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EC number: 264-885-7
CAS number: 64417-98-7
Effects on fertility: via oral route
No data are available on the toxicity of yttrium zirconium oxide to
reproduction. One study exists wit the read across substance zirconium
acetate. Rossiello (2013) performed a combined repeated dose toxicity
study with reproduction/developmental toxicity screening test via oral
route in rats according to OECD guideline 422 (GLP). A NOAEL of >=1000
mg/kg bw/day was obtained (based on anhydrous zirconium acetate).
The overall results of the test formulation
analyses were within the limits of acceptance for concentration (15% of
the theoretical concentration).
Effects on fertility: via oral route:
No information on the potential effects of yttrium zirconium oxide on
reproduction is available. Because yttrium oxide, according to the read
across justification attached to IUCLID Section 13, is not expected to
affect the toxicological properties of zirconium dioxide (the main
component in the crystal lattice of yttrium zirconium oxide), data on
zirconium dioxide can be used for endpoint coverage. However, since no
data on zirconium dioxide are available either, read across data are
used from zirconium acetate, a water soluble zirconium compound,
supported by the read across justification as included in the zirconium
dioxide registration dossier.
Zirconium dioxide is an insoluble zirconium compound and therefore
extremely low bioavailability is expected. Absorption factors of 10%
have been proposed as worst case for oral, inhalation and dermal
exposure although some evidence is available that this is a substantial
The assessment of all the toxicological data identified for zirconium
dioxide shows that this substance is of extremely low toxicological
concern after acute and repeated exposure of test animals. Toxicological
data from other zirconium compounds (both insoluble and 'water soluble')
support the assumption that zirconium compounds are barely bioavailable
and of extremely low toxicological concern.
In addition, so far, none of the zirconium compounds tested were shown
to be mutagenic or clastogenic (zirconium dioxide, zirconium basic
carbonate, zirconium acetate, zirconium sulfate, zirconium dichloride
oxide) both in absence and presence of metabolic activation.
The results of a 60-day repeated dose toxicity study after inhalation
exposure to zirconium dioxide (Spiegl et al., 1956) showed no abnormal
findings after histopathological evaluation of animal testes. This
supports the assumption that exposure to zirconium dioxide does not
affect at least the male reproductive organs. Details on this study can
be found in endpoint 7.5.
The systemic toxic effects of the read across substance zirconium
acetate after repeated oral dosing, as well as any toxic effects on
reproduction and development, were investigated in Sprague Dawley rats
up to early lactation (day 4 post partum) by Rossiello (2013). The study
was performed according to OECD guideline 422 and under GLP principles.
Three groups of 10 males and 10 females each received the test item, by
oral gavage, at 100, 300 and 1000 mg anhydrous zirconium acetate/kg
bw/day. A similar constituted control group received the vehicle alone
during the treatment period. 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 parental 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, determination of organ weights, and histopathological
examination, including the spermatogenic cycle, were performed. Pups
were also checked for sex, body weight, clinical signs and macroscopic
No mortality occurred in the study. No treatment related findings were
observed either during the in vivo phase or at post mortem examination
of parent animals. Microscopically, a treatment related finding was seen
in males receiving 300 and 1000 mg zirconium acetate/kg bw/day
consisting of minimal focal vacuolation of squamous epithelium (limiting
ridge) of the 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 a forestomach or structural
analogue to the forestomach, this finding is not considered of
toxicological relevance. In addition, no abnormalities were found during
the evaluation of the spermatogenic cycle. No treatment related effects
were observed in the number of oestrous cycle, pre-coital intervals,
copulatory and fertility indices between treated and control groups. No
significant differences were observed in the number of implantations,
corpora lutea, total litter size, pre-implantation loss, pre-birth loss
and gestation length between control and treated groups.
No effects were noted on reproduction and development at any dose. On
the basis of the results obtained in this study, the NOAEL for
reproduction/developmental toxicity was considered to be >= 1000 mg/kg
bw/day (expressed as anhydrous zirconium acetate), i.e., the highest
Taking into account the concept of the more water soluble is the
substance the higher is its potential for systemic bioavailability, it
can be concluded that reproduction/developmental toxicity (if any) after
repeated oral exposure to zirconium dioxide (an insoluble zirconium
substance) will be of even lower concern than for zirconium acetate.
Annex IX further testing:
An OECD 422 test (Rossiello, 2013) has been performed according to GLP
principles with the read across substance zirconium acetate, a 'water
soluble' zirconium compound. Based on the lack of toxicologically
relevant effects on reproductive organs/tissues or reproductive
performance of parent animals, the NOAEL for reproductive/developmental
toxicity was considered to be higher than or equal to 1000 mg/kg bw/day
(the highest dose tested, expressed as anhydrous zirconium acetate). The
results of this test (Rossiello, 2013) indicate that zirconium acetate
is a substance of low toxicological concern for this endpoint.
Taking into account the concept that the more water soluble is the
substance the higher is its potential for systemic bioavailability, it
can be assumed that zirconium dioxide (an insoluble
zirconium substance) will be of an even lower concern than zirconium
acetate for reproduction. Evaluating available data on zirconium dioxide
and other zirconium compounds, extremely low absorption and toxicity of
zirconium dioxide is observed/expected. Therefore, no further testing
(i.e., OECD 443) is deemed necessary for zirconium dioxide.
The same conclusion is reached for yttrium zirconium oxide, as yttrium
oxide is, according to the read across justification attached to IUCLID
Section 13, not expected to affect the toxicological properties of
zirconium oxide. Therefore, no additional test is proposed for animal
welfare reasons (e.g. OECD 443). The read across justification is added
in Section 13 of IUCLID. The full justification for waiving based on all
available data and expert judgement is similar as for further testing on
developmental toxicity and is also attached to IUCLID Section 13.
No key experimental data are available on the developmental toxicity of yttrium zirconium oxide. Because yttrium (oxide) is, according to the read across justification attached to IUCLID Section 13, not expected to affect the toxicological properties of zirconium dioxide, the toxicological profile of yttrium zirconium oxide is expected to be similar to that of zirconium dioxide.However, no data on developmental toxicity are available for zirconium dioxide either. Therefore, as in the zirconium dioxide registration dossier, all available data for zirconium dioxide as well as relevant information from other zirconium compounds (including the results of an OECD 422 study with the read across substance zirconium acetate, in which no adverse effects on developmental toxicity parameters were observed (Rossiello, 2013)), no testing is currently deemed necessary. The extended argumentation has been given in a document attached to IUCLID Section 13.
Developmental effects: oral route
In the read across justification document, it is concluded that the
addition of yttrium (oxide) to the crystal lattice of zirconium dioxide
does not alter the unhazardous properties of zirconium dioxide.
Therefore, higher toxicological endpoints in this dossier are covered by
information generated for zirconium dioxide. However, no key
experimental information on developmental toxicity is available for
yttrium zirconium oxide, zirconium dioxide, or any other zirconium
compound. The results of the OECD 422 study performed with the read
across substance zirconium acetate however offers supporting screening
Since the results of an OECD 422 study alone cannot be considered
sufficient for waiving further testing on this endpoint, an assessment
has been made based on all available (relevant) information on zirconium
dioxide (an insoluble zirconium compound) and several other zirconium
compounds (including both insoluble (zirconium basic carbonate) and
'water soluble' zirconium compounds (zirconium dichloride oxide,
zirconium sulfate, zirconium acetate)). This evaluation has been
presented in a document attached to IUCLID Section 13.
The following elements were considered to support the conclusion that
further testing (prenatal developmental toxicity study) is not
whether from an insoluble or ‘water soluble’ zirconium compound, is
extremely poorly soluble at environmentally and physiologically relevant
is sufficient evidence indicating that zirconium is barely absorbed
neither from the gastrointestinal tract nor after exposure via
inhalation or contact with the skin and thus, the probability to reach
the reproductive organs and the unborn offspring is considered to be
compounds have a very low potential for causing toxicity, both acutely
and long-term, and regardless of the route of exposure. Not much
difference exists among the zirconium compounds considered in this
evaluation, although there is some evidence (based on acute LD50 values)
for ‘water soluble’ compounds to be slightly more toxic (may be due to
the effect of the counter ions (acidification)). Read across from ‘water
soluble’ to insoluble zirconium compounds therefore guarantees that the
extrapolation is on the safe side.
available repeated dose toxicity studies did not report any adverse
effects on specific organs (including reproductive organs),
biochemistry, hematology, etc.
far none of the zirconium compounds tested has been found to be a
genetic toxicant in vitro.
OECD 422 study with zirconium acetate did not reveal any adverse effects
on reproduction or development of rats up to the highest dose tested
(NOAEL >= 1000 mg anhydrous zirconium acetate/kg bw/d). This study can
be extrapolated to zirconium dioxide.
to the extremely low absorption and toxicity, it will be scientifically
unjustified to perform a prenatal developmental toxicity study, since
this study reasonably requires testing up to doses that cause maternal
toxicity. Based on the evaluation and results mentioned above, it is
considered acceptable to assume that effects on reproduction or
development are not to be expected (if at all) at exposure levels well
below the unbound values from the repeated dose toxicity studies.
considerations on exposure were added to the argumentation (only
occupational exposure, inhalation exposure never up to doses as high as
the unbound NOAEC levels from the repeated dose toxicity studies – which
are above the occupational exposure limits anyway, risk management
measures advised in the guidance on safe use (local exhaust ventilation,
respiratory protection), etc.).
The read-across justification is added in section 13 of IUCLID.
Based on all information available (OECD 422 test with zirconium acetate
yielding a NOAEL >= 1000 mg/kg bw/day, and information on the
toxicokinetic behaviour and the physicochemical and toxicological
properties of zirconium dioxide and other relevant zirconium compounds)
zirconium dioxide was concluded not be classified as toxic for
reproduction. Zirconium substances appear to be poorly bioavailable and
are of low (if any) toxicological concern since none of the available
studies (short-term and long-term) so far have reported adverse effects.
Since yttrium oxide is, according to the read across approach, not
expected to alter the toxicological properties of zirconium dioxide,
yttrium zirconium oxide can also be concluded not to be classified as
toxic for reproduction.
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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