Summary

Minimizing exposure to endocrine disruptors (EDs) is high on the political agenda, both in the EU and in the Nordic region. One tool to speed up these efforts is by regulating groups of substances. This project analysed case examples of groupings of EDs. For each case example, advantages, challenges, uncertainties and regulatory perspectives were discussed and learnings were extracted. On this basis, recommendations for grouping of EDs were developed and incorporated in a simplified workflow, which can guide grouping of EDs. Main findings were that EDs can be grouped like other chemicals, their complex hazard profiles require special attention, and groupings should start with the broadest group possible. To facilitate competence building for grouping of EDs in EU regulatory process, the report was presented to chemical authorities across the EU at a webinar in November 2024.

Recommended workflow

Step 1 Define purpose and hypothesis
Define the regulatory purpose Define the grouping hypothesis

Step 2 Include relevant substances
Start with the broadest group possible. Use (Q)SARs to check if additional substances should be included. Include substances under regulatory scrutiny (For EDs: Regulatorily identified EDs) or registered in high tonnages under REACH for use as source substances if possible Use well-argued inclusion and exclusion criteria, refrain from excluding substances based on current regulatory status or use. Make sure that all substances are characterized in detail, including impurity profiles.

Step 3 Produce a data matrix
Include in silico, in vitro, in vivo data Include relevant metabolites and ADME data For EDs: Consider complex hazard profiles, including different effects depending on timing of exposure and investigation, low dose and non-monotonic effects etc.

Step 4 Redefine the group and define sub-groups, as appropriate
For EDs: Consider that different molecular moieties may be relevant for different mechanisms and thereby modes of action and adverse effects. Some overlap may occur, but this should ideally be analyzed and described. For EDs: Consider that many endocrine disruptors act through more than one mechanism/mode of action and that several different mechanisms/mode of actions can lead to the same adverse effects. Consider that if in vitro data are used to define sub-groups, ADME must be considered and that if ADME/in vivo information is considered, the sub-groups may have different boundaries. Use QSARs to check if more substances could be added to the (sub-)group.

Step 5 Read-across to fill data gaps

Step 6 Conclude on results, revisit the hypothesis, as apppropriate

Figure 1 Recommended workflow for (sub-)grouping of endocrine disruptors with the ultimate aim of filling data gaps by read-across. General recommendations are provided at relevant steps in the workflow. Recommendations specific for endocrine disruptors are highlighted in bold.