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Diss Factsheets

Administrative data

Description of key information

Skin irritation: irritating in rabbits (OECD TG 404)

Eye irritation: irritating in rabbits (Draize test)

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)

Additional information

Data on physical and chemical properties, eco-toxicity and toxicity can be used for read-across from 2,4-TDI to 2,6-TDI and mixed TDI isomers (i.e. 80/20, 65/35, 2,4/2,6 ratios).  2,4 TDI is the major component of the TDI mixed isomers and so has the major influence on their properties and effects. The reactivity of the 2,6-TDI isomer is somewhat less than that of 2,4-TDI but is of the same order of magnitude. It may therefore be concluded that the effects of 2,6-TDI will be similar to those of 2,4-TDI. This is in fact observed where there are overlapping data.

Skin irritation: 

Unfortunately no OECD-guideline skin irritation study performed under GLP conditions is available. There are several skin irritation studies, all showing evidence 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 4h. Edema was described to be severe immediately after removal of the test substance, but was only barely perceptible 72h later. 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)applied0.5 ml of a TDI-isomer mixture for 1 or 4h 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 seenfollowing 4h of semiocclusive application. Erythema was not fully reversible within the observation period. Additionally slightly brownish discolorations and desquamation were described. Histopathology revealeda damage of the epidermis ulcerating into the outer part of the dermis. The extend of this full thicknessnecrosison 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 regnerated 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 4h required by the OECD guideline. These studies are therefore summarized for completeness:

In a skin irritation assay with a 24h exposure period, 0.5ml 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 apolymerisation reaction of TDI and consequently an adhesion of the pad to the skin.

A bioassay in rats demonstrates that with long exposure periods (8h) and high application volumes (100µl), no macroscopical signs of necrosis occured (Gamer, 2007, see7.1.2). This may be partly due to the lower sensitivity of rat skin compared to rabbit skin. Though, histopathologigal 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 summarized studies is demonstrating a strong skin irritatating 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 4h. 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 is 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, unter guideline conditions (4h, 50µl). 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 a 8h exposure on rat skin (100µl), the extend of the full thickness necrosis identified by hisopathology 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 uncertanties a conclusive evaluation of the indications of skin corrosion according to the described legal guidance is not possible. Therfore the current legal classification in Annex I to Directive 67/548 as a strong skin irritant (R38, 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 ofTDImixed 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-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.

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Justification for classification or non-classification

Official EU classification according to Directive 67/548/EEC is Xi; R36/37/38, Irritating to eye, respiratory system and skin,

and by EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008), is Eye irritation 2, Skin irritation 2, Causes serious eye irritation, causes skin irritation.

Skin irritation/ corrosion: Category 2, causes skin irritation

Eye irritation/corrosion: Category 2, causes serious eye irritation