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Toxicological information

Carcinogenicity

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Description of key information

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
1 mg/m³
Study duration:
chronic
Species:
rat
Quality of whole database:
The study is GLP compliant and is of sufficient quality (Klimisch score=2)

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Carcinogenicity - read-across with other MDI substances

In a combined chronic toxicity and carcinogenicity study, rats were exposed for 6 hours/day, 5 days/week for 2 years to polymeric MDI aerosol concentrations of 0, 0.2, 1.0 or 6.0 mg/m3 (analytical conc.: 0, 0.19, 0.98, 6.03 mg/m3) (Reuzel et al., 1990). This GLP reliability 2 key study was conducted according to OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies). Histopathology of the organs/tissues investigated showed that exposure to 6.0 mg/m³ was related to the occurence of pulmonary tumors in males (6 adenomas and 1 adenocarcinoma) and females (2 adenomas). Therefore, polymeric MDI was carcinogenic in rats after long-term inhalation to aerosol concentrations of 6.0 mg/m3. It was also concluded that exposure to polymeric MDI at concentrations not leading to recurrent lung tissue damage will not produce pulmonary tumors.

In a long-term inhalation study over a maximum of 24 months including satellite groups with 3, 12, and 20 months exposure, by Hoymann et al. (1995), the chronic toxicity and the carcinogenicity of monomeric 4,4-MDI were investigated. Female Wistar rats in groups of 80 animals, were exposed in 6m3 inhalation chambers for 17 hours/day, 5 days/week to 0.23, 0.70, and 2.05 mg/m3 MDI in aerosol form, a control group was exposed to clean air. Essentially, a dose-dependent impairment of the lung function in the sense of an obstructive-restrictive malfunction with diffusion disorder, increased lung weights, an inflammatory reaction with increased appearance of lymphocytes (but not of granulocytes) in the lung in the high dose group as a sign of specific stimulation of the immune system by MDI, a moderately retarded lung clearance in the high dose group as well as dose-dependent interstitial and peribronchiolar fibrosis, alveolar bronchiolisations and a proliferation of the alveolar epithelium as well as a bronchiolo-alveolar adenoma (at 2.05 mg/m3) were ascertained. There was no MDI-related increase in the organ-specific tumor rate. The number of tumor-bearing rats was identical, and the total number of tumors did not significantly differ between the control and the high dose group 2.05 mg/m3. The proof of MDA-DNA adducts in marginal amount after 12 months MDI exposure is possibly feigned by the strong protein binding. The toxicological relevance of this finding is doubtful since MDI leads only in high concentrations to degeneration of the olfactory epithelium (Greim H (ed.) 2008, in: Occupational Toxicants - Critical data evaluation for MAK values and classification of carcinogens, Wiley-VCH, Weinheim, Vol. 14).

It has to be noted that there was an untypical high mortality due to tumors of the pituitary gland, in all groups (control group included), which limits the evaluation of this study. With this study it cannot be clarified whether prolonged exposure would have resulted in tumour formation. Another point for discussion is the exposure scenario (17 hours/day). A 17-hour daily exposure is unusual and prevents normal spontaneous healing processes after contact with irritating substances. As it is well known that the used concentrations are locally irritating (irritation was shown in all dose groups), this again limits the evaluation of the study.

Based on the review by III Biochemistry Task Force (1999), it is concluded that MDI should not be classified as carcinogenic in animals as the few tumours result from an irritaint effect of an aerosol than is not encountered in the workplace. Several valid epidemiological studies have failed to find an association between working in the polyurethane industry and increased cancer incidence (see cohort study by Sorahan and Nichols (2002).


Justification for selection of carcinogenicity via inhalation route endpoint:
Only one key study available

Carcinogenicity: via inhalation route (target organ): respiratory: lung

Justification for classification or non-classification

Based on the classification of monomeric MDI according to Directive 67/548/EEC and Regulation (EC) No. 1272/2008 (CLP) the following classification is recommended for MDI-TPG (read-across based on grouping of substances - category approach):

Carcinogenicity

Based on the results of the available carcinogenicity studies, MDI was classified according to Directive 67/548/EEC with R40 (Carc. Cat 3; limited evidence of a carcinogenic effect) and according to Regulation (EC) No. 1272/2008 (CLP) with Carc. Cat 2 (H351: suspected of causing cancer by inhalation).