P27-26 Case study on Geraniol: critical assessment of Geraniol potential (1) endocrine activity on the thyroid-modality and (2) downstream adversities

Geraniol (CAS No. 106-24-1) is a naturally occurring component of essential oils and also produced synthetically for consumer applications in personal care, home and air care as well as flavour. Relevant regulations involve REACH, the EU Cosmetic Products and Flavour Directives. Further, the Biocides Directive applies, wherein a requirement for the assessment of “Endocrine Disruption” (ED) has been established. Meanwhile, as ED has been implemented as a CLP hazard class relevant for REACH, guidance on ED criteria has been finalized by the end of 2024. For Biocides and Pesticides, the joint guidance by ECHA & EFSA (2018) had served as the basis for the ED-assessment of Geraniol starting in 2020. Geraniol has been found to induce alterations in thyroid histopathology, suggesting a potential thyroid disrupting MoA, as observed in an EOGRTS-study (OECD 443). This case study assesses the human relevance of the potential endocrine activity on the T-modality and any adversities in vivo as a possible consequence. In vitro data on potential direct effect of Geraniol on the T-modality and in vivo studies in rats have been described in the REACH registration dossier. In the present study, a comparative liver enzyme induction assay was used to establish potential species difference between humans and rats. Cryopreserved rat and human sandwich-cultured hepatocytes were exposed to Geraniol up to the highest non-cytotoxic concentration for up to 7 days. CYP inducers Phenobarbital (rat and human), Rifampicin (human) or PCN (rat) were used as control test items. Cyp2b1/CYP2B6 and Cyp3a1/CYP3A4 mRNA expression and related enzyme activities, Ugt/UGT mRNA expression and UGT activity towards T4 (T4-UGT activity) were assessed. Direct endocrine activity of Geraniol on the T-modality could be excluded using literature data. Thecomparative in vitro study in rat versus human hepatocytes demonstrated that Geraniol induced CYP2B6 and UGT1A1/1A3/1A9 mRNA expression in human hepatocytes, while T4-UGT relative activity was only barely increased. Geraniol did not induce Cyp2b1 nor Ugt2b1 mRNA expression but increased T4-UGT relative activity in Wistar rat hepatocytes. Absolute and relative UGT activity values were both much higher in Wistar rat compared to human hepatocytes. The observed thyroid effects occurring in rats indicate an indirect liver enzyme mediated MoA which is not relevant to humans and does not lead to downstream adversity (i.e., carcinogenicity or neurodevelopmental toxicity). Potential direct effects could be excluded for Geraniol (and metabolites). Consequently, Geraniol is concluded to have no human health concern for ED.