Registration Dossier

Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

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

Genetic toxicity in vivo

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

Additional information

The ability of zinc bis(dibutyldithiocarbamate) (ZDBC) to induce gene mutations in bacteria was studied in three independent assays, all leading to the same conclusion. Out of these studies, the most recent one, performed in accordance with OECD Guideline 471, was chosen as a key study (Tinkler et al., 1998). The mutagenicity of zinc bis(dibutyldithiocarbamate) was studied in SalmonellaTA 1535, TA 1537, TA1538, TA 98 and TA 100, with and without metabolic activation, at test concentrations 25, 79, 250, 790 and 2500 µg/plate, using DMSO as a vehicle. Inhibition growth was seen in all strains at the highest dose tested (also at 250 and 790 µg/plate in TA100). There was no increase in the number of revertants observed in any strain, in either presence or absence of S9-mix. Based on the result, zinc bis(dibutyldithiocarbamate) was concluded to be not mutagenic in Ames test, which was confirmed by the other two studies.

Two in vitro guideline studies on gene mutations and chromosome aberrations in mammalian cells were available. In the first one, mouse lymphoma L5178Y cells were treated with the test substance at concentration levels up to 15.0 µg/ml, with and without metabolic activation, using DMSO as a vehicle. Although isolated cases of increased mutant colony numbers in test cultures were seen, neither these numbers nor the calculated mutation frequencies showed clear or reproducible increases after any ZDBC treatment. Based on the results of the study, the substance was concluded to be negative in mouse lymphoma assay in vitro.

The ability of zinc bis(dibutyldithiocarbamate) to induce chromosome aberrations in vitro was studied in human lymphocytes, using DMSO as a vehicle. The cells were harvested 24 and 48 hr after the treatment and the test concentrations were up to 20µg/ml in experiments without metabolic activation for both harvesting times, up to 50µg/ml with metabolic activation for 24 hr harvesting time and up to 100µg/ml with metabolic activation for 48 hr harvesting time. Statistically significant increases in aberrant cell frequency were seen following ZDBC exposure in cells harvested at 24 hr, both with and without S9-mix. These increases were small; in some cases not sufficiently large to exceed the historical solvent control range of the testing laboratory (0-5% excluding gaps). At the 48-hr harvest, the single case of statistically significant increase in the frequency of aberrant cells (ZDBC at 10 µg/ml) was not considered biologically significant. When gap-type aberrations were taken into account, a generally similar pattern of small increases over control values was seen. The reproducibility of the effect seen in the presence of S-9 mix at the 24-hr harvest time was considered evidence of weak clastogenic activity.

An apparent increase in the incidence of polyploidy and endoreduplication in ZDBC-treated cultures was observed, since these effects were not determined quantitatively, no further conclusion can be drawn. Overall, it was concluded that ZDBC showed weak clastogenicity in this assay, at exposure levels which reduced cell division (mitotic index) by some 0-60%.

In addition, two reliable in vivo studies with zinc bis(dibutyldithiocarbamate), liver UDS test with rats and micronucleous test with mice, were available for assessment (Tinkler, 1998). In the first study, 4 male rats were orally administered the test substance at doses 1000, 1500 and 2000 mg/kg. Two experiments were performed, with rats killed 2 and 16 hours post-dosing. Rats dosed with ZDBC showed no adverse reactions to treatment. Hepatocyte viabilities were generally high among control rats and those dosed at 1000 or 1500 mg/kg bw (73-93%); in rats dosed at 2000 mg/kg bw they appeared slightly lower (69-78%). Statistical analysis revealed no significant differences between test and control groups for nuclear grain count (NG), net nuclear grain count (NNG) or % IR. No individual test animal gave an NNG value greater than 0 on both slide preparations scored for grain counts. It was concluded that ZDBC gave negative results in this in vivo liver UDS assay.

In the micronucleous test, conducted in accordance with OECD Guideline 474, 5 CD-1 mice of each sex received 200, 1000 or 5000 mg/kg of the test substance in corn oil by oral gavage. Post-exposure period was 24 hours for low and mid-level groups, and 24, 48 and 72 hours for high dose and control test groups. No significant adverse reactions were observed at any dose, there was no evidence of effect in the bone marrow. However, the maximum dose tested was both high and the maximum normally employed in studies of this type. No significant difference in frequency of micronucleated polychromatic erythrocytes between test and vehicle control animals was found at any of the dosages or times. In conclusion, zinc bis(dibutyldithiocarbamate) was concluded to be negative in in vivo micronucleous test. Overall, based on the results of available in vivo studies, the substance is considered to be non-genotoxic in vivo.


Short description of key information:
Zinc bis(dibutyldithiocarbamate) (ZDBC) gave negative results in three independent Ames tests and in an in vitro mouse lymphoma assay. The results of in vitro chromosome aberration test with human lymphocytes were equivocal. The results of two in vivo tests, a UDS test with rats and micronucleous test with mice, were negative. Based on these findings, it is concluded that zinc bis(dibutyldithiocarbamate) is not genotoxic.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Based on the negative results of in vivo UDS test with rats and micronucleous test with mice, classification of zinc bis(dibutyldithiocarbamate) for genotoxicity is not warranted in accordance with Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.