Outcome of the pesticides peer review meeting on general recurring issues in mammalian toxicology

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1 TECHNICAL REPORT APPROVED: 25 July 2016 Outcome of the pesticides peer review meeting on general recurring issues in mammalian toxicology Abstract European Food Safety Authority This technical report reflects the outcome of the mammalian toxicology experts meeting on general recurring issues noted during the EFSA peer reviews of pesticide active substances under Regulation (EC) No. 1107/2009. The main issues identified were related to the quality and level of details of the renewal assessment reports and the adherence to the new data requirements, in particular regarding in vitro metabolism studies, phototoxicity and photomutagenicity testing. General issues regarding the assessment of metabolites and impurities, the assessment of the potential for endocrine disruption, the proposals for classification and labelling and the assessment of literature search were also discussed. Conclusions and further recommendations on these issues are reported. European Food Safety Authority, 2016 Key words: pesticides, mammalian toxicology, endocrine disruption, phototoxicity, in vitro comparative metabolism, metabolite, impurity. Requestor: EFSA Question number: EFSA-Q Correspondence: EFSA Supporting publication 2016:EN-1074

2 Suggested citation: EFSA (European Food Safety Authority), Technical report on the outcome of the pesticides peer review meeting on general recurring issues in mammalian toxicology. EFSA supporting publication 2016:EN pp. European Food Safety Authority, 2016 Reproduction is authorised provided the source is acknowledged. 2 EFSA Supporting publication 2016:EN-1074

3 Summary During the EFSA peer review of pesticide active substances under Regulation (EC) No. 1107/2009, several aspects in the area of mammalian toxicology were identified by EFSA that needed discussion with experts from national Authorities in order to enhance the harmonisation of the risk assessment of active substances. The main issues identified were related to the quality and level of details of the renewal assessment reports and the adherence to the new data requirements, in particular regarding in vitro metabolism studies, phototoxicity and photomutagenicity testing. General issues regarding the assessment of metabolites and impurities, the assessment of the potential for endocrine disruption, the proposals for classification and labelling and the assessment of literature search were also discussed. All these issues were discussed in a general mammalian toxicology meeting, the Pesticide Peer Review Meeting 137 that took place from 14 to 15 January Recommendations were compiled on the basis of the discussions and conclusions achieved at the meeting and further input from the experts of the EFSA Scientific Panel on Plant Protection Products and their Residues. Horizontal issues for future developments were identified. These recommendations will be applied during the EFSA peer review of the active substances, and are expected to provide additional clarifications to applicants and rapporteur Member States regarding the scientific interpretation of the relevant guidance documents when preparing the dossiers and the renewal assessment reports. 3 EFSA Supporting publication 2016:EN-1074

4 Table of contents Abstract... 1 Summary Introduction Points of discussions and meeting s conclusions Renewal assessment report (RAR) New data requirements according to Regulations (EU) No. 283/2013 and 284/ Good Laboratory Practice (GLP) requirement status Analytical methods Toxicokinetic parameters and in vitro comparative metabolism study Phototoxicity/photomutagenicity Genotoxicity testing and follow up on positive in vitro results In vivo follow-up for in vitro gene mutation Aneugenicity Tissue exposure Assessment of the toxicological profile of metabolites and impurities Metabolites Impurities Endocrine disruptive properties Proposals for classification Literature search Recommendations of the EFSA PPR Panel Overall EFSA conclusions and recommendations References Abbreviations EFSA Supporting publication 2016:EN-1074

5 1. Introduction During the EFSA peer review of pesticide active substances under Regulation (EC) No. 1107/ EFSA identified several general recurrent issues in the area of mammalian toxicology which deserved experts consultation and agreement in order to enhance the harmonisation of the risk assessment of active substances. To this purpose a general meeting was organised which took place in January 2016 (Pesticide Peer Review Meeting 137, January 2016). Member States representatives with expertise in toxicology attended this meeting. Some Member States provided written comments before the meeting. One member of the EFSA Scientific Panel on Plant Protection Products and their Residues (PPR Panel) participated as external expert representing the Panel and reported back to the Panel. The recommendations of the Panel are also quoted in this technical report. The Scientific Committee (SC) and Emerging Risk Unit presented its activities in the area of toxicokinetics and toxicodynamics in chemical risk assessment during the peer review meeting 137 and at the 79th plenary meeting of the PPR Panel (10-11 February 2016). The main issues identified were related to the quality and level of details of the renewal assessment reports and the adherence to the new data requirements, in particular regarding in vitro metabolism studies, phototoxicity and photomutagenicity testing. General issues regarding the assessment of metabolites and impurities, the assessment of the potential for endocrine disruption, the proposals for classification and labelling and the assessment of literature search were also discussed. Other general issues were also identified and proposed for discussion. These were related to new available scientific knowledge or to the evaluation of the validity of old studies using new criteria (within the peer review on the renewal of the approval of active substances). There are several general issues that were not discussed but should be taken into consideration for future discussion in a similar manner. These include but are not limited to the use of historical control data, cumulative effects, data requirements for co-formulants and formulated products. In the following sections, for each issue identified, the background, the EFSA proposal and the outcome of the meeting reflecting the opinion of the majority of the participating experts are reported. Concluding recommendations based on EFSA s view are given. In addition, the following documents are available as background documents of this technical report: the report of the scientific consultation with Member State experts; the comments received from Member States before the meeting; the minutes of the 79th Scientific Panel on Plant Protection Products and their Residues Plenary meeting; ; the comments received on the draft technical report following the written procedure launched from 1 June 2016 to 14 June It is noted that the written procedure was performed with the purpose to enhance readability and correct possible inconsistencies. Since the scope of this technical report was to reflect the meeting discussions and conclusions, the commenting round was not meant to reopen the discussions or to change the outcome of the meeting. 2. Points of discussions and meeting s conclusions 2.1. Renewal assessment report (RAR) The Annex I Renewal (AIR) Regulation for substances established that the supplementary dossiers shall contain: - information demonstrating that the approval criteria from Regulation (EC) No. 1107/2009 are fulfilled, 1 Regulation (EC) No 1107/2009 of the European Parliament and of the Council of 21 October 2009 concerning the placing of plant protection products on the market and repealing Council Directives 79/117/EEC and 91/414/EEC. OJ L 309, , p EFSA Supporting publication 2016:EN-1074

6 - data and risk assessments reflecting changes in legal requirements, - data and risk assessments reflecting changes in scientific and technical knowledge. The rapporteur Member State (RMS) shall make an independent, objective and transparent assessment in the light of current scientific and technical knowledge. The Guidance Document (European Commission, 2014) on renewal of approval established that: - EFSA may request for more elaborated study summaries and/or in some areas advances in science may trigger the need for a new evaluation of old studies, - the previously submitted and accepted data should not be re-opened, unless such is necessary in the light of current scientific and technical knowledge which may require a re-assessment of old data. EFSA recommendation In order to guarantee an independent scientific assessment, sufficient details should be provided about the old studies in order to judge if their assessment is still aligned with current scientific and technical knowledge. EFSA would recommend the RMS to request the applicant to provide updated robust OECD (Organisation for Economic Co-operation and Development) summary reports for old studies. This will facilitate the work of the RMS. One expert proposed to strictly follow the European Commission (EC) Guidance Document and not reopen previously submitted and accepted data; another expert indicated that the renewal assessment should include further evaluations of data submitted for the first peer review. Some experts pointed out that sometimes robust summary reports are not provided by the Applicant upon request by the RMS and that for key studies, additional information/tables were included in the revised version of the RAR. Different experiences were reported depending on the substances. The majority of experts agreed with the EFSA proposal that sufficient details should be provided about the old studies in order to judge if their assessment is still aligned with current scientific and technical knowledge. One expert disagreed with the EFSA proposal in order to avoid unnecessary burden to the Member States and to be in line with EC Guidance Document. In addition, it was agreed that a distinction should be made in the RAR between what the applicant drafted and what is the RMS s assessment. It was also agreed that changes to first approval conclusion should be clearly indicated in the RAR New data requirements according to Regulations (EU) No. 283/2013 and 284/ Good Laboratory Practice (GLP) requirement status Commission Regulations (EU) No. 283/ and 284/ establish that tests and analyses shall be conducted in accordance with the principles of good laboratory practice (GLP) as laid down in Annex I of Directive 2004/10/EC 4 where testing is done to obtain data on human or animal health or the environment safety. The GLP status was required in the original legislation concerning the placing of plant protection products on the market (91/414/EC 5 ) and implemented within two years after notification (i.e. for all 2 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. OJ L 93, , p Commission Regulation (EU) No 284/2013 of 1 March 2013, setting out the data requirements for plant protection products, 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. OJ L 93, , p Directive 2004/10/EC of 11 February 2004 of the European Parliament and of the Council, on the harmonisation of laws, regulations and administrative provisions relating to the application of the principles of good laboratory practice and the verification of their applications for tests on chemical substances (codified version). OJ L 50, , p Council Directive of 15 July 1991 concerning the placing of plant protection products on the market. OJ L 230, , p EFSA Supporting publication 2016:EN-1074

7 studies performed from July 1993). The studies for active substances conducted before July 1993, although not fully compliant with GLP requirements or with current test methods, may be integrated into the assessment, when accepted by the competent authorities as scientifically valid, thereby removing the need for repeating animal tests, especially for carcinogenicity and reproductive toxicity studies. The experts prefer studies with GLP status but there are cases in which non-glp studies are appropriate (e.g. mechanistic data) and acceptable (pending availability of raw data and welldocumented study report) Analytical methods During the first review and renewal assessment for the substances under the 1 st and 2 nd programme, the validation of the analytical methods for body fluids and tissues only needed to be provided for substances classified 6 as: Acute toxicity: categories 1, 2, 3 Specific Target Organ Toxicity by Single Exposure (STOT-SE): category 1 Specific Target Organ Toxicity by Repeated Exposure (STOT-RE): category 1 Carcinogenic, Mutagenic or Reproductive toxicant (CMR): categories 1A and 1B For the 3 rd renewal programme following Regulation (EU) No. 283/2013, in contrast, analytical methods for body fluids and tissues have always to be provided. Furthermore, according to Regulation (EU) No. 283/2013 the analytical methods to be used in toxicity studies shall be specific for the entity to be measured and shall be adequately validated. The limit of quantification (LOQ) shall be adequate for the measurement of the range of concentrations anticipated to occur in the generation of the toxicokinetic data. Validation of the analytical methods needs to be provided for all studies with non-radiolabelled test material, including the old studies (of the original peer review) and the new studies (for the renewal), and this is applicable to all areas of the risk assessment (i.e. for the purposes of toxicological, ecotoxicological, environmental, residue and physico-chemical properties testing). EFSA proposal An assessment of the analytical methods and of their validation data should be provided for all studies (old and new) with active substances and metabolites. This information should be assessed and sufficiently described in the RAR (Volume 3, chapter B.5) for its peer review by experts evaluating the physico-chemical properties and analytical methods of the active substance and its formulation(s). The assessment should be in line with the guidance for generating and reporting methods of analysis (European Commission, 2004). The experts agreed that the assessment of the analytical methods and of their validation data should be included in the volume 3 of the RAR, in the chapter B.5; cross references might be included as well in other sections. Some issues were identified for old toxicity studies: the amount of test substance administered and the identity of what was fed to animals (i.e. in relationship to possible isomers, impurities, variants, etc.) was not always reported. Another issue was the extraction efficiency, for which at least a 6 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. OJ L 353, , p EFSA Supporting publication 2016:EN-1074

8 justification should be required to show that the extraction method was appropriate. All these points represent sources of uncertainties to be identified during the re-evaluation of old studies. The experts expressed concerns about the possible consequences of analytical methods for old studies not validated according to current guidance. It was clarified that, in the section about physicochemical properties and analytical methods, it can be concluded that the method is not validated according to current guidance but is nevertheless fit-for-purpose and supports the toxicological studies. As example, chromatographic methods can be not properly validated but fit-for-purpose in the case of dietary analysis. In the cases where the method is not considered fit-for-purpose, this plays a role in the assessment of the quality and reliability of the study, which can be considered not acceptable for setting reference values. A case-by-case evaluation should be performed and the experts agreed that repeating a study would be an extreme case (generally not required). Regarding the analytical methods for body fluids and tissues, one expert highlighted a discrepancy between the guidance for post-registration control and monitoring (European Commission, 2010) and the new data requirements according to Regulation (EU) No. 283/2013. Considering the new data requirements, validated analytical methods should now be provided for all substances and not only to those classified and labelled for acute toxicity, STOT-SE/RE or CMR as proposed in the guidance (European Commission, 2010) Toxicokinetic parameters and in vitro comparative metabolism study According to Regulation (EU) No. 283/2013 information on blood and tissues concentrations for the active substance and relevant metabolites, for example around the time to reach the maximum plasma concentration (Tmax), shall be generated in short and long term studies on relevant species to enhance the value of the toxicological data generated in terms of understanding the toxicity studies. The main objective of toxicokinetic data is to describe the systemic exposure achieved in animals and its relationship to the dose levels and the time course of the toxicity studies. A key parameter is systemic bioavailability (F), obtained by comparison of the area under the curve (AUC) after oral and intravenous dosing. When intravenous dosing is not feasible a justification shall be provided. The design of the kinetic studies required shall include: a) An evaluation of the rate and extent of oral absorption including maximum plasma concentration (Cmax), AUC, Tmax and other appropriate parameters, such as bioavailability; b) The potential for bioaccumulation; c) Plasma half-lives; d) The distribution in major organs and tissues; e) Information on the distribution in blood cells; f) The chemical structure and quantification of metabolites in biological fluids and tissues; g) The different metabolic pathways; h) The route and time course of excretion of active substance and metabolites; i) Investigations to show whether and to what extent enterohepatic circulation takes place. Concerning in vitro metabolism studies, Regulation (EU) No. 283/2013 establishes that comparative in vitro metabolism studies shall be performed on animal species to be used in pivotal studies and on human material (microsomes or intact cell systems) in order to determine the relevance of the toxicological animal data and to guide the interpretation of the findings and to further define the testing strategy. An explanation shall be given or further tests shall be carried out where a metabolite is detected in vitro in human material and not in the tested animal species. 8 EFSA Supporting publication 2016:EN-1074

9 EFSA proposal Additional toxicokinetic parameters should be presented in the renewal dossier, according to the data requirements in Regulation (EU) No. 283/2013. Considering the data requirement for an interspecies comparative in vitro metabolism study, this should be maintained unless a scientific justification is provided, supporting the fact that the risk assessment can be completed without submission of comparative metabolism data. The argument that no validated test method (e.g. OECD) is available is not considered valid (European Commission, 2013). These types of studies are widely used for pharmaceuticals in various stages of development, from a new chemical entity characterisation to a pre-clinical safety assessment. This type of study would be also of particular interest to confirm that a significant chiral conversion of the active substance does not occur in different species. Protocols are available in the public domain (e.g. EURL-ECVAM: and in relevant publications (Jia et al., 2007; Dow, 2006). As an example, a general framework to guide designs and protocols for in vitro drug metabolism studies can be found in the literature (Jia et al., 2007). These protocols include hepatic and nonhepatic microsomes, cdna-expressed recombinant human CYPs expressed in insect cells or human B lymphoblastoid, chemical P450 inhibitors, S9 fraction, hepatocytes and liver slices. If considered appropriate (with the support of the Pesticide Steering Network), EFSA could be mandated to provide further guidance on the minimum requirements in conducting and assessing in vitro metabolism data. Meanwhile relevant modules or parts of modules of the draft EFSA PPR guidance on the residue definition might apply to the assessment of unique human metabolites. The experts supported the EFSA proposal to ask for additional toxicokinetic parameters and in vitro metabolism data in the renewal dossier, according to the data requirement in Regulation (EU) No. 283/2013. One expert noted that information on some of the toxicokinetic parameters is missing in old studies and it has to be decided on a case-by-case basis if this lack of data is crucial or not. For the data requirement on interspecies comparative in vitro metabolism, internationally validated methods and criteria for the interpretation of the results are missing. As a first step, the experts supported the need for guidance on in vitro metabolism, in order to satisfy the data requirement. This practical guidance should provide clear indications on how to perform and how to interpret in vitro metabolism studies. As a second step, other toxicokinetic endpoints should be addressed in further guidance, in order to address inter-species and intra-species variability (e.g. in relationship with bioavailability, phase 2 metabolism, transporters, etc.) Phototoxicity/photomutagenicity Regulation (EU) No. 283/2013 establishes that an in vitro study shall be required where the active substance absorbs electromagnetic radiation in the wavelength range of 290 to 700 nm and is liable to reach the eyes or light-exposed areas of skin, either by direct contact or through systemic distribution. If the Ultraviolet/visible molar extinction/absorption coefficient of the active substance is less than 10 L/mol x cm, no phototoxicity testing is required. Concerning photomutagenicity special testing requirements may be indicated by the structure of a molecule. If the Ultraviolet/visible molar extinction/absorption coefficient of the active substance and its major metabolites is less than 1000 L x mol -1 x cm -1, photomutagenicity testing is not required. The in vitro 3T3 Neutral Red Uptake phototoxicity (NRU-PT) test (OECD 432) (OECD, 2004b) was shown to be predictive of acute phototoxicity effects in animals and humans in vivo, however according to the OECD 432 guideline it does not predict: 9 EFSA Supporting publication 2016:EN-1074

10 - adverse effects resulting from combined action of chemical and light, - photogenotoxicity, photoallergy or photocarcinogenicity, - phototoxic potency, - indirect mechanisms of phototoxicity, effects of metabolites, or effects of mixtures. EFSA proposal This data requirement should be addressed unless a scientific justification is provided, supporting the fact that the risk assessment can be completed without submission of further studies/data. The argument that no agreed test method or guidance is available is not considered a valid justification. The recommended OECD Test Guideline 3T3 NRU-PT test might be not completely applicable to evaluate phototoxicity of a substance at UVB-wavelengths because irradiation of cells in vitro at wavelengths below 320 nm results in massive cytotoxicity even in the absence of test substance. EFSA noted that depending on the light source and filters used, the ratio of UVB to UVA can be adjusted so that it is possible to assess UVB-induced phototoxicity in the 3T3 NRU-PT test. Alternatively, in vitro skin models, which better tolerate UVB, could be considered (ICH, 2015). The International Council on Harmonisation (ICH) guidance (2015) also considers: Initial test for phototoxicity: in vitro 3T3 NRU-PT, negative results are accepted as sufficient evidence because of high sensitivity, positive results: in vivo phototoxicity study could be required, In vivo phototoxicity assays: not formally validated, no standardised study design. The adequacy of these assays should be demonstrated using suitable reference compounds (compounds that are phototoxic in humans and that represent different chemical classes and mechanisms of phototoxicity). Testing for photogenotoxicity is not recommended as part of the standard photosafety testing program. In the past, guidelines have recommended a photoclastogenicity assay (chromosomal aberration or micronucleus test) in mammalian cells in vitro. However experience has indicated that these tests are substantially oversensitive and even incidences of pseudo-photoclastogenicity have been reported. Furthermore, the interpretation of photogenotoxicity data regarding its meaning for clinically relevant enhancement of UV-mediated skin cancer is unclear (ICH, 2015). A statement on photogenotoxicity testing is available from UK Committee on Mutagenicity (2013). This Committee recommends a revision of the OECD Test Guideline 432, in order to require phototoxicity assessment if the ultraviolet/visible molar extinction/absorption coefficient of the active substance and its major metabolites is greater than 1000 L x mol -1 x cm -1 (instead of 10 as mentioned in Regulation (EU) No. 283/2013 and in the OECD Guideline 432). The experts agreed that further guidance is needed with regard to the ultraviolet/visible molar extinction/absorption coefficient of the active substance for values between 10 and 1000 L x mol -1 x cm -1. The UK Committee on Mutagenicity (2013) recommends that if there is a negative response from the phototoxicity test, no photomutagenicity test is required; in the case the test is positive, no specific guidance is provided. The experts agreed that the concern regarding positive results in the phototoxicity test should be raised to the risk managers in the conclusion of the peer review. In addition, the experts agreed that photomutagenicity testing is not required for the time being, unless further guidance is provided. For a light source emitting wavelengths mainly below 320 nm, it was agreed that more guidance is needed on how to interpret the data and on how to perform the test with a light source emitting between 290 and 320 nm. In the OECD Test Guideline it is mentioned that cytotoxicity increases 1000-fold as the wavelength goes from 313 to 280 nm. Although the data requirement in Regulation (EU) No. 283/2013 is for substances absorbing electromagnetic radiation in the wavelength range nm, it is acknowledged that there are difficulties in testing below 320 nm and therefore further guidance is necessary EFSA Supporting publication 2016:EN-1074

11 The experts proposed that the phototoxicity test should not be performed if it has been demonstrated that the test material only absorbs at wavelengths lower than 313 nm and there is insufficient absorption at longer wavelengths to trigger testing in the absence of further guidance Genotoxicity testing and follow up on positive in vitro results In vivo follow-up for in vitro gene mutation According to Regulation (EU) No. 283/2013 if either of the in vitro gene mutation tests is positive, an in vivo test to investigate the induction of gene mutation shall be conducted, such as the Transgenic Rodent Somatic and Germ Cell Gene Mutation Assay. Historically the in vivo UDS test was the common in vivo follow-up of positive results in either of the in vitro gene mutation tests. According to the new data requirements and given the recognised low sensitivity of the in vivo UDS test to follow-up positive results for in vitro gene mutation, negative results in the in vivo UDS test are no longer considered sufficient to overrule positive results in either of the in vitro gene mutation tests. EFSA proposal EFSA would recommend conducting a Transgenic Rodent Somatic or a Germ Cell Gene Mutation Assay (OECD, 2011) to follow up the positive results in the in vitro gene mutation assay, as indicated in the new data requirements and also in line with the recommendations of the EFSA Scientific opinion on genotoxicity testing strategies applicable to food and feed safety assessment (EFSA Scientific Committee, 2011). The in vivo UDS test should not be considered for the follow up of positive results in the in vitro gene mutation assay. One expert mentioned that, in the absence of carcinogenicity or reproductive toxicity, a negative in vivo UDS test would be sufficient to overrule a positive result in the in vitro gene mutation assay. Some experts considered that transgenic models are expensive and a valid alternative would be the in vivo Comet assay (OECD, 2014c). However, since the Comet assay is an indicator test measuring DNA damage and not gene mutation another expert would support the use of the test with transgenic animals instead to avoid false positives. The majority of experts overall agreed that the applicant can provide a Comet assay or a test with transgenic rodent gene mutation assay according to the EFSA Scientific opinion on genotoxicity testing strategies applicable to food and feed safety assessment (EFSA Scientific Committee, 2011). One expert maintained that the in vivo UDS assay may still be a valid and acceptable test under certain circumstances Aneugenicity According to Regulation (EU) No. 283/2013 if the in vitro micronucleus test for numerical chromosome aberrations on mammalian cells is positive or the in vitro mammalian chromosome test is positive for numerical chromosome changes, an in vivo micronucleus test shall be conducted. In case of positive result in the in vivo micronucleus assay, appropriate staining procedure such as fluorescence in-situ hybridisation (FISH) shall be used to identify an aneugenic and/or clastogenic response. Aneugenicity might not be adequately investigated with: - negative results in Ames and in vitro gene mutation tests, and - in vitro chromosome aberration test measuring only structural aberrations, and - no in vivo micronucleus test, or an in vivo micronucleus (MN) test with no evidence of bone marrow exposure EFSA Supporting publication 2016:EN-1074

12 EFSA proposal The nature of the positive response in the in vitro and in vivo MN test should be investigated (clastogenicity or aneugenicity). If the test battery did not address properly aneugenicity EFSA would recommend conducting an in vitro MN test. The experts agreed with the EFSA proposal to investigate the nature of the positive response in the in vitro and in vivo MN test and to require an in vitro MN test if the test battery did not address properly aneugenicity Tissue exposure According to Regulation (EU) No. 283/2013 there shall be convincing evidence that the relevant tissue will be reached by the chosen exposure route and application method. Exposure to the test tissue (such as cell toxicity or toxicokinetic data) should be demonstrated in the in vivo genotoxicity tests. EFSA proposal If cell toxicity to the test tissue is not demonstrated in the in vivo genotoxicity test EFSA would recommend toxicokinetic data to be generated. Systemic toxicity alone is not sufficient to demonstrate tissue exposure. This is of particular importance for substances positive in the in vitro chromosome/aberration test or in the in vitro MN test and the follow-up in vivo test (i.e. in vivo clastogenicity/mn test) is negative without evidence of tissue exposure. This follows the data requirements and updated OECD Test Guidelines on genotoxicity (474, 475) (OECD, 2014a, b). For parent compounds toxicokinetic studies might address tissue exposure; however for metabolites toxicokinetic studies are normally not conducted. The discussion was mainly focussed on metabolites since for active substances toxicokinetic studies can be used to demonstrate exposure of the target tissue (e.g. bone marrow). For the in vivo genotoxicity test (e.g. micronucleus test), some experts recommended the use of intraperitoneal (i.p) route instead of the oral one to ensure bone marrow exposure. The other experts did not agree with such proposal, considering that the i.p. route could introduce further uncertainty since it does not include the metabolism of the compound after oral administration. A concern was raised for cases where negative results are obtained with oral administration at a limit dose of 2000 mg/kg bw and it is not clearly demonstrated that the bone marrow has been exposed. One expert considered that a negative result in an in vivo genotoxicity test (e.g. micronucleus test), where the test item was administered at the limit dose, via the oral route, is an acceptable and valid outcome under most circumstances. EFSA commented that the genotoxic potential of a metabolite should be clearly excluded, in particular when carcinogenicity and reproductive toxicity studies on the metabolite are not available. Information regarding validation of the method of analysis should be provided when toxicokinetic investigations (e.g. plasma concentrations of non-radiolabelled compound) are conducted EFSA Supporting publication 2016:EN-1074

13 2.4. Assessment of the toxicological profile of metabolites and impurities Metabolites The relevance of groundwater metabolites needs to be assessed according to the EU guidance (European Commission, 2003) and will not be further discussed under this point. For the assessment of the toxicological profile of metabolites found as residues (plant and livestock), no guidance document is currently implemented and a case-by-case approach is used. EFSA proposal The assessment of plant and livestock metabolites found as residues should follow the current practice outlined below. The list of metabolites, candidates to be considered for a toxicological assessment, should be identified by the residue experts. The assessment of each metabolite is focussed on whether the metabolite is of higher, equal or lower toxicity than the parent. The metabolic pathway of the parent and specific toxicity data for the metabolite, including genotoxicity, should guide how the decision is taken. The conclusion that the metabolite is of equal or lower toxicity than the parent would imply that reference values of the parent could apply to the metabolite for the consumer s risk assessment. If the toxicological profile of the metabolite is qualitatively different from the parent or if the metabolite is quantitatively of higher toxicity than the parent, this would imply that specific reference values should be derived for the metabolite. The EFSA PPR opinion (EFSA PPR Panel, 2012) is not aimed to be used as guidance. The draft EFSA PPR Guidance on the establishment of the residue definition for dietary risk assessment has been recently published for public consultation. The experts supported the EFSA proposal. The guidance for the residue definition is under finalisation. It was noted that it will be difficult to match the guidance on residue definition with the guidance on groundwater metabolites, since different tools are used in each of them Impurities The assessment of the impurities should be performed within the following remits: 1. Check of the compliance of the test material used for the toxicity studies in comparison with the technical specification. 2. Check of the equivalence of different technical materials. 3. Ensure the monitoring of product quality for manufacturing and trading. The available EU guidance (European Commission, 2012) addresses the point 2. Member States also use this guidance to address point 1. EFSA proposal Considering all points described above, the assessment of the toxicological relevance of impurities should rely on whether slight changes in their content can alter the toxicity profile of the active substance (i.e. lower reference values and/or different hazard classification would be triggered). The assessment should start with publically available information on impurities (literature search should be conducted and toxicity databases should be consulted). The assessment should mainly rely 13 EFSA Supporting publication 2016:EN-1074

14 on hazard assessment focussing on CMR endpoints; in particular mutagenicity given that in most of the cases the technical material is of high purity grade and with low content of impurities. If toxicity data are not available, EFSA recommends the use of (Q)SAR analysis performed according to internationally recognised models such as the OECD toolbox; details of the analysis such as the applicability domain and reliability of the results should be assessed and reported. In particular cases like genotoxic and carcinogenic impurities, exposure estimates might be necessary to support the maximum content. EFSA recommends following the EFSA Scientific Committee Statement on the applicability of the Margin of Exposure approach for the safety assessment of impurities which are both genotoxic and carcinogenic in substances added to food/feed (EFSA Scientific Committee, 2012) to derive the point of departure. Furthermore, the worst-case assumptions should be considered for the exposure estimates (i.e. maximum exposure should be 100% of reference value, since the maximum content should be independent of representative uses). The assessment of the impurities should be performed within the following remits: 1. Compliance of the batches used in toxicity studies with the technical specification: For this purpose EFSA would support the use of the EU guidance (European Commission, 2012). The analysis of batches tested at least in CMR studies and in critical studies (basis for the derivation of reference values) should be available and should support the proposed specification. If the analysis of batches used in toxicity studies is not available, a robust case should be presented to exclude the toxicological relevance of impurities, demonstrating that even without this information the technical specification can be supported from a toxicological point of view. If the analysis of batches used in toxicity studies is available, impurities of unknown toxicological concern which have been adequately tested in toxicity studies should also be evaluated for their toxicological relevance. Impurities which present a hazard higher than or different from the active substance (i.e. which are toxicologically relevant) might be of no concern at the level proposed in the specification but should still be considered as relevant impurities. They might alter the toxicological profile of the active substance if their levels are increased due to changes or variability in production process or during storage for example. If the compliance of the batches used in toxicity studies compared to the technical specification has not been demonstrated and the toxicological relevance of the impurities in the technical specification cannot be clearly excluded, this will be considered as a critical area of concern in the EFSA conclusion. 2. The equivalence of different technical materials. The EU guidance (European Commission, 2012) is specifically applicable to this point. However, it is not meaningful to address such equivalence if the reference specification is not supported by the composition of the test material used in toxicity studies. 3. The monitoring of product quality for manufacturing and trading. An impurity designated as toxicologically relevant will trigger further analytical requirements since the active substances and relevant impurities in plant protection products must be analytically monitored to guarantee the product quality during manufacturing and trading. This is the reason why impurities of unknown toxicological concern that have been adequately tested in toxicological studies should not be designated as non-relevant. The lack of knowledge of their hazardous properties should be considered as a data gap; however EFSA would not consider it as an issue that could not be finalised. 1. Compliance of the batches used in toxicity studies compared to the technical specification: The experts agreed that a critical area of concern should be raised when no information is provided on the detailed composition of batches used in toxicity studies, and the toxicological relevance of the impurities in the technical specification cannot be clearly excluded. 2. The equivalence of different technical materials. No discussion took place during the meeting since the EU guidance (European Commission, 2012) is specifically applicable to this point EFSA Supporting publication 2016:EN-1074

15 3. The monitoring of product quality for manufacturing and trading: Some experts did not support the proposal provided by EFSA, since they consider the toxicological relevance of impurities as covered when the batches used in toxicity studies are concluded representative of the technical specification. In this particular case, EFSA commented that the relevance of impurities should be assessed for monitoring purposes, with regards to their intrinsic toxicological properties. It might not be sufficient to consider that they have been tested at representative concentrations in the batches used in the toxicity studies (even when these batches are considered as covering the technical specification). EFSA pointed out that the relevance of impurities should be assessed with alternative tools to animal models (e.g. (Q)SAR). There are different (Q)SAR tools and some are freely available. (Q)SAR would provide systematic and objective evaluations. Expert judgement is anyway required to interpret the results. (Q)SAR is considered a scientifically validated tool complementary to other tools Endocrine disruptive properties Regulation (EC) No. 1107/2009 requires EFSA to adopt a conclusion on whether an active substance can be expected to meet the approval criteria which inter alia, state that an active substance, safener or synergist shall only be approved if it is not considered to have endocrine disrupting properties that may cause adverse effects in humans, unless the exposure of humans is negligible. Pending the adoption of specific scientific criteria for the assessment of potential endocrine disrupting properties, the purpose of the assessment is to provide: a) An opinion whether the substance can be expected to meet the interim approval criteria (Annex II, point 3.6.5, paragraph 3 and 4 of Regulation (EC) No. 1107/2009). b) The outcome of the scientific assessment regarding potential endocrine disrupting properties, in line with the opinion of the Scientific Committee (EFSA Scientific Committee, 2013). No specific data requirements regarding endocrine disruption are mentioned in Regulation (EU) No. 283/2013, however it is stated: if there is evidence that the active substance may have endocrine disrupting properties, additional information or specific studies shall be required: - to elucidate the mode/mechanism of action. - to provide sufficient evidence for relevant adverse effects. EFSA proposal a) Regarding the 2 nd interim criteria substances such as those that are or have to be classified, in accordance with the provisions of Regulation (EC) No. 1272/2008, as toxic for reproduction category 2 and which have toxic effects on the endocrine organs, may be considered to have such endocrine disrupting properties, as there is no clear definition on the meaning of endocrine organs, careful considerations should be given whether the substance may affect endocrine organs in a broad interpretation in order to give all relevant information to risk managers for their decision making. b) Regarding the outcome of the scientific assessment, it is proposed to follow the EFSA Scientific Committee opinion on the hazard assessment of endocrine disruptors (2013): Definition of endocrine active substance (EAS): - Any chemical that can interact directly or indirectly with the endocrine system, and subsequently result in an effect on the endocrine system, target organs and tissues (EFSA, 2010) Definition of endocrine disruptor (ED): - An ED is an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism or its progeny, or (sub)populations (WHO/IPCS, 2002) 15 EFSA Supporting publication 2016:EN-1074

16 Definition of an adverse effect: - An adverse effect is a change in the morphology, physiology, growth, development, reproduction, or, life span of an organism, system, or (sub)population that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress, or an increase in susceptibility to other influences (WHO/IPCS, 2009) Test methods should follow the OECD Conceptual Framework; guidance document No. 150 on standardised test guidelines for evaluating chemicals for endocrine disruption (OECD, 2012). One expert proposed to ask for Level 2 data of the OECD framework to be provided by the applicant during the renewal process, in the case the data is very poor (e.g. old reproductive toxicity studies where sensitive parameters to endocrine-mediated effects are not investigated). Other experts suggested a case-by-case approach. It was noted that the interim criteria may lead to false positive and false negative results. The majority of experts considered that interim criteria will be applied until final criteria are implemented. A list of potentially endocrine-related organs is not considered realistic for the time being, since endocrine-mediated effects can be observed in many different organs. Some experts suggested that only the estrogen, androgen, thyroid and steroidogenesis (EATS) modalities should be considered although other endocrine systems can be affected (e.g. pancreas). A clear link between an adverse effect and an endocrine-mediated mechanism is sometimes difficult to identify. A question that needs to be addressed is if it is necessary to ask for additional mechanistic data in the case an effect is observed in a particular endocrine organ: the severity of the effect and the dose where it was observed could be taken into account. As an example, the adversity of an endocrine-mediated effect on the adrenals could be supported by histopathological findings. Regarding the thyroid effects, mechanistic tests are available for the mammalian toxicity evaluation (which is not the case for the pancreas). An expert suggested developing Adverse Outcome Pathways (AOP) for the thyroid; a draft AOP being already available in the AOP Wiki. It was highlighted that the development of AOP knowledge would be a way to address a better identification of endocrinemediated mechanisms relevant to humans. In conclusion, a case-by-case basis approach is suggested for the time being. In case the data is very poor during the renewal process, a data gap may be identified in the EFSA Conclusion Proposals for classification Concerning classification and labelling two points need to be considered: 1. The approval criteria in the Regulation (EC) No. 1107/2009 (Annex II) take into consideration classification for CMR. European Commission clarified that the EFSA peer reviewed Classification and Labelling proposals shall be the basis for the interpretation of has to be classified. 2. For substances with harmonised classification and labelling as carcinogen category 1A or 1B and/or as toxic for reproduction category 1A or 1B the applicant should clearly indicate at the time of application if they apply for negligible exposure or/and essential use (article 4(7)) and evidence should be provided to demonstrate it. EFSA proposal In relation to point 1, EFSA considers that a detailed comparison with CLP criteria (ECHA, 2015) at least for the CMR hazard classes should be done. The comparison with CLP criteria should be provided both in the case of classification and non-classification proposals. In relation to point 2, the RMS should also assess the evidence for negligible exposure and essential use if the applicant applied for it. EFSA acknowledged that no final agreed guidance is currently available. A draft technical guidance is available for negligible exposure (European Commission, 2015). Protocols under development and close to finalisation will be available for essential use EFSA Supporting publication 2016:EN-1074

17 The experts agreed with the EFSA proposal. Some experts indicated that detailed assessment of classification should be limited to CMR properties. One expert highlighted that STOT classification should be assessed as well taking into account that it is also relevant for persistent, bioaccumulative and toxic (PBT) criteria. Overall the experts indicated that better collaboration between ECHA and EFSA would be of benefit. EFSA noted that the applicants need to indicate at the time of application if they apply for negligible exposure and/or essential use in the case a harmonised classification category 1A or 1B (carcinogenicity and/or reproductive toxicity) is already in place Literature search Article 8 (5) of Regulation (EC) No. 1107/2009 requires all available and relevant data from the scientific peer-reviewed open literature, as determined by the Authority, on the active substance and its relevant metabolites dealing with side-effects on health, the environment and non-target species and published within the last 10 years before the date of submission of the dossier to be added by the applicant to the dossier. EFSA proposal The literature search should follow the EFSA guidance for the submission of scientific peer-reviewed open literature for the approval of pesticide active substances under Regulation (EC) No. 1107/2009 (EFSA, 2011). It could be recommended to use the ToxRTool as proposed in the case studies presented in the External Scientific Report Case studies for the application of the Guidance of EFSA on Submission of scientific peer-reviewed open literature for the approval of pesticide active substances under Regulation (EC) No 1107/2009, using substances for which dossiers are submitted under Regulation (EU) No. 1141/2010 (Berger et al., 2013), for the evaluation of the reliability of the published data. The experts discussed the issues of peer reviewed papers and GLP studies. The ToxRTool is considered a useful tool for an independent quality assessment, but further improvement would be welcome since ToxRTool lacks assessment of bias (Segal et al., 2015). BfR is intending to publish a similar tool taking into account the limitations described in Segal et al. The RMS is not required to repeat the literature review submitted by the applicant, but to check if it has been performed adequately. For the mammalian toxicology section, the literature would mainly indicate alerts that would need to be clarified by the applicant. Literature should be considered in a weight of evidence approach, on a case-by-case basis EFSA Supporting publication 2016:EN-1074

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