Tetrakis(phenylmethyl)thioperoxydi(carbothioamide)

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus

Type of information:

experimental study

Adequacy of study:

key study

Study period:

April 22, 1988 to September 28, 1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

Guideline study performed in compliance with GLP, available as unpublished report, no restrictions, fully adequate for assessment.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1988

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)

Version / remarks:

(1983)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test)

Version / remarks:

(Directive 84/449/EEC)

Deviations:

no

GLP compliance:

yes

Type of assay:

other: Mammalian Erythrocyte Micronucleus Test

Test material

Test material information

Constituent 1

Reference substance name:

Tetrakis(phenylmethyl)thioperoxydi(carbothioamide)

EC Number:

404-310-0

EC Name:

Tetrakis(phenylmethyl)thioperoxydi(carbothioamide)

Cas Number:

10591-85-2

Molecular formula:

C30H28N2S4

IUPAC Name:

N,N-dibenzyl[(dibenzylcarbamothioyl)disulfanyl]carbothioamide

Test animals

Species:

mouse

Strain:

Swiss

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

Corn oil

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Doses / concentrations 2

Dose / conc.:

2 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

Male: 0 mg/kg; No. of animals: 5; Sacrifice time: 24 hours
Male: 0 mg/kg; No. of animals: 5; Sacrifice time: 48 hours
Male: 0 mg/kg; No. of animals: 5; Sacrifice time: 72 hours
Male: 2000 mg/kg; No. of animals: 5; Sacrifice time: 24 hours
Male: 2000 mg/kg; No. of animals: 5; Sacrifice time: 48 hours
Male: 2000 mg/kg; No. of animals: 5; Sacrifice time: 72 hours
Female: 0 mg/kg; No. of animals: 5; Sacrifice times: 24 hours
Female: 0 mg/kg; No. of animals: 5; Sacrifice times: 48 hours
Female: 0 mg/kg; No. of animals: 5; Sacrifice times: 72 hours
Female: 2000 mg/kg; No. of animals: 5; Sacrifice times: 24 hours
Female: 2000 mg/kg; No. of animals: 5; Sacrifice times: 48 hours
Female: 2000 mg/kg; No. of animals: 5; Sacrifice times: 72 hours

Control animals:

yes, concurrent vehicle

Positive control(s):

cyclophosphamide
- Justification for choice of positive control(s): -
- Route of administration: Oral
- Doses / concentrations: 50 mg/kg body weight

Examinations

Tissues and cell types examined:

Bone marrow

Statistics:

The Wilcoxon rank-sum test was used to assess significant differences between the numbers of micronuclei in the treatment and control groups, in which P

Results and discussion

Test results

Test results 1

Sex:

male

Genotoxicity:

negative

Toxicity:

no effects

Remarks:

Doses producing toxicity: No signs of toxicity at 2000 mg/kg (maximum dose based on solubility of the test substance in corn oil.

Vehicle controls validity:

valid

Positive controls validity:

valid

Test results 2

Sex:

female

Genotoxicity:

negative

Toxicity:

no effects

Remarks:

Doses producing toxicity: No signs of toxicity at 2000 mg/kg (maximum dose based on solubility of the test substance in corn oil.

Vehicle controls validity:

valid

Positive controls validity:

valid

Remarks on result:

other: The small but statistically significant increase in the number of micronuclei in bone marrow of female mice at the 48-hour sampling time is considered to be not biologically significant, as the increase is just borderline.

Additional information on results:

Observations:
A small, but statistically significant increase in the number of micronuclei was observed in females at the 48-hour sampling time only. As the increase is borderline it is concluded that this result might not be biologically significant.
Control (cylophosphamide 50 mg/kg) showed toxic effects and significant increase in number of micronuclei.

RESULTS OF RANGE-FINDING STUDY
- Dose range: In a preliminary study 6 animals (3 males and 3 females) were dosed orally with 2000 mg/kg body weight.
- Solubility: Higher concentrations could not be dosed because of aggregates of the test substance in the suspension.
- Clinical signs of toxicity in test animals: The mice did not show any signs of reaction to treatment.
- Other: Based on the results of this pilot study 2000 mg/kg body weight was selected as an appropriate dose for the Micronucleus Test.

Applicant's summary and conclusion

Conclusions:

It is concluded that this test is valid and that TBzTD induced a small but statistically significant increase in the number of micronuclei, under the experimental conditions described in this report. However, as the increase is just borderline, this increase might be not biologically significant.

Executive summary:

Tetrabenzylthiuram disulfide (TBzTD) was tested in the Micronucleus Test in mice. Three groups (D to F), each comprising 5 males and 5 females, received a single oral dose of 2000 mg/kg body weight. Bone marrow was sampled at 24, 48 and 72 hours after dosing. Corresponding vehicle treated groups (A to C) served as negative controls. Bone marrow from a positive control group, treated with a single oral dose of cyclophosphamide (CP) at 50 mg/kg body weight, was harvested at 48 hours after dosing only. The test substance induced a statistically significant increase in the number of micronuclei in polychromatic erythrocytes in female mice at the 48 hour sampling time.

It is concluded that this test is valid and that TBzTD induced a small but statistically significant increase in the number of micronuclei, under the experimental conditions described in this report. However, as the increase is just borderline, this increase might be not biologically significant.