Zirconium acetate

Endpoint summary

Description of key information

No experimental data is available on toxicokinetics for this substance. 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.

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 toxicokinetic data (human or animal studies) are available on zirconium acetate (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.

Indeed, 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 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.

No vapour pressure is reported for zirconium acetate 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. No particle size distribution has been determined as the substance is marketed as aqueous solution.

It should be noted that the toxicokinetic behaviour of the counter ion is not evaluated.

Absorption

Oral: Gastrointestinal (GI) absorption

Zirconium acetate is an organo-metallic compound which acts, through its solubility products (zirconium and acetate), as a significant source of zirconium ion and therefore the concepts of an inorganic substance are considered to be applicable. When present in compounds, zirconium mainly exists in its highest oxidation state (IV+) as it is the most stable oxidation state. Zirconium acetate is highly soluble in water (> 1000 mg/L) at 20°C and low pH (pH = 3.5). This high solubility is however influenced by the pH of the medium: at initial pH 9 the solution became an immobile gel (Fox, 2013). In this study the author also reported that, when adjusting the pH to values > 5, ICP-MS analyses showed no traceable amount of zirconium in solution (< 0.1 mg/L). Based on this information, it is expected that zirconium acetate 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 system. With respect to absorption by passive diffusion, the lipid solubility and the ionization are important. However, inorganic salts of metals are usually not lipid soluble and are thus poorly absorbed by passive diffusion (Beckett, 2007). Although zirconium acetate is an organo-metallic compound, it acts, through its solubility products (zirconium and acetate), as a significant source of zirconium ion. It is, however, not expected that the metal ion Zr⁴⁺ will absorb by passive diffusion across biological membranes.

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 it is believed that 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 physicochemical properties of zirconium acetate (i.e. decreased solubility in the intestinal tract and the anticipated hampered diffusion as ionized substance), low oral absorption is expected. The expected limited absorption after oral exposure is confirmed by the extremely low toxicity of zirconium acetate after both acute and repeated exposure.

In a publication (Cochran et al., 1950), the acute oral toxicity of zirconium acetate was evaluated in rats and a LD50 > 2000 mg/kg bw was obtained. The expected limited absorption after oral exposure is confirmed by the low toxicity observed in a combined oral repeated dose toxicity study with reproduction/developmental toxicity screening (Rossiello, 2013). In this study, rats were exposed to 100, 300 and 1000 mg zirconium acetate/kg bw/day (expressed as zirconium acetate anhydrous). 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.

As indicated previously, comparison of the water solubility can be used as a surrogate to assess bioavailability. Therefore information on other ‘water soluble’ zirconium salts, as for example zirconium dichloride oxide is used to estimate the absorption and bioavailability of the common metal ion Zr^IV+.

In the registration dossier of zirconium dichloride oxide there is some supporting evidence (Klimisch 3 study) that oral absorption is extremely low. 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 (maximum absorption was between 0.007 and 0.05% of the administered dose after 6 h for both species). In the same publication, the acute toxicity to zirconium dichloride oxide after oral exposure of female mice was also evaluated. The oral LD50 was calculated to be 4330 mg/kg bw. It is also reported that iterative administration of zirconium oxychlorure at a dose of 800 mg/kg bw/day to rats during 16 days had no significant impact on growth, water consumption and diuresis.

Consequently, the physicochemical properties of zirconium acetate and the available toxicological information on this substance and on zirconium dichloride oxide (both ‘water-soluble’ zirconium compounds) confirm that zirconium acetate is barely absorbed after oral exposure. Taking into consideration all abovementioned information, the oral absorption factor for zirconium acetate is estimated to be 10% for risk assessment purposes.

Respiratory absorption

No toxicokinetic studies exploring the absorption of zirconium acetate following inhalation exposure of humans or animals have been identified.

Regarding the physicochemical properties of zirconium acetate, the substance degrades at approximately 243°C before melting by dehydratation and dehydroxilation, the resulting compound being zirconium dioxide. As a result of this decomposition it is concluded that it is technically not feasible to experimentally determine the vapour pressure of zirconium acetate and thus it is unlikely that zirconium acetate is available for inhalation as a vapour.

No particle size distribution test is included in the registration dossier of the substance as it is marketed as aqueous solution. Therefore, the human exposure potential by the inhalation route is not expected to be significant. Despite the fact that inhalation exposure is not considered significant, the absorption of the potentially inhaled particles of zirconium acetate is assessed here below.

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. Zirconium acetate is a ‘water-soluble’ zirconium compound but the solubility decreases with increasing pH. Therefore, once deposited in the airways, it is expected that the solubility significantly decreases due to the pH of the lung mucosae (the composition of the lung mucosae is mainly water with a pH about 6.6 in healthy individuals) and absorption from the lung to the circulatory system is expected to be minimal.

Particles deposited in the alveolar region would thus mainly be engulfed 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 acetate is expected. Although there are no toxicological data after acute or repeated inhalation exposure to zirconium acetate, 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 inhalation exposure.

Based on the physicochemical properties of zirconium acetate 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.

Dermal absorption

Studies evaluating absorption following dermal exposure in humans or animals are not available. Therefore a qualitative assessment of the toxicokinetic behavior based on zirconium acetate physicochemical properties is performed, taking other toxicological data on this substance (obtained after dermal exposure) into consideration.

Zirconium is not expected to cross the intact skin after exposure to ‘water soluble’ zirconium acetate. This assumption is based on the qualitative assessment of the physicochemical properties of the substance: the solubility of the substance rapidly decreases when pH increases (generally pH of the skin ranges from pH 4.0 to 7.0). Thus no significant uptake by the intact skin is expected. Although a part of the substance remains dissolved, the amount would significantly decrease with time due to the epidermis buffer potential.

The expected limited absorption after dermal exposure is confirmed by the extremely low toxicity of zirconium acetate after acute dermal exposure. In an acute dermal toxicity study (Longobardi, 2013a), rats were exposed for 24 hours to 2000 mg/kg bw (limit concentration) of zirconium acetate, 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 substance is poorly absorbed (low bioavailability) and by consequence that the substance is of very low toxicity. Furthermore, zirconium acetate is neither a skin irritant (Longobardi, 2013b) nor skin sensitizer (Longobardi, 2013c). Therefore, it is unlikely that the low dermal absorption is increased by local effects (i.e. irritation or sensitization) of the substance in contact with the skin.

In the absence of measured data on dermal absorption, current guidance (ECHA, 2012) suggests the assignment of either 10% or 100% default dermal absorption rates. However there is available scientific evidence on dermal absorption of some metals (e.g. Zn sulphate, Ni acetate; based on the experience from previous EU risk assessments) showing that lower figures than the lowest proposed default value of 10% could be expected (HERAG, 2007).

Based on the above considerations, a dermal absorption factor of 10% is suggested for risk assessment purposes.

 

Distribution and accumulation                                        

Due to the low absorption rates, no significant or very low levels 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 bioavailable zirconium acetate in humans or animals are not available. Toxicological studies can sometimes give an indication of the distribution pathway after exposure to a substance or on a potential target organ. For zirconium acetate, 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).

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. 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).

One additional 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 done for the distribution of the substance throughout the body.

Metabolism

The term “metabolism of metals” is now usually restricted to those biochemical reactions that change the oxidation state of the metals or that form organometallic complexes, whereas this term was previously used to include the kinetics of metal disposition in the body (Beckett, 2007).

No reliable in vivo experimental data are available on the metabolism of zirconium as ion. However, zirconium acetate was not mutagenic to bacteria in a reliable Ames test (Scarcella, 2013), not clastogenic in a reliable in vitro Chromosome Aberration test in Chinese hamster ovary cells (Ciliutti, 2013) and not mutagenic in a reliable in vitro Mammalian Cells gene mutation test in mouse lymphoma cells (Bisini, 2013c), all of them in the presence and in the absence of metabolic activation.

Based on the abovementioned information it is not possible to predict whether or not zirconium, as ion, is ‘metabolized’.

 

Excretion

Because of the hampered absorption in the GI tract, it is expected that a majority of the orally administered zirconium acetate 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 dioxide.

References

Beckett (2007). Routes of exposure, dose and metabolism of metals. Chapter 3 of Handbook on the toxicology of metals (3rd Edition).

Bisini (2013c). Zirconium acetate solution mutation in L5178Y TK+/- mouse lymphoma cells (fluctuation method). RTC laboratories technical report.

Ciliutti (2013). Zirconium acetate solution chromosome aberration in Chinese hamster ovary cells in vitro. RTC laboratories 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, 4, 437-447.

ECHA guidance on information requirements and chemical safety assessment (ECHA Chapter R.7.c, 2012)

Fox (2013). Zirconium acetate: determination of density and water solubility. 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.

Longobardi (2013c). Zirconium acetate solution: Local lymph node assay (LLNA: BrdU-ELISA method). RTC laboratories Ltd. technical report.

Rossiello (2013). Zirconium acetate solution: combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats. RTC laboratories Ltd. technical report.

Scarcella (2013). Zirconium acetate solution bacterial mutation assay (S. typhimurium and E. coli). 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.