Halogenated Solvents Industry Alliance (United States)

ABSTRACT Carbon tetrachloride (CCl4) has been extensively used and reported to produce toxicity, most notably involving the liver. Carbon tetrachloride metabolism involves CYP450-mediated bioactivation to trichloromethyl and trichloromethyl peroxy radicals, which are capable of macromolecular interaction with cell components including lipids and proteins. Radical interaction with lipids produces lipid peroxidation which can mediate cellular damage leading to cell death. Chronic exposure with CCl4 a rodent hepatic carcinogen with a mode of action (MOA) exhibits the following key events: 1) metabolic activation; 2) hepatocellular toxicity and cell death; 3) consequent regenerative increased cell proliferation; and 4) hepatocellular proliferative lesions (foci, adenomas, carcinomas). The induction of rodent hepatic tumors is dependent upon the dose (concentration and exposure duration) of CCl4, with tumors only occurring at cytotoxic exposure levels. Adrenal benign pheochromocytomas were also increased in mice at high CCl4 exposures; however, these tumors are not of relevant importance to human cancer risk. Few epidemiology studies that have been performed on CCl4, do not provide credible evidence of enhanced risk of occurrence of liver or adrenal cancers, but these studies have serious flaws limiting their usefulness for risk assessment. This manuscript summarizes the toxicity and carcinogenicity attributed to CCl4, specifically addressing MOA, dose-response, and human relevance.

The United States Environmental Protection Agency (EPA) regulates chemicalmanufacture, import, processing, distribution, use, and disposal under the 2016amended Toxic Substances Control Act (TSCA) for the purposes of protecting thepublic and sensitive populations—including workers—from chemical exposure risk.The publication of several TSCA risk evaluations provided a unique opportunityto evaluate the evolving regulatory approach for assessing the dermal exposurepathway in occupational settings. In this analysis, the occupational dermalexposure assessment methods employed in several TSCA risk evaluations wereassessed. Specifically, a methodology review was conducted for the occupationaldermal scenarios of manufacturing and feedstock use in the risk evaluations ofthree chlorinated organic chemicals: trichloroethylene, carbon tetrachloride,and perchloroethylene. Additionally, alternative exposure estimates weregenerated using the exposure model IH SkinPermTM. The review andalternative exposure analyses indicate that the current TSCA modeling approachmay generate total dermal absorbed doses for chlorinated chemical manufacturingand feedstock use scenarios that are 2- to 20-fold higher than those generatedby IH SkinPerm. Best-practice recommendations developed in the methodologyreview support a tiered, integrated approach to dermal exposure assessment thatemphasizes collecting qualitative data; employing validated, peer-reviewedmodels that align with current industrial practices; and gathering empiricalsampling data where needed. Collaboration among industry, EPA, and otherstakeholders to share information and develop a standard approach to exposureassessment under TSCA would improve the methodological rigor of, and increaseconfidence in, the risk evaluation results.