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Endpoint summary

Description of key information

The LD50 of the test substance after oral administration to rats was found to be greater than 2000 mg/kg bw (BASF SE, 2003). 
In an OECD403 acute inhalation toxicity study with an allophanate-type HDI-oligomer-isoform (Desmodur XP 2580) an LC50 of 314mg/m3 was determined for female rats and 264mg/m3 for male rats (Bayer AG, 2011). 
The test substance caused dose-dependent pulmonary irritation in rats after 6 hour inhalation exposure (BASF SE, 2003; Bayer AG 2013).

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral toxicity:

In a GLP-compliant study, performed according to OECD guideline 423, the acute oral toxicity of the test substance following single oral administration in female Wistar rats was investigated (BASF, 2003). Single doses of 2000 mg/kg body weight of test material preparations in olive oil Ph.Eur./DAB were given to two administration groups of three fasted female animals, by gavage in a sequential manner. No mortality occurred. No clinical signs and findings were observed. The mean body weights of the administration groups increased throughout the study period. No macroscopic pathologic abnormalities were noted in the animals examined at the end of the observation period. Under the conditions of this study the LD50 of the test substance after oral administration was found to be greater than 2000 mg/kg body weight in rats.

Acute dermal toxicity:

No data available.

Acute inhalation toxicity:

A GLP-compliant acute toxicity study was performed according to the guideline TRGS 430 (Isocyanate-Exposition und Überwachung). The early pulmonary response of male Wistar rats exposed nose-only to the test substance as a liquid aerosol was examined (BASF, 2003). The time course of the acute pulmonary toxicity in rats exposed to target concentrations of 0, 0.5, 3, 15 mg test substance/m³ was determined. The duration of the exposure was 6 hours, followed by serial sacrifices 1 day, 3 days and 7 days post exposure. Bronchoalveolar lavage fluid (BALF) was analyzed for markers indicative for injury of the bronchoalveolar region. For target concentration 0.5, 3 and 15 mg/m³, respectively, mean concentrations of 0.8, 3 and 16.7 mg/m³ were measured, and particle size distribution (mean MMAD (µm)/GSD) of 2.3/1.9, 1.8/1.9 and 1.8/1.9, respectively. In none of the test groups clinical signs of toxicity or a treatment related influence on body weight development was found. Examination of BALF showed increase of total protein, enzyme activities, polymorphonuclear neutrophilic granulocytes and other inflammatory cells in the test groups exposed to 16.7 mg/m³, when lavaged 1 day or 3 days post exposure. These symptoms were not observed when the animals were lavaged on day 7 post exposure.

An increased total protein in BALF was supposed to be the most sensitive marker indicative for lung injury. With respect to the increase of the total protein concentration in BALF of animals exposed to 16.7 mg/m³ on study day 1, the no adverse effect concentration of the test substance was considered to be the intermediate concentration tested (3 mg/m³). This NOAEC was supported by an alternative calculation by means of the concentration response curve of relative increase of total protein in BALF on day one after exposure.

 

In a comparative investigation of the pulmonary irritant potency, two allophanate-type HDI oligomers were tested according to TRGS430 (Desmodur XP 2580 and Basonat HA 3000). A NOAEC of 3.4 mg/m³ was derived for both substances (Bayer, 2013).

Summarized, comparable NOAECs of approx. 3 mg/m³ were identified for the allophanate-type HDI oligomers. These NOEACs were derived based on an increase of the total protein concentration in BALF as the most sensitive marker indicative for lung injury when tested according to TRGS430.

 

Based on identical NOAECs for respiratory irritation identified for both “Allophanate-type HDI oligomers”, read across for acute LC50 is justified (see attached document for read-across Justification). In an acute aerosol inhalation toxicity study (OECD TG 403) with an allophanate-type HDI oligomer (Desmodur XP 2580) a LC50 values (4h, nose only) of 314 mg/m³ for female rats and 264 mg/m³ for male rats (approximate values) were determined (Bayer, 2011). Clinical signs indicative for lower respiratory irritation were described in exposed animals. Furthermore, e.g. bradypnoea, labored breathing, reduced motility, serous nasal discharge were observed up to postexposure day 10. No signs of systemic toxicity were observed.

 

Justification for classification or non-classification

Based on the results of an oral acute toxicity study, the substance does not need to be classified for acute oral toxicity according to Directive 67/548/EEC and according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

 

Despite the 4 hour LC50 of 314 mg/m³ for female rats and 264 mg/m³ for male rats (approximate values) the substance 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 21^stJanuary 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, November 2012).

For the allophanate-type HDI oligomer the prerequisites for employing split-entry are given, e.g. the substance is a viscous 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 (Bayer AG, 2011; BASF SE 2003, Bayer AG, 2013). Furthermore this portal of entry toxicity (local irritation) in absence of systemic toxicity is well characterised in acute and repeated exposure animal assays for structurally similar substances (e.g. HDI, oligomerisation product (isocyanurate-type), Desmodur N3300).

Currently available information on particle size during worst-case end-use of the HDI oligomer suggest 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). Specific studies regarding the particle size distribution are presently ongoing.