4-methyl-m-phenylene diisocyanate

Carcinogenicity

Description of key information

Inhalation exposure is the most appropriate route for assessing occupational risk in humans. Effects from chronic exposure of animals to TDI are limited to 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 inhalation route

Endpoint conclusion

Dose descriptor:

NOAEC

1.086 mg/m³

Justification for classification or non-classification

Official EU classification according to Directive 67/548/EEC is Carc Cat 3; R40. Limited evidence of a carcinogenic effect, and by EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008), Carc.2. Suspected of causing cancer.

Additional information

Data on physical and chemical properties, eco-toxicity and toxicity can be used for read-across from 2,4-TDI to 2,6-TDI and mixed TDI isomers (i.e. 80/20, 65/35, 2,4/2,6 ratios).  2,4 TDI is the major component of the TDI mixed isomers and so has the major influence on their properties and effects. The reactivity of the 2,6-TDI isomer is somewhat less than that of 2,4-TDI but is of the same order of magnitude. It may therefore be concluded that the effects of 2,6-TDI will be similar to those of 2,4-TDI. This is in fact observed where there are overlapping data.

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). 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 mouse.

The results of the studies using oral administration are compromised by severe deficiencies in test substance handling that led to the fact 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.

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 the inappropriate exposure route.

3.      Human studies show no evidence of carcinogenic hazard.(see section 7.10.2, summarised in 7.10.2a Collins 2009)

4.      Based on this evidence there is a strong case that TDI should not be classified as a carcinogen.