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Administrative data

Description of key information

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional 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.

Skin irritation:

In the initial study, the test substance 4,4 '-MDI/4,4'-MDI homopolymer was found to be irritating to the skin of rabbits according to the EEC Irritation Rating and the GHS Classification was Corrosive (category 2) (Mallory VT, 2009b). A confirmatory in vitro assay was performed (Mallory VT, 2010) that demonstrated that the test material is not a corrosive substance.

In a guideline irritation study with generic MDI (Desmodur VP.PU1806) erythema and eschar formation was observed, which was most distinct 7 days after the application of the test substance (Märtins, 1991). Since these effects were not reversible within an observation period of 14 days, the test substance has to be classified as a skin irritant according to EU (R38) and GHS (Cat.2).

Only mild irritation was observed in an older, well conducted non GLP-study with 4,4´-MDI applied under occlusive dressings (Schreiber, 1981). The reported irritation scores would not result in a classification as a skin irritant according to EU and GHS standards, but the reversibility of the effects can not be adequately addressed due to a missing reading time point 14 days following application of the test substance.

Results obtained from an acute dermal study in rabbits and rats with polymeric MDI (Wazeter, 1964), and further irritation studies with technical MDI (Duprat et al., 1976) equally resulted in slight skin irritation.

Summarized the results of the key study (Märtins, 1991) together with human occupational case reports (NIOSH 1994) support the official classification as skin irritant (EU: H315, GHS: Cat2).

Eye irritation: 

In a guideline eye irritation study with the same batch of generic MDI (Desmodur VP.PU1806) as used for the skin irritation key study, no irritation to the eyes according to the EU and GHS regulations was observed (Märtins, 1991). Likewise no eye irritation was observed when monomeric 4,4´-MDI was applied to the eyes of rabbits without rinsing (Schreiber, 1981).

Slight eye irritation was observed in a group of 6 female rabbits when technical MDI was applied (Duprat et al., 1976). The study result was obtained according to the method of Kay and Calandra, but due to incomplete reporting no classification according to EU and GHS is possible.

Summarized the available animal data would not support classification of MDI as an eye irritant. But together with human occupational case reports ( NIOSH, 1994) in which symptoms of eye irritation were reported the legal classification as eye irritant (EU: H319; GHS: Cat2) should be applied.  

Respiratory tract irritation:

In an acute inhalation study with mice, pulmonary irritation of 4,4`-MDI was assessed by recording respiratory patterns and frequency (Weyel and Schäfer, 1985). MDI acted primarily as a pulmonary irritant and with a concentration of 32mg/ the respiratory rate was decreased  by 50%. The magnitude of effect was dependent on the duration of exposure and the exposure concentration. Increases in lung weight were observed in all tested MDI concentrations (lowest tested concentration 6.7mg/ ). The pulmonary irritation properties of MDI were confirmed by exposing mice via tracheal cannula to 23.6 mg/m³ MDI.

Other studies:

The following studies on respiratory irritation are discussed in IUCLID and CSR sections on specific investigations.

In a short-term inhalation toxicity study of polymeric MDI in rats acute irritation was correlated to the alteration of surfactant activity (Pauluhn et al., 1999). When single exposures of various concentrations were applied for 150 min, stimulation of pulmonary irritant receptors was assumed to occur at exposure levels in the range of 2.4 mg/m³. In the second part of the study, rats exposed to 3.3 and 13.7 mg/m³ for 14 days, experienced mild signs of respiratory tract irritation. Light and transmission electron microscopy suggested that this irritation was accompanied by an accumulation of refractile, yellowish-brownish material in alveolar macrophages, with concomitant activation of type II pneumocytes. Additionally increased levels of intracellular phospholipids and an increase of bromodeoxyuridine-labelled epithelial cells were detected. The authors suggested that polymeric MDI appears to interact directly with pulmonary lining fluid surfactant.

In a further study with a similar study design, acute exposures to all tested pMDI-atmospheres (10, 30, or 100 mg/m³) resulted in signs of respiratory tract irritation (abnormal respiratory noise, breathing rate reduced and depth increased, mucous secretions from the nose) and a pattern of lung responses that was consistent with exposure to irritant aerosols (Kilgour et al., 2002). An exposure concentration related body weight loss and increase in lung weight were seen post-exposure, with complete recovery by day 10. Analysis of lung lavage fluid revealed irritation related changes in the lung over the initial days following exposure. These consisted of a pattern of initial toxicity, rapid and heavy influx of inflammatory cells (alveolar macrophages) and soluble markers of inflammation and cell damage, increased lung surfactant, with a subsequent recovery and epithelial proliferative phase (e.g. bronchiolar and type II cell hyperplasia). Finally (by day 30 post exposure), a return to the normal status quo of the lung (by day 30 post exposure) was observed.

In the same report repeated exposure over 28 days (1, 4, or 10 mg/m³) produced an increase in lung weight in the high dose group, which resolved following the 30-day recovery period. Other effects seen were again consistent with exposure to irritant aerosols, but were less severe than those seen in the acute study. 1 mg/m³ was derived as the LOAEL for effects on surfactant homeostasis (NOAEL 1 mg/m³) and (reversible) bronchiolitis, whereas the NOAEL for pneumonitis was less than 10 mg/m³.

Pauluhn (2000) examined the acute pulmonary response of rats to respirable polymeric MDI aerosol atmospheres (0.7, 2.4, 8, or 20 mg MDI/m³). The time course of the relationship between acute pulmonary irritation and ensuing disturbances of the air/blood barrier was determined by analyzing the bronchoalveolar lavage (BAL) fluid for markers indicative of injury of the bronchoalveolar region. The most sensitive markers of dysfunction of the air/blood barrier were identified to be angiotensin-converting enzyme (ACE), protein, and alkaline phosphatase. Except increased glutathione in lung tissue, changes returned to the level of the air-exposed controls on day 7.

Partially glutathione-depleted rats exposed to 20 mg/m³ experienced a more pronounced increase in BAL protein than normal rats (Pauluhn, 2000) indicating that respirable polymeric MDI aerosol interacts directly with the air/blood barrier causing increased extravasation of plasma constituents as a result of increased permeability of capillary endothelial cells.

A transient change of the pulmonary epithelial air/blood barrier occurred at a level as low as 0.7 mg/m³ and was interpreted as representative of a normal homeostatic response of pulmonary surfactant. There is currently no consensus expert opinion, whether to define these reversible observations as an adverse effect leading to a physiological response, and therefore whether to define the effective concentration of 0.7 mg/m³ as LOAEL or NOAEL. Since no cytotoxicty or pulmonary functional changes occurred at this dose level, the exact biological significance of such transient increase in protein and ACE in the bronchoalveolar lavage is not known.

In a further study of Pauluhn (2002), an acute irritant threshold concentration of 0.5mg/m3 was estimated for pMDI, which may serve as a conservative NOAEL for further risk characterization.

Summarized MDI should be classified as a respiratory tract irritant (EU: H335, GHS: STOTsingleCat3).

Justification for selection of skin irritation / corrosion endpoint:
OECD 404 Guideline study with GLP

Justification for selection of eye irritation endpoint:
OECD 405 Guideline study with GLP

Effects on skin irritation/corrosion: irritating

Effects on respiratory irritation: irritating

Justification for classification or non-classification

The results of the key study (Mallory, 2009) together with human occupational case reports (NIOSH 1994) support the official classification as skin irritant (EU: H315, GHS: Cat2).

The available animal data would not support classification of MDI as an eye irritant. But together with human occupational case reports ( NIOSH, 1994) in which symptoms of eye irritation were reported the legal classification as eye irritant (EU: H319; GHS: Cat2B) should be applied.  

The available data support the classification of MDI as a respiratory tract irritant (EU: H335, GHS: STOTsingleCat3).

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