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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.

As aromatic diisocyanates are virtually insoluble in water an organic solvent is required to ensure homogeneous dispersion in in vitro genotoxicity assays. Dimethylsulphoxide (DMSO) has been used routinely as the vehicle of choice for such assays. The validity of using DMSO as a solvent was queried by Gahlman et al (1993) when it was found that there was a chemical conversion of TDI to TDA in the solvent which could explain a number of positive responses recorded in some in vitro genotoxicity assays. A detailed evaluation of the stability of TDI in dimethylsulphoxide (DMSO) by Seel et al (1999) showed there is a rapid breakdown of TDI in DMSO with less than 60% of the initial amount remaining after 15 minutes. A HPLC examination of the breakdown products showed TDA was first detected at 15 minutes rising to 8% after 30 minutes. The authors concluded that in traditional bacterial mutation assays with Salmonella typhimurium using DMSO as the solvent conversion of TDI to ureas, polyureas and TDA would be complete within minutes and the TDI would not have been tested. To determine if the positive results seen in in vitro genotoxicity assays when TDI was dissolved in DMSO was in fact a consequence of the chemical break down of TDI to TDA Seel et al (1999) undertook a series of mutagenic investigations using dry ethyleneglycol dimethylether (EGDE) as the organic solvent as investigations indicated TDI was stable in this solvent with 98 to 99% of original TDI remaining after 1 hour and more than 85% after 4 hours with no detectable formation of TDA. The studies with Salmonella typhimurium showed quite clearly the absence of any mutagenic response when TDI was dissolved in EGDE. Based on such evaluation the authors concluded that positive results seen in vitro genotoxicity studies undertaken using solvents such as DMSO must be treated with caution as such effects are very well be an artifact of the testing conditions caused by the breakdown of TDI to TDA which is known to produce mutations in Salmonella typhimurium. Based on these observations the use of results from in vitro tests in aqueous cell systems are problematic because of interaction with the test system components. These studies are considered to be invalid, and not useful for determining the genotoxic potential of TDI. For this reason mammalian cell gene mutation assays in vitro are not feasible and assessment relies on the in vivo studies.

A number of in vivo genotoxicity studies have been carried out with TDI. A slight increase in numbers of micronucleated erythrocytes was measured in a non-GLP micronucleus assay in rats exposed to TDI via inhalation (Owen, 1980, Loeser 1983). As the increase was not significant, occurred at only one dose level and because of the probably hyperthermia caused by the treatment the result was not considered to be biologically significant. Negative results were obtained with mice in the same study using similar exposures. Negative results have also been seen in a well conducted micronucleus assay in mice using inhalation route of exposure (Mackay, 1992) and an unscheduled DNA synthesis assay examining effects in liver and lungs in rats after acute and sub-acute inhalation exposures to TDI (Benford and Riley, 1988). Commercial grade TDI was also inactive in inducing sister chromatid exchanges and micronuclei in lung cells after intratracheal instillation in rats (Whong et al, 1991). Studies examining DNA adduct formation have produced mixed results and are inconclusive as to their relevance to human exposures.

Overall the data on genotoxicity show:

•Weight of scientific evidence supports the conclusion that TDI is not mutagenic or genotoxic

•As TDI is unstable in solvents such as DMSO and rapidly degrades to TDA results from the majority of in vitro genotoxicity test results are unsuitable for assessing the genotoxic potential of TDI.

•Inhalation of TDI does not induce micronuclei formation or DNA damage as measured by unscheduled DNA synthesis •Supplemental investigations of DNA binding have proven inconclusive as data were, in the main, obtained with non-validated methodologies and the results are difficult to interpret

Justification for classification or non-classification

Not classified as mutagenic according to Directive 67/548/EEC and Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008).