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EC number: 200-843-6
CAS number: 75-15-0
disulphide was examined for its mutagenic activity in four
histidine-dependent auxotrophs ofSalmonella typhimurium, strains
TA98, TA100, TA1535, TA1537. Agar plates, seeded with the tester
strains, were exposed to the test material in vapour phase, in the
abscence and presence of metabolic activation, in the following nominal
concentrations: 0.005%, 0.01%, 0.025%, 0.05% and 0.1% v/v (nominal).
These concentrations were selected following preliminary toxicity tests
in strain TA 98. Carbon disulphide did not exhibit any
mutagenic activity under the conditions of this test. No increases in
revertants were obtained in any of the four tester strains following
exposure to carbon disulphide at the concentrations tested. Inhibition
of bacterial growth, observed as thinning of the background lawn of
non-revertant cells and reduction in revertant colony numbers, occurred
in all strains with carbon disulphide at a nominal concentration of 0.1%v/v.
The positive and negative controls were valid.
was performed according to the OECD Guidelines for Testing of Chemicals
No. 471 (1983) and US EPA (TSCA) Guideline §
798.5265 (1985, amended 1987).
number of mutant colonies per 106cells of each solvent
control plus 126
was not continued since a minimum of four concentrations is required by
was performed to investigate the potential of Carbon disulfide to induce
mutations at the mouse lymphoma thymidine kinase locus using the cell
was conducted according to the procedures indicated by the following
internationally accepted guidelines and recommendations:
Addendum to the OECD Guidelines for the Testing of Chemicals, February
adopted July 21, 1997, Guideline No. 476 "In vitro Mammalian Cell Gene
Regulation (EC) No. 440/2008 B.17: ”Mutagenicity – In vitro Mammalian
Cell Gene Mutation Test“, dated May 30, 2008.
was performed in two independent experiments, using two parallel
cultures each. The first main experiment was performed with and without
liver microsomal activation and a treatment period of 4 h. The second
experiment was performed with a treatment period of 24 hours in the
absence of metabolic activation and 4 hours in the presence of metabolic
experiments were evaluated at the following concentrations:
95.1; 190.3; 380.5; 761.0 µg/mL
with S9 mix: 47.6;
95.1; 190.3; 380.5; 761.0 µg/mL
medium was checked for precipitation visible to the naked eye at the end
of the 4 hours treatment just before the test item was removed. No
precipitation meeting the criteria mentioned above was noted in the
pre-experiment and in both main experiments.
cytotoxic effects indicated by a relative total growth of less than 50 %
of survival in both parallel cultures were observed at 761 µg/mL in the
first experiment with metabolic activation and in the second experiment
without metabolic activation.
substantial and reproducible dose dependent increase of the mutation
frequency was observed in both main experiments up to the maximum
concentration with and without metabolic activation. The threshold of
126 above the corresponding solvent control was not reached or exceeded.
regression analysis (least squares) was performed to assess a possible
dose dependent increase of mutant frequencies using SYSTATâ11
statistics software. No significant dose dependent trend of the mutation
frequency indicated by a probability value of <0.05 was determined in
any of the experimental groups.
study the range of the solvent controls was from 64 up to 240 mutant
colonies per 106cells; the range of the groups treated with
the test item was from 51 up to 296 mutant colonies per 106cells.The
highest solvent control value (240 colonies per 106cells)
exceeded the recommended
50 – 170 x 106control range as stated in the
acceptability criteria of this report.The
corresponding control value of the parallel culture however, was fully
acceptable. Even the solvent controls of both cultures of the first
experiment with metabolic activation slightly exceeded the threshold of
170 per 106cells (197 and 200).The
data are acceptable however, since the range of 50-200 colonies per 106cells
recommended by the IWGT in 2003 was covered. The cloning efficiency of
the solvent control of the second culture of the first experiment and of
the first culture of the second experiment without metabolic activation
exceeded the upper limit of 120%. The data are acceptable however, since
the parallel culture remained within the recommended range and the
absolute values of the cloning efficiency were used to calculate the
mutation frequency. The total suspension growth exceeded the upper limit
of 32 in the first culture of the first experiment with metabolic
activation.The data are
acceptable since again, the parallel culture remained within the
acceptable range and the absolute value of the total suspension growth
was used to calculate the relative total growth.
µg/mL in experiment I and 13.0 µg/mL in experiment II) and CPA (3.0 and
4.5 µg/mL) were used as positive controls and showed a distinct increase
in induced total mutant colonies and an increase of the relative
quantity of small versus large induced colonies with at least one of the
The effect of carbon disulphide on
chromosome structure in the bone marrow erythrocytes of mice was
examined. The animals (males and females) were exposed via inhalation
snout-only, for 6 h to the following concentrations: 0, 467, 1558, 4675
mg/m3 (0, 150, 500, 1500 ppm). The exposure concentrations were based on
a preliminary toxicity test. Chlorambucil (30 mg/kg bw) was used as a
positive control, adminstered via the oral route. Animals were
sacrifised and examined 24 and 48 h after exposure. No evidence of
induced chromosomal or other damage leading to the formation of
micronuclei in erythrocytes of the bone marrow was detected, uder the
present test condition, after exposure of the animals to CS2 via
inhalation. Mice exposed at 1500 ppm, however, showed a small increase
in the ratio of polychromatic/mature cells, which may indicate
disturbance of erythropoiesis.
Carbon disulphide was tested for induction
of micronuclei in the bone marrow ertythrocytes of mice according to the
OECD Guidelines 474 (1983).
CS2 has been tested for its
genotoxicity in a series of in-vitro tests and in-vivo tests. The main
results are summarized in the table below.
Type of test and quality
Gene mutations in bacteria (GLP study); adequate
Gene mutations in mammalian tissue-culture cells (GLP study); adequate
Cytogenetic effects in primary human lymphocytes; adequate
Weak and doubtful effects (gaps) for chromosomal aberrations – judged as negative
Small but significant and dose dependent increase of sister chromatid exchanges - positive
Unscheduled DNA synthesis in tissue-culture cells; low purity (86%) of the test compound
Inconclusive; it cannot be excluded that the weak, doubtful positive response is caused by impurities
Cytogenetic effects in human sperm; absence of data on purity
Positive; it cannot be excluded that the positive response is caused by impurities
Cytogenetic effects in rat bone marrow (inhalation); low purity (86%) of the test compound
Micronuclei in mouse bone-marrow erythrocytes (inhalation; GLP study); adequate
Host-mediated assay with mice (host) and Salmonella typhimurium TA98 (indicator) (inhalation); doubtful adequacy due to lack of positive control, low purity of test compound (86%) and low survival at the highest concentration in the males
Drosophila melanogaster sex-linked recessive lethal assay (vapour-phase exposure); low purity (86%) of the test compound
Sperm-head abnormality test with rats and mice (inhalation); doubtful adequacy because of the low purity (86%) of the test compound and the weak response obtained with the positive control
Dominant-lethal test with rats (inhalation); low purity (86%) of the test compound
Chromosomal aberrations in female rats and their fetuses after treatment during preganancy (inhalation); quote from the Priority Substance List Assessment Report of Health Canada and Environment Canada.Carbon disulfide induced chromosomal aberrations and polyploid cells in the bone marrow of female rats and in rat embryos exposed on days 10–13 of gestation. It is difficult to assess the validity of these findings, as the reporting was brief (e.g., the statistical significance was often not indicated) and the effective dose was not reported, except to indicate that it was one-tenth of the LD50.
Positive; doubt as regards the validity due to lack of information.
Positive; doubtful as regards the validity due to lack of information; only published in the form of a meeting abstract
Sperm-head abnormality test with rats
CS2 was found to be negative in fully
adequate standard GLP in vitro tests for gene mutations with bacteria
and mammalian tissue culture cells.
However, an in vitro test for
chromosomal aberration test with primary human lymphocytes suggested a
weak positive effect based on gaps, while in the same cells a
significant and dose-dependent increase of sister chromatid exchanges
was found. A weak positive effect was also found in a non-standard
unscheduled DNA systhesis test in an established human cell line. The
latter test was not fully adequate, because the carbon disulfide tested
has a low purity, which points to the possibility that the effect was
caused by an impurity. The positive effects obtained in these tests
depended on the presence of metabolic activation with S9 fractions.
An in vitro test with human sperm cells yielded a positive result;
however, there is no information about the purity of the test
The in-vivo data show a negative and
fully adequate GLP test for micronuclei in mouse bone marrow and
negative tests for dominant-lethals with rats, sperm-head abnormalities
with rats and mice, chromosomal aberrations in bone marrow with rats and
a host-mediated assay with mice as hosts and Salmonella typhimurium TA98
as indicator. Three in vivo studies showed positive results. The study
by Vasil’eva (1982) used as endpoint the induction of chromosomal
aberrations in bone marrow of female rats (dams) and their fetuses after
inhalation of carbon sulfide. It is hard to judge the validity of this
study, and in the reviews by internationally recognized bodies it is
regarded doubtful. The same holds for the study of Bao et al. (1996), in
which chromosomal aberrations were observed in oocytes and prenuclei
zygotes of exposed adult female mice. The sperm head abnormality test of
Kumar et al., (1999)
suggests genotoxic potential of CS2
but only sperm shape was evaluated. Nonetheless, the method is not
validated, and the publication does not give sufficient experimental
In conclusion, with regard to the
database on the genotoxicity of carbon disulfide, although in three
studies a positive result was found, it can be concluded that there are
clear doubts regarding their validity due to a lack of information on
essential methodological details and or the fact they follow a design
that has not been validated. In contrast there are 3 GLP studie reports
(Ames test, MLA, and an in vivo MN test) showing clear negative results.
In conclusion, 3 GLP study reports for
standard toxicity testing (Ames test - OECD 471, MLA - OECD 476, and an
in vivo MN test - OECD 474) show clear negative results, as such no
classification is needed for genotoxicity.
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