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EC number: 231-717-9
CAS number: 7699-43-6
In vitro mutagenicity in bacteria
A single reliable (Klimisch 2) key study is published (Mortelmans,
1986), performed according to OECD guideline 471. In this study,
zirconium dichloride oxide did not show mutagenic activity in the
applied bacterium tester strains in the absence or presence of metabolic
activation under the conditions of the test system.
In vitro mammalian chromosome aberration test
A single reliable (Klimisch 1) key study is available (Ciliutti, 2013),
performed according to OECD guideline 473 and conform GLP requirements.
In this study, the test substance did not induce structural chromosome
aberrations in chinese hamster ovary cells after in vitro treatment,
under the reported experimental conditions.
In vitro gene mutation study in mammalian cells
No in vitro gene mutation study in mammalian cells with zirconium
dichloride oxide is available. Data generated with zirconium acetate is
used for endpoint coverage. Justification of this read-across approach
is included in section 13. It was concluded from the study that
zirconium acetate does not induce mutation at the TK locus of L5178Y
mouse lymphoma cells in vitro in the absence or presence of S9 metabolic
activation under the reported experimental conditions. The same is
assumed for zirconium dichloride oxide.
Genetic toxicity in vitro:
In vitro gene mutation study in bacteria
An Ames test with zirconium dichloride oxide is performed by Mortelmans
et al. (1986). The test has been performed with Salmonella typhimurium
strains TA98, TA100, TA1535 and TA1537. Both with and without Aroclor
1254-induced rat and hamster liver S9 mix, zirconium dichloride oxide
tested negative in this study. This study was considered as key study
for this endpoint.
In vitro chromosome aberration test in mammalian cells
Ciliutti (2013) performed an in vitro Chromosome Aberration test
in Chinese hamster ovary cells (OECD 473) with zirconium dichloride
oxide. Two experiments were performed using different test
concentrations with and without S9 activation. Both negative and
positive controls were considered to be valid. On the basis of the
results obtained, it was concluded that zirconium dichloride oxide did
not induce structural chromosome aberrations after in vitro treatment
and under the reported conditions. This study was selected as key study
for this endpoint.
In vitro mammalian cell gene mutation test
No reliable data are available for zirconium dichloride oxide for this
endpoint. Therefore, read across data from zirconium acetate, another
'water soluble' zirconium compound with similar behaviour as zirconium
dichloride oxide, were used to cover the endpoint. In this read across
study, Bisini (2013) performed an in vitro mammalian gene mutation assay
in L5178Y TK+/- lymphoma cells using the fluctuation method according to
OECD Guideline 476. Two experiments were performed using different
concentrations with and without metabolic S9 activation (experiment I)
and without metabolic S9 activation (experiment II). Plates were tested
in duplicate. Plates were exposed for 3 h (experiment I) and 24 h
(experiment II). The positive and negative (vehicle) controls were
considered to be valid. It was concluded that the test substance did not
induce mutation at the TK locus of L5178Y mouse lymphoma cells in vitro
in the absence or presence of S9 metabolic activation under the
Next to the abovementioned key studies, some other in vitro data on
genetic toxicity of zirconium dichloride oxide have been identified as
well, more specifically from a publication of Ghosh et al. (1992),
presenting the results of three in vitro tests conducted using
human lymphocytes collected from several age groups. The three tests
include a chromosome aberration test, a micronucleus test and a sister
chromatid exchange assay. These studies were however not considered
reliable (Klimisch 3).
In the publication from Ghosh et al. (1992) the effects of age on in
vitro genetic toxicity were assessed. Human lymphocytes from various
age groups and from both men and women were collected and used to assess
chromosome aberrations, micronuclei and sister chromatid exchanges. No
metabolic activation system was used. Zirconium dichloride oxide caused
an increase in the number of chromosome aberrations in all cultures
tested, but mostly not significant compared to the controls. The
substance also caused an increase in the number of micronuclei in all
cultures, but not to a significant extent. The number of sister
chromatid exchanges were increased significantly in various age groups
in both males and females, but not in all age groups. Taking into
account the reliability of the study, it can be concluded that the
positive results in some of the age groups are ambiguous and can be
Conclusion based on in vitro testing
Based on the available information, zirconium dichloride oxide is
considered negative for in vitro genetic toxicity.
Genetic toxicity in vivo:
According to REACH Annex IX section 8.4, column 2, no further in vivo
testing is required as no positive results were obtained in any of the
three in vitro studies performed according to REACH Annexes VII and VIII
An in vivo mouse bone marrow chromosome aberration test is
available (Ghosh et al., 1990). This study was not considered reliable
(Klimisch 3). Under the test conditions the frequencies of aberrations
were directly proportionate to the concentration used. Female mice were
found to be more susceptible than male mice, though not to a
significantly higher level.
However, after a critical review of the study, it was concluded that the
results are ambiguous and therefore the study is disregarded.
The results of the study should be treated with great care for the
1) Only total chromosomal abnormalities are presented, which include
structural chromosome aberrations and spindle disturbances, the latter
being polyploidy. Polyploidy is a disturbance in mitotic processes and
cell cycle progression. An increase in polypoloidy may indicate that a
chemical has the potential to induce numerical aberrations. However,
polyploidy is not related to clastogenicity, and should therefore be
included separately from the structural chromosome aberrations. As this
study does not distinguish between the two, a conclusion on
clastogenicity cannot be drawn.
2) An aqueous solution of zirconium oxychloride is given to the mice. It
is known from water solubility/hydrolysis experiments that the substance
in water will cause a drop in pH by the release of H+ ions. Apart from
the fact that the mice have probably been dosed corrosive solutions,
there is some evidence that H+ ions can cause chromosomal damage (refer
to IARC monograph 54-8 (1992; p. 203) on hydrochloric acid). It can thus
not be ruled out that the observed effects in the bone marrow have been
caused by the low pH after dissolving the test substance in water.
3) No data were presented on whether the substance has actually reached
the bone marrow and whether this test is thus biologically relevant.
Some evidence exists that zirconium oxychloride is poorly absorbed by
mice after oral administration of an aqueous solution of 1500 mg/kg
(Delongeas et al., 1983, J. Pharmacol. 14(4) 437-447). It reaches the
blood and after 6 h a maximal blood concentration of 2.9 mg Zr/L (i.e.
about 10 mg zirconium oxychloride per liter) was reached. In a similar
but more extensive study in rats given aqueous solutions of 3000 mg
zirconium oxychloride/kg, the maximal blood concentration was reached
after 6 hours being about 0.3 mg Zr/L (i.e. about 1 mg zirconium
oxychloride per liter). Using metabolic cages it was shown that within
24 hours 90-98% of the given dose was excreted via feces and minimal
amounts via urine. This shows that the substance is hardly absorbed as
it is excreted via feces. In the same study of Delongeas et al. (1983),
tissue distribution reveals that the small absorbed fraction is
distributed and fixed in the ovaries, liver and lung, and to a lesser
degree in bone and CNS. All together this raises the question whether
the substance in the current study has reached the bone marrow to a
sufficient extent in order to induce effects.
No reliable studies are available for zirconium dichloride oxide.
However, since the results of all in vitro tests were negative, no in
vivo testing is needed according to the REACH Regulation.
Based on the results of three different types of in vitro tests, the
substance is considered not to be genotoxic. Therefore the substance
does not need to be classified for mutagenicity.
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