Registration Dossier

Administrative data

Description of key information

MDI-TPG is irritating to skin, eyes and respiratory tract in humans.

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin irritation

Mondur PF (MDI-TPG) was not classed as a primary skin irritant in a skin irritation test on male and female rabbits after occlusive conditions. 24 hours after application slight erythema and very slight to slight edema were observed. All effects were fully reversible within 7 days (Birch, 1977).

Eye irritation

Mondur PF (MDI-TPG) was not classed as an eye irritant in an eye irritation test on male and female rabbits. Slight to moderate erythema was observed 24 hours after instillation, which was fully reversible within 7 days (Birch, 1977).

Respiratory tract irritation - read-across with other MDI substances

In an acute inhalation study with mice, pulmonary irritation of 4,4-MDI was assessed by recording respiratory patterns and frequency (Weyel and Schaffer, 1985). MDI acted primarily as a pulmonary irritant and with a concentration of 32 mg/m³ 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 6.7 mg/m³). The pulmonary irritation properties of MDI were confirmed by exposing mice via tracheal cannula to 23.6 mg/m³ MDI.

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 surfactant lining fluids.

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 is 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, a subsequent recovery and epithelial proliferative phase (e.g. bronchiolar and type II cell hyperplasia). Finally, 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 is 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 dysfunction of the pulmonary epithelial air/blood barrier occurred at a level as low as 0.7 mg/m³ and was interpreted as a dysfunction 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: R37, GHS: STOTsingleCat3).


Justification for selection of skin irritation / corrosion endpoint:
see "Discussion" and "Justification for classification or non-classification"

Justification for selection of eye irritation endpoint:
see "Discussion" and "Justification for classification or non-classification"

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Effects on respiratory irritation: irritating

Justification for classification or non-classification

Based on the results of the available skin and eye irritation studies with Mondur PF (MDI-TPG), classification for skin and eye irritation is not warranted according to Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. But together with human occupational case reports on 4,4-MDI (NIOSH, 1994), in which symptoms of skin and eye irritation were reported, the following legal classification of MDI as skin and eye irritant should be applied:

Skin irritation

With regard to skin irritation MDI was classified with R38 (irritating to skin) according to Directive 67/548/EEC and with Skin Irrit. Cat. 2 (H315: causes skin irritation) according to Regulation (EC) No. 1272/2008 (CLP).

Eye irritation

With regard to eye irritation MDI wasclassified with R36 (irritating to eyes) according to Directive 67/548/EEC and with Eye Irrit. Cat. 2 (H319: causes serious eye irritation) according to Regulation (EC) No. 1272/2008 (CLP).

Respiratory irritation

Due to respiratory irritation effects MDI was classified with R37 (irritating to respiratory system) according to Directive 67/548/EEC.

This classification corresponds to STOT Single Exp. Cat 3 (H335: may cause respiratory irritation) according to Regulation (EC) No. 1272/2008 (CLP).