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EC number: 238-694-4
CAS number: 14644-61-2
No reliable toxicokinetic data (human or animal studies) and only limited information on toxicity in animals is available for zirconium sulfate. Therefore, a qualitative assessment of absorption, distribution/accumulation, metabolism and elimination is performed on the basis of the physico-chemical properties of the substance and any other available information.
No toxicokinetic data (human
or animal studies) are available on zirconium sulfate (a ‘water-soluble’
zirconium compound). 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 their inherent
properties are taken into account. 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 inorganic
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.
The substance is very
soluble in water at 20°C and low pH whereas progressive precipitation of
zirconium occurs with increasing pH (here, no evidence is presented in
the water solubility study, but observations in aquatic ecotoxicity
studies confirm that the behaviour in water is similar to that of other
'water soluble' zirconium compounds such as zirconium acetate and
zirconium dichloride oxide - no dissolved zirconium could be obtained in
aquatic test media at levels above the LOQ).
No vapour pressure is
reported for zirconium sulfate as it has a relatively high
melting/degradation point making the vapour pressure less relevant. No
log P value or pKa value has been defined for this substance as these
concepts do not apply for inorganic substances. The D50 values for
particle size are roughly in the range of 20 to 90 μm, depending on the
production batches (Coustet, 2011, 2012). The substance is however also
brought on the market as aqueous solution.
It should be noted that the
toxicokinetic behaviour of the counter ion (sulfate) 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 (acid release).
Studies evaluating the
absorption of zirconium sulfate following oral exposure in animals
and/or humans are not available.
Very limited data (Klimisch
3) on the absorption of zirconium dichloride oxide (another 'water
soluble' zirconium compound) following oral exposure in animals are
available. Delongeas et al. (1983) exposed mice and rats (single dose)
by oral gavage to zirconium dichloride oxide (1.5 g/kg bw for mice and 3
or 5.3 g/kg bw for rats) and sampled animals 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).
Zirconium sulfate is highly
soluble in pure water (669 mg/L) at 20°C and low pH (1.1-1.2) (Fox,
2013). 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 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. approximately 20 µg Zr/L) in any of the test solutions, including
100% v/v saturated solutions (Harris, 2014a,b; Vryenhoef and Mullee,
2014). Based on this
information, it is expected that zirconium sulfate 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
The assessment of the
physicochemical properties of zirconium sulfate clearly supports the
assumption of low oral absorption of zirconium. The expected limited
absorption of zirconium after oral exposure is confirmed by the
extremely low toxicity of zirconium substances after both acute and
For zirconium sulfate
specifically, a publication (Cochran et al., 1950) indicates that the
LD50 of the substance is 3500 mg/kg bw for rats. Similar results were
obtained with other zirconium substances (whether 'water soluble' or
not, see the read across justification attached to IUCLID Section 13).
No oral repeated dose toxicity data are available for zirconium sulfate,
but an OECD 422 study (combined oral repeated dose toxicity study with
reproduction/developmental toxicity screening) performed with zirconium
acetate (another 'water soluble' zirconium compound) 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 (No Observed
Adverse Effect Level) 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.
physicochemical properties of zirconium sulfate and the available
toxicological information on this substance and on other 'water soluble'
zirconium compounds such as zirconium acetate and zirconium dichloride
oxide support the assumption that zirconium sulfate is barely absorbed
after oral exposure. Taking into consideration all abovemention
information, the oral
absorption factor for zirconium sulfate is estimated to be 10% for risk
No toxicokinetic studies are
available exploring the absorption of zirconium sulfate
exposure of humans or animals.
No vapour pressure is
reported for zirconium sulfate as the test was considered technically
not feasible (decomposition). As a result, it is considered unlikely
that zirconium sulfate is available for inhalation as a vapour.
As the D50 values are
roughly in the range of 20 to 90 μm, depending on the production batches
(Coustet, 2011, 2012), it
is expected that they are efficiently filtered by nasal passage and do
not penetrate down to the alveoli of the lungs. The substance is also
brought on the market as 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 healthy individuals.
Therefore, in the case of zirconium sulfate, 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
sulfate is expected. Although there are no toxicological data after
acute or repeated inhalation exposure to zirconium sulfate, information
on other 'water soluble' zirconium compounds, such as zirconium
dichloride oxide, can be used to estimate the absorption and
bioavailability of the common metal ion Zr+4.
Limited experimental data on
the toxicity of zirconium dichloride oxide after repeated inhalation
exposure are available. 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 sulfate and the supporting toxicological
information on zirconium dichloride oxide (another ‘water soluble’
zirconium compound) after inhalation exposure, 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 sulfate physicochemical properties is
performed, taking toxicological data (obtained after dermal exposure)
into account of similar 'water soluble' substances such as zirconium
not expected to cross the intact skin after exposure to 'water soluble'
zirconium sulfate. 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 solid zirconium sulfate 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
sulfate 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 zirconium acetate (another 'water soluble'
zirconium compound), using a semi-occluded system on intact skin.
There were neither deaths,
nor 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 the 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 sulfate because zirconium acetate is not corrosive or
irritating to skin (Longobardi, 2013b).
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). Due to the corrosive properties,
which might enhance dermal penetration, lower figures than 10 % for
dermal absorption are not proposed.
Based on the above
considerations, a dermal absorption factor of 10% is suggested
for risk assessment purposes.
Due to the low absorption
rates, no significant or very low amounts of bioavailable zirconium are
expected after exposure via oral, inhalation or dermal route.
However, the distribution of potentially bioavailable zirconium is
evaluated here below. In this perspective, all the data available on
this substance and other 'water soluble' zirconium compounds (as source
of bioavailable zirconium) are considered.
Reliable studies evaluating
the distribution of zirconium (sulfate)
in humans or animals
are not available. There
are three publications containing relevant information (de
Bartolo et al., 2000; Berry
et al., 1990; Schroeder
et al., 1968) but due
to the lack of quality, the results of these studies are not considered
Although there is no
reliable in vivo information on zirconium sulfate,
there is some information available on other zirconium compounds.
Toxicological studies can
sometimes give an indication of the distribution pathway after exposure
to a substance, especially when a specific target organ is identified. For
zirconium acetate (another 'water soluble' zirconium compound), some
experimental data after acute (oral and dermal exposure) and repeated
oral exposure are available. However, no significant toxicity was
observed after acute exposure (Cochran et al., 1950; Longobardi, 2013a)
and 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 (Rossiello, 2013).
Olmedo et al. (2002) studied
the dissemination of zirconium dioxide (an insoluble zirconium compound)
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.
Delongeas et al. (1983)
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 (a 'water soluble' zirconium
compound). 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
A repeated dose toxicity
study after inhalation exposure to zirconium dichloride oxide is
available (Spiegl et al., 1956) but no relevant information can be
extracted to support the evaluation of the distribution of bioavailable
zirconium as no target organ was identified.
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, another ‘water-soluble’
zirconium compound. Thus, Delongeas et al. (1983) suggested that
bioavailable zirconium would be excreted via the urine whereas the
non-absorbed zirconium would be eliminated via the faeces as zirconium
Beckett (2007). Routes of
exposure, dose and metabolism of metals. Chapter 3 of Handbook on the
toxicology of metals (3rd Edition).
Berry et al. (1990).
Subcellular localization of zirconium in nodular lymphatic cells after
administration of soluble salts. Study by electron microprobe.
Toxicology 62, 239-246.
Cochran et al. (1950). Acute
toxicity of Zirconium, Columbium, Strontium, Lanthanum, Cesium,
Tantalum, and Yttrium. Industrial Hygiene and Occupational Medicine 1:
Coustet (2011, 2012). CE
diameter report - volume distribution. Saint Gobain. Internal technical
Delongeas et al. (1983).
Toxicité et pharmacocinétique de l'oxychlorure de zirconium chez la
souris et chez le rat. J.
Pharmacol. (Paris) 14, 437-447.
de Bartolo et al. (2000).
Determination of biokinetic parameters for ingestion of radionuclides of
zirconium in animals using stable tracers. Radiat. Environ. Biophys 39:
ECHA guidance on information
requirements and chemical safety assessment (ECHA Chapter R.7.c, 2012)
Fox (2013). Zirconium
Sulfate: Determination of Water Solubility. Harlan Laboratories Ltd.
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.
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,
Rossiello (2013). Zirconium
acetate solution: combined repeated dose toxicity study with the
reproduction/developmental toxicity screening test in rats. RTC
laboratories Ltd. technical report.
Schroeder et al. (1968).
Zirconium, Niobium, Antimony and Fluorine in mice: effects on growth,
survaival and tissue levels. J. Nutrition 95: 95 -101.
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.
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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