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

3. Human toxicity

Inhalation of glutaraldehyde at vapour levels below 0.8 mg/m³ (0.2 ppm) has been reported to cause nose and throat irritation, nausea and headaches (Burge 1989 - quoted from Beije & Lundberg 1997).

A patient was exposed to residual glutaraldehyde via a crack in an anaesthesia mask, this resulted in eye irritation. No information on exposure level is given. (Murray & Ruddy 1985 - quoted from Beauchamp et al. 1992).

Glutaraldehyde solutions may cause mild to severe irritation in the skin, depending on the concentration of the solution and the duration of exposure/contact (Beije & Lundberg 1997).

Inhalation

In studies at hospitals (NIOSH 1991 - quoted from Beije & Lundberg 1997), a relationship between exposure to glutaraldehyde and irritation of eyes and upper respiratory pathways has been demonstrated. The concentration of glutaraldehyde was 0.2 ppm (0.8 mg/m³) or higher. After reconstruction of the occupational setting, the concentration was lowered to 0.1 ppm (0.4 mg/m³) or less and there were no symptoms of irritation.

Norbäck (1988) carried out a questionnaire study aimed to investigate skin and respiratory symptoms among hospital personnel working in areas with possible glutaraldehyde exposure. The glutaraldehyde solution used was a 2% alkaline solution. To be regarded as an area with possible glutaraldehyde exposure at least one litre of the solution should be used per month in the unit. From the questionnaire, the staff of the units selected were divided into an exposed and an unexposed group. The exposed group consisted of 39 persons and the unexposed group of 68 persons. As unexposed, one handled glutaraldehyde less than once a month. Air sampling revealed exposure levels from <0.01 to 0.57 mg/m³ with most determinations being in the range of 0.02 to 0.14 mg/m³. In the comparison between the exposed and the unexposed group, the exposed group reported nasal catarrh, nasal obstruction, smarting of the throat, headache, nausea, rashes on the hands, and eczema significantly more often than the unexposed group. When the mean number of symptoms recorded was compared with the number of days of exposure to glutaraldehyde within the last 6 months, a clear exposure and symptom relationship was found, with a mean number of 5 symptoms being recorded for the group with more than 20 exposure days.

From 65% of 167 nurses working in endoscopy units there have been complaints of eye irritation, skin irritation, headache and cough or shortness of breath. Where measurements were performed, the air conccentration of glutaraldehyde was less than 0.2 ppm (0.8 mg/m³) (Calder et al. 1992 - quoted from Beije & Lundberg 1997).

Nine members of an endoscopy unit were surveyed to find symptoms associated with exposure to vapour from 2% glutaraldehyde in a disinfectant. Air samples taken for one hour during cold sterilisation ranged from 0.05 to 0.12 ppm (0.2 - 0.5 mg/m³). Eight of the workers reported ocular and nasal irritation. (Jachuck et al. 1989 - quoted from CIR 1996).

Four nurses working in endoscopy units complained of respiratory symptoms when exposed to a disinfectant containing 2% glutaraldehyde. In tests designed to simulate occupational exposure, each nurse had three 20-minutes exposures, separated by 40 minutes intervals. Two had positive reactions, one had both immediate and delayed responses, and one had an isolated delayed response. No information on exposure levels is given. (Corrado et al. 1986).

A surveillance of occupational asthma found that 3 of 8 workers exposed to glutaraldehyde were symptomatic (Matte et al. 1990 - quoted from CIR 1996).

Eight workers were referred for investigation of suspected occupational asthma following direct or indirect exposure to glutaraldehyde at work. Seven of them had peak expiratory flow records suggestive of occupational asthma and positive specific bronchial challenge tests to glutaraldehyde. The mean level of glutaraldehyde during the challenge test was 0.068 mg/m³. Thirty personal air samples were collected in 13 hospital endoscopy units, twelve of these used manual methods of disinfecting. The mean personal short term air concentrations of glutaraldehyde was 0.16 mg/m³. (Gannon et al. 1995).

Dermal contact

In an irritancy test, a 10% solution of glutaraldehyde was applied to the anterior, lateral, and posterior ankle and posterior heel of 12 subjects 5 days/week for 4 weeks, and thereafter 3 days/week for further 4 weeks. No irritation (erythema, pruritus, or isolated vesicles and papules) was observed during the first week, however, in 11 subjects the skin was discoloured after 5 applications. During the second week, all subjects were significantly discoloured and 5 subjects had minimal irritation on the anterior ankle which subsided during the third and fourth weeks. One of the 5 subjects became sensitised to glutaraldehyde. During the last four weeks of application, there was no evidence of irritancy, even among those who had previously experienced some irritation. (Reifenrath et al. 1985 - quoted from Beije & Lundberg 1997).

Glutaraldehyde is a skin sensitizer. There are many case reports and smaller studies on allergic contact dermatitis to glutaraldehyde (CIR 1996), larger studies include the following:

Among 657 patients with eczematous dermatitis patch-tested with 2% glutaraldehyde, one showed positive reaction. (Angelini et al. 1985 - quoted from CIR 1996).

Among 884 patients patch-tested with 0.1% glutaraldehyde, two subjects had allergic reactions, one of which had clinical relevance. (Hansen & Menne 1990 - quoted from CIR 1996).

Among 160 patients patch-tested with 1% glutaraldehyde (pH 7.5), no positive reactions occurred. (Juhlin & Hansson 1968 - quoted from CIR 1996).

Glutaraldehyde was tested for sensitisation in 102 male subjects. Ten occlusive induction patches containing 0.1% glutaraldehyde in petrolatum were applied to the upper lateral portion of the arm for 48 to 72 hours over 3 weeks. A non-treatment period of 2 weeks was followed by an occlusive challenge patch containing 0.5% glutaraldehyde in petrolatum. No sensitisation was observed among the 102 men. The experiment was repeated with 30 men and with 5% glutaraldehyde induction patches and a 0.5% glutaraldehyde challenge patch. Seven (23.3%) of the men were sensitised. (Marzulli & Maibach 1974 - quoted from CIR 1996 and from Beije & Lundberg 1997).

Patch tests were performed on 109 volunteers (males and females) using 0.1, 0.2, and 0.5% aqueous solutions of glutaraldehyde with the same concentration being used for induction and challenge. For induction, the glutaraldehyde doses were applied to the skin of the backs under occlusion for 48 to 72 hours. A total of ten induction applications were made over a 3 week period. Two weeks after removal of the final induction patch, a challenge patch was applied under occlusion for 48 hours to a site not used for induction. The reaction was recorded 24 hours after removal of the challenge patch. The two lowest doses produced no evidence for a sensitisation reaction, but at 0.5% there was a definite reaction to the challenge patch in one of the 109 subjects. While 0.1 and 0.2% glutaraldehyde solutions were not significantly irritating to the skin, a 0.5% solution produced mild to moderate local erythema in 16 of the 109 subjects. (Ballantyne & Berman 1984 - quoted from CIR 1996 and from Beije & Lundberg 1997).

No data on reproductive effects following exposure to glutaraldehyde have been found in the literature.

The assessment of spontaneous abortions and foetal malformations have been studied in Finnish hospital nurses and staff who had been exposed to glutaraldehyde used as a sterilising agent. No increase in risk of either endpoint was found. (Beije & Lundberg 1997).

No data on genotoxic effects following exposure to glutaraldehyde have been found in the literature.

3.5 Carcinogenic effects

A mortality study has been performed on 186 male workers assigned to glutaraldehyde production or drumming from 1959 to 1978 and followed through 1988. Exposure data (available from 1977 to 1992) ranged from 0.01 to 0.17 ppm (0.04-0.7 mg/m³) with a TWA (8-hour time-weighted average) of 0.05 ppm (0.2 mg/m³) but suggest somewhat higher levels in 1977 and 1978 (TWA of 0.08 and 0.07 ppm (around 0.3 mg/m³), respectively). Based on comparison to the general US population, there was a statistically significant deficit of deaths due to all causes, with 14 deaths observed among the 186 study subjects and 25.4 expected. The rate for total malignant neoplasms was less than expected, with 4 cancer deaths versus 6.1 expected. The 4 cancers included one each due to stomach, lung, and brain and a death due to lymphosarcoma. (Teta et al. 1995).