m-tolylidene diisocyanate

Endpoint summary

Description of key information

Skin irritation:

The skin irritation potential of the test substance was cHaracterized in an weight of evidence approach, considering several publications (Knapp/Baker, 1974; Sudberg, 1984; Peschel, 1970). The studies where performed in rabbits,rats, or guinea pigs. The test substance showed a skin irritating potential.

Eye irritation:

In an eye irritation study according to Draize, the test substance showed eye irritation properties in rats (Wazeter, 1964).

Respiratory irritation:

The test substance showed a respiratory irritation potential in an acute (Doe/Horspool, 1980) and in a chronic study (Owen, 1980). Both studies were conducted in rats.

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: 

There were several skin irritation studies available but none of them conducted under GLP-conditions. All studies showed evidences of strong irritation of various severity. Knapp and Baker (1974) evaluated the skin reactions of rabbits after an occlusive application of 0.5 mL TDI (presumably mixed isomers) for 4 h. Edema was described to be severe immediately after removal of the test substance, but was only barely perceptible after 72 h. Furthermore mild erythema was described. Both effects were not fully reversible after 7 days. No later reading and no histopathology is reported. The reliability of this assay is limited by the demonstrated inconsistencies in reporting and study conduction at the Industrial Bio-Test Laboratories within the time frame of the study performance. Even though according to the Manual for Investigation of HPV Chemicals (OECD, 2005) mostly non acute assays were affected, this irritation study can be used within a weight of evidence classification at the most. Suberg (1984) applied 0.5 mL of a TDI-isomer mixture for 1 or 4 h on both flanks of 6 rabbits. One flank was covered occlusively, the other semiocclusively. Macroscopical readings were performed for up to 13 days and on days 6, 13 and 28, two animals were sacrificed for histopathology, respectively. Macroscopically, persistent erythema, sclerema, edematous swelling indicative for a strong skin irritation were seen after 4 h of semiocclusive application. Erythema was not fully reversible within the observation period. Additionally, slightly brownish discolorations and desquamation were described. Histopathology revealed a damage of the epidermis ulcerating into the outer part of the dermis. The extend of this full thickness necrosis on the application area was not described in detail. Furthermore an intense and almost complete reepitheliation 13 to 28 days after removal of the test substance was described. An increased hair growth was detected on most of the regenerated skin area, which is not indicative for a scar-tissue. Alopecia is a key characteristic of scar tissue and by this of irreversible tissue damage.

In the following irritation assays exposure times were way longer than 4 h as required by the OECD guideline. These studies are therefore summarized for completeness: In a skin irritation assay with a 24 h exposure period, 0.5 mL of the 2,4 -isomer were applied on the skin of rabbits (Duprat, 1976). Moderate, reversible erytema and edema were reported (though not supported by individual readings). At intact skin areas necrosis of various severity was described. Histopathology revealed epidermal atrophy and cellular infiltration of the dermis 3 days following removal of the test substance and in one animal scar formation was desribed after 10 days. The authors speculate, that this may partly be due to a polymerisation reaction of TDI resulting in an adhesion of the pad to the skin. A bioassay in rats demonstrated that with long exposure periods (8 h) and high application volumes (100 µL), no macroscopical signs of necrosis occured (Gamer, 2007, see 7.1.2). This may be partly due to the lower sensitivity of rat skin compared to rabbit skin. Though, histopathological examination revealed multifocal to coalescing epidermal full thickness necrosis. The assay was performed with the single isomers (2,4- and 2,6-TDI) but no significant differences in skin response was described. Only mild irritation was observed on guinea pig skin exposed to an unknown amount of mixed TDI for an unknown exposure period (Peschl, 1970).

Summarized, the weight of evidence of the studies is demonstrating a strong skin irritating reaction of TDI. By definition skin corrosion is an irreversible damage to the skin. It should be a visible necrosis through the epidermis into the dermis, following the application of a test substance for up to 4 h. Corrosive reactions are typified by ulcers, bleeding, bloody scabs and, by the end of observation at 14 days, by discoloration due to blanching of the skin, complete areas of alopecia and scars. A final evaluation and assessment of skin corrosion of TDI according to these criteria was not possible due to significant deficiencies in study perfomance or reporting of most studies. In non of the presented studies a strong discoloration was reported after exposure of rabbits, under guideline conditions (4 h, 50 µL). At the most, a slightly brownish discoloration was reported by Suberg. Full thickness necrosis was identified by means of histopathology but the extend and severity (punctual or extensive) could not be unequivocally dissolved from the study report. Following an 8 h exposure on rat skin (100 µL), the extend of the full thickness necrosis identified by histopathology was described as multifocal to coalescing, though not planar. Finally, it can not be resolved to which extend chemical reaction of TDI to the skin surface is contributing to the observed effects.

Due to the described uncertainties a conclusive evaluation of the indications of skin corrosion according to the described legal guidance is not possible. Therefore the current legal classification in Annex I to Directive 67/548 as a strong skin irritant (GHS cat 2) seems to be appropriate.

Eye irritation:

In a Draize study (Wazeter et al., 1964) of acceptable quality (validation criteria 2), a sample of TDI mixed isomers (not further specified) was tested in 3 groups of 3 rabbits. One group was tested in unwashed eyes, one with eyes washed after 2 seconds exposure and the other washed after 4 seconds. Irritation was scored at 30 minutes, 1.5, 4, and 8 hours and daily up to 30 days. The test material was irritating to the eyes causing moderate to severe corneal opacity, severe irritation of the conjunctivae, purulent discharge and depilatory effects. Irritation was more persistent in the unwashed group with corneal opacity persisting in 2 rabbits until day 30. These results show that TDI is a severe eye irritant.

Respiratory irritation:

Signs of respiratory irritation were apparent in acute and chronic inhalation studies in rodents. In an acute study in rats wheezing and gasping were observed (Doe and Horsepool, 1980) and in a chronic study in rats rhinitis was observed at a dose level of 0.05 ppm (Owen, 1980).

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008.

Eye and skin irritating properties were documented. As a result the substance should be classified as eye irritating (category 2, H319) and skin irritating (category 2, H315) under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776.