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Administrative data

Key value for chemical safety assessment

Additional information

Partly cited from SIAR for SIAM 23 (Jeju, Korea, October 17-20, 2006):

Studies in Animals

In vitro Studies

"In an Ames test performed according to Directive 84/449/EEC B.14 (1984) with Salmonella typhimurium TA 1535, TA 1537, TA 1538, TA 98 and TA 100, test substance concentrations of up to 5000 µg/plate (without preincubation) and up to 1000 µg/plate (with preincubation) were employed in the presence and absence of Aroclor-induced rat liver S9 mix. A significant increase in mutant frequency was not observed." Cytotoxicity was observed at 1000 µg/plate (+/- S9 without preincubation) and at 1000 or 500 µg/plate (+/- S9, with preincubation) (Hüls AG, 1993). "Neither Salmonella typhimurium TA 102 nor Escherichia coli WP2 were tested in these Ames tests, as it was not required by the EC guideline in 1984 when these studies were performed. This is an acceptable restriction compared to OECD TG 471 because it can be assumed that 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate has no oxidizing or cross-linking potential which may be detected by S. typhimurium TA 102 or E. coliWP2. A negative result was also obtained by Mortelmans et al. (1986) in the Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537 using the preincubation method and concentrations up to 33 000 µg/plate both with and without Aroclor 1254-induced Wistar rat Syrian hamster liver S9 mix, respectively. Concentrations above 10 000 µg/plate were cytotoxic.

In a test performed according to OECD TG 473 (1997), 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate induced dose dependent chromosomal aberrations in Chinese hamster ovary cells both in the presence and absence of S9 homogenate prepared from Sprague-Dawley rat livers, induced with phenobarbital and ß-naphthoflavone. Test concentrations were 0.625; 1.25; 2.50; 5.0; 10.0; 20.0; 40.0; 80.0 µg/ml, and cytotoxicity was observed at ca. 40 µg/ml and higher (RTC, 2003). Appropriate reference substances were used as positive controls in thesein vitro studies and showed the expected genotoxic result."

The substance Isophorone Diisocyanate was tested for its ability to induce gene mutations at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus in Chinese hamster ovary (CHO) cells in vitro (Schulz and Landsiedel, 2007). Four independent experiments were carried out with and without the addition of Aroclor-induced rat liver S9 mix. On the basis from the results of the present study, the test substance did not cause any increase in the mutant frequencies without and with S9 mix in four experiments performed independently of each other. Thus, under the experimental conditions of this study, Isophorone Diisocyanate has no mutagenic activity in vitro in the CHO/HPRT forward mutation assay neither in the absence nor in the presence of metabolic activation.

In vivo Studies

"In order to further clarify the relevance of the positive findings in the in vitro chromosomal aberrations test, an in vivo micronucleus test according to OECD TG 474 was performed. 18 (main study) plus 5 (satellite for respiratory function measurements) male NMRI mice per dose group were exposed once for six hours by nose-only inhalation (vapor/aerosol) to target concentrations of 0, 5, 15, or 40 mg/m3. Sampling times for bone marrow were 24, 48, and 72 hours after test substance administration. No indication of a clastogenic effect was observed." The positive control, cyclophosphamide, caused a clear increase in the number of polychromatic erythrocytes with micronuclei (Herbold, 2006).

Studies in Humans

"There are no data available."


Short description of key information:
Partly cited from SIAR for SIAM 23 (Jeju, Korea, October 17-20, 2006):
"3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate was not genotoxic in bacterial systems in vitro (Ames test). Neither Salmonella typhimurium TA 102 nor Escherichia coli WP2 were tested in these Ames tests, however, this is an acceptable restriction because it can be assumed that 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate has no oxidizing or cross-linking potential which may be detected by S. typhimurium TA 102 or E. coli WP2."
The test substance Isophorone Diisocyanate has no mutagenic activity in vitro in the CHO/HPRT forward mutation assay neither in the absence nor in the presence of metabolic activation under the experimental conditions of this study.
"In a chromosomal aberrations test performed on Chinese hamster ovary cells according to OECD TG 473, results were positive both with and without metabolic activation. In vivo, no mutagenic activity was detectable in a micronucleus assay on mice according to OECD TG 474 using the inhalation route of administration. However, as the micronucleus test only covers systemic genotoxic effects and given the well known high local reactivity of the substance local genotoxic effects cannot be excluded."

Endpoint Conclusion:

Justification for classification or non-classification

Regarding genetic toxicity the substance 3-Isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate is not classified according to the criteria of EC Directive 67/548/EEC.