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Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

Skin sensitisation - read-across with other MDI substances

Animal data indicates that MDI is a strong skin sensitiser, however animals appear to have lower thresholds than humans based on the limited findings of dermal sensitisation in workers and in case reports. This discordance is particularly evident for skin sensitisation where occupational experience shows that MDI and other diisocyanates are relatively weak inducers of allergic contact dermatitis while the mouse LLNA indicates MDI is a strong skin sensitiser.


Migrated from Short description of key information:
The key study was performed according to the Buehler method in guinea pigs. This study demonstrated that at epicutaneous, occlusive induction doses of 0.25%, 0.75%, and 2.5% MDI, animals exhibited equivocal responses (2/15, 4/15, 5/15) to high challenge concentrations of the test material. Only one definitive response (score of 1) was seen at a low induction dose to the mid-high challenge concentration. The dose response data indicates that this is a threshhold phenomena with a study NEL of 100 mM (2.5%) (Davis et al., 1984).

As supporting studies, two mouse local lymph node assays (LLNA) and mouse IgE studies demonstrated a skin sensitisation potential of MDI. There was a dose-response relationship found in the Mouse IgE Test for MDI, provoking a substantial increase in serum IgE levels compared with historical control values and statistically significant changes with respect to concurrent vehicle-treated controls. In the LLNA, exposure to MDI resulted in a substantial increase in IgE and a stimulation index of 3.45 at a dose of 0.03% MDI (Hilton et al., 1995, Dearman et al., 1992).

Justification for selection of skin sensitisation endpoint:
Only one key study available

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

Respiratory sensitisation - read-across with other MDI substances

A recently performed key study describes a 5-day inhalation exposure (days 0–4) of BN rats to two concentration x exposure time (C×t) relationships of 1000, 5000, and 10,000 mg MDI/m3 × min at exposure durations of either 10 or 360 min. This was followed by four 30 min inhalation challenges to 40 mg MDI/m3 on target days 20, 25, 50, and 65. After the last challenge, changes in breathing patterns delayed in onset were recorded and allergic lung inflammation was investigated by bronchoalveolar lavage (BAL). The high concentration delivered to the respiratory tract during the 10 min exposure period elicited a more vigorous response than the similar C × t at 360 min. In a subsequent study groups of rats were sensitised using the 10 min C × t protocol and challenged 3 times at 40 mg MDI/m3. At the fourth challenge a dose escalation regimen was used to determine the elicitation threshold on ‘asthmatic’ rats. The most sensitive endpoints characterizing an allergic pulmonary inflammation were BAL-neutrophils and physiological measurements showing respiratory changes delayed in onset. The dose escalation challenge yielded an elicitation threshold (NOAEL) of 5 mg MDI-aerosol/m3 at 30 min challenge duration (Pauluhn and Poole, 2011).

 

In another key study groups of guinea pigs were exposed to MDI by intradermal injection, topical application, or inhalation exposure for induction and by inhalation to 25-44 mg/m3 MDI for the challenge exposure. Attempts to sensitise guinea pigs by inhalation exposure to MDI were unsuccessful; no animals exhibited pulmonary responses following challenge with MDI. Intradermal injection or topical application of MDI induced specific antibody responses and pulmonary responses in 12-65% of guinea pigs depending upon induction dose and route. The differences in immunogenicity observed clearly reflect variation in exposure route rather than the concentration of MDI used for sensitisation (Rattray et al., 1994ab).

 

In a study using intradermal induction, 12.5% of the MDI sensitised guinea pigs showed a marked non-specific pulmonary reaction after an inhalation challenge of 35 mg/m3 MDI which was not observed in sham or vehicle controls. An association between increased airway responsiveness, increased airway eosinophilia, and increased levels of IgG1 anti-MDI antibody titers could not be established (Pauluhn, 1994).

 

In a study using three intradermal and a single, nose only, 15 minute inhalation induction exposure followed on day 21 by a 30 min, nose only inhalation challenge to 3.4-60 mg/m3 MDI or 35mg/m3 MDI-guinea pig serum albumin conjugate (MDI-GPSA), only MDI concentrations above the irritant threshold evoked a pronounced respiratory response. An increase in non-specific airway hyper-responsiveness was observed during acetylcholine-challenge in animals challenged previously with 60 mg/m3 MDI. Conclusive delayed onset respiratory responses were neither observed following the MDI nor the MDI-GPSA conjugate challenge. Respiratory responses were only provoked in animals challenged with overtly irritant MDI-concentrations ( Pauluhn and Mohr, 1994).

Another guinea pig study used an inhalation induction to 132 mg/m3 MDI, nose only for 15 minutes and an inhalation challenge to 3, 15, and 35 mg/m3 MDI for 20 min/concentration for a total of 60 minutes on day 21. Only a borderline response was seen with this protocol. Mild MDI-specific immediate-onset responses were observed mainly during challenge to slightly irritant concentrations (35 mg/m3). A marked increase of neutrophilic or eosinophilic granulocytes could not be established. Animals sensitised to high concentrations of aerosolized MDI showed a mild airway hypersensitivity without concomitant influx of inflammatory cells (Pauluhn, 1995).

An inter-laboratory study for the evaluation and validation of an animal model for low molecular weight chemicals to exhibit respiratory allergy in guinea pigs used intradermal induction of 0.0003 to 1% and an inhalation challenge on day 22 to 18-55 mg/m3 MDI. The results demonstrated that the intradermal injection of MDI was able to induce high titre antigen-specific antibodies in guinea-pigs. Inhalation exposure to MDI, approx. 3 weeks after sensitisation with MDI, induced a pulmonary response characterized by changes in respiratory rate (Blaikie et al 1995).

Although there are no guidelines available for respiratory sensitisation studies, several researchers have shown respiratory changes and/or antibody production in animals after induction exposure and subsequent challenge with MDI. The studies showed some type of respiratory response (alterations in respiratory rate, non-specific hyperreactivity, influx of inflammatory cells) however differences in immunogenicity observed clearly reflect variation in induction exposure route. Attempts to sensitise guinea pigs by single inhalation exposure only to MDI showed borderline responses at best. MDI-induced respiratory reactions were borderline as compared with potent respiratory sensitisers such as ova albumin and trimellitic anhydride. Respiratory responses were only provoked in animals challenged with overtly irritant MDI concentrations.

The BN rat MDI respiratory allergy study demonstrates the existence of a threshold for the elicitation of respiratory sensitisation following a multiple inhalation induction protocol and subsequent multiple challenges. The derived elicitation threshold C × t appears to be plausible relative to human evidence. The close association of C × t products triggering an elicitation response in asthmatic rats with the acute pulmonary irritation threshold C × t is intriguing and supports the view that for this class of chemicals portal of entry related allergic responses appear to be linked with pulmonary and/ or lower airway irritation. Accordingly, high concentrations delivered to the respiratory tract during short exposure periods appear to bear a higher sensitising potency than equal C × t products during longer exposure periods.

There are clinical case reports of occupational diisocyanate asthma after initial exposure to presumably high concentrations of MDI. Occupational challenge tests or specific inhalation challenges have demonstrated asthmatic responses to low levels of MDI in sensitised individuals. Although antibody testing is appealing as a diagnostic tool, unlike high molecular weight agents, these serologic markers are insensitive and non-specific for disease detection (Ott et al., 2007).

A current epidemiological study reports the decline of absolute number of diisocyanate asthma cases during the period of 1998 to 2002 in Canada: 30 ISO claims/yr during 1980 to 1993 as compared to 7.4 ISO claims/yr in the present study (Buyantseva et al, 2011). A more recent study in France has shown a significant decrease of work related asthma over the period 2001–2009 for cases related with isocyanate exposures (Paris C et al., 2012). In addition, a majority of diisocyanate asthma cases reported at least an improvement in respiratory symptoms at their last assessment; and 46% reported clearing of all of their symptoms (Buyantseva et al, 2011).


Migrated from Short description of key information:
MDI is a known human respiratory sensitiser. A recent key dose response study demonstrates that a threshold exists for the induction of respiratory sensitisation (Pauluhn and Poole, 2011). A 5-day inhalation exposure key study of BN rats to two concentration x exposure time (C×t) relationships of 1000, 5000, and 10,000 mg MDI/m3 ×min at exposure durations of either 10 or 360 min. This was followed by four 30 min inhalation challenges to 40 mg MDI/m3 on target days 20, 25, 50, and 65. The dose escalation challenge yielded an elicitation threshold (NOAEL) of 5 mg MDI aerosol/m3 at 30 min challenge duration.

Justification for selection of respiratory sensitisation endpoint:
No study was selected, since all available key studies on respiratory sensitisation of MDI (Rattray et al., 1994; Pauluhn and Poole, 2011) were positive.

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):

Skin and respiratory sensitisation

Animal data as well as studies in humans provide evidence of possible skin sensitisation and of respiratory sensitisation due to MDI.

With regard to sensitisation MDI was classified with R42/43 (may cause sensitisation by inhalation and skin contact) according to Directive 67/548/EEC. This classification corresponds to Skin Sens. Cat 1 (H317: may cause an allergenic skin reaction) and Resp. Sens. Cat 1 (H334: may cause allergy or asthma symptoms or breathing difficulties if inhaled) according to Regulation (EC) No.1272/2008 (CLP).