Xylene substances have wide industrial and consumer uses and are currently undergoing dossier and substance evaluation under REACH. New repeated dose toxicity studies identified the thyroid as a potential target organ in rats. This weight of evidence review asks whether these thyroid changes are secondary to liver enzyme induction, and whether they are large enough to raise human health concerns.
The review drew on published literature, several newly generated OECD 422, 408 and 414 guideline studies, in vitro data from the US EPA ToxCast database, and metabolomic analysis using MetaMap®Tox. Xylene caused mild, reversible liver enlargement consistent with a normal adaptive response, which in rats speeds up the breakdown of thyroid hormones. Only minimal to slight thyroid changes were seen, with no severe or irreversible effects and no effects in offspring. ToxCast showed no evidence that xylene interacts directly with the thyroid. The metabolomics data supported an indirect, liver-driven effect, with no signs of direct thyroid toxicity.
Together, the evidence shows that xylene’s effects on the thyroid hormone system work through an indirect, liver-mediated mechanism that is not considered relevant to humans and does not raise concern for developmental neurotoxicity. The data do not support classifying xylene as an endocrine disruptor through the thyroid modality under the EU CLP Regulation (EU) 2023/707. Nor do they support the need for a developmental neurotoxicity cohort in any subsequent extended one-generation reproductive toxicity study (EOGRTS).
Authors
A. Benhida, L. G. Higgins, K. Morris-Schaffer, N. Aygun Kocabas, F. Faulhammer, A. Cordova, E. Freeman, H. Kamp, M. Nahar, E. Richmond, M. Rooseboom
EUROTOX 2025, Poster P28-36 (Session PV03, Reproductive and Developmental Toxicology), Abstract ID 1065.