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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Additional information

Genetic toxicity in vitro:

A number of results from genetic toxicity studies conducted in vitro were available:

Ishidate et al. (1984) reported about the primary mutagenicity screening of food addivites used in Japan at the time. Various S. typhimurium strains were tested in a bacterial reverse mutation assay with and without metabolic activation. The test concentrations ranged from 1 - 10000 ug/plate. A positive result was found. The reliability of these data is restricted due to shortcomings in reporting: No data was provided with regards to bacteriotoxicity or precipitation of the test item. This information is especially relevant in light of the fact that positive results were only found at the highest tested concentration of 10 mg/plate in TA 1535 and TA 100, respectively.

NTP (2001, previously reported by Zeiger et al., 1992) reported a positive Ames test result with and without metabolic activation using S. typhimurium strains TA 98 and TA 100. The test concentrations used were between 100 - 1000 ug/plate.

Ishidate and Odashima (1977) reported an in vitro mammalian chromosome aberration test using Chinese hamster cells. Test concentrations used were up to 1.0 mg/ml; testing was done without metabolic activation. A positive result was found. A number of deficiencies in reporting restrict the reliability of this publication: Only 3 concentrations were tested, which were not exactly specified. Also, information on statistical evaluation was not included in the report.

Kodama et al. (1976) reported an in vitro mammalian cell gene mutation asssay using the FM3A cell line from C3H mammary carcinoma. The test concentrations ranged from 69 - 690 ug/ml (1 - 10 mMol). This test was done without metabolic activation. A positive result was reported, however, without any information on cytotoxicity, choice of concentrations, replicates or statistical evaluation.

Genetic toxicity in vivo:

NTP (2001) reported two bone marrow micronucleus tests using male rats and mice, respectively. In the rat study, the animals were administered intraperitoneally concentrations of 6.25, 12.5, 25, 50, 100 or 200 mg/kg for 3 times at 24-h intervals. In the mouse study, the animals were administered intraperitoneally 7.81, 15.63, 31.25, 62.5, 1250 or 250 mg/kg for 3 times at 24-h intervals. In both tests, a negative result was reported.

El-Nahas and Globus (1984) reported an in vivo chromosome aberration assay in rats. Female rats were offered 1.25 g/l (= ca. 210 mg/kg b.w./day) via the drinking water. The animals were treated for a period of 13 days (from day 5 - 18 of gestation). Chromosomal aberrations comprising chromatid gaps, breaks (mainly chromatid, including fragments and deletions), centric fusions, and dicentrics were induced in the bone marrow of adults and the liver of transplacentally exposed embryos. All aberrant cells had one aberration, with the exception of a few cells where two or more aberrations were found. Pregnant and nonpregnant females treated with nitrite showed a significant increase (p<0.01) in chromosomal aberrations of bone marrow cells over the control. However, there was no difference between the two groups and their results were pooled. In the liver of transplacentally exposed embryos, there was also a significant increase (p<0.001) in the number of cells with chromosomal aberrations. The number of cells with hypoploidy was not stastically significant in maternal bone marrow and embryo liver of treated and control groups. Cells with hyperploidy were rare in both bone marrow and embryonic liver.

The number of metaphases evaluated per animal was low in this study, and only one dose was applied. A conclusion regarding dose response can therefore not be drawn. Furthermore, no information concerning maternal toxicity or historical control data was provided, which makes interpretation of the data difficult. For these reasons, the study by El-Nahas and Globus is considered less reliable than the NTP assays.


In conclusion, the positive results reported in vitro were not confirmed in vivo. Two bone marrow micronucleus tests conducted by NTP in rats and mice, respectively, were negative, and 2-year chronic toxicity/carcinogenicity studies in rats and mice gave no indication of a carcinogenic activity of the test substance.

Endpoint Conclusion:

Justification for classification or non-classification

Several positive test results in vitro were not confirmed by two reliable micronucleus tests in vivo and two 2-year chronic toxicity/carcinogenicity studies in mice and rats, respectively. Therefore, classification for genetic toxicity is not considered warranted.