[No public or meaningful name is available]

Endpoint summary

Description of key information

Read Across from Desmodur N3300: 
Subchronic study: NOAEC: 3.3 mg/m³ (rat, 90 d, local) 
Subacute study: NOAEC: 4.3 mg/m³ (rat, 3 weeks, local)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

3.3 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

reliable

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

As no repeated-dose data are available for the registered substance, read-across from Desmodur N 3300 is used:

A subacute inhalation toxicity study (3 weeks) according to OECD TG 412 was conducted on 10 test animals per sex and dose group. In this study the animals were head/nose exposed to the aerosolised substance (5days/week, 6h/day) at concentrations of 4.3, 14.7, and 89.8 mg. The aerosol was of adequate respirability for the rats.

No substance induced mortality was observed in the course of the study. Clinical signs occurred for the mid and the high dose groups only. These included bloody noses of slight to moderate intensity; reduced motility on the first two exposure days and for males reduced body weight gain were observed for the high dose group only (89.8 mg/m³). As the symptoms diminished within the course of the study an adaptive effect must have occurred for the rats.

At necropsy increased lung weights were seen at dose group 14.7 mg/m³ and above. Histopathological examinations revealed especially for animals exposed to 89.8 mg/m³ inflammatory changes in the lung and hyperaemia with detritus of the nose mucosa. These effects were unspecific and most probably related to the irritant properties of the substance.

No other target organs than the respiratory tract were affected.

Thus, the NOAEL of this study was 4.3 mg/m³.

A subchronic inhalation toxicity study (90 days) according to OECD TG 413 was conducted on 10 test animals per sex and dose group. In this study animals were head/nose exposed to the aerosolised substance (5 days/week, 6h/day) at concentrations of 0 (vehicle control), 0.5, 3.3, and 26.4 mg/m³. The aerosol was of adequate respirability for the rats (MMAD approx. 1.5 µm, GSD approx. 1.4.). Investigations also included lung function measurements after acetylcholine challenge towards the end of the study.

No substance induced mortality was observed in the course of the study. All animals tolerated the treatment virtually without symptoms, except one male of the high dose group (26.4 mg/m³) that exhibited laboured breathing. A slightly reduced body weight gain was observed for the male rats of the 26.4 mg/m³ group towards the end of the study. Body weight gain was not affected for female animals. Lung function tests provided indications of a chronic obstructive lung disorder in rats of the 26.4 mg/m³ group.
The absolute and relative lung weights were significantly increased in male and female rats of the 26.4 mg/m³ dose group. Histopathologically, inflammatory changes in the respiratory tract (focal fibrosis, proliferation of connective tissue, and increase in macrophages) were seen in the 26.4 mg/m³ dose group and haematological investigations revealed increased leukocyte counts in the same dose group. Other haematological, clinical chemistry and urine analysis parameters remained unchanged.

Conclusively, all tests and examinations provided evidence that changes were confined to the respiratory tract of rats repeatedly exposed to 26.4 mg/m³. The location of the damage was essentially limited to the lung periphery. All changes were nonspecific and are thus attributed to the primary irritant potential of the test substance. There were no indications for damages to organs except for the respiratory tract.
The NOAEL of this study was 3.3 mg/m³.

Justification for classification or non-classification

According to Regulation (EC) No 1272/2008, Annex I, no classification is warranted for repeated dose toxicity. Classification as STOT repeated is not justified, due to lack of cumulative toxicity. As it could be shown, no systemic effects were observed in the repeated dose studies. The local effects observed did not give evidence for a major time-dependent change of the response threshold, as the NOAECs were 3.3 mg/m³ for the subchronic key study (concentrations tested 0, 0.5, 3.3, 26.4 mg/m³) and 4.3 mg/m³ for a subacute (3 weeks) study (concentrations tested 0, 4.3, 14.7, 89.8 mg/m³). Moreover, there is scientific evidence that for non-volatile polyisocyanates that act predominantly as pulmonary irritants even the NOAECs from acute pulmonary irritant potency studies, where bronchoalveolar lavage endpoints as markers for pulmonary irritation were investigated (recommended in the Technical Rule for Hazardous Substances 430, published by the German Federal Ministry of Labour and Social Affairs), does not essentially differ from NOAECs of long(er)-term repeated inhalation studies (Pauluhn, Journal of Applied Toxicology, 24, 231-247, 2004). In fact, the NOAEC of the pulmonary irritant potency study revealed a NOAEC for the substance of 3 mg/m³.