P28-36 A Weight of Evidence Review on the Mode of Action, Adversity, and the Human Relevance of Xylene's Observed Thyroid Effects in Rats

Xylene substances have wide industrial and consumer uses and are currently undergoing dossier and substance evaluation under Registration, Evaluation, Authorization and Restriction of Chemicals (REACH). Decisions for further toxicological testing include consideration of an additional neurotoxicological testing cohort to an extended one-generation reproduction toxicity study (EOGRTS). New repeated dose study data on xylenes identify the thyroid as a potential target tissue, and therefore a weight of evidence review (WoE) is provided to investigate if xylene-mediated changes on the hypothalamus-pituitary-thyroid (HPT) axis are secondary to liver enzyme induction, and of a magnitude that is relevant for neurological human health concerns. Data from literature, from multiple studies (OECD 422, 408 and 414) on xylenes and xylene reaction mass substances including data from the United States Environmental Protection Agency (US EPA) Toxicity Forecasting (ToxCast) database in combination with metabo-lomic analysis (MetaMap®Tox) were reviewed to compile the WoE for xylene mediated effects on the HPT axis. Published studies confirm xylene-mediated increases in liver weight, hepatocellular hypertrophy, and liver enzyme induction, including an increase in uridine 5’-diphospho-glucuronosyltransferase (UDP-GT) activity, a key step in thyroid hormone metabolism in rodents. Only minimal to slight increases in thyroid follicular cell hypertrophy have been observed in some repeated-dose studies, with no associated robust or consistent perturbance of thyroid hormone changes across the studies. None of the effects observed were carried through to offspring indicating adaptive homeostatic maintenance of the maternal HPT axis in response to xylene exposure does not manifest in offspring. Importantly, in vitro data from US EPA ToxCast provides supporting evidence of xylene's inability to directly perturb thyroidal functionality. In-depth metabolom-ics analysis (MetaMap®Tox) of xylene showed a tentative match to compounds that demonstrate extra-thyroidal effects on the HPT axis as a consequence of liver enzyme induction. Lastly, the slight HPT axis changes mediated by xylene were well-below the published literature thresholds for developmental neurotoxicological outcomes established for thyroidal changes in animals and humans. Data and evidence individually and collectively demonstrate that xylene mediated changes in the HPT axis, via a secondary extra-thyroidal mode of action (i.e. liver enzyme induction), do not raise a human health concern with regards to developmental neurotoxicity. Available toxicological data do not support the classification of xylene as a known or suspected endocrine disruptor, specifically through the thyroid modality, as per CLP regulation and do not support the need for a neurotoxicological cohort evaluation in any subsequent EOGRTS.