European Food Safety Authority (EFSA)

TECHNICAL REPORT APPROVED: 06 April 2017 doi:10.2903/sp.efsa.2017.en-1210 Outcome of the preliminary pesticides peer review meeting on the assessment of endocrine disrupting properties in mammalian toxicology and ecotoxicology Abstract European Food Safety Authority (EFSA) This document reflects the outcome of the experts discussions during the joint session on the assessment of endocrine disrupting properties in mammalian toxicology and ecotoxicology adjacent to the Pesticides Peer Review meetings 148 and 149. The main scope of the meeting was to have a first discussion on the scientific implementation of the European Commission (EC) draft criteria for the identification of an endocrine disruptor in the area of mammalian toxicology and ecotoxicology for plant protection products, and the type of information possibly needed for this implementation. This also gave the possibility to the experts to raise questions, to express their view and to provide suggestions which could be taken into consideration during the drafting of the EFSA and the European Chemicals Agency (ECHA) guidance entitled Guidance Document for the Implementation of the Hazard-based Criteria to Identify Endocrine Disruptors. Conclusions and further recommendations on these issues are reported. European Food Safety Authority, 2017 Key words: pesticides, mammalian toxicology, ecotoxicology, endocrine disrupting properties Requestor: European Commission Question number: EFSA-Q-2017-00069 Correspondence: pesticides.peerreview@efsa.europa.eu www.efsa.europa.eu/publications 1 EFSA Supporting publication 2017:EN-1210

Suggested citation: EFSA (European Food Safety Authority), 2017. Technical report on the outcome of the preliminary pesticides peer review meeting on the assessment of endocrine disrupting properties in mammalian toxicology and ecotoxicology. EFSA supporting publication 2017:EN-1210. 11 pp. doi:10.2903/sp.efsa.2017.en-1210 ISSN: 2397-8325 European Food Safety Authority, 2017 Reproduction is authorised provided the source is acknowledged. www.efsa.europa.eu/publications 2 EFSA Supporting publication 2017:EN-1210

Summary On 15 June 2016, the European Commission (EC) presented the proposed scientific criteria for the determination of endocrine disrupting properties (ED) in the field of plant protection products and biocides and asked the European Food Safety Authority (EFSA) and the European Chemicals Agency (ECHA) to start activities that will allow the implementation of these criteria as soon as they will be approved (European Commission, 2016a, 2016c). Subsequently, on 17 October 2016 EC sent a mandate to EFSA and ECHA to prepare a common guidance document on the hazard identification of endocrine disruptors in the context of Regulations (EC) No 1107/2009 and (EU) No 528/2012 (European Commission, 2016e) based on the proposed criteria. In the frame of these activities and in direct collaboration with ECHA, EFSA organised a joint meeting aiming at having an exchange of views with Member States (MS) experts on the assessment of endocrine disrupting properties in mammalian toxicology and ecotoxicology. The meeting was meant to give the possibility to the experts to raise questions, to express their views and their possible suggestions regarding the guidance that is to be developed by EFSA and ECHA. This joint meeting took place in October 2016 as part of the Pesticides Peer Review meetings 148 on mammalian toxicology and 149 on ecotoxicology. An introductory presentation was given by EFSA regarding the EC proposed criteria. Afterwards, experts from the Benaki Phytopathological Institute (BPI) gave a presentation on three case studies with the purpose to facilitate the discussion. These case studies were part of the BPI work, as EC external contractor, for the implementation of the Join Research Centre (JRC) methodology on screening the ED properties of preselected chemicals (European Commission, 2016b) in order to be used in the EC impact assessment. A discussion between all the participants followed. The issues discussed were on the practical aspects of the implementation of the criteria, on the possible use of the methodology developed by JRC, the data requirements and the adequacy of testing protocols. In addition, it was discussed which elements should be included in the guidance that will be developed by EFSA and ECHA. The experts views and conclusions from the meeting are presented in this report and will be taken into consideration during the drafting of the EFSA / ECHA guidance. www.efsa.europa.eu/publications 3 EFSA Supporting publication 2017:EN-1210

Table of contents Abstract... 1 Summary... 3 1. Introduction... 5 2. Points of discussions... 5 2.1. JRC methodology: clarifications and possible use... 5 2.2. Implementation of the criteria: information needed... 6 2.3. Use of non-standard studies and old protocols... 7 2.4. Elements to be considered in the guidance document... 8 3. Overall EFSA conclusions and recommendations... 8 References... 10 Abbreviations... 11 www.efsa.europa.eu/publications 4 EFSA Supporting publication 2017:EN-1210

1. Introduction On 15 June 2016, the European Commission (EC) presented the proposed scientific criteria for the determination of endocrine disrupting properties (ED) in the field of plant protection products and biocides and asked the European Food Safety Authority (EFSA) to start activities that will allow the implementation of these criteria as soon as they will be approved (European Commission, 2016a, 2016c). Subsequently, on the 17 October 2016 EC sent a mandate to EFSA and the European Chemicals Agency (ECHA) to prepare a common guidance document on the hazard identification of endocrine disruptors in the context of Regulations (EC) No 1107/2009 1 and (EU) No 528/2012 2 (European Commission, 2016e) based on the proposed criteria. Before setting the draft criteria, EC implemented an impact assessment for the evaluation of the potential health, socio-economic and environmental impacts of applying different options for the criteria (European Commission, 2016d). In the frame of this impact assessment the Joint Research Centre (JRC) developed a screening methodology for ED identification without intention to pre-empt regulatory conclusions that may eventually be made under different pieces of EU legislation (JRC, 2016). Later on, this methodology was applied by the Benaki Phytopathological Institute (BPI), as external contractor, on a list of pre-selected substances provided by JRC (European Commission, 2016b; 2016f). In order to start the discussion with the Member States (MS) experts, EFSA organised a joint mammalian toxicology / ecotoxicology session that took place on 26 October 2016 as part of the Pesticides Peer Review meeting 148 on mammalian toxicology and 149 on ecotoxicology. The scope of this meeting was to have an exchange of views with the Member States experts on the assessment of endocrine disrupting properties in mammalian toxicology and ecotoxicology, in view of the on-going discussions on the implementation of the proposed criteria. The meeting was meant to give the possibility to the experts to raise questions, to express their view and their possible suggestions regarding the guidance that is to be developed by EFSA and ECHA. An introductory presentation was given by EFSA regarding the EC proposed criteria. Afterwards, experts from the Benaki Phytopathological Institute (BPI) gave a presentation on three case studies with the purpose to facilitate the discussion. These case studies were part of the BPI work, as EC external contractor, for the implementation of the JRC methodology on screening the ED properties of preselected chemicals in order to be used in the EC impact assessment. A discussion between all the participants followed. The issues discussed were related to the JRC methodology and its possible use, to the practical aspects of the implementation of the criteria, including data requirements and adequacy of testing protocols. In addition, it was discussed which elements should be included in the guidance that will be developed by EFSA and ECHA. 2. Points of discussions 2.1. JRC methodology: clarifications and possible use As mentioned above a presentation was given during the meeting on the application of the methodology developed by JRC (JRC, 2016) to 600 pre-selected chemicals (European Commission, 2016b). This was followed by a discussion where a number of clarifications were provided by BPI regarding the implementation of the methodology: Though the avian reproduction studies were initially captured, later they were not considered of added value as effects observed in these studies may be indicative of an endocrine mode of action (MoA), but cannot be exclusively linked to that. However, the experts expressed the view that those data should be included in the weight of evidence (WoE), as they may be highly relevant when considered together with other existing evidence. The amphibian metamorphosis studies were considered in the assessment, when available. 1 Regulation (EC) No 1107/2009 of 21 October 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. OJ L 309, 24.11.2009, p. 1 50. 2 Regulation (EU) No 528/2012 of the European Parliament and of the Council of 22 May 2012 concerning the making available on the market and use of biocidal products. OJ L 167, 27.6.2012, p. 1 123. www.efsa.europa.eu/publications 5 EFSA Supporting publication 2017:EN-1210

The causality and plausibility of the link between the adverse effect and the endocrine mode of action were judged by the BPI experts, since no specific guidance was given on this matter by the JRC methodology. It was not considered necessary to capture the information regarding the ecotoxicological relevance at the population level in the Data sheet. This was addressed finally in the Evaluation sheet after gathering all effects in the data summary sheet. Potential categorisation of a compound was derived even in the absence of mechanistic data, based only on the manifested adversity as in this exercise the request for further data was not an option. All data were used as presented in the available reports without re-evaluation by the contractor. Read across approaches were not performed by BPI but only used when and as reported on the assessments already available. Considering the time constraints and the related scope (impact assessment), some rules and assumptions had to be set in order to speed up the process. This screening and the related assessment were not meant to substitute an in depth assessment by the Authorities. Some experts highlighted the fundamental difference between the absence of data and the existence of negative data and the possible influence on the conclusion. BPI clarified that this difference was not considered by the methodology and its implementation, meaning that in the decision trees the answer no for the questions in vivo mechanistic effects or in vitro mechanistic effects may mean absence of data or presence of negative response. It was noted, however, that although the answer was the same, the reasoning was included in the Evaluation sheet. Some experts expressed the view that all evidences should be considered in combination, in order to weight their value and to reach a final conclusion. The screening methodology served the needs of the impact assessment. The experts expressed the view that it is of limited value as such for the regulatory assessment but it could be further considered for the development of a fit for purpose methodology and data evaluation. 2.2. Implementation of the criteria: information needed EFSA proposed to the experts to discuss, as starting point, the information needed for the identification of endocrine properties. For example, it was considered whether a minimum dataset should be identified for assessing ED properties of any substance under evaluation. The views expressed are presented below: General EC highlighted that, when additional data and specific studies are required, these should be adequate and sufficient to draw a conclusion without further requests. Experts questioned whether the studies mentioned in the data requirements (Commission Regulations (EU) No 283/2013 3 ) have the power to detect ED effects. Some experts pointed out that, in principle, these data could provide sufficient evidence to identify potential candidates for further ED assessment. Currently the parameters that should be used as alerts of ED properties have not been well defined and should be further identified together with the studies to be required for the clarification of the endocrine mode of action. It was also questioned by the experts whether in vitro mechanistic studies should be requested by default for all substances or only when available studies provide some evidence/indication of ED properties. Furthermore, it was questioned whether it is appropriate to conclude on the basis of in vitro data (in case of positive evidence) or whether it is necessary to ask for in vivo mechanistic studies. 3 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, 3.4.2013, p. 1 84. www.efsa.europa.eu/publications 6 EFSA Supporting publication 2017:EN-1210

Some experts expressed the view that it should be the responsibility of the applicant to demonstrate the absence of ED properties, and therefore it should also be their responsibility to identify the appropriate set of studies to demonstrate this. Some experts referred to the possibility to implement the level 1 of the conceptual framework of the OECD guidance document 150 (OECD, 2012) and proposed to consider this issue in the future EFSA/ECHA guidance document. It was also highlighted that this framework was built for being applied also to substances for which no information is available (and so only level 1 can be used), and this is never the case for pesticides for which experimental data are always available in the dossier. Discussing the OECD 150 guidance document, some experts highlighted that the studies included are not appropriate to conclude on clear mechanistic effects. In addition, it was noted that it is not appropriate to move in a linear fashion through the Conceptual Framework and it was further suggested to give feedback or interact with the OECD to update guidelines. Some experts commented that, in principle, new vertebrate studies should not be requested. It was generally discussed that it may be appropriate to establish a step wise approach for data requirements. It was also pointed out that the guidance should address which data should be requested whenever some indications of ED properties are identified in a first step. Mammalian toxicology Some experts commented that, with the standard available dataset (Commission Regulations (EU) No 283/2013 3 ), there are insufficient data in the area of mammalian toxicology to conclude on the ED properties of the substance. Other experts pointed out that, although in the toxicological part ED related mechanistic studies are not mandatory, several data might be already available (e.g. in vitro data, studies with a more mechanistic focus), and these could also inform the ecotoxicological section. Ecotoxicology It was pointed out by some experts that no in vitro studies are currently included in the data requirements for ecotoxicological assessment (Commission Regulations (EU) No 283/2013 3 and No 284/2013 4 ). It was highlighted that even in the presence of the same mechanistic onset the apical consequence could be different among different taxa. Some experts expressed the wish to include in vitro data in the ecotoxicology data requirements. Some experts pointed out that in the OECD guidance document 150 there are proposed ED related ecotoxicological studies, covered by specific technical guidelines (TG). These studies are not part of the legal data requirements but the experts suggested that they should be included. Some experts questioned whether invertebrates should be considered in the guidance EFSA and ECHA will develop. 2.3. Use of non-standard studies and old protocols It was commented that sometimes in a complete dossier no evidence of ED properties is seen in the legally required and submitted studies. Nevertheless, available non-standard literature data may capture aspects that are not covered in the dossier. In such cases, further data may be requested to confirm / exclude the concern raised in the non-standard study. Some experts expressed their concern that criteria are missing for evaluating the quality and the results of non-standard studies from the literature. The experts highlighted that some of the studies performed according to old versions of the OECD guidelines miss investigating endpoints that are relevant for ED assessment. 4 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, 3.4.2013, p. 85 152. www.efsa.europa.eu/publications 7 EFSA Supporting publication 2017:EN-1210

2.4. Elements to be considered in the guidance document The experts mentioned the following elements as important issues to be included in the EFSA / ECHA guidance: List of the relevant studies among the data requirements (especially for the area of ecotoxicology). List of endpoints and effects to look at in terms of specific / generic effects. How to assess the available information from public literature (relevance / reliability)? How to perform the read-across between substances? How to decide whether effects on non target organisms are relevant at population level Criteria for the WoE for minimising the expert judgement. How to structure the assessment covering both mammalian toxicology and ecotoxicology? Need for a decision scheme based on the available data / evidence. Need for a set of case studies. Update of the information included in the OECD guidance document 150 (in terms of available study protocols). Which aspects/parameters should be looked at in the old studies regarding ED properties and how to fill the gap between the old and the new protocols? How data gaps should be addressed. How to assess epidemiological data? Criteria for the definition of adversity. Evaluation and WoE of the ToxCast in vitro data (https://www.epa.gov/chemical-research/toxicityforecasting, March 2017). Assessment of uncertainty. Development of adverse outcome pathways (AOPs) for ED. Minimum data requirements to identify the MoA. How to deal with contradictory results? Clear indications on how to establish a plausible link (biological relevance). 3. Overall EFSA conclusions and recommendations During the meeting a number of clarifications were given regarding the JRC methodology and its implementation by the contractor. The screening methodology serves the needs of the impact assessment. The experts expressed the view that it is of limited value as such for the regulatory assessment but it could be further considered for the development of a fit for purpose methodology and data evaluation. It was clear from the overall discussion that setting a well-defined set of data as the minimum requirement for the identification of ED is a challenging task. It is also clear that the main gap in the data requirements set in the Commission Regulations (EU) No 283/2013 3 and No 284/2013 4 is related to mechanistic information. It is highly probable that in a number of cases additional data would be needed. The extension and nature of these data should be further discussed and they should be considered on a case-by-case basis. The use of studies performed with old protocols or non-standard studies should be considered but further discussion is needed regarding their quality assessment and weight to be given. A step wise approach and/or a decision scheme are considered by the majority of the experts as an appropriate methodology. www.efsa.europa.eu/publications 8 EFSA Supporting publication 2017:EN-1210

The experts proposed a number of issues to be addressed in the EFSA / ECHA guidance. In overall, the comments and views expressed during this joint session regarding both mammalian toxicology and ecotoxicology will be taken into consideration during the development of the guidance. EFSA acknowledged the contributions from the experts, and indicated that additional information on the involvement of MS experts in the guidance development was to be discussed with ECHA and included in the EFSA / ECHA outline paper entitled Outline of Draft Guidance Document for the Implementation of the Hazard-based Criteria to Identify Endocrine Disruptors. This outline paper was published on 20 December (EFSA and ECHA, 2016). www.efsa.europa.eu/publications 9 EFSA Supporting publication 2017:EN-1210

References EFSA (European Food Safety Authority) and ECHA (European Chemicals Agency), 2016. Outline of Draft Guidance Document for the Implementation of the Hazard-based Criteria to Identify Endocrine Disruptors. 20 December 2016, 12 pp. European Commission, 2016a. Commission presents scientific criteria to identify endocrine disruptors in the pesticides and biocides areas. Press release, 15 June 2016, 2 pp. European Commission, 2016b. Selection of chemical substances to be screened in the context of the impact assessment on criteria to identify endocrine disruptors. 15 June 2016, 23 pp. European Commission, 2016c. Criteria for the determination of endocrine-disrupting properties under the PPP Regulation EFSA s key role for their implementation. Ares(2016)2782652 15 June 2016, 2 pp. European Commission, 2016d. Commission Staff working document impact assessment, Defining criteria for identifying endocrine disruptors in the context of the implementation of the plant protection products regulation and biocidal products regulation, Main report, 15 June 2016, SWD(2016) 211 final, 414 pp. European Commission, 2016e. Mandate to EFSA and ECHA for scientific and technical assistance in order to develop a common Guidance Document for the implementation of the hazard based criteria to identify endocrine disruptors. Ares(2016)5971523 17 October 2016, 3 pp. European Commission, 2016f. Screening of available evidence on chemical substances for the identification of endocrine disruptors according to different options in the context of an Impact Assessment, Specific Contract SANTE/2015/E3/SI2.706218, Final report, ISBN 978-92-79-59005-4 doi: 10.2875/328498. 503 pp. JRC (Joint Research Centre), 2016. Screening methodology to identify potential endocrine disruptors according to different options in the context of an impact assessment; EUR 27955 EN; doi:10.2788/73203. 54 pp. OECD (Organisation for Economic Co-operation and Development), 2012. Series on Testing and Assessment: No 150: Guidance Document on Standardised Test Guidelines for Evaluating Chemicals for Endocrine Disruption. ENV/JM/MONO(2012)22, 524 pp. www.efsa.europa.eu/publications 10 EFSA Supporting publication 2017:EN-1210

Abbreviations a.s. active substance AOP Adverse Outcome Pathway BPI Benaki Phytopathological Institute EC European Commission ECHA European Chemical Agency ED endocrine disruptor, endocrine disruption EU European Union JRC Joint Research Centre MoA mode of action MS Member State OECD Organisation for Economic Co-operation and Development TG technical guideline ToxCast EPA's Toxicity Forecaster WoE weight of evidence www.efsa.europa.eu/publications 11 EFSA Supporting publication 2017:EN-1210