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EC number: 239-594-3
CAS number: 15546-11-9
IN VITRO GENE MUTATION STUDY IN BACTERIA
Krul et al (2002) was performed to the OECD Guideline no. 471 and in
compliance with GLP, the study was considered reliable and adequate for
assessment. As the study was performed on a read-across substance,
dibutyltin maleate, which was considered to be stucturally similar to
the substance in question. The results the results obtained with the
test substance in Salmonella typhimurium strains TA 1535, TA
1537, TA 98 and TA 100, and in the Escherichia coli strain WP2
uvrA, in both the absence and the presence of the S9-mix, indicate that
2,2-dibutyl-1,3,2-dioxastannepin-4,7-dione (dibutyltin maleate) was not
mutagenic under the conditions employed in this study.
2,2-Dibutyl-1,3,2-dioxastannepin-4,7-dione (dibutyltin maleate) was
toxic to all strains at the highest concentration both in the absence
and presence of S9-mix, as was evidenced by a decrease in the mean
number of revertant colonies.
IN VITRO CYTOGENICITY STUDY IN MAMMALIAN CELLS OR IN
VITRO MICRONUCLEUS STUDY
Reimann R & Gramlich U (1990) was provided as the key study for this
data requirement. The study was performed in compliance with GLP and the
method was comparable to that of OECD 473. The study was accordingly
assigned a reliability score of 2 and considered reliable and adequate
for assessment. An evaluation of the clastogenic potential in the human
lymphocyte test indicated clastogenic potential of the test material in
the human lymphocyte test in vitro at clearly cytotoxic concentrations.
From the four assays conducted without and with an extrinsic
metabolizing system in two independent studies, one assay without and
one with S9 mix gave statistically significant (P < 0.05) increases in
the frequency of chromosomal aberrations at the highest concentrations
evaluated, whereby in the remaining assays the results were borderline
negative. In each assay of this investigation, the test material was
tested up to cytotoxic concentrations as indicated by an obvious
reduction of the mitotic index.
The CHO gene mutation study from the publication by Li AP et al (1982)
was provided as a supporting study to this endpoint. The study was
conducted to good scientific principles (GLP status was not reported),
however the study did not include metabolic activation. The study was
accordingly assigned a reliability score of 2. The LC50 value of DBTC
for CHO cells, as determined by cloning efficiency, was approximately
0.35 µg/ml (1.12 µM). DBTC induced mutations at the HGPRT gene locus in
CHO cells. The mutant frequency increased with dose up to 0.2 µg/ml
(0.66 µM) for DBTC. A decrease in mutant frequency was observed at
IN VITRO GENE MUTATION STUDY IN MAMMALIAN CELLS
Lang R & Schmitt R (1989) was provided as the key study for this data
requirement. The study was well documented, performed in compliance with
GLP and to a method comparable to OECD 476. The study was assigned a
reliability score of 2 and considered reliable and adequate for use. The
study was a HGPRT-test with V79 cells. The test material was found to
have cytotoxic effects without metabolic activation by S9 mix at 0.00006
µl/ml and with metabolic activation a clear toxic effect could be
observed at 0.0003 µl/ml in the first experiment and at 0.0005 µl/ml in
the second assay of the second experiment. The test material did not
show a mutagenic potential in the HGPRT/V79 mammalian cell gene mutation
test neither in the absence nor in the presence of rat liver S9 mix in
two independently performed experiments.
IN VIVO MUTAGENICITY
Dance C (1991) was provided as the key study for this data requirement.
The study was performed in compliance with GLP and according to the
guideline OECD 474 (and EU Method B.12). The study was therefore
assigned a reliability score of 1 and considered reliable and adequate
for assessment. The study investigated the clastogenic action on bone
marrow erythrocytes in a micronucleus. The test material showed evidence
of induced chromosomal or other damage leading to micronucleus formation
in polychromatic erythrocytes of mice treated orally with DBTC at 50
mg/kg and sacrificed 48 or 72 hours later. A biologically and
statistically significant increase in the incidence of micronucleated
polychromatic cells was observed in the bone marrow of mice treated with
DBTC at 50 mg/kg and killed 48 and 72 hours later (0.01<p<0.05): this
effect was seen more clearly in females than in males. No such effect
was apparent for any group treated with DBTC and killed 24 hours later
(p>0.05). Statistically significant increases over controls were also
seen in positive control group animals given chlorambucil at 30 mg/kg
A further in vivo mutagenicity study, (Lang R & Wedel JV 1990) was
provided as supporting information. The GLP status of the study was not
reported and no guidelines were listed. The study was performed to a
good scientific standard with a good level of reporting of the
methodology and the results. The study investigated the mutagenic
potential of the test material in the mouse micronucleus test. The test
material failed to show any evidence of mutagenic potential, when
administered by gavage up to the toxic dose level of 200 mg/kg in the
mouse micronucleus test. Triaziquone, the positive reference, gave the
expected mutagenic response. After application of the high dose four
males and one female died; after application of the mid dose, one male
died. More than half of the animals of the two highest dose groups
showed signs of toxicity (e.g. apathy, eyelid closure, ruffled fur).
In the second part to the Li AP et al (1982) study, a test was performed
to determine the cytotoxicity of the test material to rat lymphocytes.
The test is not a standard endpoint and was therefore provided for
information purposes only. The study was performed to a good scientific
standard with a good level of reporting. The LC50 for lymphocytes as
determined by dye-exclusion was approximately 50 µg/ml (0.16 mM). At the
same concentration of DBTC, the number of antibody-forming cells (AFC)
was reduced to approximately 10 % of the control.
A read-across approach was considered
appropriate from dibutyltin chloride to other dibutyltins. Under gastric
conditions dibutyltins are hydrolysed to form dibutyltin chloride. This
is demonstrated in various dibutyltin compounds presented in the TNO
report V5047, (presented as individual reports as under Toxicokinetics).
European Food Safety Authority (EFSA) in the Option of the Scientific
Panel on Contaminants in the Food Chain on request from the Commission
to assess the risks to consumers associated with exposure to organotins
in foodstuffs (2004), concluded
that (organotins in general) did not exhibit any significant genotoxic
potential in vivo, and that carcinogenicity seen with some organotin
compounds was likely attributable to hormonal or immunotoxic actions.
Dibutyltin salts are recommended for classification as mutagenic (R68)
within the EU classification system. The available data for dibutyltin
chloride as described above are inadequate to challenge that
According to Directive 67/548/EEC the substance is assigned the
classification Mutagenicity category 3 and labelled with R68 – possible
risk of irreversible effects. According to Regulation (EC) No 1272/2008
the test substance would be classified as Muta. 2 with the Hazard
statement: H341: Suspected of causing genetic defects and should be
accompanied with the signal word 'Warning'.
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