1,2,3-Benzotriazole. Health-based recommended occupational exposure limit

At the request of the Minister of Social Affairs and Employment, the Health Council of the Netherlands recommends health-based occupational exposure limits for the concentration of toxic substances in air at the workplace. These recommendations are made by the Council’s Dutch Expert Committee on Occupational Standards. They constitute the first step in a three-step procedure that leads to legally-binding limit values.
In the present report, the committee discusses the consequences of occupational exposure to 1,2,3-benzotriazole (further referred to as benzotriazole) and, if appropriate, recommends a health-based occupational exposure limit. The committee’s conclusions are based on scientific publications prior to March 2000.

Occurrence, physical and chemical properties

Benzotriazole is an odourless, white to tannish crystalline powder. It is sparingly soluble in water and soluble in a number of organic solvents. It has a low vapour pressure, and it is therefore likely to occur as dust at the workplace. When finely divided and mixed with air, dust explosions may occur.
Benzotriazole is an industrial compound primarily used as a corrosion inhibitor, as a plastic stabilizer, and as a chemical intermediate.

Monitoring

In view of the low vapour pressure at room temperature, it is likely that benzotriazole will only occur as dust at the workplace. A general method for measuring inhalable dust should than be suitable for measuring benzotriazole. The benzotriazole content in the dust may be assessed by analytical-chemical methods after extraction with a suitable solvent. In view of the specificity and the height of the detection limit, UV-spectrophotometry or a HPLC or GC-MS method may be most appropriate.

Limit values

No occupational exposure limits/standards for benzotriazole have been established or recommended in the Netherlands, the Nordic countries, the UK, and the USA (ACGIH). In Germany, benzotriazole was listed among the compounds for which no limit could be established.

Kinetics

The committee did not find data on the toxicokinetics of benzotriazole. Based on physico-chemical data, dermal absorption might be expected. In an in vitro experiment using rat liver microsomes and a one-hour incubation period, it was metabolized to 4- and 5-hydroxybenzotriazole at a low rate.

Effects

In metal workers, contact dermatitis was observed after skin exposure to benzotriazole.
In experimental animals, benzotriazole appeared to be a severe eye irritant and, at most, a slight skin irritant; Benzotriazole is not a skin sensitizer. Based on acute letal toxicity data (inhalation LC50 rat: 2153 mg/m3; oral LD50 rat: 500-965 mg/kg bw) and using EC-classification criteria, benzotriazole should be classified as harmful following inhalation and oral exposure.

Apart from oral carcinogenicity studies in rats and mice, the committee did not find data from valid repeated-dose toxicity (including developmental toxicity) studies.

In the carcinogenicity studies, higher incidences of — mostly benign — tumours in some organs were observed in treated than in concurrent control animals. These tumours had mostly higher incidences in the low-dose than in the high-dose group, and occurred at fairly high rates in historical controls. The committee could not assess a NOAEL since several effects were observed at the lowest dose tested. The LOAELs were set at 295 and 1455 mg/kg bw/day in rats and mice, respectively.

Benzotriazole is, in vitro, mutagenic in S. typhimurium TA 1535 and in E. coli, but not in chinese hamster ovary cells. The SOS chromotest in E. coli, an indicator test for DNA damage was negative. In vivo, benzotriazole was negative in an oral mouse bone marrow micronucleus assay.

Hazard assessment

Based on the human and/or experimental animal data, the committee concludes that eye irritation following occupational exposure to benzotriazole cannot be excluded.

From the carcinogenicity studies with rats and mice, the committee concludes that there is inconclusive evidence that benzotriazole is carcinogenic. Although higher incidences of — mostly benign — tumours in some organs were observed in treated than in concurrent control animals, these tumours had mostly higher incidences in the low-dose than in the high-dose group, and occurred at fairly high rates in historical controls.

In view of the inconclusive evidence for carcinogenic potential of benzotriazole in rodents and the mutagenic effects of benzotriazole in bacterial systems along with the absence of mutagenic and genotoxic effects in vitro in mammalian cells and in vivo in experimental animals, the committee considers the data base too poor to justify a conclusion regarding genotoxicity and carcinogenicity of this chemical. Clearly, the data base is inadequate to classify benzotriazole as a probable carcinogen to humans, but it may raise concern for humans. Therefore, 1,2,3-benzotriazole is classified as a suspect carcinogen.

Assuming — for the time being — benzotriazole does not possess carcinogenic properties, one might use the available oral data to derive an occupational exposure limit. The LOAEL of 295 mg/kg bw/d from the chronic rat study could be used as a starting point. It will be clear that extrapolation from this LOAEL applying the usual considerations and assumptions will lead to a limit value much higher than the maximum accepted concentrations set in the Netherlands for respirable and inhalable nuisance dust, viz, 5 and 10 mg/m3, respectively. Since benzotriazole at room temperature will be present at the workplace as dust, these values could then be applied as occupational exposure limits for benzotriazole.

Since, however, it cannot be excluded that benzotriazole is a genotoxic carcinogen, the committee deemed it desirable to calculate the cancer risk associated with an occupational exposure level of 10 mg/m3. Using a "worst-case" approach (see Annex), occupational exposure to 10 mg/m3 for 40 years should be associated with an excess cancer mortality risk of 5 per 10.000.

Furthermore, benzotriazole appeared to be a slight eye irritant in experimental animals. This may indicate that eye and/or respiratory tract irritation can not be excluded to occur in workers exposed to benzotriazole concentrations of 5 mg/m3 for respirable particles and to 10 mg/m3 for inhalable ones. Since no eye irritation studies in humans were available and repeated-dose inhalation toxicity studies in experimental animals were absent, the committee concludes that it is not justifiable to derive a health-based occupational exposure limit from the available data.

Health-based recommended occupational exposure limit

The Dutch Expert Committee on Occupational Standards considered the data base on benzotriazole too poor to justify recommendation of a health-based occupational exposure limit.

The committee classifies 1,2,3-benzotriazole as a suspected human carcinogen.

Committee