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EC number: 701-124-4
CAS number: -
The principal route of concern for human exposure is via inhalation. Reliable repeated dose inhalation toxicity data is available for the source substances 4,4’-MDI and pMDI (Hoymann et al. 1995., Reuzel et al. 1994) and are read across to the target substance. Since all substances of the MDI category contain significant levels of monomeric MDI, 4,4’-MDI represents a worst case with the highest levels of reactive free NCO groups. For the repeated dose toxicity endpoint, the observation in the respiratory tract, especially the lung noted in both source substances is consistent with the hypothesized MoA. As a MDI substance enters the lung, NCO groups react with biological nucleophiles at the MDI/lung fluid interface to form MDI-conjugates. Formation of these MDI-adducts depletes protective nucleophiles in the lung and results in pulmonary irritation and inflammatory cell influx. As these acute effects become chronic this result in histopathological changes characterized by interstitial fibrosis, hyperplasia of the alveolar epithelium and a low incidence of bronchiolo-alveolar adenoma, the latter occurring in the high exposure groups of both chronic source substance studies (Hoymann et al. 1995., Reuzel et al. 1994). The available animal toxicity data shows that the content of bioaccessible NCO groups is the driving factor of lung toxicity after repeated inhalation with a negligible contribution from the higher molecular weight components and a lack of any systemic exposure or toxicity. This supports the conclusion that data generated for 4,4’-MDI and pMDI can be used as a worst-case source for read across to the target substance, which has in common with the source substances a high content of bioaccessible monomeric MDI. Accordingly, the CLP classification (STOT RE 2, H373) for 4,4’-MDI and pMDI is adopted for all other substances in the MDI category, including the target substance 4,4-MDI/TPG.
In summary, the available data on the endpoint repeated dose toxicity are considered adequate and sufficient for classification and labelling. To support the weight of evidence additional testing is planned. It is considered to perform a sub-chronic inhalation toxicity study (OECD 413) with boundary substance 4,4’-MDI/DPG/HMWP. Additional, combined Repeated Dose Toxicity studies with Reproductive/ developmental Toxicity Screening tests (OECD 422) will be performed on 9 substances representing all sub-groups and key structural/chemical characteristics (see Test Proposal Summary attached in Chapter 13). These studies will confirm the proposed MoA on repeated dose toxicity or identify substances that may require additional testing.
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