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EC number: 231-717-9
CAS number: 7699-43-6
No reliable toxicokinetic data (human or animal studies) and only limited information on toxicity in animals is available for zirconium dichloride oxide. Therefore, a qualitative assessment of absorption, distribution/accumulation, metabolism and elimination is performed on the basis of the physicochemical characteristics of the substance and any other available information. Data from other zirconium compounds are described to support this assessment.Absorption factors of 10% for the oral, dermal and inhalation route of exposure were estimated in the absence of key experimental information on the toxicokinetic behaviour of zirconium dichloride oxide.
No reliable toxicokinetic
data (human or animal studies) are available on zirconium dichloride
oxide (a ‘water-soluble’ zirconium compound). Only supportive data were
identified (Delongeas et al., 1983). Therefore, a qualitative
toxicokinetic assessment has been performed based on the physicochemical
characteristics of the substance and on the available reliable
toxicological data presented in this dossier. Data from other zirconium
compounds are described to support this assessment.
It is generally assumed that
for metals and metal compounds, the metal ion (regardless of the
counterparts of the metal in the respective metal compounds), is
responsible for the observed systemic toxicity. Information on other
zirconium compounds can thus be used as long as account is taken of
their inherent properties. In addition, as indicated in ECHA’s guidance
on QSAR and grouping of chemicals (ECHA Chapter R.6, 2008), comparison
of the water solubility can be used as a surrogate to assess the
bioavailability of metals, metal compounds and other inorganics
compounds. This simplistic approach assumes that a specific
water-soluble metal-containing compound (target chemical) will show the
same hazards as other very water-soluble metal-containing compounds with
the same specific metal ion. Based
on the abovementioned considerations on solubility, data mainly from
other ‘water-soluble’ zirconium compounds are
described in this document to support the assessment.
Zirconium dichloride oxide
is an inorganic zirconium compound with zirconium in its highest
oxidation state (+4), i.e. its most stable oxidation state.
The substance is very
soluble in water at 20°C and low pH whereas progressive precipitation of
zirconium occurs with increasing pH (O'Connor and Woolley, 2010).
Observations in aquatic test media (e.g., Harris, 2014; Vryenhoef, 2014)
confirm that the behaviour in water is similar to that of other 'water
soluble' zirconium compounds such as zirconium acetate and zirconium
sulfate - no dissolved zirconium could be obtained at levels above the
No vapour pressure is
reported for zirconium dichloride oxide as the substance was shown to
decompose before melting starting from ca. 60°C (Bradshaw, 2010). No log
P value or pKa value has been defined for this substance as these
concepts do not apply for inorganic substances. The D50 value for
particle size was reported to be 391 µm (information from a single
production batch of one of the manufacturers, Butler, 2010). The
substance however also exists as aqueous solution.
It should be noted that the
toxicokinetic behaviour of the counter ion is not evaluated. The only
toxicological effects that can be ascribed rather to the counter ion
than to zirconium are the local corrosive effects in skin and eye, which
are expected based on the potential to release acid in aqueous media.
There are currently no
reliable studies evaluating the absorption of zirconium dichloride oxide
following oral exposure in animals and/or humans, however, supporting
experimental information in mouse and rat has been published by
Delongeas et al. (1983). In this study, mice and rats were exposed by
oral gavage (single dose) to zirconium dichloride oxide (1.5 g/kg bw for
mice and 3 or 5.3 g/kg bw for rats) and animals were sampled after
regular intervals up to 6 or 72 h after dosing. It was reported that the
substance was hardly absorbed in the gastrointestinal tract (maximal
absorption was between 0.007 and 0.05% of the administered dose after 6
h for both species). Although the results reported in this publication
are not considered sufficiently reliable due to the lack of information
provided on methods and results, other data available in this dossier
can be used to evaluate the absorption of zirconium dichloride oxide
after oral exposure.
Zirconium dichloride oxide
is highly soluble in water (> 1000 mg/L) at 20°C and low pH (pH 0.05)
(O'Connor and Woolley, 2010). This high solubility is however influenced
by the pH of the medium, as well as the presence of certain ligands such
as carbonates and phosphates. In the water solubility study performed by
O'Connor and Woolley (2010) it was reported that the precipitate
obtained upon increase of the pH of the test medium (i.e., pure water)
was most probably the insoluble hydrolysis product zirconium dioxide. In
environmentally and physiologically relevant test media, all zirconium
can be expected to be precipitated from the solution through
pH-dependent precipitation of zirconium hydroxides, zirconium dioxide
and/or zirconium carbonates and/or phosphate complexation, which is
rather independent of pH. This behaviour is confirmed by zirconium
analysis in test media for acute aquatic ecotoxicity tests, which did
not yield any measurements above the LOQ (i.e., 11-51 µg Zr/L, depending
on the study) in any of the test solutions, including 100% v/v saturated
solutions (Harris, 2014; Vryenhoef, 2014). Based on this information, it
is expected that zirconium dichloride oxide will readily dissolve into
the gastric fluid (low pH conditions). Once in the intestines, the
solubility will decrease significantly and dissolved zirconium will
precipitate. Consequently, it will not easily pass through aqueous pores
or will not be carried through the epithelial barrier by the bulk
passage of water.
In general, absorption from
the gastrointestinal lumen can occur by two mechanisms: by passive
diffusion and by specialized transport systems. With respect to
absorption by passive diffusion, the lipid solubility and the ionization
are important. However, inorganic metal compounds are usually not lipid
soluble and are thus poorly absorbed by passive diffusion (Beckett,
2007). Relatively new
information has become available on mechanisms of active transport and
distribution of metals in the body. In particular, it has been shown
that several metals can cross cell membranes by specific carriers and
ion channels intended for endogenous substrates (Beckett, 2007). But,
for zirconium compounds, there is no information available on such
mechanism of transport. In addition, the free metal cation (Zr4+)
will not exist at a significant concentration in solution due to the
decreased solubility under the pH conditions in the gastrointestinal
Based on the evaluation of
the physicochemical properties of zirconium dichloride oxide, limited
absorption is expected after oral exposure. This
is supported by the results of the study by Delongeas et al. (1983).
Further support can be found in the extremely low toxicity of zirconium
substances observed after both acute and repeated exposure.
For zirconium dichloride
oxide specifically, a publication (Cochran et al., 1950) indicates that
the LD50 of the substance is 3500 mg/kg bw for rats. This assumption is
supported by a less reliable publication (Klimisch 3) in which the LD50
in female mice was reported to be 4330 mg/kg bw (Delongeas et al.,
1983). Similar results were obtained with other zirconium substances
(whether 'water soluble' or not, see the read across justification
attached to IUCLID Section 13). Such high LD50 values already give an
indication of limited absorption after oral exposure.
In the publication of
Delongeas et al. (1983), it is reported that iterative administration of
zirconium dichloride oxide at a dose of 800 mg/kg bw/day to rats during
16 consecutive days had no significant impact on growth, water
consumption and diuresis. However, the results of this study cannot be
considered entirely reliable (scored Klimisch 3). Therefore, the results
of an OECD 422 study (combined repeated dose toxicity study with
reproduction/developmental toxicity screening) performed with the read
across substance zirconium acetate (another 'water soluble' compound
with similar behaviour as zirconium dichloride oxide) can give an
indication of the absorption after repeated oral exposure to zirconium
substances. This study did not observe any systemic adverse effects in
rats exposed to 100,
300 and 1000
mg/kg bw/day (expressed as zirconium acetate anhydrous) (Rossiello,
2013). The NOAEL for systemic toxicity of the parent animals and
reproduction/developmental toxicity was considered to be >= 1000 mg/kg
bw/day (the highest dose tested). There were no effects on mortality of
parent animals, no clinical findings (daily or weekly), no differences
in the functional observational battery (including grip strength and
locomotor activity), no differences in mean absolute or relative organ
weights, and no overt macroscopical findings of toxicological relevance.
Histophatological evaluation showed a treatment-related effect on the
forestomach of the rat due to repeated gavage. These changes were
however considered to be a local effect rather than one of systemic
toxicological relevance. No differences on the completeness of stages or
cell populations of the testes were recorded between controls and high
dose animals. Litter data, pup weights and sex ratio were not affected
by treatment. No clinical signs of pups were reported.
the physicochemical properties of zirconium dichloride oxide and the
available toxicological information on this substance and on other
'water soluble' zirconium compounds such as zirconium acetate support
the assumption that zirconium dichloride oxide is barely absorbed after
oral exposure. Taking
into consideration all abovementioned information, the oral
absorption factor for zirconium dichloride oxide is estimated to be 10%
for risk assessment purposes.
No toxicokinetic studies are
available exploring the absorption of zirconium dichloride oxide
following inhalation exposure of humans or animals.
physicochemical properties of zirconium dichloride oxide, the substance
starts to decompose at a relatively low temperature (60°C) by the
release of attached water and hydrochloric acid, the resulting compound
being zirconium dioxide (Bradshaw, 2010). As a result of this
decomposition, it is not possible to determine the vapour pressure of
this substance at elevated temperatures. In addition, it is technically
difficult to obtain and contain the anhydrous form of zirconium
dichloride oxide. Based on the above rationale, it is considered unlikely
that zirconium dichloride oxide is available for inhalation as a vapour.
Values for particle size
distribution determined on a single production batch of the substance
were reported to be 83 μm, 391 μm and 875 μm for the D10, D50 and D90,
respectively (Butler, 2010). Therefore,
it is likely that the particles are efficiently filtered by nasal
passage, that they are deposited in the upper respiratory tract, and
that they do not penetrate down to the alveoli of the lungs. The
substance also exists as an aqueous solution, for which inhalation
exposure is not relevant.
In general, solubilized
substances will rapidly diffuse into the epithelial lining and become
available for absorption. The rate at which the particles dissolve into
the mucus will limit the amount that can be absorbed directly. Deposited
particles may also be subject to clearance by other mechanisms such as
mucociliary or cough clearance, transported out of the respiratory tract
and swallowed. In that last case the substance needs to be considered as
contributing to the oral/gastrointestinal absorption rather than to
absorption via inhalation.
The composition of the lung
mucosae is mainly water with a pH of about 6.6 in health individuals.
Therefore, in the case of zirconium dichloride oxide, particles
potentially deposited in the alveolar region are not expected to
dissolve but are expected to be engulfed mainly by alveolar macrophages.
The macrophages will
then either translocate particles to the ciliated airways or carry
particles into the pulmonary interstitium and lymphoid tissues.
Particles which settle in the tracheo-bronchial region would mainly be
cleared from the lungs by the mucociliary mechanism and swallowed.
However, a small amount may be taken up by phagocytosis and transported
to the blood via the lymphatic system.
Based on abovementioned
information, low absorption after inhalation exposure to zirconium
dichloride oxide is expected. This is supported by the limited experimental
data on the toxicity of zirconium dichloride oxide after repeated
inhalation exposure. In a reliable study (Spiegl et al., 1956), cats,
dogs, guinea pigs, rabbits and rats were exposed to 11.3 mg/m3 zirconium
dichloride oxide for 60 days. No significant changes in mortality rate,
growth, biochemistry, hematology values or histopathology were reported.
The absence of systemic effects in this study therefore supports the
assumption that zirconium dichloride oxide is barely absorbed following
Based on the physicochemical
properties of zirconium dichloride oxide and the supporting
toxicological information mentioned above, an inhalation absorption
factor of 10% is proposed in the absence of specific data.
absorption following dermal exposure in humans or animals are not
available. Therefore a qualitative assessment of the toxicokinetic
behaviour based on zirconium dichloride oxide physicochemical properties
is performed, taking toxicological data (obtained after dermal exposure)
into account of similar 'water soluble' substances such as zirconium
Zirconium is not expected to
cross the intact skin after exposure to ‘water soluble’ zirconium
dichloride oxide. This assumption is based on the qualitative assessment
of the physicochemical properties of the substance: the solubility of
the substance is extremely limited at environmentally and
physiologically relevant circumstances (e.g., generally pH of the skin
ranges from pH 4.0 to 7.0). Therefore, no significant uptake is expected
to occur. The buffering potential of the sweat on the skin may however
be overruled upon dissolution of zirconium dichloride oxide or contact
with an aqueous solution of the substance. In that case some zirconium
may be dissolved in sweat and available for uptake. The resulting low pH
levels can also be expected to result in adverse effects on the skin (or
the eye). Corrosion can enhance absorption via the dermal route.
No toxicological information
is available for animals after acute or repeated exposure to zirconium
dichloride oxide via the dermal route. However, the expected limited
absorption after dermal exposure is confirmed by an acute dermal
toxicity study (Longobardi, 2013a) in which rats were exposed for 24 h
to 2000 mg/kg bw (limit concentration) of zirconum acetate (another
'water soluble' zirconium compound), using a semi-occluded system on
intact skin. There were neither deaths, no signs of toxicity (clinical
observations) or abnormalities at necropsy. The absence of systemic
signs of toxicity after acute dermal exposure to zirconium acetate
supports the assumption that zirconium acetate is poorly absorbed (low
bioavailability) and by consequence that it is of very low toxicity.
However, there may be some differences for zirconium dichloride oxide
because zirconium acetate is not corrosive or irritating to skin
In the absence of measured
data on dermal absorption, current guidance suggests the assignment of
either 10% or 100% default dermal absorption rates. Furthermore, the
currently available scientific evidence on dermal absorption of metals
(predominantly based on the experience from previous EU risk
assessments) yields substantially lower figures than the lowest proposed
default value of 10% (HERAG, 2007). Nonetheless, due to the corrosive
properties of zirconium dichloride oxide, which might enhance dermal
penetration, lower figures than 10 % for dermal absorption are not
Based on the above
considerations, a dermal absorption factor of 10% is suggested
for risk assessment purposes.
No significant or very low
amounts of bioavailable zirconium are expected after exposure via oral,
inhalation or dermal route to zirconium dichloride oxide. Reliable
studies evaluating the distribution of bioavailable zirconium in humans
or animals are not available. Delongeas et al. (1983), i.e. a study
which was scored as not entirely reliable (Klimisch 3), reported that
zirconium was detected in ovaries, liver, lung and to a lesser degree in
bone and central nervous system of rats after repeated oral exposure to
zirconium dichloride oxide. Although the amount distributed in each
organ compared to the administered dose is unknown, it is expected that
it will be extremely low based on the low amounts of bioavailable
zirconium reported in this study (i.e. 0.01 to 0.05% of the administered
dose of 800 mg/kg bw/day).
Toxicological studies can
sometimes give an indication of the distribution pathway after exposure
to a substance, especially when a specific target organ is identified.
Although a repeated dose toxicity study after inhalation exposure to
zirconium dichloride oxide is available (Spiegl et al., 1956), no
relevant information can be extracted to support the evaluation of the
distribution of bioavailable zirconium as no target organ was
For zirconium acetate
(another 'water soluble' zirconium compound), the histopathological
results in a combined repeated dose toxicity study with
reproduction/developmental toxicity screening (OECD 422) in rats were
limited to a treatment-related local effect on forestomach mucosa. These
changes were considered to be a local effect of the test item rather
than of systemic toxicological relevance. In addition, no target organ
was identified in this study either (Rossiello, 2013).
As discussed in previous
sections, the solubility of zirconium
dichloride oxide at physiologically relevant conditions is limited
(except under the acidic conditions in the stomach) and zirconium
precipitates from the solution as insoluble compounds such as zirconium
dioxide. Olmedo et
al. (2002) studied the distribution of zirconium dioxide after
intraperitoneal administration of this substance in rats. The
histological analysis revealed the presence of abundant intracellular
aggregates of metallic particles of zirconium in peritoneum, liver, lung
and spleen. These data should be treated with care as the substance was
mainly administered via intraperitoneal injection and thus difficult to
compare with the substance behaviour after administration via the oral,
dermal or inhalation route.
Based on the available data,
relevant parameters such as tissue affinity, ability to cross cell
membranes and protein binding are difficult to predict. No further
assessment is thus performed for the distribution of the substance
throughout the body.
Bioavailable zirconium is
not expected to be metabolized within the human body. However, no data
were identified on potential metabolism, hence no conclusions can be
Because of the hampered
absorption in the GI tract,
it is expected that a majority of the orally administered zirconium is
excreted via the faeces.
Bioavailable zirconium, as
ion, is expected to be eliminated by urine. This assumption is supported
by data available on zirconium dichloride oxide: Delongeas et al. (1983)
suggested that bioavailable zirconium would be excreted via the urine
whereas the non-absorbed zirconium (i.e., the majority) would be
eliminated via the faeces as zirconium dioxide (or other insoluble
Beckett (2007). Routes of
exposure, dose and metabolism of metals. Chapter 3 of Handbook on the
toxicology of metals (3rd Edition).
Bradshaw (2010). Melting
point determination of zirconium dichloride oxide (ZOC). MEL Chemicals
Butler (2010). Particle size
distribution determination of zirconium dichloride oxide (ZOC). MEL
chemicals. Internal technical report.
Cochran et al. (1950). Acute
toxicity of Zirconium, Columbium, Strontium, Lanthanum, Cesium,
Tantalum, and Yttrium.Industrial
Hygiene and Occupational Medicine 1: 637-650.
Delongeas et al. (1983).
Toxicité et pharmacocinétique de l'oxychlorure de zirconium chez la
souris et chez le rat. J.
ECHA guidance on information
requirements and chemical safety assessment (ECHA Chapter R.7.c, 2012)
Harris (2014). Zirconium
dichloride oxide: Daphnia sp., 48-hour acute immobilization test. Harlan
Laboratories Ltd. technical report.
Health risk assessment
guidance for metals (HERAG) fact sheet (2007). Assessment of
occupational dermal exposure and dermal absorption for metals and
inorganic metal compounds. EBRC Consulting GmbH.
Zirconium acetate solution: acute dermal toxicity study in rats. RTC
laboratories Ltd. technical report.
Zirconium acetate solution: acute dermal irritation study in rabbits.
RTC laboratories Ltd. technical report.
O’Connor and Woolley (2010).
Determination of water solubility and investigation/determination of
reactivity with water. Harlan laboratories. Technical report.
Olmedo et al. (2002). An
experimental study of the dissemination of Titanium and Zirconium in the
body. Journal of Materials Science: Materials in Medicine, Volume 13,
Rosiello (2013). Zirconium
acetate solution: combined repeated dose toxicity study with the
reproduction/developmental toxicity screening test in rats. RTC
laboratories Ltd. technical report.
Spiegl et al. (1956).
Inhalation Toxicity of Zirconium Compounds: Short-Term Studies. Atomic
Energy Commission Project, Rep. No. UR-460, University of Rochester,
Rochester, NY, pages 1-26.
Vryenhoef (2014). Zirconium
dichloride oxide: Algal growth inhibition test. Harlan Laboratories Ltd.
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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