sweden, 2016), and the peer review report, both documents are considered as background documents to this conclusion and thus are made publicly available. It is recommended that this conclusion report and its background documents would not be accepted to support any registration outside the European Union (EU) for which the applicant has not demonstrated that it has regulatory access to the information on which this conclusion report is based. The active substance and the formulated product Propyzamide is the IS common name for 3,5-dichloro-N-(1,1-dimethylprop-2-ynyl)benzamide (IUPAC). The representative formulated product for the evaluation was Kerb Flo 400 (GF-3300), a suspension concentrate (SC) containing 400 g/l propyzamide. The representative uses evaluated were post-emergence spray applications in winter oilseed rape and lettuce, to control grasses and some broad leafed weeds. Full details of the Good Agricultural Practices (GAPs) can be found in the list of end points in Appendix A. Data were submitted to conclude that the use of propyzamide according to the representative uses proposed at the EU level results in a sufficient herbicidal efficacy against the target weeds following the guidance document SANC/10054/2013 rev. 3 (European Commission, 2013). A data gap has been identified for a more detailed assessment of the literature review of the active substance and its relevant metabolites, dealing with side effects on health, the environment and non-target species and published within the 10 years before the date of submission of the dossier, to be conducted and reported in accordance with EFSA guidance on the submission of scientific peerreviewed open literature for the approval of pesticide active substances under Regulation (EC) No 1107/2009 (EFSA, 2011). Conclusions of the evaluation 1. Identity, physical/chemical/technical properties and methods of analysis The following guidance documents were followed in the production of this conclusion: SANC/3029/ 99-rev. 4 (European Commission, 2000a), SANC/3030/99-rev. 4 (European Commission, 2000b), SANC/ 10597/2003-rev (European Commission, 2012), SANC/825/00-rev. 8.1 (European Commission, 2010). The reference specification for the first approval was updated. The proposed specification is based on batch data from industrial scale production and quality control (QC) data. The minimum purity of the technical material is 950 g/kg. The assessment of the data package revealed no issues that need to be included as critical areas of concern with respect to the identity, physical, chemical and technical properties of propyzamide or the representative formulation. The main data regarding the identity of propyzamide and its physical and chemical properties are given in Appendix A. Adequate methods are available for the generation of pre-approval data required for the risk assessment; however, data gaps were identified for additional validation data for two methods for the determination of impurities in the technical material. Methods of analysis are available for the determination of the active substance in the technical material and representative formulation. 7 EFSA Journal 2016;14(8):4554

8 The quick, easy, cheap, effective and safe (QuEChERS) multiresidue method and also a single residue method are available for monitoring propyzamide in food and feed of plant origin by liquid chromatography with tandem mass spectrometry (LC MS/MS) with limit of quantifications (LQs) of 0.01 mg/kg in each commodity group. An analytical method for monitoring residues in food and feed of animal origin is not needed as no maximum residue levels (MRLs) were proposed for the animal matrices. An appropriate LC MS/MS method is available enabling the determination of the compounds included in the residue definition proposed for monitoring purposes in soil (propyzamide and its metabolites RH and RH-24580) with LQs of 5 lg/kg for each analyte. Residues of propyzamide and its metabolite RH can be monitored in surface water and drinking water by LC MS/MS with LQs of 0.05 lg/l for both compounds. Residues of propyzamide in air can be determined by LC MS/MS with a LQ of 0.6 lg/m 3. An LC MS/MS method exists for monitoring propyzamide residues in urine and blood with a LQs of 0.05 mg/l. 2. Mammalian toxicity The following guidance documents were followed in the production of this conclusion: SANC/221/ 2000-rev. 10-final (European Commission, 2003), SANC/10597/2003-rev (European Commission, 2012) and Guidance on dermal absorption (EFSA PPR Panel, 2012). Propyzamide was discussed by Member States experts in the teleconference TC 131 (April 2016). The information provided in the dossier was considered insufficient to draw any conclusion on the toxicological relevance of the impurities (data gap), and information on the composition of batches used in toxicity studies was missing in order to conclude that they were representative of the technical specification (critical area of concern). With an oral absorption value of 88%, propyzamide was shown to be well distributed, extensively metabolised and not bioaccumulating. Comparative in vitro metabolism data, addressing differences between test species and with humans were not available (data gap). f low acute toxicity, it was not irritant to the skin or the eyes, not sensitiser and not predicted to have a phototoxic potential. In short-term studies, the target organ triggering the no observed adverse effect levels (NAELs) was the liver. The NAEL for the rat was 4.5 mg/kg body weight (bw) per day based on increased absolute liver weight (> 20%), the NAEL for the mouse was 15 mg/kg bw per day based on increased liver weight and hepatocellular hypertrophy, whereas a lowest observable adverse effect level (LAEL) of 12 mg/kg bw per day was identified in the 1-year dog study, based on an increased absolute and relative liver weight in females. No NAEL could be derived in the 90-day and 2-year dog studies because of their limitations. n the basis of the available in vitro and in vivo genotoxicity tests, propyzamide is considered as having no genotoxic potential relevant to humans. The long-term toxicity in rats is characterised by reduced body weight gain, liver effects (increased weight, centrilobular hypertrophy), thyroid effects (increased weight, follicular cell hyperplasia) and ovarian effect (sertoliform tubular hyperplasia), triggering a systemic NAEL of 8.5 mg/kg bw per day. In mice, chronic effects included increased absolute and relative liver and kidney weights with a systemic NAEL of 5 mg/kg bw per day. Tumours were observed in both species: benign Leydig cell and thyroid tumours in rats, liver adenomas and carcinomas in mice. The human relevance of these liver tumours could not be excluded based on the lack of human in vitro and epidemiological data on simultaneous constitutive androstane receptor (CAR) and peroxisome proliferator activated receptor alpha (PPARa) activation. For the thyroid tumours, considering the uncertainties about the contribution of alternative pathways, and recent data indicating deregulation of thyroid hormones in human cancer, the human relevance could not be excluded as well. For the Leydig cell tumours, it was agreed that these tumours are unlikely to be relevant to humans. The NAELs for tumours in both species were the same as for systemic effects. The majority of the experts supported the classification as carcinogen category 2; H351 suspected of causing cancer, as reported in the Annex VI of Regulation (EC) No 1272/ (CLP Regulation) for propyzamide. In the multigeneration rat study, no adverse effect was observed on the reproductive parameters up to the highest dose tested (97.7 mg/kg bw per day). The parental and offspring NAEL was 12.1 mg/kg bw per day based on decreased body weight (parents and pups) and on histopathological 3 Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006. J L 353, , p EFSA Journal 2016;14(8):4554

9 findings in the liver, adrenal, thyroid and pituitary gland (parents only). In the developmental toxicity studies, no adverse effect was observed in fetuses up to the highest dose tested. The maternal NAEL in rats was 20 mg/kg bw per day based on decreased body weight gain, whereas it was 5 mg/kg bw per day in rabbits based on clinical signs. Further investigations of potential endocrine-mediated effects were performed in a battery of in vitro and in vivo assays. Based on the available results, propyzamide was concluded as unlikely to have a direct effect on receptors of the endocrine system, including oestrogen, androgen and thyroid pathways. The antiandrogenic and antioestrogenic effects of propyzamide are likely to occur through modulating the metabolism of steroid hormones by inducing the liver metabolising enzymes. Propyzamide is classified as carcinogen category 2 but not as reproductive toxicant, in accordance with the provisions of Regulation (EC) No 1272/2008, and therefore, the conditions of the interim provisions of Annex II, Point of Regulation (EC) No 1107/2009 concerning human health for the consideration of endocrine-disrupting properties are not met. n the basis of the available data and current knowledge (ECD Conceptual Framework, as analysed in the EFSA Scientific pinion on the hazard assessment of endocrine disruptors, (EFSA Scientific Committee, 2013)), it is concluded that propyzamide is unlikely to be an endocrine disruptor. In the acute neurotoxicity study with propyzamide, a LAEL of 40 mg/kg bw per day was identified on the basis of reduced motor activity on the first day after treatment. In the 90-day neurotoxicity study, no neurotoxic effect was observed up to the highest dose tested (60 mg/kg bw per day) and the systemic NAEL was 2.4 mg/kg bw per day on the basis of decreased body weight. Several metabolites were identified in significant concentrations in primary and rotational crops: conjugates of RH-24848, RH-25891, RH-26521, RH-26059, RH-25337, RH-26702, and free RH As they were not major metabolites identified in the rat metabolic pathway, their toxicological profile cannot be considered covered by the reference values of propyzamide (data gap). The groundwater metabolite RH is toxicologically relevant according to the guidance document (European Commission, 2003) because the available data were insufficient to demonstrate that it did not qualify for the same carcinogenic properties as propyzamide. It is noted that no reference values can be derived on the basis of the available data. The acceptable daily intake (ADI) from the first peer review (amended in 2007) was 0.02 mg/kg bw per day based on the 2-year mouse study. The ADI agreed for the renewal is 0.05 mg/kg bw per day, taking into account the results of short-term and long-term studies, and applying an uncertainty factor (UF) of 100. No acute reference dose (ARfD) was derived from the first peer review. For the renewal, the agreed ARfD is 0.13 mg/kg bw, based on the acute neurotoxicity study, and applying an increased UF of 300 for the use of a LAEL. The same value is valid for the acute acceptable operator exposure level (AAEL). The acceptable operator exposure level (AEL) from the first peer review was 0.08 mg/kg bw per day based on the rabbit developmental study and applying a correction factor for an oral absorption value of 80%. For the renewal, an AEL of 0.05 mg/kg bw per day was agreed, taking into account the results of short-term and long-term studies, and applying an UF of 100 (without correction for the oral absorption value, considered higher than 80%). In the absence of a dermal absorption study with the representative formulation, bridging of dermal absorption data for another formulation was discussed and considered acceptable. The resulting dermal absorption values for propyzamide in GF-3300 are 0.7% for the concentrate and 14% for the field dilution. The operator exposure estimates with the German model (75th percentile) are below the AEL for the application in oilseed rape, with the use of personal protective equipment (PPE). For the application in lettuce, the operator exposure is predicted to be above the AEL even with the use of PPE (German model). The exposure estimates for bystanders and residents were below the AEL. Re-entry workers harvesting lettuce are supposed to use PPE in order to have exposure levels below the AEL. 3. Residues The assessment in the residue section is based on the European Commission guideline document on MRL setting (European Commission, 2015), the Joint Meeting on Pesticide Residues (JMPR) recommendations on livestock burden calculations (JMPR, 2004, 2007) and the ECD publication on MRL calculations (ECD, 2011). Propyzamide was discussed in the teleconference TC 132 (April 2016). Metabolism of propyzamide in primary crops was investigated in leafy (lettuce), pulses/oilseeds (alfalfa, rapeseed) and root (sugar beet) crop groups using the 14 C-propyzamide labelled on the phenyl 9 EFSA Journal 2016;14(8):4554

10 ring. The active substance was applied both pre- and post-emergence on lettuce and post-emergence on alfalfa, rapeseed and sugar beet at early growth stages (GSs) BBCH At harvest in mature plants, propyzamide was present in significant proportions in lettuce and in alfalfa (42.5% and 58% total radioactive residue (TRR), respectively). In rapeseed forage and root, it accounted for up to 15.5% TRR and the compound RH was identified predominantly in the roots (45% TRR). The parent compound was not detected in rapeseeds and in sugar beet leaves and root where the major part of the radioactive residues were characterised as polar compounds that accounted for 37% TRR in rapeseeds and up to 71% TRR in sugar beet root and leaves. Although recovered at low proportions (< 10% TRR) in lettuce only, the glucoside conjugated metabolites (aglycons RH-24848, RH-25891, RH-26521, RH-26059) ( mg eq/kg), the malonyl glucoside conjugated metabolites (aglycons RH-24848, RH-25891, RH-26521) ( mg eq/kg) and metabolite RH (0.11 mg eq/kg) were identified at high absolute concentrations considering the metabolism study conducted at a 1.5N rate. Residues of glucoside and malonyl glucoside conjugated forms of RH also occurred in alfalfa in significant proportions (14% TRR). It is noted that the available metabolism data did not enable the identification of a predominant compound in the bulk of the conjugated metabolites as the relative proportion of each individual compound/aglycon was not determined in this study. A confined rotational crop metabolism study was conducted with bare soil application of propyzamide labelled on the phenyl ring at a dose of application of 4.48 kg a.s./ha (3N rate). Lettuce, carrot and wheat were planted at different plant back intervals (PBIs) (30, 180 and 365 days). TRRs in mature lettuce were significant at 30 days PBI (0.74 mg eq/kg) and decreased substantially to 0.05 mg eq/kg and mg eq/kg at 180 days and 365 days PBIs, respectively. TRRs in carrot root were low at 180 days and 365 days PBIs (0.025 and < 0.01 mg eq/kg, respectively), while the total residues in wheat forage, straw and grain at 365 days PBI amounted up to, respectively, 0.1 mg eq/kg, 0.18 mg eq/kg and mg eq/kg. Parent propyzamide was identified in significant proportions in lettuce (15 42% TRR) and in carrot top (17% TRR). The mannoside conjugate of RH was found to be a major compound of the total residues in lettuce (12 36% TRR), in carrot top (18 28% TRR) and in wheat forage and straw (26.6% TRR and 14.7% TRR, respectively), although the absolute concentrations of this compound in carrot and wheat plant parts were much lower compared to those recovered in lettuce. The glucoside of RH was the most abundant metabolite observed in lettuce (18 37% TRR). Metabolites identification was not carried out in carrot root and wheat grain. Even though considering the overdosed metabolism study, significant residue levels of parent propyzamide and conjugates of RH and RH are expected for short-cycle crops as lettuce planted 30 days after treatment (DAT) and a data gap was set to conduct rotational crops field trials on leafy crops, root crops and small grain crops for the determination of propyzamide, mannoside conjugate of RH and glucoside of RH residues at 30 days PBI (data gap). verall, the major routes of metabolism of propyzamide in plants included hydroxylation, oxidation on the alkyl side chain, cyclisation with the formation of the oxazoline ring and conjugations. Based on the metabolism data in primary and rotational crops, the residue definition for monitoring was proposed as propyzamide only. For risk assessment, the experts of the meeting discussed the possibility to set a specific residue definition for risk assessment for leafy crops only as the relevant compounds were identified mostly in lettuce as a primary crop and as a crop grown in rotation. However, a general consensus was finally reached to derive the residue definition as sum of propyzamide and all metabolites (and their conjugates) bearing the 3,5-dichlorobenzoic acid (DCBA) moiety, expressed as propyzamide for all crop categories following foliar application. This residue definition should be regarded as provisional as the toxicological profile of the pertinent metabolites identified in primary and in rotational crops, i.e. conjugates of RH-24848, RH-25891, RH-26521, RH-26059, RH-25337, RH and free RH was not addressed and is required (see data gap Section 2). As the parent compound is classified as carcinogenic category 2, and in the absence of specific studies on the structurally related metabolites, these compounds should be considered as toxicologically relevant. If these metabolites were to be demonstrated as being of a different toxicity profile compared with propyzamide, the proposed residue definition for risk assessment will have to be revised accordingly. Furthermore, sufficient residue field trials, respectively, on lettuce and rapeseed and analysing the magnitude of residues of all metabolites included in the residue definition for risk assessment should also be provided in order to perform the consumer dietary risk assessment (data gap). A sufficient number of residue field trials conducted according to the cgap conditions are available, respectively, on lettuce and rapeseed, determining residues of parent propyzamide only. The results obtained in these residue field trials are supported by acceptable storage stability data for propyzamide. The proposed MRLs on these crops should, however, be regarded as provisional 10 EFSA Journal 2016;14(8):4554

11 considering the outstanding data on the toxicity and the magnitude of the pertinent metabolites included in the residue definition for risk assessment. Propyzamide remained stable under the standard hydrolysis conditions representative of pasteurisation, baking/brewing/boiling and sterilisation. The metabolism studies in livestock (laying hens and lactating goats) showed that the parent compound was predominant in milk (33% TRR), muscle (66% TRR), fat (88% TRR) and eggs (20% TRR), while it was extensively degraded in liver (2% TRR) and kidney (7.4% TRR). DCBA compound was a significant compound of the total residues in muscle, kidney and liver (17 18% TRR) and all the other identified metabolites were found to contain the DCBA moiety. Although the goat metabolism study was not conducted in accordance with the current guidance recommendations concerning the dosing period and the deficiencies identified in terms of rate of metabolites identification in kidney and liver, the majority opinion was, however, that the metabolism of propyzamide in livestock was sufficiently addressed and was found to be similar to the rat metabolism. A pig metabolism study is therefore not required. Based on the overall metabolic pattern, the experts agreed that the parent compound is a valid residue marker in most of the animal commodities and the residue definition for monitoring was set as propyzamide only. For risk assessment, the residue is defined as sum of propyzamide and all metabolites (and their conjugates) bearing the DCBA moiety, expressed as propyzamide. For the time being and assuming that propyzamide alone is the relevant residue in feed items for livestock exposure and based on the livestock dietary burden, the metabolism studies indicated that residues > 0.01 m/kg are not expected in animal matrices and the transfer of residues into animal commodities does not need to be investigated. MRLs for livestock matrices are not required. This assessment should be reconsidered pending upon the outcome of the outstanding data on the magnitude of the pertinent compounds identified in primary and rotational crops and their relative toxicity. In that specific case, feeding studies may be requested to determine the residues of propyzamide alone and all components included in the residue definition for risk assessment. The proposed residue definitions for monitoring and risk assessment set for plant and animal commodities have been changed compared with those proposed in the framework of the review of the existing MRLs for propyzamide (EFSA, 2012). Indeed for plants, the pertinent metabolites recovered at high concentrations in primary (lettuce) and rotational crops were not considered in the residue definition for risk assessment while propyzamide alone was not proposed as the valid residue marker to be enforced in livestock matrices as an analytical method for the determination of propyzamide was not available. Furthermore, the residue definitions for plants have been extended to all categories of crops considering the additional metabolism study on root crops submitted for the renewal of the approval of propyzamide. Furthermore, the ADI has been changed and an ARfD has been allocated for propyzamide. The established MRLs under Article 12 of Regulation (EC) No 396/2005 and the overall consumer dietary risk assessment have therefore to be revised. Currently, a consumer risk assessment can only be provisionally conducted for parent propyzamide. Using the EFSA Pesticide Residues Intake Model (PRIMo), long-term and short-term intake concerns were not identified for the consumers as the highest chronic and acute intakes were estimated to be < 1% of the ADI (Spanish adult) and 12% of the ARfD (lettuce).the consumer risk assessment cannot be finalised with regard to all the pertinent metabolites (and their conjugates) bearing the DCBA moiety considering the outstanding data on their relative toxicity and their respective level in plants. Moreover, the level of metabolite RH in groundwater exceeding 0.75 lg/l for a number of lettuce and oilseed rape scenarios (Section 4) and the absence of toxicological reference values for this compound have led to the consumer risk assessment through drinking water not being conducted. The data requirement for the determination of the residues in pollen and bee products for human consumption resulting from residues taken up by honeybees from crops at blossom could not be addressed considering the outstanding residue field trials on rapeseed and on rotational crops analysing the relevant metabolites (data gap). 4. Environmental fate and behaviour Environmental exposure and fate and behaviour of propyzamide into the environment were discussed by Member States experts in the teleconference TC 129. The route and rate of degradation of propyzamide ( 14 C labelled at the phenyl ring) under dark aerobic conditions was investigated in eight different soils with reliable experiments. Propyzamide exhibited moderate to high persistence in these studies. Two major metabolites were identified: RH (max. 41.5% applied radioactivity (AR) after 71 days) and RH (max. 24% AR after 11 EFSA Journal 2016;14(8):4554

12 45 days). From the studies performed with the parent, it was possible to derive four formation fractions and associated degradation rates for metabolite RH (nevertheless due to volatilisation in two of the soils the formation fractions derived from these two kinetic analyses are considered to be underestimated). In these four experiments, this metabolite exhibited moderate to medium persistence. Degradation rate of metabolite RH was determined in two of the experiments performed applying the parent propyzamide. In these experiments, RH exhibited moderate to medium persistence. The peer review identified a data gap for a reliable aerobic soil period required for 50% dissipation (DT 50 ) for metabolite RH from an incubation in at least a third soil where volatile trap analysis is included following Forum for the Co-ordination of Pesticide Fate Models and their Use (FCUS) kinetic guidance regarding volatiles to complete the data set to the minimum of three reliable half-lives required by the guidance. Unextractable radioactivity increased up to 26.7% AR (after 120 days) and volatiles trapped in the alkaline trap (assumed to be C 2 ) increased up to a maximum of 47.6% AR (after 120 days). Propyzamide degradation in soil under anaerobic conditions was investigated in one soil. In these conditions, the same metabolites already formed under aerobic conditions were identified. Photolysis in soil was investigated in a soil under moist conditions (pf2) irradiated by a Xenon lamp at 20 C. Contribution of photolysis to degradation in soil of propyzamide was apparently marginal. No new metabolites were identified in this experiment. Two of the field dissipation studies done in USA (Wisconsin and California), presented in the dossier for the first approval (Choo, 1996 in the RAR, 2015), have been found that meet the quality criteria and are still considered valid by the RMS. However, data from these studies would need to be reanalysed following current guidance and have not been used for this exposure assessment. Experiments in five European additional sites have been presented in the renewal dossier. Results from field dissipation studies are not normalised and are considered only as persistence trigger end points (propyzamide DissT 90 = days). Predicted environmental concentration in soil (PEC soil ) were calculated for parent propyzamide and metabolites RH and RH using worst-case laboratory aerobic half-life (DT 50 = days) and standard assumptions. Reliable batch soil adsorption/desorption studies were performed with propyzamide (eight soils) and with metabolites RH (three soils), RH (four soils) and RH (seven soils). According to these studies, propyzamide and metabolite RH may be considered to exhibit slight to low mobility in soil, metabolite RH medium to high mobility and metabolite RH medium mobility. A lysimeter study performed in Germany in two lysimeters for 1 and 2 years is also available. In both lysimeters, propyzamide and a number of metabolites are found in the leachate at levels above 0.1 lg/l. Hydrolysis of propyzamide in water was investigated in buffered solutions (ph 5, 7 and 9) at 20 and 50 C. Propyzamide can be considered stable to hydrolysis under these conditions (< 10% hydrolysis). Aqueous photolysis (direct and indirect) of propyzamide was investigated in different studies, both in buffered and natural water. According to these experiments, photolysis may contribute to the degradation of propyzamide into the aquatic environment, being the effect more significant in natural water or when indirect photolysis mechanisms can occur. Aqueous photolysis metabolites DCBA and 3,5-dichlorobenzamide trigger assessment with respect to the aquatic environment. In the absence of a readily biodegradation study, propyzamide is considered not to be readily biodegradable. Propyzamide was stable under the conditions of the aquatic mineralisation study available (20 C). Fate and behaviour of propyzamide in dark water sediment systems under aerobic conditions was investigated in a study with two systems. Propyzamide partitioned slowly to the sediment (max. 44.5% AR after 30 days). Propyzamide was persistent in both systems (DT 50 whole system = days). ne major metabolite was formed in the sediment phase: RH (max sed. 20.5% AR after 105 days, end of study). In the water phase, metabolite RH (max water 5% AR after 105 days, end of the study) was considered needing further assessment as its levels were still increasing at the end of the study. PEC in surface water/sediment (PEC SW/sed ) were calculated for parent and metabolites RH-24644, RH-24580, RH-24655, DCBA, 3,5-dichlrobenzamide and RH with FCUS SW tools up to step 2. FCUS SW calculations up to step 3 were performed for parent and metabolites RH-24644, RH-24580, RH For parent propyzamide and metabolites, RH and RH-24580, it was necessary to consider possible mitigation equivalent to that resulting frοm 20 m buffer spray drift and run-off vegetative strips to conclude on the risk assessment. However, risk managers and others may wish to 12 EFSA Journal 2016;14(8):4554

13 note that while run-off mitigation is included in the step 4 calculations available, the FCUS (FCUS, 2007) report acknowledges that for substances with Freundlich organic carbon adsorption coefficient (K Foc ) < 2,000 ml/g, the general applicability and effectiveness of run-off mitigation measures had been less clearly demonstrated in the available scientific literature, than for more strongly adsorbed compounds. Potential for ground water contamination was assessed by calculation of 80th percentile of 20 years annual average leachate concentrations at 1 m depth with FCUS GW PEARL and FCUS PELM models for the representative uses in winter oilseed rape and lettuce. For oilseed rape, different application dates (from September to February) were simulated. Also, yearly and triennial applications were simulated in order to take into account potential mitigating effect of rotation in this crop. Limit of 0.1 lg/l was not exceeded by parent propyzamide and metabolite RH for any of the seven relevant lettuce scenarios and of the six oilseed rape scenarios. Level of metabolite RH exceeded 0.1 lg/l in five to six lettuce scenarios and five of six oilseed rape scenarios when yearly application is simulated. In the case of triennial application in oilseed rape, metabolite RH still exceeds 0.1 lg/l in one of the scenarios. When yearly application is simulated, the calculated annual average concentration level of 0.75 lg/l in the leachate is exceeded by metabolite RH for a number of scenarios (four lettuce scenarios, one oilseed scenario for yearly applications). It is noted that as only two reliable soil degradation rates remain available for metabolite RH after the peer review, worst-case DT 50 has been used for groundwater modelling following current guidance recommendations. Metabolite RH is considered a ground water toxicologically relevant metabolite as the parent is classified as carcinogenic category 2 and no studies are available to demonstrate that toxicological properties of the parent are not shared by RH (see Section 2). Therefore, a critical area of concern for potential ground water contamination is identified. The fact that in the lysimeter experiments a number of metabolites are found in the leachate at annual average levels above 0.1 lg/l parent equivalents (one metabolite at the level > 0.75 lg/l) is considered a critical area of concern with respect to ground water contamination by propyzamide as long as the parent compound is classified as carcinogenic category 2 (in the absence of specific studies for the metabolites, these lysimeter metabolites should be considered as toxicologically relevant). Propyzamide has been found at levels > 0.1 lg/l in ground water monitoring samples (Denmark, France, Italy and the UK) and in surface water (Denmark, France, Italy, Sweden and the UK). The highest reported concentration of propyzamide was 6 lg/l in ground water and 310 lg/l in surface water. During the peer review, some Member States informed that propyzamide is among the herbicides being detected in surface water, with reference to the Water Framework Directive 4 and 0.1 lg/l limit and has been considered one of the top five surface water contaminants in the UK. The applicant did not provide appropriate information to address the effect of water treatments processes on the nature of the residues that might be present in surface water and groundwater, when surface water or groundwater are abstracted for drinking water; especially taking into account the findings of propyzamide in surface water and the classification of propyzamide as carcinogenic category 2. This has led to the identification of a data gap (see Section 7) and results in the consumer risk assessment not being finalised (see Section 9). The PEC in soil, surface water, sediment and groundwater covering the representative uses assessed can be found in Appendix A of this conclusion. 5. Ecotoxicology The risk assessment is based on the following documents: SANC/10329/2002 rev.2 final (European Commission, 2002a), SANC/3268/2001 rev 4 (final) (European Commission, 2002b; SETAC, 2001; EFSA, 2009, 2013). According to Regulation (EU) No 283/2013 5, data should be provided regarding the acute and chronic toxicity to honeybees and data to address the development of honeybee brood and larvae. As the European Commission (2002a) does not provide a risk assessment scheme which is able to use the chronic toxicity data for adult honeybees and the honeybee brood when performing the risk assessment according to European Commission (2002a), the risk to adult honeybees from chronic toxicity and the risk to bee brood could not be finalised due 4 Directive 2000/60/EC of the European Parliament and of the Council of 23 ctober 2000 establishing a framework for Community action in the field of water policy. J L 327, , p Commission Regulation (EU) No 283/2013 of 1 March 2013 setting out the data requirements for active substances, 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. J L 93, , p EFSA Journal 2016;14(8):4554