Five case examples were included in the project. The examples were chosen to represent both analogue and category approaches and also include cases developed for both scientific and regulatory purposes.
It was not possible to find many different examples of groupings of endocrine disruptors for regulatory purposes, and this affected the case selection for the project. Please note that the case examples of Isobutyl and Brominated Flame Retardants were developed by our own team at DTU Food. Therefore, in these instances, we assess our own work, while in other cases, we evaluate projects developed by external parties.
Several regulatory proposals for grouping of endocrine disruptors are under preparation but not yet available for analyses and inclusion in this project as case examples. We therefore had to focus on available examples, and this project includes two case examples for bisphenols and one for a paraben, which all had a clear regulatory scope. ECHA has published many Assessments of Regulatory Needs (ARNs) for different groups of substances, which potentially include endocrine disruptors. The ARN for bisphenols was included in this project to complement the two other case examples on bisphenols. The Isobutylparaben case was included as it is an example of application data gap filling by read-across to identify an endocrine disruptor. In addition, a comparative study of endocrine activity of bisphenols was included as a case example as it was referenced in the other case examples for bisphenols. Finally, we included an example of preliminary structural grouping of brominated flame retardants, supported by (Q)SAR predictions, which ultimately focused on (genotoxic) carcinogenicity as endpoint.
Even though the main focus of this work was not endocrine disruption, we included it here as a learning example using an approach that could also be applied in groupings of endocrine disruptors.
In this report, for each case example, the purpose of the assessment and the methodology applied was described in brief. Each case example was analysed using the frameworks of the OECD GD 194 on Grouping of Chemicals (OECD 2014) and the ECHA RAAF (ECHA 2017). The OECD GD on Grouping of Chemicals lays out stepwise procedures for analogue and category approaches. The RAAF provides a framework for examining read-across cases in the context of the REACH Regulation with specified assessment elements (AEs) depending on the relevant assessment scenario (1–6), as outlined in Figure A in Annex 1.
Both documents discriminate between the use of analogue and category approaches. For each case example it was therefore identified which of these approaches was appropriate and applied. In an analogue approach, the aim of the assessment is to fill a data gap for one target substance. In a category approach, the aim is to assess a given property of all the individual substances in the category based on available information for the category source substances and fill data gaps for the target substances. A ‘category’ in these documents is a group of structurally similar substances. Within an established group of structurally similar substances, a data gap might be filled by read-across. In practical terms, the use of the phrases ‘category’ and ‘group’ are often used interchangeably (see also section on definitions).
Both documents describe several critical aspects of the read-across with specific aspects and questions to be considered. For the RAAF, all the assessment steps can be concluded with an assessment of the overall reliability (score 1–5) as shown in Figure B in Annex 1.
The five different case examples included in the report had different objectives, and therefore different approaches were used. Two of the bisphenol cases (the ECHA ARN case and the restriction proposal case) did not aim at data gap filling, but rather focused on category formation. The last bisphenol case was a comparative study, which did not even aim at category formation, but rather on identifying structural alerts for specific ED mechanisms of action of bisphenols. However, the bisphenols in the comparative study were part of the in the category formation in the two other bisphenol case examples. In contrast, the aim of the isobutylparaben case and the brominated flame retardants case was data gap filling and therefore both category formation steps and additional steps recommended in the OECD GD 194 and the ECHA RAAF were included in these cases. However, in all case examples, the included steps, including the category formation steps, were analysed according to the OECD GD 194 and the ECHA RAAF, respectively. This meant that even though the objective of some of the case examples was not data gap filling by read-across, the category formation conducted was evaluated in the perspective of potential subsequent data gap filling by read-across.
On this basis, for all case examples, advantages, challenges, uncertainties and regulatory perspectives were discussed. Learnings, also those specific to endocrine disruptors, were extracted.
Based on the analyses and discussion of the case examples, recommendations for (sub-)grouping of endocrine disruptors were developed with the ultimate aim of filling data gaps by read-across.