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Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
no data
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
A Klimisch 3 score is assigned because there is 1. no guideline reported, 2. no data on substance origin and purity, 3. no data on origin of animals and acclimation period for animals, 4. no data on controls, 5. no information whether or not animals were fastened the day before dosing.
Reason / purpose for cross-reference:
reference to same study
Principles of method if other than guideline:
Single dose administration of zirconium oxychlorure diluted in distilled water.
Dose of 1.5 g ZOC/kg for mouses, doses of 5.3 g ZOC/Kg and 3 g/kg for rats.
Series of 12 mouses are then sacrified after 30 min, 1h, 2h, 3h, 4h, 6h, 8h, 18h, 24h, 48h and 72h.
Series of 3 rats are then sacrified after 30 min, 1h, 2h, 3h30, 6h (Dose of 5.3 g/kg).
Series of 3 rats are then sacrified after 30 min, 1h, 3h, 6h, 24h, 72h (Dose of 3 g/kg).
GLP compliance:
not specified
Radiolabelling:
no
Species:
other: mouse & rat
Strain:
other: Swiss & Wistar
Sex:
not specified
Route of administration:
oral: gavage
Vehicle:
water
Duration and frequency of treatment / exposure:
Single administration
Remarks:
Doses / Concentrations:
1.5 g ZOC/kg (0.425 g Zr/kg) to mouse (mouse of 25 g) - 37.5 mg ZOC / 10.6 mg Zr
5.3 g ZOC/kg (1.5 g Zr/kg) & 3 g/kg (0.85 g Zr/kg) to rat (rat of 150 g) - 795 mg ZOC / 225 mg Zr and 450 mg ZOC / 128 mg Zr
No. of animals per sex per dose / concentration:
11 series of 12 mouses (131)
5 series of 3 rats (15) for the 1.5 g Zr/kg dose
6 series of 3 rats (18) for the 0.85 g Zr/kg dose
Control animals:
no
Details on absorption:
After administration zirconium oxychlorure passes the digestive barrier as it is found in blood.
For mice the maximal concentration in blood is after 6 h and is 2.9 mg Zr/L blood or 10.15 mg ZOC/L blood. For a mouse having approximately 2 mL of blood, 0.02 mg of ZOC were bioavailable after 6 hours so around 0.05% of the substance administered.

For the rats at the dose of 0.850 g Zr/kg, the maximal concentration in blood is after 6 hours and is 1.15 mg Zr/L blood or 4.025 mg ZOC/L blood. For a rat having approximately 7 mL of blood, 0.03 mg of ZOC were bioavailable after 6 hours so around 0.007% of the substance administered.
For the rats at the dose of 1.5 g Zr/kg the maximal dose in blood is after 3h30 and is 3.4 mg Zr/L blood or 12 mg ZOC/L blood. For a rat having approximately 7 mL of blood, 0.084 mg of ZOC were bioavailable after 6 hours so around 0.01% of the substance administered.
Details on distribution in tissues:
Bones, liver, kidneys, lungs, ovaries and CNS were analysed for zirconium. Zirconium is predominantly found in the ovaries and in the lungs. It is also found in bones and in a lower degree in the CNS.
Details on excretion:
After administration, fecal elimination is important, 88 to 97% of the administered zirconium is found in the feces after 24 hours. Less than 0.001% is found in the feces between 24h and 72h after administration of the substance.
Elimination via urinary tract is unimportant (0.001%). Nevertheless the concentration eliminated via urinary tract is more important after 72h than after 24h.
Metabolites identified:
not specified
Conclusions:
In this study, mice and rats were administered zirconium dichloride oxide in water via oral gavage. Absorption in the blood is limited and the maxima (after 6 h) varied between 0.007 and 0.05% of the administered dose.
Because the substance is hardly absorbed in the GI tract it is predominantly excreted via the feces. From the small portion absorbed, part of it is released via the urinary tract (6% after 24h - 20% after 72h).
The small absorbed fraction is distributed and fixed in the ovaries, liver and lung, and to a lesser degree in bone and CNS.

Description of key information

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.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
10
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
10

Additional information

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 LOQ.

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.

Absorption

Oral/Gastrointestinal (GI) absorption

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 lumen.

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.

Consequently, 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.

Respiratory absorption

No toxicokinetic studies are available exploring the absorption of zirconium dichloride oxide following inhalation exposure of humans or animals.

Regarding the 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 inhalation exposure.

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.

Dermal absorption

Studies evaluating 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 acetate.

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 (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). Nonetheless, due to the corrosive properties of zirconium dichloride oxide, 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.

 

Distribution and accumulation                                        

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 identified.

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.

 

Metabolism

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 drawn.

 

Excretion

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 complexes).

References

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 internal report.

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. Pharmacol.,14, 437-447.

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.

Longobardi (2013a). Zirconium acetate solution: acute dermal toxicity study in rats. RTC laboratories Ltd. technical report.

Longobardi (2013b). 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, Number 8.

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. technical report.