Search

Xylene is a high production volume chemical that is widely used as a solvent and polymer precursor, and is currently undergoing substance evaluation under Registration, Evaluation, Authorization and Restriction of Chemicals (REACH). Xylenes recently received testing decisions on one-generation reproductive toxicity (EOGRT) studies with additional developmental neurotoxicity (DNT) cohorts for each of the three isomers. Xylene presents a unique opportunity to investigate the need for additional animal DNT toxicology testing because it is a legacy industrial chemical for which a significant amount of animal and human data already exists on its toxicity profile, including central nervous system effects. Therefore, to address the need for further vertebrate testing, a comprehensive weight of evidence (WOE) review of published and previously unpublished new studies of xylene substances was performed. Evidence topics included the pharmacokinetics, narcotic effects in humans and animals, narcotic mode of action (MOA), and strength of DNT signal for xylene. Pharmacokinetic data indicate minimal distribution of the unmetabolized parent compound to the fetus relative to parental brain tissue, and rapid metabolism of xylene to methyl hippuric acid (MHA), which is also rapidly excreted in both humans and animals. Xylene exposure has also resulted in transient, nonspecific neurological effects including delays in reaction time of human volunteers and reductions in motor activity of animals. This narcotic MOA for xylene occurs by the nonspecific perturbation of nervous cell membrane phospholipids, such that membrane-bound proteins and their respective functions are impaired. Furthermore, an in-depth review of the available DNT data indicates significant methodological deficiencies in several studies in the literature purported to provide evidence of a DNT concern following xylene exposure and no DNT concern reported in one reliable study. In conclusion, based on xylene's pharmacokinetics, narcotic effects on the central nervous system observed in animal and human studies, its narcotic MOA, and the lack of a robust signal from the published DNT studies, there is no trigger for the additional EOGRT study DNT cohort to be conducted for xylene. Further, the findings on narcotic effects and MOA underscore the difficulty in separating transient, acute intoxication effects via direct exposure of the offspring from investigating DNT effects (as investigated in a standard guideline (426) DNT study) in the EOGRT study, therefore producing unreliable data, which is ethically at odds with REACH and 3 R principles. [ABSTRACT FROM AUTHOR]

AbstractXylene substances have wide industrial and consumer uses and are currently undergoing dossier and substance evaluation under Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) for further toxicological testing including consideration of an additional neurotoxicological testing cohort to an extended one-generation reproduction toxicity (EOGRT) study. New repeated dose study data on xylenes identify the thyroid as a potential target tissue, and therefore a weight of evidence review is provided to investigate whether or not xylene-mediated changes on the hypothalamus-pituitary-thyroid (HPT) axis are secondary to liver enzymatic induction and are of a magnitude that is relevant for neurological human health concerns. Multiple published studies confirm xylene-mediated increases in liver weight, hepatocellular hypertrophy, and liver enzymatic induction via the oral or inhalation routes, including an increase in uridine 5′-diphospho-glucuronosyltransferase (UDP-GT) activity, the key step in thyroid hormone metabolism in rodents. Only minimal to slight increases in thyroid follicular cell hypertrophy have been observed in some xylene repeated dose studies, with no associated robust or consistent perturbance of thyroid hormone changes across the studies or carried through to offspring indicating adaptive homeostatic maintenance of the HPT axis. Also importantly, in vitro human cell line data from the United States Environmental Protection Agency (US EPA) Toxicity Forecasting (ToxCast) provides supporting evidence of xylene’s inability to directly perturb thyroidal functionality. A further supplemental in-depth metabolomics analysis (MetaMap®Tox) of xylene showed a tentative match to compounds that also 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. In summary, the data and various lines of scientific evidence presented herein individually and collectively demonstrate that xylene’s mediated changes in the HPT axis, via a secondary extra-thyroidal MOA (i.e. liver enzyme induction), do not raise a human health concern with regards to developmental neurotoxicity. As such, the available toxicological data do not support the classification of xylene as a known or suspected endocrine disruptor, specifically through the thyroid modality, per Regulations Commission Delegated Regulation (EU) 2023/707 of 19 December 2022 amending Regulation (EC) No 1272/2008 and do not support the need for a neurotoxicological cohort evaluation in any subsequent EOGRTS. [ABSTRACT FROM AUTHOR]