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EC number: 239-622-4
CAS number: 15571-58-1
In vitro studies : Ames tests
In the key study (1979), an Ames test
was carried out with a mixture of 70% dioctyltin
bis(2-ethylhexylmercaptoacetate) and 30% mono-octyltin
tris(2-ethylhexylmercaptoacetate). This mixture was tested in strains of
S. typhimurium (TA 1535, TA 1537, TA 98 and TA 100), with or without S9,
and there are positive and negative controls. No mutagenic activity was
observed in this test.
Others studies were used as supporting
studies because they are less complete than the key study. All these
studies used the same mixture as the key study, DOTE:MOTE, 70:30%. One
of these studies gave negative results, and two old studies showed a
(weak) positive response without metabolic activation.
In vitro studies : Mouse lymphoma
A GLP study guideline (OECD 473) was
available. DOTE was examined for its potential to induce gene mutations
at the TK-locus of cultured mouse lymphoma L5178Y cells, in both the
absence and the presence of a metabolic activation system (S9-mix). DOTE
was cytotoxic in both the absence and presence of S9-mix.
In the absence of S9-mix no increase in
mutant frequency was observed at any test substance concentration
evaluated. In the presence of S9-mix at 72 μg/ml the mutant frequency
was significantly increased by 238 mutants per 1,000,000 clonable cells
compared to the negative control. Since relatively small intervals
(0.85) were used and the increase was observed at a single concentration
causing more than 90% cytotoxicity compared to six concentrations
causing 50-70% cytotoxicity which showed no increase in mutant
frequency, it is concluded that this increase is not indicative for
It is concluded that under the
conditions used in this study, the test substance DOTE isnot mutagenicat
the TK-locus of mouse lymphoma L5178Y cells.
In vivo studies.
Two in vivo micronucleus studies
available on the mixture Dioctyltin bis(IOMA) [CAS No.
26401-97-8]:Octyltin tris(IOMA) [CAS No.26401-86-5] (80:20). Information
from these studies has been read across to the registered substance on
the basis Dioctyltin bis (IOMA) and dioctyltinnbis (2-EHMA) are
isomers of the same compound and are structural analogues of each other.
Based on the recently conducted developmental toxicity studies in two
species it is considered that DOTI is likely to be more toxicoligically
active and therefore use of data on this substance would be considered
to be a worst case assessment of the registered substance.
Both studies followed methods similar to
those which are outlined in standardised guideline OECD 474 and were
assigned a reliability score of 2 in line with the criteria of Klimisch;
these studies are regarded as key studies in the overall assessment of
the genetic toxicity of the registered substance.
In the first of the two studies, the
effect of ZK 30 434 on the incidence of micronucleated polychromatic
erythrocytes from the bone marrow of mice was tested with doses of 2250,
4500, and 9000 mg/kg bodyweight administered by oral gavage in two equal
doses separated by an interval of 24 hours. Negative control (1%
methycellulose by oral gavage) and positive control group (14 mg/kg
mitomycin C by injection) were run concurrently. After 6 hours of the
second dose bone marrow smears were examined for the presence of
micronuclei in 2000 polychromatic and 2000 normochromatic erythorcytes
At all doses of ZK 30 434 both the group
mean micronucleated cell counts were comparable with the concurrent
control values. The ratio of normochromatic to polychromatic cells was
comparable to controls for 2250 mg/kg group and significantly higher for
4500 and 9000 mg/kg groups (by Kruskal-Wallis method). Positive control
produced expected increase in micronucleated cell count and ratio. It
was concluded that ZK 30 434 failed to show any evidence of mutagenic
potential when administered orally in the test procedure. However,
evidence of bone marrow depression was observed, which is an indication
that the test item reached the bone marrow.
In the second of the two studies, the
effect of ZK 30 434 on the incidence of micronucleated polychromatic
erythroctyes in mice was assessed; a total doseage of 4500 mg/kg
bodyweight was administered by oral gavage in 2 equal doses, separated
by 24 hours. A negative control group (1% methylcellulose) and positive
control group (methotrexate, 40 mg/kg body weight) were run
concurrently. Mice were sacrificed 12, 24, 36, and 48 hours after the
second dose and bone marrow smears were examined for the presence of
micronuclei in 2000 polychromatic and 200 normochromatic erythrocytes
per mouse. The ratio of normochromatic to polychromatic cells was also
determined in each mouse.
The group mean micronucleated cell
counts in polychromatic and normochromatic erythrocytes obtained after
ZK 30 434 treatment were comparable with the concurrent control after
12, 24 and 36 hours. After 48 hours the micronucleated normochromatic
cell count was slightly higher than that of the concurrent control
(least significant difference method). At 48 hours the micronucleated
polychromatic erythrocyte count was comparable to control.
The normochromatic to polychromatic
ratio at each period was higher than that for the concurrent control
value. The positive control produced the expected increase in both the
group mean micronucleated cell counts and also in the normochromatic to
polychromatic erythrocyte ratio at 12, 24, 36 hours. After 48 hours the
micronucleated normochromatic erythrocyte count was comparable with the
concurrent control. There were too few polychromatic cells to count and
was not possible to use this parameter in analysis.
It therefore was concluded that ZK 30
434 did not show mutagenic potential when administered orally in the
test procedure. However, evidence of bone marrow depression was observed
at each kill. The small increase in micronucleated normochromatic cells
at the 48 hour timepoint, though significantly different from the
concurrent control, cannot be considered evidence of mutagenic potential
since a corresponding rise in micronucelated polychromatic cells had not
been observed in an earlier time point.
Three in vivo studies with the test
material Dioctyltin Dichloride (DOTC) are included in the dataset since
the substance was initially considered to be a relevant substance to use
for read-across purposes since findings from a gastric hydrolysis study
showed that DOT(2-EHMA) was readily hydrolysed to
Dichlorodioctyltilstanane (CAS no.3542-36-7) under physiological
conditions (see section 7.1.1). Thus DOTC(Dichlorodioctylstannane) was
considered to be an appropriate anchor compound and surrogate for the
mammalian toxicology endpoints of repeated dose, in vivo genetic
toxicity, reproduction and developmental effects, when it is dosed via
the oral route of administration.
Read-across to the substance DOTC is no
longer considered as wholly appropriate based on the results of the
recent Hydrolysis study, as reported by Naßhan, H, 2014 (see section
7.1.1) which indicate the substance DOTECl is the only metabolite of
DOTE which is formed in a simulated mammalian gastric environment; no
dioctyltindichloride was formed under the conditions of the study. The
three in vivo studies with DOTC have therefore been disregarded in the
overall assessment of the registered substance with regards to genetic
to Directive 67/548/EEC and
to regulation EC no.1272/2008 (CLP), DOTE is not classified for genetic
Justification based on weight of evidence
approach: Ambiguous results in Ames tests, negative results in the mouse
lymphoma assay performed on DOTE, and negative results in in vivo
micronucleus test performed with the hydrolysis product (DOTC).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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