Sodium dibutyldithiocarbamate

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian cell study: DNA damage and/or repair

Remarks:

Type of genotoxicity: DNA damage and/or repair

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2003

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2003

Report date:

2003

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 486 (Unscheduled DNA Synthesis (UDS) Test with Mammalian Liver Cells in vivo)

Deviations:

no

GLP compliance:

yes

Type of assay:

unscheduled DNA synthesis

Test material

Test material information

Constituent 1

Reference substance name:

Sodium dimethyldithiocarbamate

EC Number:

204-876-7

EC Name:

Sodium dimethyldithiocarbamate

Cas Number:

128-04-1

Molecular formula:

C3H7NS2.Na

IUPAC Name:

sodium dimethyldithiocarbamate

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Ltd, Margate, Kent, UK
- Age at study initiation: 6-7 weeks
- Weight at study initiation: 161-198 g

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

purified water

Duration of treatment / exposure:

one application of 10 mL/kg bw

Frequency of treatment:

n.a.

Post exposure period:

2-4 h, 12-14 h

Doses / concentrations

Remarks:

Doses / Concentrations:
400, 1000 mg/kg bw
Basis:
other: concentration in vehicle: 40, 100 mg /mL

No. of animals per sex per dose:

4

Control animals:

yes

Positive control(s):

2-4 h preparation interval: 2-Acetylaminofluorene (2-AAF), 75 mg/kg bw, in corn oil,
12-14 h preparation interval: Dimethylnitrosamine (DMN), 10 mg/kg bw, in water

Examinations

Tissues and cell types examined:

- Tissue: Liver
- Type of cells: Hepatocytes

Details of tissue and slide preparation:

- Number of animals: 4 per dose (hepatocytes were prepared from 3)
- Number of cells: 4.5×105 cells per slide

Evaluation criteria:

- Parameters: 3H-incorporation (silver grain formation)

Results and discussion

Test results

Sex:

male

Genotoxicity:

negative

Toxicity:

no effects

Vehicle controls validity:

valid

Negative controls validity:

not applicable

Positive controls validity:

valid

Additional information on results:

One animal (2-4h, 400 mg/kg SDDC) had a cell viability of 44%. Because of slide analysis that was considered to have no effect on the test system.

Any other information on results incl. tables

Table 7.6.2-B1: Net nuclear grain values and percentage of cells in repair Treatment Period Dose [µg/mL] NNG [mean ± SD] % of cells in repair (NNG ≥ 5) [mean ± SD] vehicle 2-4 h – -0.9 ± 0.2 1.0 ± 1.0 SDDC 2-4 h 400 -1.0 ± 0.6 1.0 ± 1.0 SDDC 2-4 h 1000 -1.1 ± 0.6 1.0 ± 1.0 DMN 2-4 h 10 10.9 ± 1.6 69.0 ± 2.6 vehicle 12-14 h – -1.0 ± 0.2 1.0 ± 0.0 SDDC 12-14 h 400 -0.6 ± 0.3 1.0 ± 1.0 SDDC 12-14 h 1000 -0.7 ± 0.5 4.0 ± 2.0 2-AAF 12-14 h 75 16.0 ± 1.0 97.7 ± 0.6 NNG = net nuclear grains

Applicant's summary and conclusion

Conclusions:

It was concluded that SDMC does not induce UDS detectable to the liver of rats under the experimental conditions employed in the present test.

Executive summary:

In the present in vivo genotoxicity study,  SDMC (41.4% w/w aqueous solution) was tested for its ability to induce unscheduled DNA synthesis (UDS) in the livers of orally dosed male rats. The test was performed according to OECD 476 and under GLP.  To determine if there were any substantial inter-sex differences in toxicity both male and female animals were tested in an initial toxicity range-finder experiment. Groups of four male rats (Han Wistar (Crl:WI (GlxIBRL/Han) BR) were treated once with the vehicle (purified water), SDDC (at 400 mg/kg or 1000 mg/kg) or the required positive control, by oral gavage, at a dose volume of 10 mL/kg. The positive controls used were 75 mg/kg 2-acetamidofluorene (2-AAF) suspended in com oil (Experiment 2) and 10 mg/kg dimethylnitrosamine (DMN) dissolved in purified water (Experiment 1). No clinical signs of toxicity were observed in Experiment 1 (2-4 hours) or Experiment 2 (12-14 hours). Approximately 2-4 hours (Experiment 1) or 12-14 hours (Experiment 2) after dosing, animals were sacrificed and their livers perfused with collagenase to provide a primary culture of hepatocytes. Cultures were made from three animals in each dose group and were treated with [3H] thymidine. Six slides from each animal were prepared with fixed hepatocytes and of these, three were dipped in photographic emulsion to prepare autoradiograms. Slides were examined microscopically after development of the emulsion and staining, and the net grain count (NNG), the number of grains present in the nucleus minus the mean number of grains in three equivalent areas of cytoplasm, was determined for each of two of the three slides, each animal and dose group. Negative (vehicle) control animals gave a group mean NNG value of less than zero with only 1% cells in repair. Group mean NNG values were increased by 2-AAF and DMN treatment to more than 10.9 and more than 50% cells found to be in repair. In this study the vehicle control NNG value was consistent with both published and historical control data, and the system was shown to be sensitive to two known DNA damaging agents requiring metabolism for their action. The assay was therefore accepted as valid. Treatment with 400 or 1000 mg/kg SDMC did not produce a group mean NNG value greater than -0.6 nor were any more than 4% cells found in repair at either dose. It was concluded that SDMC did not induce UDS detectable under the experimental conditions employed.