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Administrative data

Description of key information

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Dose descriptor:
LD50
5 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Dose descriptor:
LC50
270 mg/m³

Additional information

Acute toxicity: oral

The acute oral toxicity was low with an LD50 value exceeding 5000 mg/kg bw in rats (cut-off value) according to OECD TG 423 (Schuengel, 2006a). At a test dose of 2000 mg/kg bw no animal died and no clinical signs were observed during the 14-day post observation period.

Acute toxicity: dermal

This information is not available.

Due to the fact that neither mortality nor clinical signs were seen after acute oral doses of 2000 mg/kg bw no systemic toxicity is expected after dermal exposure of up to 2000 mg/kg bw (limit dose).

Acute toxicity: inhalation

The acute LC50 of NDI was 270 mg/m3 (0.27 mg/l) in rats for a 4-hour aerosol exposure according to OECD TG 403 (Pauluhn, 1995). Exposure to concentrations of 96 mg/m3 and higher were followed by concentration-dependent signs suggestive of irritation of the respiratory tract (e.g. bradypnoea, dyspnoea, laboured breathing pattern, rales, nose/snout area with red encrustations, serous discharge from nose, cyanosis, hypothermia) and non-specific signs such as reduced motility, body weight gain, emaciation, and flaccid muscle tone. Exposure to concentrations equal or less than 189 mg/m3 test compound were tolerated without mortality. Necropsy findings support the conclusion that a causal relationship between lethality and lung damage existed.

A further acute inhalation study in rats (OECD TG 403; Pauluhn, 2003) was conducted to analyze bronchoalveolar lavage (BAL) parameters following a single 4-hour exposure (nose-only) to NDI concentrations of 56 to 1050 mg/m3 air using a solid aerosol with variable respirability (MMAD ranging from 3 -10 µm). This study suggests that respirable NDI aerosol appears to interact directly with the air-blood barrier causing a temporarily increased extravasation of plasma proteins as a result of a transiently permeability of the capillary endothelial cells. The data show unequivocally that not the concentration per se rather than the concentration of actually respirable particulates (i.e., these are those penetrating the alveolar region) is most important for the elicitation of irritant-related acute toxicity (mortality). These results support the conclusion that for hazard characterization both the concentration as well as the respirability of NDI dust needs to be considered.

Justification for classification or non-classification

Acute toxicity: oral

Not classified under Annex I of Directive 67/548/EEC. According to Annex I of Regulation (EC) No 1272/2008 no classification is required for acute oral toxicity (LD50 cut-off: >= 5000 mg/kg bw).

Acute toxicity: dermal

Not classified under Annex I of Directive 67/548/EEC or Annex VI-1 of Regulation (EC) No 1272/2008.

Acute toxicity: inhalation

Classified under Annex I of Directive 67/548/EEC with R20 (harmful by inhalation). This classification corresponds to Category 4* (minimum classification: harmful if inhaled) according to Annex VI-1 of Regulation (EC) No 1272/2008.

Note on classification of acute inhalation toxicity:

Without further information a LC50 value of 270 mg/m3 (4 hrs, aerosol) from an acute rat inhalation study with NDI (Pauluhn, 1995) would lead to classification with Category 2 (H330: fatal if inhaled) according to Annex I of Regulation (EC) No 1272/2008 or with R23 (toxic by inhalation) according to Annex I of Directive 67/548/EEC.

 

But 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 (2008) 1 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 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 particles present in the product as commercialized and used (= thoracic fraction). The proportion of the "thoracic fraction", in relation to NDI as it is produced, handled and used, is 0.02 % (IGF, 2010) 2. With respect to Directive 94/79EEC, the particle mass <50 μm was also less than approximately 1%. Thus, this particle-size analysis per se is not triggering

the determination of the acute inhalation toxicity bioassay with NDI. Therefore, the results obtained with the micronized test article under conditions which were utilizing additional technologies to maximize the concentration of respirable particles have limited relevance, if any, for classification (for detailed information see attached expert opinion of Prof. J. Pauluhn, Nov. 25, 2010). Therefore, the current legal classification of the acute inhalation toxicity with R20 (Cat.4) is maintained.

1 Pauluhn (2008): Inhalation toxicology - Methodological and regulatory challenges. Experimental and Toxicologic Pathology 60: 111-124

 

2 IGF (2010): Bericht über die Untersuchung von einer Materialprobe mit der Bezeichnung "Desmodur 15 Pt.P3YN000900" zur Beurteilung des Staubungsverhaltens durch Ermittlung der A-, T- und E-Staubwerte gemäß DIN 33897-2 "Kontinuierlicher Fall im Gegenstrom" und EN 15051, Methode B. Unpublished report of IGF (Institut für Gefahrstoff-Forschung der Berufsgenossenschaft Rohstoffe und chemische Industrie), Report No. A 7011/10, Bochum, Germany, Oct. 25, 2010