Chloroform
MAK Value Documentation, addendum – Translation of the German version from 2022
Andrea Hartwig1 (Chair of the Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, Deutsche Forschungsgemeinschaft)MAK Commission2
1 Institute of Applied Biosciences, Department of Food Chemistry and Toxicology, Karlsruhe Institute of Technology (KIT), Adenauerring 20a, Building 50.41, 76131 Karlsruhe, Germany
2 Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, Deutsche Forschungsgemeinschaft, Kennedyallee 40, 53175 Bonn, Germany
Abstract
The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re-evaluated the occupational exposure limit value (maximum concentration at the workplace, MAK value) of chloroform [67-66-3] considering all toxicological end points. Relevant studies were identified from a literature search and also unpublished study reports were used. There are no human data to derive a MAK value. In 1999, a NOAEC of 5 ml/m3 was determined in a 13-week inhalation study based on the increased cell proliferation in the kidneys and liver of rats and mice. A MAK value of 0.5 ml/m3 was established on the basis of these findings. This value has now been confirmed also after taking the increased respiratory volume at the workplace into account (see List of MAK and BAT values, Section I b and I c). In a new 2-year inhalation study, respiratory metaplasia of the olfactory epithelium and thickening of the bone in the nasal cavity was observed at the lowest chloroform concentrations tested of 10 ml/m3 in rats and 5 ml/m3 in mice. Toxicity in the olfactory epithelium can be a local as well as a systemic effect. After considering the two possible modes of action and the increased respiratory volume at the workplace, the MAK value derived from effects in the nose would correspond to 1 ml/m3. The present MAK value of 0.5 ml/m3 thus protects also against effects in the nose. As the critical effect is systemic, chloroform remains classified in Peak Limitation Category II with an excursion factor of 2. A developmental toxicity study with inhalation exposure of rats determined a NOAEC of 10 ml/m3. Additionally, malformations in rats observed in another developmental toxicity study at 100 ml/m3 are suggestive of teratogenicity. The NOAEC in this study was 30 ml/m3. Furthermore, the NOAEL for developmental toxicity after gavage administration was 50 mg/kg body weight and day in rats and 35 mg/kg body weight and day in rabbits. Overall, the margins between the concentrations at the workplace calculated to be without effects and the MAK value are sufficient. Therefore, as damage to the embryo or foetus is unlikely to occur if the MAK value is not exceeded, chloroform remains assigned to Pregnancy Risk Group C. Chloroform causes tumours of the thyroid gland in rats and liver tumours in mice as well as renal tumours in both species. However, chloroform is not expected to induce these tumours via a genotoxic mode of action and has thus been classified in Carcinogen Category 4. There are no data for sensitizing effects in humans and no reliable positive results from animal and in vitro studies. Data for sensitization of the respiratory tract are not available. Uptake via the skin can contribute significantly to systemic toxicity. Therefore, chloroform remains designated with an “H”.
