Registration Dossier

Administrative data

Description of key information

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:
no adverse effect observed
Dose descriptor:
NOAEC
6 mg/m³
Study duration:
chronic
Species:
rat
Quality of whole database:
The study is GLP compliant and is of sufficient quality (Klimisch score=2)

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
0.2 mg/m³
Study duration:
chronic
Species:
rat
Quality of whole database:
The study is GLP compliant and is of sufficient quality (Klimisch score=2)

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

Repeated dose toxicity - read-across with other MDI substances

Since no data on repeated dose toxicity are available for MDI-TPG, such data have been 'read across' from polymeric MDI. Inhalation exposure is the most appropriate route for assessing occupational risk 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 Duideline 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 occurence of pulmonary tumors 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) has been 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 proof of MDA-DNA adducts in marginal amount after 12 months MDI exposure is possibly feigned 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).

In a chronic rat study with polymeric MDI the NOAEC was 0.2 mg/m3 after aerosol exposure over 2 years (6 hours/day, 5 days/week) (Reuzel et al. (1990,1994). A comparison of the both chronic rat studies with 4,4'-MDI and polymeric MDI has shown very good consistency across the studies with respect to gradation of inhaled dose and the observed histopathological changes. In this review it was concluded that a daily 17 hr-exposure of 0.23 mg/m3 4,4-MDI corresponds approximately to a daily 6 hr-exposure of 1 mg/m3 polymeric MDI (Feron et al. (2001), Arch. Toxicol. 75: 159-175).

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.


Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Only one key study available

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Only one key study available

Justification for classification or non-classification

Based on the classification of monomeric MDI according to Directive 67/548/EEC and Regulation (EC) No. 1272/2008 (CLP) the following classification is recommended for MDI-TPG (read-across based on grouping of substances - category approach):

Repeated inhalation toxicity

With regard to repeated dose inhalation toxicity MDI was classified according to Directive 67/548/EEC with R48/20 (danger of serious damage to health by prolonged exposure) and according to Regulation (EC) No. 1272/2008 (CLP) with STOT Repeated Exp. Cat 2 (H373: may cause damage to the respiratory system through prolonged or repeated exposures).