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Description of key information

The test substance is covered by the category approach of methylenediphenyl diisocyanates (MDI). Hence, data of the category substances can be used to cover this endpoint. The read-across category justification document is attached in IUCLID section 13. It is important to note that the MDI category approach for read-across of environmental and human hazards between the MDI substances belonging to the MDI category is work in progress under REACH. Therefore the document should be considered a draft.

Inhalation exposure is the most appropriate route for assessing occupational risk of 4,4'-MDI in humans.  Reuzel et al. (1990, 1994) and Hoymann et al. (1995) showed in rats that, after chronic inhalation, major pulmonary effects of MDI were characterized by hyperplasia, interstitial fibrosis and a (with a low incidence) bronchiolo-alveolar adenoma.  A similar qualitative response was seen following exposure to polymeric and monomeric MDI.  A LOAEC of 1 mg/m³ was derived from the study by Reuzel et al. (1990, 1994).

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:
adverse effect observed
Dose descriptor:
LOAEC
1 mg/m³
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

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

Inhalation exposure is the most appropriate route for assessing occupational risk of 4,4'-MDI in humans. Effects from repeated exposure of animals to 4,4'-MDI are limited to effects on the respiratory tract caused by local irritation.

In a combined chronic toxicity and carcinogenicity key study (Reuzel et al., 1990, 1994; GLP, reliability 2 study conducted according to OECD Guideline 453 - combined chronic toxicity/carcinogenicity studies) rats were exposed for 6 hours/day, 5 days/week for 1 year (satellite groups) or 2 years (main groups) to polymeric MDI aerosol concentrations of 0, 0.2, 1.0 or 6.0 mg/m³ (analytical conc.: 0, 0.19, 0.98, 6.03 mg/m³) . The effect of chronic exposure of rats to respirable polymeric MDI aerosol was confined to the respiratory tract. The compound-related changes were found in the nasal cavity, the lungs and the mediastinal lymph nodes, and to some degree they were already present after 1 year of exposure. Histopathology of the organs/tissues investigated showed that exposure to 6.0 mg/m³ over 2 years was related to the occurrence of pulmonary tumours in males (6 adenomas and 1 adenocarcinoma) and females (2 adenomas). In this 2-year rat study the NOAEC was 0.2 mg/m³ for the repeated dose toxicity of polymeric MDI. The LOAEC was set on 1.0 mg/m³.

A chronic inhalation study (Hoymann et al., 1995) was conducted with monomeric 4,4’-MDI. Female Wistar rats were exposed to 0.23, 0.70 or 2.05 mg/m³ 4,4’-MDI aerosols for 17 hours/day, 5 days /week for up to 24 months. Essentially, a dose-dependent impairment of the lung function in the sense of an obstructive-restrictive malfunction with diffusion disorder, increased lung weights, an inflammatory reaction with increased appearance of lymphocytes in the lung in the high dose group as a sign of specific stimulation of the immune system by MDI, an intermediately retarded lung clearance in the high dose group as well as dose-dependent interstitial and peribronchiolar fibrosis, alveolar bronchiolisations and a proliferation of the alveolar epithelium, which was classified as preneoplastic, as well as a bronchiolo-alveolar adenoma were ascertained. Therefore, the LOAEC for the female rat was 0.23 mg/m³ after long-term inhalation of 4,4'-MDI aerosols. The finding of marginal amounts of MDA-DNA adducts in olfactory epithelium, but not the lung, after 12 months MDI exposure is considered to be a confounded by the strong protein binding. The toxicological relevance of this finding is doubtful since MDI leads only in high concentrations to degeneration of the olfactory epithelium (Greim H (ed.) 2008, in: Occupational Toxicants - Critical data evaluation for MAK values and classification of carcinogens, Wiley-VCH, Weinheim, Vol. 14).

A comparison of the pulmonary effects described in female rats from the two chronic studies was published by Feron et al. (2001). To assist the comparison, the authors normalized the different MDI doses to total inhalation exposures calculated as 559, 1972, 2881, 6001, 17575 and 17728 mg MDI.h/m³. The major pulmonary effects in the two studies were characterized by hyperplasia, interstitial fibrosis and a low incidence of bronchiolo-alveolar adenoma, the latter occurring in the high exposure groups of both studies (i.e. total inhalation exposures of 17728 and 17575 mg MDI.h/m³). Both studies also reported the presence of particle-laden macrophages predominantly in the alveoli close to the alveolar ducts which in some cases, particularly in high dose groups, were associated with areas of fibrosis. There was a clear quantitative dose response in both studies with the lowest dose of 559 mg MDI.h/m³ from the study reported by Reuzel et al. (1994) being described as the no-observed-adverse-effect-level (NOAEL). It was also suggested (Feron et al., 2001) that the mild histopathological changes seen in the low exposure animals (0.23 mg MDI/m³) in the study reported by Hoymann et al. (1995), would not have occurred if the exposure had been for 6 hours/day. An exposure of 0.2 mg MDI/m³ over a 6 hour period was judged to be the NOAEL in both studies. Overall the analysis concluded that both studies showed similar qualitative responses to exposures to pMDI or mMDI.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

GLP compliant study with reliability 2, conducted according to OECD Guideline 453 (combined chronic toxicity/carcinogenicity studies)

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: lung

Justification for classification or non-classification

Classified as R48/20 according to the DSD (including the 30th and 31st ATP): Danger of serious damage to health by prolonged exposure. Classified as STOT RE 2 according to CLP: May cause damage to the respiratory system through prolonged or repeated exposures.