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Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Zinc bis(diethyldithiocarbamate) (ZDEC) induced an increased number of revertants in Salmonella typhimurium TA100 and TA1535 strains, both with and without metabolic activation, and increased chromosome aberration frequency in human lymphocytes in vitro. The result of the bone marrow micronucleous assay with mice was negative, while the result of live UDS test with rats was equivocal. Nevertheless, based on the fact that zinc bis(diethyldithiocarbamate) did not induce neoplastic lesions in a chronic toxicity study with rats and carcinogenicity study with mice, the substance is concluded to be non genotoxic.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

Genetic toxicity of zinc bis(diethyldithiocarbamate) (ZDEC) has been studied in a number of in vitro and in vivo assays. Three Ames tests were available for assessment, testing the ability of zinc bis(diethyldithiocarbamate) to induce gene mutations in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 (Tinkler et al., 1998; Hedenstedt et al., 1979; Litton Bionetics, Inc., 1977). One of them (Litton Bionetics, Inc., 1977) gave negative results with and without metabolic activation in all strains at concentration levels up to 500 μg/plate, while the study of Tinkler et al., 1998 reported the increase in the number of revertants in TA100 strain with metabolic activation, using concentration levels up to 2500 μg/plate, and the study of Hedenstedt et al., 1979 reported the increase in mutation frequencies in TA100 strain with and without metabolic activation, and in TA1535 strain without metabolic activation already at concentration levels up to 300 μg/plate.

The results of a mouse lymphoma test in vitro, reported by Tinkler et al., 1998, were negative both in the presence and absence of metabolic activation at concentration levels up to 0.05 µg/ml (- S9) and 0.6 µg/ml (+ S9). Also the results of in vitro cell transformation assay in BALB/3T3 mouse cells without metabolic activation at concentration levels up to 25.0 µg/ml were negative (Litton Bionetics, Inc., 1982). Zinc bis(diethyldithiocarbamate) induced the increased chromosome aberration frequency in human lymphocytes in vitro at 24 and 48 harvest time, with the activity of the test substance most marked at the presence of the metabolic activating system.

Two in vivo tests, a liver USD test with rats and a bone marrow micronucleous test with mice, were available for assessment (Tinkler et al., 1998). In the first one, groups of 4 male Sprague-Dawley rats were dosed with the test substance in corn oil at three different dose levels (500, 1000 and 1500 mg/kg bw). Two experiments were performed, with the rats killed 2 hours post-administration in the first and 16 hours post-administration in the second experiment. Signs of toxicity were observed. A total of four treated rats killed 16 hours post-dose (three dosed at 100 mg/kg, one each at 500 and 1500 mg/kg bw) showed small increases in net nuclear grain count such that their individual values for this parameter exceeded 1.0 (a threshold for consideration of a positive result in the liver UDS assay). The rats also showed increased numbers of cells undergoing DNA synthesis. However, only one of these animals showed net nuclear grain count greater than 0 on both of the replicate slides scored for grain count; in addition, no dose-relationship or other response pattern was evident. Furthermore, evaluation on a group basis found no significant effect of the test substance at any dose level, therefore the study was concluded to give equivocal results.

In a micronucleous test with mice, groups of 5 CD-1 mice of each sex were dosed at 80, 400 and 2000 mg/kg bw. The bone marrow from mice receiving low and intermediate doses was collected at termination 24 hours after dosing; control and high-dose mice were killed 24, 48 and 72 hours post-dosine. After appropriate slide staining, a minimum of 2000 erythrocytes from each animals were examined microscopically for the presence of micronuclei. The signs of toxicity were observed at the highest dose. There was no significant difference in frequency of micronucleated polychromatic erythrocytes in any test group at any kill time, compared with vehicle controls. Based on this, the result of the study was concluded to be negative.

Overall, the available data suggest that zinc bis(diethyldithiocarbamate) exhibits genotoxicity in in vitro experiments. It did not induce chromosome aberrations in vivo; however, the results of the UDS test were equivocal. Nevertheless, the available chronic toxicity and carcinogenicity studies suggest that chronic exposure to zinc bis(diethyldithiocarbamate) does not induce neoplastic lesions in rats and mice, so the substance does not induce genetic damage in vivo. Therefore it is concluded that the substance is not genotoxic in vivo.

Justification for classification or non-classification

Taking into account the overall evidence from available genotoxicity studies and based on the results of negative chronic toxicity and carcinogenicity studies with rats and mice, respectively, classification of zinc bis(diethyldithiocarbamate) (ZDEC) as genotoxic is not warranted in accordance with EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.