m-tolylidene diisocyanate

Carcinogenicity

Description of key information

In two chronic inhalation studies according to OECD 453 in rats the effects of chronic exposure to TDI on carcinogenicity were determined (Owen, 1980; Loeser, 1983). The results showed limited effects on the respiratory tract caused by local irritation. No signs of tumor formation or systemic toxicity were observed.

The oral and dermal route of exposure are not relevant for assessment (see repeated dose toxicity).

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

1.086 mg/m³

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The available experimental test data with m-tolylidene diisocyanate are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result the test substance is considered to be classified for carcinogenicity (Category 2, H351) under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776.

Additional information

The most relevant assessment of carcinogenicity in animals comes from a 2-year chronic inhalation toxicity and carcinogenicity study with TDI in rats and mice (Owen, 1980 + 1986; Loeser, 1983). The animals were whole body exposed to 0, 0.05, and 0.15 ppm of TDI (80/20) vapour for 6 hours/day, 5 days/week. No evidence of any increase in treatment-related tumors in either species was observed. An MTD was achieved in rats and mice as characterized by decreased body weights and moderate to severe rhinitis. Therefore, the NOAEC for carcinogenicity after long-term inhalation of TDI vapour is 0.15 ppm (1.086 mg/m³) for both species.

In contrast, an increase in the number of tumors in various organs was observed in rats and mice after oral long-term administration of TDI over 2 years (NTP, 1986; Dieter et al., 1990). Doses of 0, 30, and 60 mg/kg bw/day (male rats), 0, 60, and 120 mg/kg bw/day (female rats and mice) or 0, 120, and 240 mg/kg bw/day (male mice) were applied. In rats increased tumor incidences were seen in subcutaneous tissue and in the pancreas (both sexes). In addition, female rats showed nodular changes in the liver and mammary gland tumors. In female mice the incidences of hemangiomas, hemangiosarcomas and adenomas of the liver were increased. No increased incidence of compound-related tumors was observed in the male mice.

The results of the studies using oral administration are compromised by severe deficiencies in test substance handling that led to the conclusion that the sample administered also contained other unidentified breakdown and reaction products of TDI, possibly including TDA. Hydrolysis of TDI to form the genotoxic and animal carcinogen TDA is the most plausible explanation for the observed tumors following oral administration of TDI. Therefore, these studies are considered "invalid" by Klimisch criteria. In addition the addition of TDI directly into the acidic environment of the stomach, bypassing the oral cavity, is an unrealistic exposure scenario which leads to generation of the diamine which would not occur in normal handling and use.

Overall Assessment:

1.      Valid animal inhalation studies showed no carcinogenic effect from TDI exposure.

2.      An oral chronic exposure study with TDI is considered invalid due to mishandling of test material and an inappropriate exposure route.

3.      Human studies showed no evidence of carcinogenic hazard (see 7.10.2, summary in 7.10.2a, Collins 2009).

Conclusion:

Based on these evidences, TDI should not be classified as a carcinogen. However, there is an official classification according to the Regulation (EC) No 1272/2008, Annex VI, table 3.1 (Index number 615-006-00-4). The test substance is classified as carcinogen, category 2 (H351, suspected of causing cancer, on the basis of evidence obtained from human and/or animal studies, but which is not sufficiently convincing to place the substance in category 1A or 1B).