Toxicological evaluation and limit values for Methyl-tertiary-butyl ether (MTBE), Formaldehyde, Glutaraldehyde, Furfural

7. Evaluation

Several studies on hospital personnel indicate that glutaraldehyde as vapour causes irritation of eyes, respiratory tract, and throat as well as nausea and headache at exposure levels ranging from 0.1 to 0.8 mg/m³. Case studies indicate that glutaraldehyde also may cause occupational asthma; in one study, mean short-term air concentration was 0.16 mg/m³ and mean concentration during the challenge test was 0.068 mg/m³. Direct skin contact with glutaraldehyde solutions can irritate and affect the skin. Glutaraldehyde is a recognised skin sensitiser. In a mortality study of workers (exposed to concentrations up to 0.7 mg/m³), no evidence of increased mortality and cancer was observed.

Data from several short-term and long-term animal studies (rats, mice and dogs) indicate that glutaraldehyde is very reactive when inhaled or when applied dermally as clear evidence of irritation and histopathological changes have been observed at the site of initial contact. No lesions have been observed in the lungs of mice and no evidence of systemic toxicity (histopathological or clinical pathology assessments) has been seen in rats, mice, or dogs. In 4 out of 5 different skin sensitisation tests, not including the guinea pig maximisation test, glutaraldehyde was positive.

The studies available on reproductive and developmental effects indicate that glutaraldehyde is neither a reproductive toxicant nor a teratogenic substance. The tests on genotoxicity show equivocal results with in vitro tests being positive and in vivo tests being negative. The lack of in vivo genotoxic effects suggests that glutaraldehyde does not pose a genotoxic risk to humans and animals. A carcinogenesis study (inhalation) on rats and mice has not yet (1997) been finalised. In an oral carcinogenicity study on rats (drinking water), an increased incidence of large granular lymphocytic leukaemia in spleen and liver was observed, however, this type of leukaemia does not have a predictive value for the occurrence of cancer in humans.

Based on the available human data as well as the studies on experimental animals, the critical effects following inhalation exposure to vapours of glutaraldehyde are considered to be the irritative effects on eyes, respiratory tract, and throat, development of occupational asthma as well as the histopathological lesions observed in the nasal passages of rats and mice. These lesions were of a similar kind as those caused by formaldehyde, although they were more anterior in the nose than those reported for formaldehyde.

The question whether long-term exposure to glutaraldehyde may lead to development of nasal cancer, as reported for formaldehyde, may await the results of the NTP study. However, the animal studies on formaldehyde show that there seems to be a threshold for the development of tumours in the nasal cavities as tumours were only found at exposure levels at which clear cytotoxic effects occur. These data on formaldehyde thus indicate that cytotoxicity is a prerequisite for the development of nasal cancer.

Based on the similarities in the nasal toxicity of formaldehyde and glutaraldehyde it is considered that protection towards the irritative effects also will protect against development of nasal lesions and cancer.

Irritation of eyes, respiratory tract, and throat has been observed at exposure levels ranging from 0.1 to 0.8 mg/m³; one study on occupational asthma showed positive effects at mean short-term air concentration of 0.16 mg/m³ and mean concentration during the challenge test of 0.068 mg/m³. Thus, the human data on irritative effects as well as on development of occupational asthma do not point to a clear NOAEL or LOAEL for exposure to glutaraldehyde. For the purpose of estimating a limit value in air, an overall LOAEL of 0.1 mg/m³ for irritative effects and development of occupational asthma is considered. This LOAEL is supported by the data from animal studies where a NOAEL for respiratory lesions in rats was 0.5 mg/m³ and a LOAEL in mice was 0.26 mg/m³. The odour threshold in air has been reported to be 0.16 mg/m³.