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

6. Summary

Description

Glutaraldehyde (pure form) is a colourless, oily liquid. Commercial solutions often have an amber tint and an odour similar to spoiled fruit. Glutaraldehyde is miscible with water. It has a low vapour pressure.

Environment

Glutaraldehyde does not appear to occur naturally. No data on ambient levels as well as fate processes have been found.

Human exposure

The most probable routes of human exposure to glutaraldehyde are dermal contact and inhalation by workers involved in the manufacture and use of the substance.

Toxicokinetics

No specific data on absorption and distribution have been found. Material balance studies in rats and mice indicate that the majority of a dermal dose remains at the application site. The metabolism of glutaraldehyde has not been studied in detail but it has been suggested that glutaraldehyde is oxidised through acidic intermediates to carbonmonoxide which is expired.

Human toxicity

Several studies on hospital personnel indicate that vapours of glutaraldehyde causes irritation of eyes, respiratory tract, throat, and skin as well as nausea and headache at exposure levels ranging from 0.02 to 0.8 mg/m³. One study has reported irritative symptoms at 0.8 mg/m³ but not at 0.4 mg/m³. Case studies indicate that glutaraldehyde also may cause occupational asthma; in one study, seven of eight workers had positive specific bronchial challenge tests to glutaraldehyde (mean short-term air concentration was 0.16 mg/m³, mean concentration during the challenge test was 0.068 mg/m³). Glutaraldehyde solutions may cause mild to severe irritation of the skin, depending on the concentration of the solution and the duration of exposure. Several case reports and studies on allergic contact dermatitis indicate that glutaraldehyde is a skin sensitiser.

Animal toxicity

LC₅₀-values (4 hours exposure) ranging from 0.1 to 0.8 mg/l have been reported for rats. Short-term studies (up to 2 weeks) have shown histopathological lesions (necrosis, inflammation, hyperplasia, squamous metaplasia) of the nasal passages and larynx of rats (from 2 mg/m³) and mice (from 1 mg/m³). One study on mice showed no recovery of the histopathological lesions two weeks after exposure (4 mg/m³), whereas partial recovery was observed four weeks after exposure; none of the exposed mice (1-11 mg/m³) showed any lesions in the lungs. RD₅₀-values of 11 and 58 mg/m³ have been reported in mice. One study indicate that glutaraldehyde is not a respiratory sensitisator in rats. In 13-week inhalation studies of rats and mice, the NOAEL for respiratory lesions in rats was 0.5 mg/m³ and the LOAEL in mice was 0.26 mg/m³ (the lowest dose in the study). The lesions observed were of a similar kind as those caused by formaldehyde, although they were more anterior in the nose than those reported for formaldehyde. No evidence of systemic toxicity (histopathological or clinical pathology assessments) was observed.

Following oral administration of glutaraldehyde in drinking water to rats, decreased food and water consumption, reduced body weight and body weight gains, and increased kidney weight (absolute and relative) were observed; a NOAEL of 50 ppm (around 5 mg/kg b.w./day) was observed. Mice and dogs appeared to be less sensitive than rats. No evidence for systemic tissue or organ toxicity was observed in these studies.

The threshold for skin irritation was around 1% and for eye irritation around 0.1% when glutaraldehyde was tested in aqueous solution. In 4 out of 5 different skin sensitisation tests, not including the guinea pig maximisation test, glutaraldehyde was positive.

Reproductive and developmental effects

No human data on reproductive effects have been found; one study did not indicate an increased risk of spontaneous abortions or foetal malformations. No effects on fertility or developmental parameters was observed in a two-generation study of rats or in teratology studies of rats and rabbits.

Genotoxicity

Glutaraldehyde has shown a genotoxic potential in vitro causing mutations in both bacterial and mammalian cells, and sister chromatid exchanges and chromosomal aberrations in mammalian cells. However, five in vivo tests (two tests in rats for unscheduled DNA synthesis, a mouse dominant lethal assay, a micronucleus test in mice, and a rat bone marrow chromosome aberration test) have shown negative results.

Adducts have been formed on reaction of glutaraldehyde with components of DNA (deoxyadenosine, deoxyguanosine and deoxycytidine, but not deoxythymidine).

Carcinogenicity

In a mortality study of workers (exposed to concentrations up to 0.7 mg/m³), no evidence of increased mortality and cancer was observed.

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.