m-tolylidene diisocyanate

Endpoint summary

Description of key information

Oral:

In a subacute oral repeated dose toxicity study in Crj: CD(SD) rats with m-tolylidene diisocyanate similar to Guideline for 28 day Repeated Dose Toxicity in Mammalian Species (Chemical Substances Control Law of Japan) a LOAEL of 30 mg/kg bw was determined (Ministry of Health Labour Welfare Japan, 2001).

Inhalation:

In a combined chronic toxicity and carcinogenicity study similar to OECD Guideline 453, CD-1 mice were exposed to m-tolylidene diisocyanate (80/20) (Owen, 1986). A LOAEC of 0.05 ppm was determined.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

30 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

3

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

0.362 mg/m³

Study duration:

chronic

Species:

mouse

Quality of whole database:

1 - 2

System:

respiratory system: upper respiratory tract

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Inhalation exposure is the most appropriate route for assessing occupational risk in humans. Effects from repeated exposure of animals to TDI are limited to effects on the respiratory tract caused by local irritation.

The most relevant evaluation of repeated dose toxicity comes from a 2-year chronic 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. In both species, body weight gain was reduced at 0.15 ppm over the first 12 weeks that persisted but did not worsen over the remaining period of the study. In rats, rhinitis was observed in males at 0.15 ppm and in females beginning at 0.05 ppm, generally characterized by squamous metaplasia/hyperplasia of the respiratory mucosa, with and without exudate in the lumen, and leucocyte infiltration in the lamina propria. This finding is considered to be due to local irritation of the anterior nasal cavity. In mice, histopathology revealed marked inflammatory processes in trachea, larynx, bronchi, lungs and predominantly in nasal turbinates (chronic and necrotic rhinitis) of male and female animals beginning at 0.05 ppm. Therefore, the LOAEC for rats and mice is 0.05 ppm (0.362 mg/m³) after long-term inhalation of TDI vapour.

The findings of the key study were supported by subchronic studies in various strains and species (Henck, 1976). 30 day whole body exposure of SD- and Fischer-rats, hamsters and mice to vapors of 0.1 and 0.3 ppm resulted in repiratory irritation (LOAEL 0.1 ppm) but no signs of systemic toxicity.

Justification for classification or non-classification

According to the CLP-Regulation (EC) No 1272/2008, no classification for systemic toxicity following repeated exposures is appropriate. Due to local irritation of the respiratory tract, STOT cat 3 according to CLP-Regulation (EC) No 1272/2008.

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. The LOAEL (oral) was 30 mg/kg bw/day and the LOAEC (inhalation) 0.362 mg/m³. As a result the substance is not considered to be classified for repeated dose oral toxicity. For irritation of the respiratory tract STOT (Category 3) is considered under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776.