Peer review of the pesticide risk assessment of the active substance mesosulfuron (variant evaluated mesosulfuron-methyl)

Transcription

1 CCLUI PETICIDE PEER REVIEW APPRVED: 20 eptember 2016 doi: /j.efsa Peer review of the pesticide risk assessment of the active substance mesosulfuron (variant evaluated mesosulfuron-methyl) Abstract European Food afety Authority (EFA) The conclusions of EFA following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member tate, France, and co-rapporteur Member tate, Poland, for the pesticide active substance mesosulfuron (variant evaluated mesosulfuron-methyl) are reported. The context of the peer review was that required by Commission Implementing Regulation (EU) o 844/2012. The conclusions were reached on the basis of the evaluation of the representative uses of mesosulfuron-methyl as a herbicide on winter wheat and winter rye. The reliable endpoints, 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 afety Authority. EFA Journal published by John Wiley and ons Ltd on behalf of European Food afety Authority. Keywords: mesosulfuron, mesosulfuron-methyl, peer review, risk assessment, pesticide, herbicide Requestor: European Commission Question number: EFA-Q Correspondence: pesticides.peerreview@efsa.europa.eu EFA Journal 2016;14(10):4584

2 uggested citation: EFA (European Food afety Authority), Conclusion on the peer review of the pesticide risk assessment of the active substance mesosulfuron (variant evaluated mesosulfuron-methyl). EFA Journal 2016;14(10):4584, 26 pp. doi: /j.efsa I: European Food afety Authority. EFA Journal published by John Wiley and ons Ltd on behalf of European Food afety Authority. This is an open access article under the terms of the Creative Commons Attribution-oDerivs License, which permits use and distribution in any medium, provided the original work is properly cited and no modifications or adaptations are made. The EFA Journal is a publication of the European Food afety Authority, an agency of the European Union. 2 EFA Journal 2016;14(10):4584

3 ummary Commission Implementing Regulation (EU) o 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) o 1107/2009. The list of those substances is established in Commission Implementing Regulation (EU) o 686/2012. Mesosulfuron is one of the active substances listed in Regulation (EU) o 686/2012. This substance is currently available on the market under its variant called mesosulfuron-methyl, which is considered to be the actual active substance. Hence, unless otherwise stated, the variant mesosulfuron-methyl has been considered in this conclusion. In accordance with Article 1 of the Regulation, the rapporteur Member tate (RM), France, and co-rapporteur Member tate (co-rm), Poland, received an application from Bayer Cropcience AG for the renewal of approval of the active substance mesosulfuron. Complying with Article 8 of the Regulation, the RM checked the completeness of the dossier and informed the applicant, the co-rm (France), the European Commission and the European Food afety Authority (EFA) about the admissibility. The RM provided its initial evaluation of the dossier on mesosulfuron which considered the variant mesosulfuon-methyl in the renewal assessment report (RAR), which was received by EFA on 15 ctober In accordance with Article 12 of the Regulation, EFA distributed the RAR to the Member tates and the applicant, Bayer Cropcience AG, for comments on 9 ovember EFA also provided comments. In addition, EFA conducted a public consultation on the RAR. EFA collated and forwarded all comments received to the European Commission on 11 January Following consideration of the comments received on the RAR, it was concluded that additional information should be requested from the applicant and that EFA should conduct an expert consultation in the areas of mammalian toxicology, and environmental fate and behaviour. In accordance with Article 13(1) of the Regulation, EFA should adopt a conclusion on whether mesosulfuron can be expected to meet the approval criteria provided for in Article 4 of Regulation (EC) o 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 mesosulfuron-methyl as a herbicide on winter wheat and winter rye, as proposed by the applicant. Full details of the representative uses can be found in Appendix A of this report. The use of mesosulfuron-methyl according to the representative uses proposed at the European Union (EU) level results in a sufficient herbicidal efficacy against the target weeds. In the section, identity, physical chemical properties and analytical methods, a data gap was identified for a monitoring method in body fluids. Regarding the mammalian toxicology area, two issues could not be finalised, the toxicological relevance of low levels of an unidentified unique human peak metabolite M-2 seen in an in vitro metabolism study and the immunotoxicity potential of mesosulfuron-methyl. Data gaps were also identified for the identification of the analytical methods used in each of the toxicity studies, for the assessment of the toxicological relevance of the individual impurities present in the technical specification and for the clarification of the skin sensitisation potential of mesosulfuron-methyl. The data available in the residue section are sufficient to carry out the required consumer exposure assessment through dietary intake for the representative uses. The data available on environmental fate and behaviour are sufficient to carry out the required environmental exposure assessments at the EU level, with the notable exception that a data gap was identified for information on the effect of water treatment processes on the nature of residues of both the active substance and its identified metabolites potentially present in surface and groundwater, when surface water or groundwater are abstracted for drinking water. This gap leads to the consumer risk assessment from the consumption of drinking water being not finalised for all the representative uses. Data gaps were also identified for field soil dissipation studies for metabolites AE F160459, mesosulfuron, AE F099095, AE F and AE F that have laboratory period required for 90% dissipation (DT 90 ) above the trigger for the provision of field information of 200 days and for the evaluation of the information on groundwater monitoring of mesosulfuron-methyl provided in the Danish Pesticide Leaching Assessment Program. The EU level assessment for the representative uses were finalised without these data. 3 EFA Journal 2016;14(10):4584

4 In the area of ecotoxicology, further information is needed to address the risk to birds and mammals for mesosulfuron-methyl metabolites (data gap). In addition, the available information was not sufficient to perform a dietary risk assessment for birds and mammals for exposure to mesosulfuron-methyl metabolites (data gap). Finally, data gaps were identified to address the risk of mesosulfuron-methyl to aquatic plants and to bees. 4 EFA Journal 2016;14(10):4584

5 Table of contents Abstract... 1 ummary... 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 (Tables 1 4) 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 (Table 5) References Abbreviations Appendix A List of end points for the active substance and the representative formulation Appendix B Used compound code(s) EFA Journal 2016;14(10):4584

6 Background Commission Implementing Regulation (EU) o 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) o 1107/ This regulates for the European Food afety Authority (EFA) the procedure for organising the consultation of Member tates, the applicant(s) and the public on the initial evaluation provided by the rapporteur Member tate (RM) and/or co-rapporteur Member tate (co-rm) in the renewal assessment report (RAR), and the organisation of an expert consultation where appropriate. It is noted that the active substance has been listed in the with the name mesosulfuron in Commission Implementing Regulation (EU) o 686/ However, the substance is currently available on the market under its variant called mesosulfuron-methyl, which is considered to be the actual active substance. Hence, unless otherwise stated, the variant mesosulfuron-methyl has been considered in this conclusion. In accordance with Article 13 of the Regulation, unless formally informed by the European Commission that a conclusion is not necessary, EFA 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) o 1107/2009 within 5 months of 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 RM, France, and co-rm, Poland, received an application from Bayer Cropcience AG for the renewal of approval of the active substance mesosulfuron. Complying with Article 8 of the Regulation, the RM checked the completeness of the dossier and informed the applicant, the co-rm (Poland), the European Commission and EFA about the admissibility. The RM provided its initial evaluation of the dossier on the mesosulfuron (variant mesosulfuronmethyl) in the RAR, which was received by EFA on 15 ctober 2015 (France, 2015). In accordance with Article 12 of the Regulation, EFA distributed the RAR to the Member tates and the applicant, Bayer Cropcience AG, for consultation and comments on 9 ovember EFA also provided comments. In addition, EFA conducted a public consultation on the RAR. EFA collated and forwarded all comments received to the European Commission on 11 January At the same time, the collated comments were forwarded to the RM 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 RM 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 EFA, the RM and European Chemicals Agency (ECHA) on 19 February n the basis of the comments received, the applicant s response to the comments and the RM s evaluation thereof, it was concluded that additional information should be requested from the applicant and that EFA should conduct an expert consultation in the areas of mammalian toxicology and environmental fate and behaviour. The outcome of the telephone conference, together with EFA 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 EFA in the format of an evaluation table. The conclusions arising from the consideration by EFA, and as appropriate by the RM, of the points identified in the evaluation table, together with the outcome of the expert consultation and the 1 Commission Implementing Regulation (EU) o 844/2012 of 18 eptember 2012 setting out the provisions necessary for the implementation of the renewal procedure for active substances, as provided for in Regulation (EC) o 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) o 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/EEC and 91/414/EEC. J L 309, , p Commission Implementing Regulation (EU) o 686/2012 of 26 July 2012 allocating to Member tates, for the purposes of the renewal procedure, the evaluation of the active substances whose approval expires by 31 December 2018 at the latest. J L 200, , p EFA Journal 2016;14(10):4584

7 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 tates via a written procedure in August eptember 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 as a herbicide on winter wheat and winter rye, as proposed by the applicant. A list of the relevant endpoints for the active substance and the formulation is provided in Appendix A. In addition, a key supporting document to this conclusion is the peer review report (EFA, 2016a), 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 (19 February 2016); the evaluation table (13 eptember 2016); the reports of the scientific consultation with Member tate experts (where relevant); the comments received on the assessment of the additional information (where relevant); the comments received on the draft EFA conclusion. Given the importance of the RAR, including its revisions (France, 2016), and the peer review report (EFA, 2016a c) 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 Mesosulfuron-methyl is the modified I common name for methyl 2-[(4,6-dimethoxypyrimidin-2- ylcarbamoyl)sulfamoyl]-a-(methanesulfonamido)-p-toluate (IUPAC). This substance is a derivative of mesosulfuron (I common name), 2-[(4,6-dimethoxypyrimidin-2-ylcarbamoyl)sulfamoyl]-amethanesulfonamido-p-toluic acid (IUPAC). The representative formulated product for the evaluation was Atlantis D, an oil dispersion (D) containing 10 g/l mesosulfuron-methyl in the form of mesosulfuron-methyl sodium (10.4 g/l), 1.9 g/l iodosulfuron-methyl in the form of iodosulfuron-methyl-sodium (2 g/l) and 30 g/l mefenpyr-diethyl as a safener. The representative uses evaluated were spray applications in winter wheat and winter rye to control annual grasses and dicotyledon 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 mesosulfuron-methyl according to the representative uses proposed at the EU level results in a sufficient herbicidal efficacy against the target weeds following the guidance document AC/10054/ rev. 3 (European Commission, 2013). A search of the scientific peer-reviewed open literature on the active substance and its relevant metabolites has been included in the RAR, dealing with side effects on health, the environment and non-target species. The criteria retained to perform this search are not completely satisfactory. However, as RM appropriately justifies the studies not taken into account in the assessment, EFA considers the literature search presented in the RAR as acceptable. 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: AC/3029/ 99-rev. 4 (European Commission, 2000a), AC/3030/99-rev. 4 (European Commission, 2000b), AC/10597/2003-rev (European Commission, 2012), AC/825/00-rev. 8.1 (European Commission, 2010) and AC/10054/2013-rev. 3 (European Commission, 2013). 7 EFA Journal 2016;14(10):4584

8 The reference specification from 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 955 g/kg. It should be noted that the active substance authorised was mesosulfuron; however, all data evaluated for the renewal belong to the derivative mesosulfuron-methyl. 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 mesosulfuron-methyl or the representative formulation. The main data regarding the identity of mesosulfuron-methyl and its physical and chemical properties are given in Appendix A. Adequate methods are available for the generation of preapproval data required for the risk assessment. Methods of analysis are available for the determination of the active substance in the technical material and representative formulation. Monitoring mesosulfuron-methyl residues in food and feed of plant origin can be done by liquid chromatography with tandem mass spectrometry (LC M/M) with limit of quantifications (LQs) of 0.01 mg/kg in all commodity groups. Adequate LC M/M analytical method for monitoring residues of mesosulfuron-methyl in food and feed of animal origin is available with LQs of 0.01 mg/kg in muscle, fat, milk, egg, liver and kidney. LC M/M methods are available enabling the determination of mesosulfuron-methyl residues in soil and water with LQs of 0.1 lg/kg and 0.05 lg/l, respectively. Residues of mesosulfuron-methyl in air can be determined by high-pressure/performance liquid chromatography-ultraviolet (HPLC-UV) with a LQ of 12 lg/m 3. A data gap was identified for a method for the determination of mesosulfuron-methyl residues in body fluids. 2. Mammalian toxicity The following guidance documents were followed in the production of this conclusion: AC/221/ 2000-rev. 10 (final) (European Commission, 2003), AC/222/2000-rev. 7 (European Commission, 2004), AC/10597/2003-rev (European Commission, 2012) and Guidance on dermal absorption (EFA PPR Panel, 2012). Mesosulfuron-methyl was discussed at the Pesticides Peer Review Experts Teleconference TC 134 in May The technical specification is supported by the batches used in the toxicity studies; however, the toxicological relevance of the individual impurities present in the technical specification has not been adequately addressed; the applicant has provided a quantitative structure activity relationship (QAR) analysis report (DEREK) on the impurities; however, a detail assessment of the QAR analysis has not been reported in the RAR and other models should be analysed and presented in details, thus a data gap has been identified. The analytical methods used in each of the toxicity studies have not been identified; therefore, it cannot be assessed whether they were validated at least in the key studies (data gap). In the toxicokinetics studies, mesosulfuron-methyl was poorly absorbed (around 2% of the administered dose) and metabolised, being hardly detected in organs and tissues; the highest residues were seen in blood and liver and it was rapidly eliminated, mainly via faeces. There was no evidence for accumulation. In an in vitro metabolism study performed with human liver microsomes, low levels of an unidentified peak metabolite M-2 should be further investigated to assess its toxicological relevance to human health. A data gap and an issue that could not be finalised are proposed. In the acute toxicity studies, mesosulfuron-methyl presented low toxicity when administered by the oral, dermal or inhalation routes to rats. It is not a skin or eye irritant. The skin sensitising potential of the substance could not be concluded as the concentration levels tested in two (negative) maximisation tests were too low with regard to the recommendations by ECD guideline 406 (ECD, 1992) and equivocal alerts were reported in a QAR analysis. o phototoxic potential is attributed to the active substance and it is agreed to waive the data requirement for photomutagenicity testing. o target organs were identified in the overall data package, except for histopathological changes in the stomach mucosa (increased foveolar mucous secretion and gastritis) of male dogs treated for 1 year and reduced body weight gain in mice treated for 18 months. The relevant short-term no observed adverse effect level (AEL) for non-dietary exposure is 648 mg/kg body weight (bw) per day from the 90-day study in dogs and the relevant long-term toxicity AEL is 103 mg/kg bw per day from the long-term toxicity/carcinogenicity study in mice. Mesosulfuron-methyl is unlikely to be 8 EFA Journal 2016;14(10):4584

9 genotoxic, and in the long-term toxicity and carcinogenicity studies in rats and mice, the compound showed no carcinogenic potential. o adverse effects were observed on the reproduction, fertility or development of rat or rabbits and there was no evidence for neurotoxicity. The substance is not proposed to be classified as carcinogenic or toxic for the reproduction category 2 in accordance with the provisions of Regulation (EC) o 1272/ and therefore, the conditions of the interim provisions of Annex II, Point of Regulation (EC) o 1107/2009 concerning human health for the consideration of endocrine-disrupting properties are not met. With regard to the scientific assessment, although a weak agonistic effect on aryl hydrocarbon receptor (AhR) function was reported in vitro, there were no indications of endocrinemediated adverse effects in apical studies, including relevant parameters investigated in the two-generation reproductive toxicity study; therefore, the substance is unlikely to be considered an endocrine disruptor in accordance with the EFA cientific pinion on the hazard assessment of endocrine disruptors (EFA cientific Committee, 2013). o specific investigations were conducted on the immunotoxic potential of mesosulfuron-methyl. Although no adverse effect was observed overall, the sensitisation potential of mesosulfuron-methyl was not concluded and immunotoxic potential cannot be completely ruled out (considering as well its weak in vitro agonist effect on AhR); a data gap and an issue that could not be finalised are therefore proposed. Genotoxicity studies have been submitted on three mesosulfuron-methyl metabolites, AE F147447, AE F and BC-CV14885, that gave all negative results; read across from mesosulfuron-methyl and metabolite AE F allowed to conclude that the metabolite AE F would also be devoid of genotoxic potential. The acceptable daily intake (ADI) of mesosulfuron-methyl is 1.0 mg/kg bw per day based on a AEL of 103 mg/kg bw per day for reduced body weight gain observed in the 18-month study in mice and applying an uncertainty factor (UF) of 100. This confirms the ADI previously established during the first review of mesosulfuron-methyl (European Commission, 2004). There is no need to establish an acute reference dose (ARfD) as already concluded during the first review of mesosulfuron-methyl (European Commission, 2004). The acceptable operator exposure level (AEL) is 0.13 mg/kg bw per day based on the AEL of 648 mg/kg bw per day from the 90-day study in dogs showing no adverse effects and applying an UF of 100; a correction factor of 2% is needed regarding the limited systemic bioavailability. This value is slightly lower than the one previously established during the first review of 0.2 mg/kg bw per day (European Commission, 2004). In line with the reasoning regarding the setting of an ARfD, there is no need to establish an acute AEL (AAEL). The RM estimated non-dietary exposure (i.e. operator, worker, bystander and resident) for the representative formulation Atlantis D, an oil dispersion (D) formulation containing 10 g/l mesosulfuron-methyl, 2 g/l iodosulfuron-methyl-sodium and the safener mefenpyr-diethyl (30 g/l), considering default dermal absorption values of 75% for the concentrate (mesosulfuron-methyl below 5% in formulation) and in-use field dilutions. Considering the use in cereals at an application rate of 15 g mesosulfuron-methyl per hectare (ha), the estimated operator and worker exposures did not exceed the AEL without the use of personal protective equipment (PPE) according to both the German Model and the UK Predictive perator Exposure Model (PEM) for operators and according to the EURPEM II for workers. Bystanders and residential exposure estimates remained below 0.1% of the AEL. 3. Residues The assessment in the residue section is based on the ECD guidance document on overview of residue chemistry studies (ECD, 2009), the ECD publication on maximum residue level (MRL) calculations (ECD, 2011), the European Commission guideline document on MRL setting (European Commission, 2015) and the Joint Meeting on Pesticide Residues (JMPR) recommendations on livestock burden calculations (JMPR, 2004, 2007). The metabolism of mesosulfuron-methyl was investigated upon foliar application at the tillering stage (growth stages of mono- and dicotyledonous plants (BBCH) 29) in cereals (wheat) using, respectively, 2-14 C-pyrimidyl and U- 14 C-phenyl labellings. The total radioactive residues (TRRs) 4 Regulation (EC) o 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) o 1907/2006. J L 353, , p EFA Journal 2016;14(10):4584

10 accounted for mg eq/kg in forage, mg eq/kg in hay, mg eq/kg in grain and mg eq/kg in straw for both labelling forms indicating a limited translocation of the radioactivity throughout the whole plant. Metabolites identification was not attempted in grain in view of the very low recovered residue levels. The parent compound was recovered at significant proportions in wheat forage and hay (23% TRR and 15% of TRR, respectively) and occurred only at a level of up to 3% TRR in straw. In wheat forage, hay and straw, mesosulfuron-methyl was shown to be degraded into metabolites identified as AE F (3.7 14% TRR), AE F (8.8 10% TRR) and AE F (5 18% TRR). These metabolites accounted for a residue concentration < 0.01 mg eq/kg. The major part of the radioactivity in these plant parts was characterised as polar fractions that globally accounted for 22 34% TRR and were constituted of several components that did not exceed each mg eq/kg. The identity of these compounds was not further investigated. A confined rotational crop metabolism study was conducted with a bare soil application of mesosulfuron-methyl labelled, respectively, on the pyrimidyl ring and on the phenyl ring at a dose rate of 15 g a.s./ha (1 rate). pinach, carrot and wheat were sown at plant-back intervals (PBIs) of 30, 120 and 365 days. The total residues in all plant parts and at all PBIs were below 0.01 mg/kg, except in wheat straw where TRRs accounted for up to mg eq/kg (30-day-PBI), mg eq/kg (120-day-PBI) and mg eq/kg (365-day-PBI) for both labelling forms. The radioactive residues in wheat straw at the 30-day-PBI were constituted of a major polar fraction (34% TRR) besides numerous minor polar fractions and a major metabolite identified as AE F (31% TRR). Hence, the metabolic pathway in the rotational crops is deemed to be similar to that depicted in the primary crops and residues are not expected to be present in rotational crops (> 0.01 mg/kg), providing that mesosulfuron-methyl is applied according to the representative uses. ince all the identified and characterised metabolites were recovered at very low concentrations (< 0.01 mg eq/kg) in wheat forage, hay and straw and in rotational crops, the residue definition for monitoring and risk assessment is proposed as mesosulfuron-methyl for cereals following post-emergence foliar application. Regarding the magnitude of residues in all crops, a sufficient number of supervised residue trials on wheat are available and compliant, respectively, with the northern and southern GAPs to derive a MRL of 0.01* mg/kg with a possible extrapolation to rye. The residue data are supported by validated analytical methods and by acceptable storage stability data where mesosulfuron-methyl was shown to be stable for up to 40 months in high starch content commodities and in straw. The investigation of effects of processing on the nature and magnitude of residues was not triggered by the representative uses. Although livestock metabolism studies are not triggered according to the representative uses, poultry and ruminants metabolism studies conducted with the U- 14 C-phenyl labelling form only were submitted. The parent compound was the predominant compound of the total residues in milk (23% TRR), liver (21 52% TRR), kidney (41% TRR) and in fat (20 70% TRR). ther compounds that occur at significant proportions, such as the alcohol metabolite AE F in fat (27% TRR), mesosulfuron-methyl or AE F in poultry liver (18% TRR) and AE F or AE F in milk (17% TRR), accounted for a very low concentration (< 0.01 mg/kg) in all matrices at the calculated dietary burden. Metabolites identification was not attempted in eggs and in the muscle because of the low recovered residue levels (0.012 and mg eq/kg, respectively). n the basis of the available metabolism studies in lactating ruminants and laying hens conducted with U- 14 C-phenyl labelled mesosulfuron-methyl only, the residue definition for both monitoring and risk assessment for animal commodities is proposed as mesosulfuron-methyl only. It is, however, highlighted that in case of future uses with feed items, the need for additional livestock metabolism data tracking the fate of the pyrimidyl ring moiety of the parent molecule should be reconsidered. Chronic consumer exposure resulting from the representative uses was calculated using the EFA Pesticide Residues Intake Model (PRIMo) rev.2a. The highest chronic dietary intake calculated with the proposed MRLs was < 0.1% of the ADI (Denmark child). o short-term intake calculation was conducted as an ARfD was not allocated for mesosulfuron-methyl. The toxicological reference values and the residue definition for both enforcement and risk assessment in plant and animal matrices have not been changed compared to those used in the review of the existing MRLs according to Article 12 of Regulation (EC) o 396/2005 for mesosulfuron (EFA, 2012). Therefore, there is no need to revise the existing MRLs under Article 12 of Regulation (EC) o 396/2005. It can confidently be concluded that 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 is addressed even though no data was provided considering the early application 10 EFA Journal 2016;14(10):4584

11 before flowering based on the representative use and the very limited translocation of the active substance throughout the plant. 4. Environmental fate and behaviour Mesosulfuron-methyl was discussed at the Pesticides Peer Review TC 135 in June The rates of dissipation and degradation in the environmental matrices investigated were estimated using FCU (2006) kinetics guidance. In soil laboratory incubations under aerobic conditions in the dark, mesosulfuron-methyl exhibited low to high persistence, forming the major (> 10% applied radioactivity (AR)) metabolites mesosulfuron (max. 16.2% AR) and metabolite AE F (max. 29.2% AR) which exhibited moderate to high persistence, metabolite AE F (max. 10.1% AR), which exhibited low to medium persistence, and AE F (max. 8.6% AR), which exhibited moderate persistence. In addition, metabolites AE F (max. 5.1% AR), AE F (max. 8.9% AR) and AE F (max. 5.8% AR) exceeded 5% AR in at least two consecutive sampling dates in the degradation experiments. Metabolite AE F exhibited low persistence, AE F exhibited moderate to high persistence and AE F exhibited moderate to medium persistence. Mineralisation of the pyrimidyl and the phenyl ring 14 C radiolabel to carbon dioxide accounted for % AR after 120 days and 9.1% AR after 120 days, respectively. The formation of unextractable residues (not extracted by acetonitrile/water) for these radiolabels accounted for % AR after 120 days. In anaerobic soil incubations, mesosulfuron-methyl transformation was slower than under aerobic conditions, with the degradation pathway being comparable to that under aerobic conditions. Mesosulfuron-methyl is not significantly photodegraded on the soil surface. The mobility in soil of mesosulfuron-methyl and its metabolites relevant for assessment was studied by batch equilibrium tests on a variety of different soils. Mesosulfuron-methyl exhibited very high to medium mobility in soil. Metabolite mesosulfuron exhibited very high to high soil mobility, metabolites AE F160459, AE F and AE F exhibited very high soil mobility, metabolite AE F exhibited high to slight soil mobility and metabolite AE F exhibited very high to low soil mobility. For metabolite AE F140584, the use of worst-case parameters was proposed which considers it would exhibit very high soil mobility. It was concluded that the adsorption of mesosulfuron-methyl and its metabolite was not ph dependent. In reliable field soil dissipation studies, mesosulfuron-methyl exhibited moderate to high persistence. According to the data requirements, field soil dissipation investigations should be made for metabolites when laboratory period required for 90% dissipation (DT 90 ) are greater than 200 days. Therefore, analysis of the field study samples for metabolites AE F160459, mesosulfuron, AE F099095, AE F and AE F was triggered, but this was not done. Therefore, a data gap was identified (see ection 7). However, the exposure assessment for the EU representative uses was completed using the available laboratory kinetic endpoints. In the first review, two lysimeter studies showed that mesosulfuron-methyl and its soil metabolites were not detected in leachates after application at 15 g/ha in spring or autumn to a silty sand soil. The annual mean concentration of total radioactivity in leachates was in the range lg/l a.s. equivalent (spring) and limit of detection (LD) < lg/l a.s. equivalent (autumn). This radioactivity mainly consisted of two unknown polar compounds. In the frame of the renewal of the mesosulfuron-methyl, an additional lysimeter study was conducted with the aim of identifying the presence of any metabolite > 0.1 lg/l in the polar fraction. In the new study, only one significant polar peak was observed in the three tested soils and identified as metabolite BC-CV For metabolite BC-CV14885, the average annual concentration of radioactivity in leachates was 0.2 lg/l (spring applications) and in the range of lg/l (autumn applications). Therefore, metabolite BC-CV14885 was included in the exposure assessment. In laboratory incubations in dark aerobic natural sediment water systems, mesosulfuron-methyl exhibited moderate persistence, forming the metabolites AE F (max. 21.6% AR in the total system), AE F (max. 10.9% AR in the total system), AE F (max. 8.4% AR in the total system), BC-CV14885 (max. 22% AR in the total system) and BC-C60720 (max. 13.1% AR in the total system). The unextractable sediment fraction (not extracted by acetonitrile/water) accounted for % AR at study end ( days) for phenyl ring 14 C radiolabel, and it accounted for % AR at study end ( days) for pyrimidyl ring 14 C radiolabel. Mineralisation accounted for % AR for phenyl ring 14 C radiolabel at study end ( days), and it accounted for % AR for pyrimidyl ring 14 C radiolabel at study end ( days). The rate of decline of mesosulfuron-methyl in a laboratory sterile aqueous photolysis experiment was slow relative to that occurred in the aerobic sediment water incubations. o chromatographically 11 EFA Journal 2016;14(10):4584

12 resolved component (excluding mesosulfuron-methyl) accounted for > 10% AR. Irradiation of phenyllabelled mesosulfuron-methyl in sterile natural water did not result in the formation of any photodegradation products. The necessary surface water and sediment exposure assessments (predicted environmental concentrations (PEC) calculations) were carried out for mesosulfuron-methyl and for its metabolites mesosulfuron, AE F160459, AE F099095, AE F092944, AE F160460, AE F140584, AE F147447, BC-CV14885 and BC-C60720, using the FCU (FCU, 2001) step 1 and step 2 approach (version 2.1 of the steps 1 and 2 in FCU calculator). For the active substance mesosulfuron-methyl, appropriate step 3 (FCU, 2001) and step 4 calculations were available. 5 The step 4 calculations appropriately followed the FCU (FCU, 2007) guidance, with no-spray drift buffer zones of up to 20 m being implemented for the drainage scenarios (representing a 90 93% spray drift reduction) and combined no-spray buffer zones with vegetative buffer strips of up to 20 m (reducing solute flux in run-off by 80% and erosion run-off of mass adsorbed to soil by 95%) being implemented for the run-off scenarios. The WA tool (version 1.1.4) was appropriately used to implement these mitigation measures in the simulations. However, risk managers and others may wish to note that while run-off mitigation is included in the step 4 calculations available, the FCU (FCU, 2007) report acknowledges that for substances with Freundlich organic carbon adsorption coefficient (K Foc ) < 2,000 ml/g (i.e. mesosulfuron-methyl), 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. The necessary groundwater exposure assessments were appropriately carried out using FCU (European Commission, 2014) scenarios and the models PEARL and PELM for the active substance mesosulfuron-methyl and its metabolites mesosulfuron, AE F160459, AE F160460, AE F099095, AE F092944, AE F140584, AE F and BC-CV The potential for groundwater exposure from the representative uses by mesosulfuron-methyl above the parametric drinking water limit of 0.1 lg/l was concluded to be low in geoclimatic situations that are represented by all FCU groundwater scenarios, except in two winter wheat scenarios where the limit was exceed. For metabolites mesosulfuron, AE F099095, AE F and AE F140584, the parametric drinking water limit of 0.1 lg/l was concluded to be low in all geoclimatic situations that are represented by all the relevant FCU groundwater scenarios. For the representative use on winter wheat, the 80th percentile annual average recharge concentrations leaving the top 1 m soil layer were estimated to be > 0.1 lg/l at four out of nine scenarios for metabolite AE F For the representative use on winter wheat, concentrations expressed on this basis were estimated to be > 0.1 lg/l at all scenarios for metabolite AE F For the representative use on winter wheat, concentrations expressed on this basis were estimated to be > 0.1 lg/l at seven out of nine scenarios for metabolite AE F For the representative use on winter rye, concentrations expressed on this basis were estimated to be > 0.1 lg/l at three out of nine scenarios for metabolite AE F For metabolite BC-CV14885, concentrations expressed on this basis were estimated to be > 0.1 lg/l at all nine scenarios for the representative use on winter wheat and three out of nine scenarios for the representative use on winter rye. Predicted metabolite concentrations were always < 0.75 lg/l; at these levels, it was concluded that metabolites AE F147447, AE F160459, AE F and BC-CV14885 were not relevant (see ections 2 and 6). It should be noted that during the peer review some modelling endpoints (i.e. soil period required for 50% dissipation (DT 50 ), K Foc and slope of Freundlich isotherm (1/n) values) for metabolites AE F and AE F were updated with the consolidated list of endpoints entry for modelling endpoints for the common metabolites of sulfonylureas. These agreed modelling endpoints were not used in the updated FCU modelling. However, taking into consideration the available PEC gw results for these two metabolites and the small differences between the values, it is considered that this inadequacy will not have an impact on the results of the groundwater exposure assessment. 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. This has led to the identification of a data gap (see ection 7) and results in the consumer risk assessment not being finalised (see ection 9). 5 imulations utilised the agreed Q10 of 2.58 (following EFA, 2008a) and Walker equation coefficient of EFA Journal 2016;14(10):4584

13 The report of the Danish Pesticide Leaching Assessment Program was provided, but the available information on groundwater monitoring of mesosulfuron-methyl were not evaluated, therefore a data gap for this evaluation was identified (see ection 7). 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 was based on the following documents: European Commission (2002), ETAC (2001), EFA (2009a, 2013), and EFA PPR Panel (2013). According to Regulation (EU) o 283/2013, 6 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 (2002) 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 (2002), the risk to adult honeybees from chronic toxicity and the risk to bee brood, could not be finalised due to the lack of a risk assessment scheme. Therefore, EFA (2013) was used for risk assessment in order to reach a conclusion for the representative uses. A low acute and long-term dietary risk to birds and mammals was concluded for mesosulfuronmethyl for all the representative uses. The available information was not sufficient to perform a dietary risk assessment for birds and mammals for exposure to mesosulfuron-methyl metabolites (data gap). The RM disagreed with this data gap and considered the risk assessment for birds and mammals for exposure to mesosulfuron-methyl metabolites as covered by dietary risk assessment conducted for the active substance noting that the plant residue definition for risk assessment is the active substance (see ection 3). A low risk via exposure through the food chain was concluded for mesosulfuron-methyl and its pertinent metabolites. It is noted that a log K ow was not available for metabolite BC-C60720; however, considering that this metabolite is structurally similar to metabolite BC-CV14885 (log K ow = 4.7) and that the active substance and its nine metabolites have a log K ow < 3, the potential for bioaccumulation of this compound and the consequent potential risk to fish-eating birds and mammals is considered to be low. For aquatic organisms, based on the available tier 1 data and risk assessment, a low acute risk (fish and aquatic invertebrates) was identified for the parent compound for all representative uses. For the use on winter wheat, using the available tier 1 data and the FCU step 4 exposure estimates, a high risk for aquatic plants was identified for two out of nine scenarios, while for the use on winter rye, using the available tier 1 data and the FCU step 3 exposure estimates, a high chronic risk was identified for one out of nine scenarios. An outdoor pond study was available as possible refinement of aquatic plants risk assessment. This study was performed with nine different aquatic plants species and was coupled with an extended laboratory study on Lemna gibba (8 weeks). From these data, L. gibba was found to be the most sensitive species; therefore, the no observed effect concentration (EC) for Lemna was further used in the risk assessment with an assessment factor (AF) of 3. This refinement was, however, not sufficient to address the risk of mesosulfuron-methyl to aquatic plants for all representative uses (data gap). Considering the fact that the assessment was based on an endpoint normally not used in the aquatic plants risk assessment (EC), the applied AF may need to be reconsidered at the Member tate level. From the available data set, the formulated product demonstrated a higher acute toxicity than the active substance for fish and aquatic invertebrates. Using the available endpoints for the formulation and the estimated PEC sw via drift at 1 m, a low acute risk to aquatic organisms was concluded for all the representative uses. The chronic risk assessment is not considered necessary as long-term exposure from the formulation is not expected. A low risk to aquatic organisms was identified for all pertinent surface water metabolites of mesosulfuron-methyl for all the representative uses. The risk assessment for honeybees was performed by EFA in accordance with the EFA (2013). Acute (contact and oral) toxicity studies for honey bees, performed with the active substance and the representative formulation Atlantis D and a chronic toxicity study on honeybee performed with the 6 Commission Regulation (EU) o 283/2013 of 1 March 2013 setting out the data requirements for active substances, in accordance with Regulation (EC) o 1107/2009 of the European Parliament and of the Council concerning the placing of plant protection products on the market. J L 93, , p EFA Journal 2016;14(10):4584

14 active substance were available. Using these data in a screening assessment in line with EFA (2013), a low acute and chronic risk to honeybees was concluded. A chronic laboratory study on honeybee larvae was not available and therefore the first-tier risk assessment for honeybee larvae could not be performed. A higher tier study performed according to omen et al. (1992) was available. In this study, adverse effects on bee brood were not observed. It is nevertheless noted that this type of study presents various shortcomings with respect to EFA (2013), for instance, the fact that bees are fed only a single application rather than continuously for 9 days. Also, in such study type, it is not demonstrated that the exposure covers the specific protection goal for exposure according to EFA (2013). A tunnel test in line with ECD 75 was available. This study was performed with a different formulation with respect to the representative one (mesosulfuron- methyl 75 water-dispersible granule (WG) + mefenpyr-diethyl WG 15) but contained the same safener as the representative formulation. In this study, Phacelia tanacetifolia was treated with the maximum application rate according to the representative uses (15 g a.s./ha). A statistically significant increase in the daily pupae mortality with respect to the control was observed on day 0, 3 and 4 after the application. This difference was not statistically significant over the entire testing period. ignificant differences compared to the control were not observed in all the other assessed parameters including adult mortality, foraging activity and development of bee brood (brood index, brood termination rate and brood compensation index). verall, considering that this study was performed with a flowering attractive plant for pollen and nectar (P. tanacetifolia), while the representative use being assessed is on cereals (early stage) on a weight of evidence basis, a low risk to honeybee brood could be concluded. o assessment for accumulative effects was available. An assessment of the effects on hypopharyngeal glands (HPG) was not available (data gap). A low (acute and chronic) risk to adult honeybees was concluded on the basis of the screening assessment for exposure to residues in surface water. Regarding the exposure via guttation fluids, a low acute risk to adult honeybees was concluded while a high chronic risk could not be excluded (data gap). An assessment of the exposure via residues in puddle water was not available (data gap). Due to the lack of toxicological endpoints, similar quantitative assessments for exposure via water consumptions were not performed for larvae and for the development of HPG (data gap). o information was available regarding metabolites occurring in pollen and nectar. Therefore, further information is needed to address the risk to honeybees for pertinent metabolites (data gap). Data to perform a risk assessment for mesosulfuron-methyl for solitary bees were not available. Acute contact toxicity data on the formulated as mesosulfuron-methyl 75 WG on bumble bees (Bombus terrestris) were available. With these data, a low acute risk for contact exposure can be concluded. A low risk to non-target arthropods was concluded for all the representative uses of mesosulfuron-methyl. A low risk to soil macro- and microorganisms was concluded for mesosulfuron-methyl and its pertinent metabolites. It is noted that data on the effects on soil microorganisms were not available for metabolite AE F n a weight of evidence approach considering the low PECs in soil of this metabolite and low toxicity to soil microorganisms of the parent compound, a low risk could be concluded. A low risk for non-target terrestrial plants was concluded in a probabilistic risk assessment (based on the derivation of an HC 5 via D) for all representative uses provided that mitigation measures up to 5 m buffer zones or 75% drift reduction are applied. A low risk for sewage treatment organisms was concluded. With regard to the endocrine disruption potential, as discussed in ection 2, it is unlikely that mesosulfuron-methyl is an endocrine disruptor in mammals; however, no firm conclusion can be drawn regarding fish and birds EFA Journal 2016;14(10):4584