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EC number: 231-717-9
CAS number: 7699-43-6
Repeated dose toxicity - oral route:Rossiello (2013) performed a combined repeated dose toxicity study (scored Klimisch 1) with reproduction/developmental toxicity screening test via oral route in rats according to OECD guideline 422. This study was performed in compliance with GLP guidelines. A NOAEL of >=1000 mg/kg bw/day was derived (expressed as zirconium acetate anhydrous). No adverse effects were reported in this study. Zirconium acetate is a water-soluble zirconium compound with similar behaviour as zirconium dinitrate oxide. Therefore the results of this study are considered relevant for zirconium dinitrate oxide too.Repeated dose toxicity: inhalation:Inhalation of 11.3 mg/m3 zirconium dichloride oxide for 60 days produced no significant changes in mortality rate, growth, biochemistry, hematology values and histopathology in various animal species. The NOAEC is therefore considered to be >= 11.3 mg/m3.
Repeated dose toxicity: dermal:No reliable data are available for repeated dose toxicity via the dermal route of exposure. Since key studies are available for two routes of exposure (oral and inhalation exposure), no testing is required via the dermal route.
The overall results of the test formulation
analyses were within the limits of acceptance for concentration (15% of
the theoretical concentration).
No impact on animal weight. No impact on water consumption. No
significant impact on diuresis.
No histopathologic impact observed for all investigated tissues except
for the ovaries.
The vessels of the ovarian medulla are dilated inconsistently at the end
of the short-term toxicity period. After the rest period, the diameter
of the vessels of the cortex and medulla is constantly increased giving
a congestive aspect to the ovarian parenchyma.
Repeated dose toxicity - oral route
On the repeated dose toxicity of zirconium dichloride oxide via the oral
route of exposure, only a study of low reliability (Klimisch 3) was
identified (Delongeas et al., 1983). This study demonstrated that
iterative administration of the substance at a dose of 800 mg/kg bw/day
to rats during 16 days has no significant impact on growth, water
consumption, and diuresis. Only a fraction of the administered zirconium
is absorbed, it binds electively to the ovaries, and more slightly to
the lungs and bones. Zirconium dichloride oxide causes
hypervascularisation of the ovaries, still visible one month after the
treatment. No deaths were observed after administration of 800 mg/kg
bw/day during 16 days to rats.
Because the available information on zirconium dichloride oxide is not
sufficient to cover the endpoint, read across is performed from a
combined repeated dose toxicity study with reproduction/developmental
toxicity screening test via oral route in rats with zirconium acetate, a
'water soluble' zirconium substance with similar toxicokinetic behaviour
as zirconium dichloride oxide. The read across justification is included
in Section 13 of IUCLID.
In this study the systemic toxic effects of zirconium acetate solution
(containing 40.7% of the active ingredient anhydrous zirconium acetate)
after administration of repeated doses, as well as any toxic effects on
reproduction and development, were investigated in Sprague Dawley rats
up to early lactation (day 4 post partum). The study (Rossiello, 2013)
was performed according to OECD guideline 422 (GLP)
Three groups of 10 males and 10 females each received the test item, by
oral gavage, at 100, 300 and 1000 mg/kg bw/day, expressed as zirconium
acetate (anhydrous). A similar constituted control group received the
vehicle alone during the treatment period. The test item was diluted in
purified water (vehicle) at concentrations of 10, 30 and 100 mg of
zirconium acetate/mL. Chemical analyses of the formulated test item were
performed during the study and the overall results were within the
limits of acceptance. The overall dosing period was 32 days for males,
which included 2 weeks before pairing and continuously thereafter up to
the day before necropsy and up to 50 days for females including 2 weeks
before pairing and thereafter during pairing, gestation and lactation
periods until day 3 post partum.
The animals were followed for daily clinical signs, weekly body weight,
food consumption, neurotoxicity assessment, oestrous cycle, mating
performance, clinical pathology evaluation including haematology and
clinical chemistry and offspring delivery. A detailed macroscopic
examination, organ weights and histopathology including the
spermatogenic cycle were performed.
No treatment-related findings were observed either during the in vivo
phase or at post mortem examination. Microscopically, treatment-related
finding was seen in males receiving 300 and 1000 mg/kg bw/day consisting
of minimal focal vacuolation of squamous epithelium (limiting ridge) of
non-glandular region of the stomach. This change may be attributed to a
local irritant effect of the compound administered by oral gavage and
since humans do not have forestomach or structure analogous to
forestomach, it is not considered of toxicological relevance.
No systemic adverse effects were therefore reported. On the basis of
these results, the NOAEL (No Observed Adverse Effect Level) for systemic
toxicity after repeated oral exposure was considered to be >= 1000 mg of
zirconium acetate/kg bw/day for both males and females.
Due to the indications for similar toxicokinetic behaviour of zirconium
zubstances such as zirconium dichloride oxide and zirconium acetate, the
results of the repeated dose toxicity study with zirconium acetate are
considered relevant for zirconium dichloride oxide.
Repeated dose toxicity - inhalation route
A reliable study (Klimisch 2, reliable with restrictions) was identified
for this endpoint: a repeated inhalation test in cats, dogs, guinea
pigs, rabbits and rarts, which demonstrated that inhalation of 11.3
mg/m3 zirconium dichloride oxide for 60 days did not cause any
significant changes in mortality rate, growth, biochemistry, hematology
values or histopathology. Therefore the subacute endpoint is covered by
this 60-day study.
Repeated dose toxicity - dermal route
A key study is available for the oral and inhalation route of exposure.
According to the REACH Regulation, only one route of exposure should be
tested for repeated dose toxicity (column 2, annex VIII, section 8.6.1).
Therefore, it is not necessary to perform a repeated dose toxicity study
via the dermal route of exposure
Annex IX further testing:
There is sufficient evidence available indicating that zirconium is
barely absorbed after exposure via inhalation (see section 7.1) and is
therefore of low bioavailability. In addition, no adverse effects have
been reported after repeated inhalation exposure of test animals during
60 days to zirconium dichloride oxide (see above). Based on this
information it is unlikely to expect any toxicity after a period of 90
days of repeated exposure via inhalation. As no adverse effect needs to
be addressed, a test proposal for a 90-day inhalation study is not
scientifically justified. Therefore, and for animal welfare reasons, a
testing proposal is not included.
On the basis of the results observed in the OECD 422 test (Rossiello,
2013) performed with the read across substance zirconium acetate (NOAEL
>= 1000 mg/kg bw/day; no systemic toxicity observed at the highest
dose), no adverse effects need to be addressed by a subchronic oral
repeated dose toxicity test. In addition, based on the toxicokinetics
assessment, low absorption of zirconium is expected after oral exposure
to 'water soluble' zirconium substances such as zirconium dichloride
oxide and zirconium acetate. Therefore, and in accordance with the REACH
Regulation (Annex IX, section 8.6.2, column 2), a test proposal for a
90-day oral study is not included for zirconium dichloride oxide as it
is not scientifically justified.
Based on the available data for repeated dose toxicity via the oral
route of exposure and according to the CLP criteria, zirconium
dichloride oxide should not be classified for STOT - repeated exposure.
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