A proposal of criteria to support the EU classification on endocrine disruption for the thyroid modality and their application to four data-rich case studies

Recently, the European Commission has implemented hazard categories to classify substances as endocrine disruptors for human health, i.e. ED HH 1 or ED HH 2, depending on the weight-of-evidence. However, specific guidance on how to differentiate between the two is unavailable. This article presents the CropLife Europe (CLE) proposal for a structured approach to support the ED HH classification for the thyroid modality. Further, the Thyroid Function-Related Neurodevelopmental Toxicity Testing and Assessment Scheme (Thyroid-NDT-TAS) has been modified in view of the new classification. Application of the CLE proposal and the modified Thyroid-NDT-TAS is illustrated in four case studies covering active substances in plant protection products that showed thyroid- and liver-related effects in laboratory animal studies (pyrimethanil, boscalid, metribuzin, ethiprole). For all four substances, there is strong and consistent evidence that the thyroid-related endocrine activity in rats is liver enzyme induction-mediated, a mode-of-action that is of questionable relevance to humans. In vitro species comparisons (unavailable for pyrimethanil) further confirm non-relevance to humans. However, pyrimethanil (and boscalid) did not elicit developmental neurotoxicity in rats. For pyrimethanil, boscalid and ethiprole, the overall weight-of-evidence determination yields the conclusion "no ED HH via the thyroid modality". For metribuzin, category ED HH 2 may be triggered due to uncertainties related to its database. The case studies underline that expert judgement is required to assess overall effect patterns, to balance the available evidence and to conclude on classification as ED HH 1, ED HH 2 or no ED HH via the thyroid modality.