Registration Dossier

Administrative data

Description of key information

Subchronic study: LOAEC: 21 mg/m³ (rat, 90 d, local) 
Subacute study: LOAEC: 17.5 mg/m³ (rat, 15d, 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
Quality of whole database:
reliable

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
3.4 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

Repeated dose toxicity inhalation:

A subacute inhalation toxicity study was performed similar to the OECD testguideline 412 (Bayer, 1985). In brief, 10 male and 10 female Wistar rats each dose level were head-nose exposes to aerosols of Hexamethylene diisocyanate, oligomers (biuret). Exposure was for 6h daily on 5 consecutive days for 3 weeks (total of 15 exposures). The analytical determination of the exposure atmospheres resulted in respirable aerosol concentrations of 3.7, 17.5, 76.6 mg/m³. Mortality occurred in the high dose group (3/20 animals). Reversible and dose dependent clinical signs of respiratory irritation (e.g. repiratory distress), increase in lung weights and histopathological findings indicative for irritation of the upper and lower respiratory tract were observed in in the mid and high dose groups. With the lowest tested exposure atmosphere (3.7 mg/m³) no signs of respiratory irritation. Unspecific local irritation at the respiratory tract was identified as the key toxicological effect and in general no signs of systemic toxicity occurred. 

 

A subchronic inhalation toxicity study was performed similar to the OECD testguideline 413 (Bayer, 1988). In brief, 10 male and 10 female Wistar rats each dose level were head-nose exposes to aerosols of Hexamethylene diisocyanate, oligomers (biuret). Exposure was for 6h daily on 5 consecutive days for 13 weeks. The analytical determination of the exposure atmospheres resulted in respirable aerosol concentrations of 0.4, 3.4 and 21 mg/m³. In addition to the assay parameters of the guideline lung function measurements (whole body plethysmography) were performed in 2 male and 2 female animals of each exposure group at the end of the exposure period.

In 7 of 20 animals of the high dose group (21 mg/m³) clinical symptoms (e.g. respiratory distress) were observed, 5 of these died or were sacrificed in a moribund state. Additionally slight and statistically significant increases in lung weights and histopathological findings indicative for pulmonary irritation were observed at this dose level (bronchioalveolar hyperplasia, mild focal histiocytosis). No histopathological findings at the upper respiratory tract were determined (trachea, olfactory epithelium, pharynx, larynx).

With the two lower tested aerosol concentrations (0.4, 3.4 mg/m³) no signs of respiratory irritation were observed. Unspecific local irritation at the respiratory tract was identified as the key toxicological effect and in general no signs of systemic toxicity occurred. In the performed lung function measurements no significant effects on breathing function were identified at all dose levels.

 

Both studies demonstrated that adverse effects were caused by unspecific irritation-related responses occurring predominantly in the lower respiratory tract. Indicators of pulmonary irritations were confined to mild respiratory distress, increased lung weights and histopathological findings in the bronchio-alveolar region (e.g. focal interstitial fibrosis, proliferation). The no observed adverse effect concentration was identified as 3.4 mg/m³ from the subchronic study (LOAEC 21 mg/m³) which well corresponded with results from the subacute study (NOAEC3.7 mg/m³, LOAEC 17.5 mg/m³), indicating that the observed effect pattern is not progressively increasing with exposure time.

Comparing all findings relevant for the determination of a NOAEC for Hexamethylene diisocyanate, oligomers (biuret), is suggesting a value in the range of 3-4 mg/m3 whether the exposure of rats was acute, subacute or subchronic (Pauluhn, 2001).

Justification for classification or non-classification

Dangerous substance Directive (67/548/EEC)

The available experimental test data are considered reliable and suitable for the purpose of classification under Directive 67/548/EEC. Based on the criteria of Directive 67/548/EEC, as amended for the 28thtime in Directive 2001/59/EC, classification for STOT (RE) is not justified, due to lack of cumulative toxicity.

 

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are considered reliable and suitable for the purpose of classification under Regulation 1272/2008. Based on the criteria laid down in Regulation (EC) No. 1272/2008, as amended for the 2ndtime in Directive EC 286/2011, classification for STOT (RE) is not justified, due to lack of cumulative toxicity.