Technical Report 130

Step I: Gathering of relevant information with regard to adverse effects and endocrine modes-of-action (MoA)

Information that is relevant for the identification of a substance includes its Chemical Abstract Service (CAS) number (where available), International Union of Pure and Applied Chemistry (IUPAC) name, any synonyms, common names, and molecular structure.

Further relevant information includes specific physico-chemical data, as appropriate. For some substances, structural alerts may provide an indication for endocrine activity.

Relevant (eco)toxicological data includes data from (a) OECD TGs; (b) other validated guidelines (e.g. the guidelines from the US EPA Office of Prevention, Pesticides and Toxic Substance (OPPTS) / Office of Chemical Safety and Pollution Prevention (OCSPP); and (c) reliable (i.e. ToxR-Reliability-Categories 1 and 2; cf. Step II) research papers (peer reviewed publications or publications that have not been submitted to scientific or regulatory peer review).

(Eco)toxicological and mechanistic information that may be indicative of endocrine disrupting properties can be retrieved from (eco)toxicological study reports that have been conducted for regulatory purposes (applying either standardised or non-standardised test methods) and by conducting open literature searches using defined terms. The endpoints investigated in the assays and studies of the OECD CF can be used as a guide to identify potentially relevant effects in publications from the open literature. However, this does not preclude the inclusion of studies that use different study designs or investigate endpoints for which validated TGs are not yet available or listed in the OECD CF. When such studies are utilised, full details of the procedures followed together with a clear description of strengths and limitations of the methodologies should be provided.

Further, reliable databases should be searched for relevant information (e.g. the US EPA ToxCast Dashboard; available at: https://www.epa.gov/chemical-research/toxcast-dashboard).

Of note, the application of (quantitative) structure activity relationships ((Q)SAR) and other in silico tools may become relevant to help identify potential MoAs, e.g., molecular initiating events within AOPs, which in turn may inform on the potential or lack of endocrine activity (Rybacka et al., 2015). However, the application of in silico tools is not further addressed in the ECETOC 7SI-ED.

Level 1 of the OECD CF provides guidance on the gathering of existing information.

To ensure that all available relevant scientific data are retrieved, the principles of systematic review should be applied (Uman, 2011), which provide transparency, rigour and reproducibility to the task of data collation and selection. For this purpose, the ECETOC 7SI-ED refers to the EFSA guidance for Submission of scientific peer-reviewed open literature for the approval of pesticide active substances under Regulation (EC) No 1107/2009 (EFSA, 2011). This EFSA guidance provides instructions on how to identify and select scientific peer-reviewed open literature for inclusion in plant protection product dossiers and how these searches should be reported. For example, recommendations are made on how to document literature search methods, databases, inclusion and exclusion criteria for study selection. Whilst the EFSA guidance requires clear a priori documentation of the relevance criteria, it does not provide specific advice on how to define relevance criteria, which will be very specific in WoE approaches to evaluate potential endocrine disrupting properties. The assessment of relevance concerns the ability of the selected study to address the specific property being investigated. Rudén et al. (2016) provide guiding questions to determine the relevance of ecotoxicological studies for regulatory decision-making by the alignment to the protection goal(s). The general considerations of this guidance with respect to biological relevance are equally applicable to the assessment of toxicological studies.