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1000
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Abstract/Summary
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The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated 1,4‐dioxane [123‐91‐1] considering all toxicological endpoints. Available publications and unpublished study reports are described in detail. The critical effect is nasal toxicity and irritation as well as carcinogenic effects in the nose, liver, and kidneys. New carcinogenicity studies with 1,4‐dioxane in drinking water confirm the previous tumour findings in rats and mice. Squamous cell carcinomas in the rat nose, also occurring in a long‐term rat inhalation study at 1250 ml/m3, are a result of direct tissue contact with 1,4‐dioxane in the drinking water. At 50 ml/m3 (LOAEC, lowest observed adverse effect level), no increase in tumour incidences, but nuclear enlargement, atrophy, and respiratory metaplasia in the nasal cavity were noted. The mechanisms involved in the tumour development in the nose are most likely cytotoxicity, inflammation, regenerative cell proliferation and hyperplasia. As the primary mode of action is non‐genotoxic and genotoxic effects play no or at most a minor part at cytotoxic doses, 1,4‐dioxane remains in Carcinogen Category 4. A NAEC of 16.67 ml/m3 (LOAEC / 3) for effects in the nose was calculated from the long‐term rat inhalation study, which is in the same range as the NOAEC of 20 ml/m3 from studies with 2‐ to 8‐hour inhalation exposure of volunteers. To provide additional protection from tumour induction in the nose, the MAK value is lowered to 10 ml/m3. As the critical effect of 1,4‐dioxane is local and no irritation was observed in the study with 2‐hour exposure of volunteers to 20 ml/m3, Peak Limitation Category I and the excursion factor of 2 are retained. There is an adequate margin between the NOAEC for developmental toxicity and the MAK value. Therefore, damage to the embryo or foetus is unlikely when the MAK value is not exceeded and 1,4‐dioxane remains assigned to Pregnancy Risk Group C. Because skin contact is expected to contribute significantly to systemic toxicity, the substance remains designated with “H”. Limited data do not show a sensitizing potential.
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