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Description of key information

The test substance is irritating to the respiratory tract. According to the effect pattern observed in various experiments it was shown that the HDI-BT aerosol is predominantly a pulmonary irritant. No signs of specific systemic toxicity were described in the varoius acute inhalation bioassays. 
The test substance was practically non-toxic in rats after a single oral dose.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Dose descriptor:
discriminating dose
Value:
5 000 mg/kg bw
Quality of whole database:
reliable

Acute toxicity: via inhalation route

Endpoint conclusion
Dose descriptor:
LC50
Value:
400 mg/m³
Quality of whole database:
reliable

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute toxicity: oral

In a standard acute oral toxicity study , the test substance (approx. 100% pure, residual monomeric HDI < 0.5%) was orally administered to groups of 10 Sprague-Dawley rats per sex per dose. Treatment was performed as a single dose application at dose levels of 5000 mg/kg bw. Animals were subsequently observed for a period of 14 day for clinical signs of toxicity, body weights changes and cases of mortality. 

No mortality was observed at any dose level. Hence the LD 50 is higher than 5000 mg/kg bw. Clinical signs of toxicity were absent and no differences concerning body weights or findings in necropsy are reported (Rhone Poulenc Inc., 1983).

This study is suitable for assessment of acute oral toxicity as it was performed according to the OECD 401 guideline and the test substance is sufficiently characterized.

In a supporting standard acute toxicity study, 10 rats (5 males and 5 females) were each orally administered the test substance as 50% solution in ethyl acetate. The limit dose was 5000 mg/kg bw (corresponding to 10000 mg/kg bw of the solution). Animals were subsequently observed for a period of 14 days. In this period clinical signs of toxicity, body weights changes and cases of mortality were noted. 

In total 2 females died within the observation period. Hence, the LD 50 is higher than 5000 mg/kg bw. Dyspnoea, staggering, atony, apathy in some cases, abdominal position, exsiccosis and poor general state were observed in surviving animals but were all reversible within 1 day (BASF AG, 1975).

This study is suitable for assessment of acute oral toxicity as it was performed according to a protocol similar to that of the obsolete OECD test guideline 401.

In a second supporting acute toxicity study the test article was administered to 10 male rats by single oral gavage, with an observation period of 14 days. The test conduct in principles was similar to the OECD TG 401; the tested dose was 5 mL/kg bw. One male died, and all animals showed increased diuresis and decreases in body weight. Thus, the LD50 was > 5 mL/kg bw (Bayer, 1977).

 

 

Acute toxicity: dermal

no data available

 

Acute toxicity: inhalation

An acute LD50 inhalation toxicity assay was performed according to the OECD 403 guideline (Bayer, 1985). Male and female rats were whole body-exposed to aerosols of HDI, oligomerisation product (biuret) for 4h. The LC50 was identified to be 402 mg/m3 for male and female animals. Notably a delayed type of mortality was observed, occurring within 2 days following exposure. Gross pathology indicated hydrothorax and/or haemorrhagic lungs.

 

In a comparative study mice and rats were exposed for 6h to an aerosol concentration of 10 mg/m3 HDI, oligomerisation product (biuret) (Pauluhn, 2008). The exposure modifying role of the content of residual HDl monomer in the polyisocyanate on pulmonary irritation was addressed by using HDI-BT containing approximately 0.1% or 2% HDl monomer (in short 0.1% HDI-BT and HDI-BT, respectively). This study confirmed the toxicological pattern of a pulmonary irritant as seen by lung function measurements and BAL analysis. For most of the endpoints examined, rats were more susceptible than mice. A difference in pulmonary irritant potency between 0.1 % HDI-BT and 2% HDI-BT aerosols was not apparent. The increase of protein in BAL 1 day following a 6h exposure to 10mg/m3 was only 2- or 8-fold the control values in mice and rats, respectively. Lung weight increase was only detected in rats (+10-13% of control). The effective dose levels in this study correlated well with the NOAECs from an acute pulmonary irritation study with HDI-IC and subchronic 3 months inhalation studies in Wistar rats with both HDI-BT and HDI-IC aerosols (NOAECs approximately 3 mg/m3).

 

Generally no signs of systemic toxicity were described in any of the above described acute inhalation bioassays.

Justification for classification or non-classification

The available experimental test data are considered reliable and suitable for the purpose of classification. No classification is required for acute oral and dermal toxicity according to Regulation (EC) No 1272/2008 Annex I and DSD.

 

Despite the 4 hour LC50 of 402 mg/m3 male/female rats (approximate value; Bayer AG, 1995) the substance currently is not classified according to Regulation (EC) No 1272/2008, Annex I for acute inhalation toxicity Cat. 2 due to the following reasons:

The Guidance on the Application of Regulation (EC) No 1272/2008 acknowledges (e.g. chapter 3.1.2.3.2) that special consideration is required if a substance is tested in a form (i.e. specific particle size distribution) that is different from the forms in which the substance is placed on the market and in which it can reasonably be expected to be used. According to Pauluhn (Experimental and Toxicologic Pathology 60, 2008, 111-124) there is an option for a modified Classification and Labelling (C&L), called “split-entry concept”.

While the current test principles for acute inhalation uses a predetermined particle size (MMAD 1 -4 µm) in the breathing zone of exposed animals in order to allow a robust relative ranking of the acute lethal toxic potency of different substances, split entry takes into account for an assessment of potential human hazards the actual percentage of the critical percentage of particles (=> thoracic fraction) present in the product as commercialized and used. This “split-entry concept” was already discussed on EU level, at the latest on 21stJanuary 2008 (Ispra, Italy) and is acknowledged in the recently published version of the ECHA-guidance on the application of the CLP criteria (Guidance on the Application of the CLP Criteria (ECHA-12-G-14-EN), Version 3.0, Nov 2012).

For HDI oligomerization product (biuret) the prerequisites for employing split-entry are given, e.g. the substance is a liquid with a very low volatility causing local toxicity (irritation) in the lower respiratory tract, but no systemic toxicity after acute inhalation exposure to rats (Pauluhn, 2001 and 1984). The irritating potential of the substance on the portal-of-entry is confirmed by other acute and repeated studies on animals, where only minor indications for systemic toxicity could be observed at all (e.g. positive skin sensitisation potential) that are not regarded to be of relevance for the assessment of acute toxicity. Currently available data on particle size during worst-case end-use of HDI oligomerization products indicate a thoracic percentage below the requested threshold justifying a modified C&L for acute inhalation toxicity for the substance. On this basis the classification for the substance is for acute inhalation toxicity Cat. 4, H332: Harmful if inhaled (Xn, R20). Further studies regarding the particle size distribution are presently ongoing.