Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
3 537.5 mg/m³

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

An acute oral toxicity study conducted on female rats according to OECD TG 423 revealed no mortalities, no clinical signs and no effects on body weight gain for the limit dose of 2000 mg/kg bw. At necropsy no gross pathological findings were observed. The LD50 cut off was estimated from the flow chart of the OECD TG 423 (2001), Annex 2d, to be 5000 mg/kg bw.

An acute inhalation toxicity study of the substance (80 % in butyl acetate) was conducted in accordance with OECD TG 403 and OECD GD 39. Rats were nose-only exposed to the liquid aerosol of the substance at 0 (butyl acetate control), 460, 1546, 3906, and 4586 mg/m³ (actual concentrations of the test substance 80 % in butyl acetate). The respirability of the aerosol was adequate, i.e. the mass median aerodynamic diameter (MMAD) was smaller than 2.5 µm and the geometric standard deviation (GSD) 1.7-2.4.

Mortality did not occur at concentrations up to 1546 mg/m³. Rats exposed at higher concentrations showed evidence of respiratory irritation with mortality patterns typical of an irritation-related acute lung edema. The LC50 was determined to be 4090 mg/m³ (actual concentration of the substance 80 % in butyl acetate); LC50 for the non-volatile fractions of the test article (based on gravimetric concentrations) = 3537.5 mg/m³. The latter value was used for hazard assessment, since the non-volatile fraction of the test article mainly reflects the substance itself, without the proportion of the solvent, that was contained in the test-substance due to technical reasons.

An acute dermal toxicity study is not available for the substance. Based on weight of evidence an assessment of the acute dermal toxicity is possible.  

IPDI oligomers, allophanate type, has an average molecular weight of about 750 g/mol, which is not favourable for dermal absorption. Due to the reactive isocyanate groups the substance is unstable towards nucleophiles, e.g. water or alcohols.

For acute and repeated (see chapter Repeated dose toxicity) inhalation the available studies reveal indications for “port-of-entry” irritant toxicity, which is typical for aliphatic isocyanates [1]. No systemic availability can be concluded from the results. This is also true for the acute oral toxicity study, as no effects at all were observed up to the maximum administered dose of 2000 mg/kg. Overall, with the exception of skin sensitisation (the LLNA exhibited a potential for skin sensitization and an acute irritation/inflammation response) none of the available studies reveal indications for systemic availability, however, due to the positive LLNA it cannot be completely ruled out. Nevertheless, despite the irritant effect which may diminish the protective function of the epidermis (worst case assumption) it is not expected for a substance with such a profile (i.e. irritancy at the port-of-entry due to isocyanate-reactivity) that systemic availability after dermal exposure is higher than after oral exposure.

Summarizing, with the mode of action outlined above, the oral LD50 > 2000 mg/kg and no signs of toxicity at all after oral exposure, it is not expected that testing on acute dermal toxicity would reveal adverse systemic effects. Local effects were already assessed by the respective skin irritation/corrosion studies. Thus, based on the weight of evidence a conclusion can be drawn that for acute dermal toxicity no hazard is expected. This is in line with recent publications[2][3], in which the benefit of performing acute dermal toxicity studies is in general questioned, in particular if there are no indications for a substance to be hazardous via the oral route. The European Competent Authorities for REACH and CLP (Caracal) have already acknowledged that. The committee agreed on proposals to amend REACH Annex VIII (8.5.3) as such that substances with no acute oral toxicity up to 2000 mg/kg would not require acute dermal toxicity data.[4][5]

[1] Brochhagen, Isocyanates, in: O. Hutzinger (Ed.), The Handbook of Environmental Chemistry, Vol. 3, Part G, Springer Verlag, Berlin, 1991

[2] Moore, Regulatory Toxicology and Pharmacology, 2013, 66, 30-37

[3] Creton, St. et al, Critical reviews in Toxicology, 2010, Vol. 40 No.1, pages 50-83

[4] http://www.piscltd.org.uk/wp-content/uploads/2014/09/20140714-110033_CA_61_2014-Acute-toxicity-testing-proposal.pdf

[5] https://chemicalwatch.com/20557/caracal-agrees-need-to-drop-acute-dermal-toxicity-tests

 


Justification for classification or non-classification

According to Regulation (EC) No 1272/2008, Annex I, the substance has to be classified as Acute Tox. 4 (H332: Harmful if inhaled).

According to Regulation (EC) No 1272/2008, Annex I, no classification is warranted for acute oral or dermal toxicity. With respect to dermal toxicity it is not assumed that testing on this endpoint would lead to a hazard classification for the substance taking into account the mode of action outlined above, the oral LD50 >2000 mg/kg, no signs of toxicity at all after oral exposure, and the expectation that systemic availability after dermal exposure will not exceed systemic availability after oral exposure. Therefore, it can be concluded that the available data are conclusive for non-classification for acute dermal toxicity.