Isoflurane
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 Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission) summarized and evaluated the data for isoflurane [26675-46-7] to derive an occupational exposure limit value (maximum concentration at the workplace, MAK value) considering all toxicological end points. Relevant studies were identified from a literature search. The critical effects are neurotoxicity in humans as well as liver toxicity and effects on reproductive organs in animals. Data on liver toxicity at non-anaesthetic concentrations are not available for humans. From a long-term study in male rats, a NOEC of 20 ml/m3 can be derived for liver toxicity, cytochrome P450 (CYP) content and serum levels of alanine aminotransferase. By analogy with halothane, the estimated NAEC for pre-narcotic effects in humans is 92 ml isoflurane/m3. Since the halothane exposure lasted 3–4 hours and the steady state for isoflurane is reached after about 100 minutes, and because a pre-narcotic effect depends only on the concentration, an effect amplification with time is not to be expected. Therefore, for the neurotoxic effect, a maximum concentration at the workplace (MAK value) of 92 ml/m3 would be derived. The most sensitive endpoint is reproductive toxicity in male rats with a NOAEC of 50 ml/m3. On this basis, a MAK value of 2 ml/m3 has been set. For the derivation of the MAK value a C × T dependence was assumed for the critical effect on the testes. Therefore, an excursion factor of 8 can be set. There are no studies in neonatal or juvenile animals at non-anaesthetic concentrations from which to derive a NOAEC for developmental neurotoxic effects of isoflurane. Therefore, isoflurane is assigned to Pregnancy Risk Group D. New studies on the carcinogenic effect of isoflurane are not available. In a long-term study in mice, no increased tumour incidences were observed up to a concentration of 4000 ml/m3. No clear genotoxic potential of isoflurane can be determined from the available data and further clarification is needed, especially in the concentration ranges present at the workplace. Skin contact is expected to lead to a relatively minor contribution to systemic toxicity. Limited data do not show clear evidence of a sensitizing potential.
