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Diss Factsheets

Toxicological information

Genetic toxicity: in vitro

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Administrative data

Endpoint:
in vitro cytogenicity / chromosome aberration study in mammalian cells
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1988
Report date:
1988

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test)
Version / remarks:
Adopted on 26 May 1983
Deviations:
no
GLP compliance:
yes
Type of assay:
in vitro mammalian chromosome aberration test

Test material

Constituent 1
Chemical structure
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:
C30-H28-N2-S4
IUPAC Name:
N,N-dibenzyl[(dibenzylcarbamothioyl)disulfanyl]carbothioamide
Test material form:
solid: particulate/powder

Method

Species / strain
Species / strain / cell type:
mammalian cell line, other: Human lymphocytes
Cytokinesis block (if used):
Fixation time: 24 hours including a 2 hr treatment with colcemid
Metabolic activation:
with and without
Metabolic activation system:
Arochlor-induced rat liver
Test concentrations with justification for top dose:
prelim study : with and without metabolic activation: 4 to 100 µg/mL
main study : 3.7 to 100 µg/ml
Vehicle / solvent:
DMSO
Controls
Untreated negative controls:
no
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Positive control substance:
cyclophosphamide
mitomycin C
Details on test system and experimental conditions:
Exposure period (with metabolic activation) 2 hours ; Exposure period (without metabolic activation) 24 hours
Duplicates were used rather than an independent repeat (the study was independently repeated later).
Chromosome aberrations were counted on four slides of each culture.

Fixation time:
24 hours including a 2 hr treatment with colcemid

200 metaphases were scored per concentration
Rationale for test conditions:
In accordance with the OECD Testing Guideline 473 adopted on 26 May 1983.
Evaluation criteria:
The major criterion to designate the results of a chromosome aberration test as positive is a dose-related, statistically significant increase in the number of cells with structural chromosome aberrations. However, a clear dose-response relationship can be absent because the yield of chromosome aberrations can vary markedly with post-treatment sampling time of an asynchronous population and because increasing doses of clastogens can induce increasing degrees of mitotic delay. A test substance producing neither a dose-related, statistically significant increase in the number of cells with structural chromosome aberrations, nor a statistically significant and reproducible positive response at any of the doses is considered non-clastogenic in this system.
Statistics:
Different types of aberrations (chromatid-type and chromosome-type) have been listed with their numbers and frequencies for all test and control cultures. As gaps are usually considered as unreliable end points for induced chromosome damage, this type of aberration was recorded separately and was not included in the final assessment of clastogenic activity. Data were analysed, when appropriate, by Fisher's exact probability test using the number of cells with aberrations to determine significant differences between test and control cultures.

Results and discussion

Test resultsopen allclose all
Species / strain:
other: human lymphocytes
Metabolic activation:
with
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
cytotoxicity
Remarks:
(>= 100 µg/mL)
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
True negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
other: human lymphocytes
Metabolic activation:
without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
cytotoxicity
Remarks:
(>= 33.3 µg/mL)
Vehicle controls validity:
valid
Untreated negative controls validity:
not examined
True negative controls validity:
not examined
Positive controls validity:
valid
Additional information on results:
The highest dose level was determined to by the limit of solubility of the test substances in the solvent DMSO.
The positive control substances, mitomycin C (in the absence of the S-9 mix) and cyclophosphamid (in the prensense of the S-9 mix) showed the expected statistically significant increase in structural chromosomal abberations.

Applicant's summary and conclusion

Conclusions:
The test substance did not induce a significant increase in the number of cells with structural chromosome aberrations at any of the concentrations used, either in the absence or in the presence of the S-9 mix.
Executive summary:

Tetrabenzylthiuram disulfide (TBzTD) was examined for its potential to induce chromosome aberrations in human lymphocytes, both in the absence and in the presence of a metabolic activation system (S-9 mix), in compliance with OECD guideline 473. The dose levels used in the chromosome aberration assay were established on the basis of the results of a preliminary toxicity test carried out with 6 concentrations of the test substance (ranging from 0.41 to 100.0 µg/ml), both in the absence and in the presence of the metabolic activation system (S-9 mix). The highest dose level for the toxicity test was determined by the limit of solubility of the test substance in the chosen solvent (DMSO). For the chromosome aberration assay in the absence of the S-9 mix, the cells were exposed to 4 concentrations of the test substance (3.70, 11.11, 33.33 and 100.0 µg/ml) for 24 hours. In the presence of the S-9 mix, the cells were exposed for only 2 hours (because of the toxicity of the S-9 mix for the cells) to the same concentrations. As positive controls, mitomycin C (in the absence of the S-9 mix) and cyclophosphamide (in the presence of the S-9 mix) were used, while the vehicle (DMSO) was used as negative control. The test substance did not induce a significant increase in the number of cells with structural chromosome aberrations at any of the concentrations used, either in the absence or in the presence of the S-9 mix.