Abstract  1,4-Dioxane, used widely as a solvent in the manufacture of chemicals and as a laboratory reagent, induced liver adenomas and carcinomas in mice and rats, and nasal tumors in rats in several long-term studies. 1,4-Dioxane has been reported to be non-genotoxic in vitro, and there is no clear conclusion concerning its in vivo genotoxicity in rodents. In the present study, we investigated the ability of 1,4-dioxane to induce micronuclei in the liver and bone marrow of rats. For the liver micronucleus test, we performed the juvenile animal method and two methods using partial hepatectomy (PH), dosing before PH or dosing after PH. We also evaluated the in vivo mutagenicity of 1,4-dioxane by Pig-a gene mutation assay using rat peripheral blood. As a result, all methods of liver micronucleus test showed an increase in the frequency of micronucleated hepatocytes by 1,4-dioxane. The dosing before PH, a suitable method for detecting structural chromosome aberration inducers, showed the clearest response for micronucleated hepatocytes induction among the three methods. This finding is consistent with a previous report that 1,4-dioxane induces mainly chromosome breakage in the liver. Negative results were obtained in the bone marrow micronucleus test and Pig-a gene mutation assay in our study. These results suggested that 1,4-dioxane is clastogenic in the liver but not genotoxic in the bone marrow of rats.

Abstract  This document presents the scope of the risk evaluation to be conducted for 1,4-dioxane. If a hazard, exposure, condition of use or potentially exposed or susceptible subpopulation has not been discussed, EPA, at this point in time, is not intending to include it in the scope of the risk evaluation. As per the rulemaking, Procedures for Chemical Risk Evaluation Under the Amended Toxic Substances Control Act (TSCA), with respect to conditions of use in conducting a risk evaluation under TSCA, EPA will first identify “circumstances” that constitute “conditions of use” for each chemical. While EPA interprets this as largely a factual determination—i.e., EPA is to determine whether a chemical substance is actually involved in one or more of the activities listed in the definition—the determination will inevitably involve the exercise of some discretion.