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Carcinogenicity

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Description of key information

One chronic toxicity study with rats and one carcinogenicity study with mice performed with zinc bis(diethyldithiocarbamate) (ZDEC) were available for assessment, both predating GLP and OECD guidelines. No increased incidence of neoplastic lesions was found in the rat study, in which rats received the test substance in diet for 2 years, up to the highest dose level of 10000 ppm (corresponding to the compound intake of 717 mg/kg bw/day). Also no increased tumor incidences were reported in the 18-month oral study with mice, albeit poorly reported. Based on this evidence, zinc bis(diethyldithiocarbamate) is considered to be non-carcinogenic.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
717 mg/kg bw/day
Study duration:
chronic
Species:
rat

Additional information

One chronic toxicity study with rats and one carcinogenicity study with mice performed with zinc bis(diethyldithiocarbamate) (ZDEC) were available for assessment, both predating GLP and OECD guidelines. In the chronic toxicity study of Blackwell Smith et al., 1953) groups of 10 male and 10 female rats were administered diet containing zinc bis(diethyldithiocarbamate) at dose levels of 0, 500, 1000, 2500, 5000 and 10000 ppm for two years. Gross and microscopic pathologic examinations were performed on all animals, except of those whose autolysis was obviously too advanced. There was apparent increased mortality in the females at the 10000 ppm level and possibly at the 5000 ppm level, but no such effect appeared in the males at any dose level. A tendency towards diminished growth appeared in both sexes at 10000 ppm level. Findings in hematological studies were within normal limits. Kidney pathology (congestion, nephritis or nephrosis) was seen in 6 of the 19 animals of the 10000 ppm group. No kidney changes were seen in the animals of 500 ppm group. One rat from 1000 ppm group, one from 2500 group and one from 5000 ppm groups showed nephritis. No other differences between the control and experimental groups were observed.

In addition, hyperplasia of thyroid gland was observed in test animals at all dose levels. The degree of hyperplasia was graded from 0 to 5+. No hyperplasia was observed in 9 out of 17 control animals, while 2 had hyperplasia of 1+ degree and 6 had hyperplasia of 2+ degree. In 500 ppm dose group, hyperplasia in degrees 1+ and above (including one animal with 4+ hyperplasia) was observed in 15 out of 16 animals. At dose levels 1000 ppm and above all animals (17 in 2500 ppm group, 14 in 2500 and 5000 ppm groups and 18 in 10000 ppm groups) showed hyperplasia of degree 2+ and above. The microscopis studies revealed malignancies in both treated and control animals, however, there was no apparent evidence of any relationship between the treatment with the test substance and the incidence of neoplastic lesions.

Based on the results of this study, no NOAEL for systemic toxicity could be established. The LOAEL for systemic effects was set at 500 ppm zinc bis(diethyldithiocarbamate) in diet, based on increased incidence of thyroid gland hyperplasia at all dose levels. Using the default parameters as reported by Paulussen et al., 1998, TNO report V98.390, this value was calculated to correspond to average dose of 36 mg/kg bw/day. As no increased tumor incidence was observed at the highest dose level, NOAEL for carcinogenicity was set at 10000 ppm; using default values proposed by Paulussen et al., 1998, this dose was found to correspond to average intake of 717 mg/kg bw/day.

The carcinogenicity study with mice (Innes et al., 1969) had severe limitations in reporting, but nevertheless was considered to contribute to the assessment. Maximal tolerated dose (which corresponded to 100 mg/kg bw/day) was administered orally to 18 male and 18 female mice of 2 different strains starting at the age of 7 days by oral gavage for the first 3 weeks and then in diet (corresponding to concentration in diet of 260 ppm) for the rest of the study period of 18 months. After this the animals were necropsied and histological evaluation of major organs and all grossly visible lesions was performed. The paper reported an overview of the results on selected pesticides and industrial compounds, amounting in total to 120 substances. Only data on 11 compounds which induced significant increase in tumor incidences were reported. No data on tumor incidences are reported for zinc bis(diethyldithiocarbamate), as it gave no significant indication of tumorigenicity according to authors.

In summary, despite the limitations of each study, the evidence from both of them suggests that zinc bis(diethyldithiocarbamate) is not carcinogenic.

Justification for classification or non-classification

Based on the negative results in a chronic toxicity study with rats and a carcinogenicity study with mice, classification of zinc bis(diethyldithiocarbamate) (ZDEC) as carcinogenic 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.