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EC number: 825-760-8
CAS number: 39290-95-4
No 'key' information was identified, however, an assessment was made
based on the physicochemical characteristics of the substance as well as
on available reliable toxicological data for tungsten zirconium
(hydroxide) oxide as well as zirconium dioxide and other relevant
zirconium substances (see read across justification document).
Preliminary (worst-case) absorption factors of 10% for the oral and
inhalation pathway and 1% for the dermal pathway were put forward in the
absence of key information from toxicokinetics experiments.
Toxicokinetics assessment of tungsten zirconium oxide
A qualitative judgement on the toxicokinetic behaviour of the
substance tungsten zirconium oxide (CAS 39290-95-4, EC 943-349-2) was
performed based on the physicochemical characteristics of the substance
as well as on available reliable toxicological data for the substance
itself as well as zirconium dioxide and other zirconium substances. No
toxicological data on tungstic acid (i.e. H2WO4, the substance used
during manufacture of tungsten zirconium oxide) or tungsten(VI) oxide
(i.e. WO3, the substance most closely describing the tungsten form
present in the final crystal lattice) have been added to the substance
dataset since these substances are not classified for any physical,
human health or environmental hazard, and because a comparison of the
available toxicological data for tungsten zirconium oxide with those
available for zirconium dioxide indicated that the addition of tungsten
to the crystal lattice of zirconium dioxide does not alter the
unhazardous character of the zirconium dioxide. Therefore, no
toxicokinetic or toxicological data specifically for tungsten
(compounds) have been discussed in this assessment.
Tungsten zirconium oxide is a white odourless powder and consists
of a stabilised zirconia crystal lattice including the elements
tungsten, zirconium and oxygen. The substance is characterised by a
molecular weight range between 126.79 g/mol and 135.82 g/mol, a median
particle size of 7.006 µm (representative sample of Luxfer MEL
Technologies, 2016), a very low water solubility (< 0.02 mg Zr/L and <
0.002 mg W/L) (Buchholz, 2018) and a relative density of 3.408 at 20.2°C
(Demangel, 2017). Based on melting point information for zirconium
dioxide and tungsten(VI) oxide, obtained from handbooks, the melting
point of tungsten zirconium oxide was concluded to be well > 300°C.
The relevant pH range for the uptake in the gut after oral
ingestion is 6 (at the entrance of the duodenum) to 7.4 (at the terminal
ileum). Because tungsten zirconium oxide is poorly soluble in water at
this pH level (see above), absorption after oral exposure is expected to
be extremely limited. During passage through the stomach, the acidic pH
of the gastric environment may however cause some dissolution of
zirconium and/or tungsten from the substance. This is rather expected
for zirconium than for tungsten, as tungsten is known to have a much
lower solubility at very low pH compared to higher pH levels (as is
clear from Eh-pH diagrams by Takeno, 2005). Any dissolved zirconium is
however expected to be rapidly precipitated in the gut due to the
presence of ligands such as phosphate and carbonate and formation of
strong, insoluble complexes with these ligands. Therefore, it is
expected that the bioavailability of zirconium for uptake in the small
intestine will be extremely limited. Any tungsten that may have
dissolved from the substance at the acidic pH in the stomach may partly
stay bioavailable for uptake in the gut, however, as dissolution is
expected to be limited at the gastric pH, uptake is also expected to be
The absence of systemic toxicity in the experiments carried out
with tungsten zirconium (hydroxide) oxide as well as the substance’s
constituent zirconium dioxide or – for some endpoints – its read across
compounds, supports the assumption of limited oral absorption:
- Following single administration by oral route at the limit dose
of 2000 mg/kg bw, no relevant systemic clinical signs or changes in body
weight and no gross abnormalities upon necropsy were observed for
tungsten zirconium (hydroxide) oxide (Appl, 2018) nor for zirconium
dioxide (Phycher Bio Developpement, 2008).
- No adverse effects have been observed in an OECD 422 study
performed with the read across substance zirconium acetate in rats
(Rossiello, 2013), resulting in NOAEL values≥1000 mg/kg bw/day (i.e. the
highest dose tested).
- No adverse effects were reported after oral administration of
the read across substance zirconium basic carbonate (containing 20.9%
zirconium dioxide equivalent) to rats during 17 weeks. The equivalent
NOAEL for zirconium dioxide was≥3150-7080 mg/kg bw/day (Harrison et al.,
No experimentally obtained data on oral absorption are available
for tungsten zirconium oxide or zirconium dioxide. Data on zirconium
dichloride oxide in mouse and rat show oral absorption to be at levels
of 0.01 to 0.05% of the administered dose (Delongeas et al., 1983). This
well water soluble compound could be regarded as a reference for
zirconium dioxide as it will instantaneously be converted to zirconium
dioxide in aqueous solution (at physiologically relevant pH levels) and
therefore higher-than-expected similarities between soluble and
insoluble zirconium compounds are expected.
Based on the arguments above, the oral absorption of tungsten and
zirconium from tungsten zirconium oxide is expected to be low and a
worst case oral absorption factor of 10% is proposed.
Low exposure to the substance is expected based on the inherent
properties of the compound. No vapour pressure value has been determined
as the product does not melt below 300°C (see above). Therefore,
inhalation of tungsten zirconium oxide as a vapour is not likely to
There are no data available on aerodynamic diameter but based on
the small median particle size of a representative sample for tungsten
zirconium (hydroxide) oxide, which was determined to be 7.006 µm (Luxfer
MEL Technologies, 2016), typical grades of the substance can be assumed
to contain both inhalable and respirable particles. When inhaled, the
substance, which has a very low water solubility (Buchholz, 2018), may
reach the alveolar region. In the alveolar region, the particles may be
engulfed by alveolar macrophages. These macrophages will then either
translocate the particles to the ciliated airways or carry particles
into the pulmonary interstitium and lymphoid tissues. For this reason,
the respiratory absorption is expected to be very low.
Currently, there are no inhalation toxicity studies available
performed on the substance itself to support the reasoning above.
However, the absence of systemic toxicity in the experiments carried out
with the substance’s constituent zirconium dioxide supports this
assumption both after single and repeated exposure. Following a single
inhalation (nose only) exposure assessment during 4 h and at the limit
dose of 4.3 mg/L ZrO2 as aerosol (Smith, 2010), no mortalities and no
specific test item related adverse effects in body weight, clinical
signs and gross pathology were observed. A sub-chronic inhalation study
(60 days) applying ZrO2 at a dose of 15.4 mg/m3 air to rats, rabbits,
guinea pigs, dogs and cats and a short-term repeated dose inhalation
study (30 days) applying ZrO2 at a dose of 100.8 mg/m3 air to rats,
rabbits and dogs showed no significant changes in mortality rate,
growth, biochemistry, hematology values or histopathology in any of the
species tested (Spiegl et al., 1956). Findings on accumulation
supporting the macrophage-mediated clean-up mechanism are further
discussed in the section on distribution.
The absence of systemic effects in the available inhalation
toxicity studies is supportive of the assumption of very low respiratory
Based on the reasoning above, a worst case inhalation
absorption factor of 10% is proposed.
Prior to penetrating the skin by diffusive mechanisms, the test
substance would have to dissolve in the moisture of the skin. However,
as the solubility of tungsten zirconium oxide is very low at
physiologically relevant pH levels (relevant to skin), no significant
dermal uptake is expected because the substance must be sufficiently
soluble in water to partition from the lipid rich stratum corneum into
Furthermore, tungsten zirconium (hydroxide) oxide was demonstrated
to be not irritating to skin (Orovecz, 2017) nor skin sensitising
(Tarcai, 2018) and therefore the expected low dermal absorption is not
expected to be enhanced by any irritating/sensitising effects.
In the absence of measured data on dermal absorption, the ECHA
guidance (2017) suggests the assignment of either 10% or 100% default
dermal absorption rates. However, the currently available scientific
evidence on dermal absorption of some metals (e.g. Zn sulphate, Ni
acetate; based on the experience from previous EU risk assessments)
indicates that lower figures than the lowest proposed default value of
10% could be expected (HERAG, 2007).
Based on the inherent properties of tungsten zirconium oxide, the
toxicological data available, demonstrating the absence of systemic
toxicity, and the experience from HERAG, no significant dermal
absorption is expected.
Based on the reasoning above, a worst case dermal absorption
factor of 1% is proposed.
Distribution and accumulation
From the above discussion, absorption of the elements zirconium
and tungsten following exposure to the substance tungsten zirconium
oxide via the oral, respiratory or dermal pathway is expected to be
(very) limited. Nevertheless, the available information on distribution
and accumulation of zirconium is discussed below in order to describe
its most likely behaviour once ending up in the circulatory system.
Since there are no oral toxicokinetics studies available informing
directly on the distribution and/or accumulation of (zirconium and
tungsten from) tungsten zirconium oxide or on the distribution and/or
accumulation of (zirconium from) zirconium dioxide or other zirconium
compounds, the findings from the available oral toxicity studies with
these compounds were considered more closely. In the 17-week oral
toxicity study performed with the insoluble zirconium basic carbonate
(containing 20.9% ZrO2 equivalent) in rats (Harrison et al., 1951), no
abnormalities were observed in heart, lungs, thyroids, thymus, liver,
spleen, kidneys, adrenals, stomach, intestines, bladder and genital
organs. In the OECD 422 study performed with the water soluble zirconium
acetate in rats (Rossiello, 2013), no abnormal findings that could
indicate accumulation of the substance in organs were made during
histopathological investigation either. Finally, macroscopic
investigation of rats that received a single dose of 2000 mg/kg bw
tungsten zirconium (hydroxide) oxide did not show any visible
accumulation of the test material in the body (Appl, 2018).
The findings of the studies mentioned above support the assumption
that no significant distribution to and no accumulation of (zirconium
and tungsten from) tungsten zirconium oxide in the organs will take
place after oral ingestion.
Administration via inhalation
Since there are no toxicokinetics studies available informing
directly on the distribution and/or accumulation of (zirconium and
tungsten from) tungsten zirconium oxide or (zirconium from) zirconium
dioxide or other zirconium compounds, the findings from the available
inhalation toxicity studies with zirconium dioxide were considered more
closely. In the short-term (30-day) repeated dose inhalation study in
dogs, rabbits and rats exposed to ZrO2 (Spiegl et al., 1956), an
apparently granular material, brownish-black and doubly refracting, was
found in the alveolar walls and in phagocytes during the
histopathological examination. Occasionally, this dust was also seen in
bronchi and lymph nodes. Similar findings were made in the sub-chronic
(60-day) study in dogs, rabbits, rats, guinea pigs and cats.
This finding suggests that accumulation of poorly soluble ZrO2 in
the lungs may occur under certain conditions, but also that the
substance may at least partly be removed by a mechanism involving
macrophages and consequent transport to/accumulation in the lymph nodes
associated with the lungs. There is no evidence though of true
absorption in the circulatory system and consequent distribution to and
accumulation in organs.
There are no dermal toxicity studies available on tungsten
zirconium oxide and zirconium dioxide, but based on the predicted very
low dermal absorption of the substance, no accumulation or distribution
is expected either.
Olmedo et al. (2002) studied the dissemination 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.
Additional data show distribution of several other zirconium
compounds through the body with main presence in bone and liver, but
also in spleen, kidney and lungs (Spiegl et al., 1956; Hamilton, 1948;
Dobson et al., 1948). Data from the latter two studies should be treated
with care as substances were administered via injection and thus not
only the chemical but also the physical form which becomes systemically
available might be different compared to administration via the oral,
dermal or inhalation route. In the study from Spiegl et al. (1956)
described above for zirconium dioxide, a repeated dose inhalation study
was also performed with zirconium dichloride oxide (i.e. a water soluble
zirconium compound). In this study, similar observations were made as in
the experiments with zirconium dioxide, but very small amounts of
zirconium were also found in femur, liver and kidney. These findings can
most likely be explained by further distribution throughout the body of
accumulated insoluble material in the lymph nodes via fagocytic cells of
the reticuloendothelial system, followed by (slow) elimination.
In conclusion, under normal conditions of exposure relevant under
REACH, no or only limited systemic distribution of tungsten zirconium
oxide is expected, depending on the route of exposure.
The elements zirconium and tungsten can be neither created nor
destroyed within the body. In addition, there are no indications of
transformation to more hazardous forms in the liver or kidney, which is
also supported by the fact that tungsten zirconium (hydroxide) oxide as
well as zirconium dioxide were demonstrated not to be mutagenic in
vitro, both in the absence and presence of metabolic activation
(Orovecz, 2018; LAUS, 2008; NOTOX, 2010a,b).
Based on the substance’s insoluble nature, low absorption and
distribution potential, and absence of obvious metabolism, it is
probable that after oral intake, non-absorbed tungsten zirconium oxide
will be eliminated via the faeces, either as tungsten zirconium oxide,
zirconium dioxide and/or other insoluble zirconium and tungsten species.
After inhalation exposure, as mentioned above, distribution of
particulate material may occur to the lung-associated lymph nodes, from
which further distribution may occur as well as (consequent) slow
excretion/elimination. No experimental data is available specifically
investigating the excretion/elimination pathways and kinetics, apart
from a study by Delongeas et al. (1983). In this study, zirconium
dichloride oxide, a water soluble zirconium compound which is
instantaneously converted to zirconium dioxide or other insoluble
zirconium species in aqueous solutions at physiologically relevant pH
levels, was administered to rats using a single oral dose of 450 mg/kg
bw (i.e., 128 mg Zr/kg bw). In this study, 90-99% of the administered
zirconium was eliminated via the faeces within 24 h. The limited
absorbed fraction (see above) was (at least partly) excreted via the
kidneys, with 0.0011 to 0.0015% of the total administered dose being
excreted within 72 h.
Appl A. Tungsten zirconium hydroxide oxide: acute oral toxicity
study in rats. CiToxLAB, Hungary, 2018.
Buchholz V. Solubility in water of one batch of tungsten zirconium
hydroxide oxide (CAS N°1037482-83-3), ANADIAG, Haguenau, France, 2018.
Delongeas JL et al. Toxicité et pharmacocinétique de l'oxychlorure
de zirconium chez la souris et chez le rat. J. Pharmacol (Paris) 1983,
14, 4, 437-447.
Demangel B. Relative density of solids by stereopycnometer method
on tungsten zirconium hydroxide oxide (CAS No. 1037842-83-3),
Défitraces, Brindas, France, 2017.
Dobson et al. Studies with Colloids Containing Radioisotopes of
Yttrium, Zirconium, Columbium and Lanthaum: 2. The Controlled Selective
Localization of Radioisotopes of Yttrium, Zirconium, Columbium in the
Bone Marrow, Liver and Spleen, University of California, Radiation
Laboratory, W-7405-eng-48A, 1948.
ECHA Guidance on Information Requirements and Chemical Safety
Assessment Chapter R.7c: Endpoint specific guidance, Version 3.0,
Hamilton JG. The Metabolic Properties of the Fission Products and
Actinide Elements, University of California, Radiation Laboratory,
Harrison et al. The acute, chronic and topical toxicity of
zirconium carbonate. J Pharmacol Exp Ther 102 (3): 179-84, 1951.
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 (2007).
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oxide with the bacterial reverse mutation test following OECD 471 and EU
B.13/14. LAUS, Germany, 2008.
Luxfer MEL Technologies, Technical data sheet: Particle size
analysis Microtrac - X100, F2261, MEL Chemicals, Manchester, UK, 2016.
NOTOX. Evaluation of the ability of zirconium dioxide to induce
chromosome aberrations in cultured peripheral human lymphocytes (with
repeat experiment), NOTOX B.V., ‘s Hertogenbosch, The Netherlands, 2010a.
NOTOX. Evaluation of the mutagenic activity of zirconium dioxide
in an in vitro mammalian cell gene mutation test with L5178Y mouse
lymphoma cells (with independent repeat), NOTOX B.V., ‘s Hertogenbosch,
The Netherlands, 2010b.
Olmedo et al. An experimental study of the dissemination of
titanium and zirconium in the body. Journal of Materials Science:
Materials in Medicine 13, 793-796, 2002.
Orovecz B. Tungsten zirconium hydroxide oxide: In Vitro Skin
Irritation Test in the EPISKINTM(SM) Model, CiToxLAB, Hungary, 2017.
Orovecz B. Tungsten zirconium hydroxide oxide: Bacterial Reverse
Mutation Assay, 17/232-007M, CiToxLAB Hungary Ltd., 2018.
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Toxicity in the Rat Acute Toxic Class Method, TAO423-PH-08/0062, Phycher
Bio Developpement, Cestas, France, 2008.
Rossiello. Zirconium acetate solution: combined repeated dose
toxicity study with the reproduction/developmental toxicity screening
test in rats. RTC laboratories Ltd. technical report, 2013.
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Albino Rats, WIL-594010, WIL Research Laboratories, Ashland, USA, 2010.
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of Zirconium Compounds: Short-Term Studies, Atomic Energy Commission
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Research Center for Deep Geological Environments, 2005.
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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