[μ-[carbonato(2-)-O:O']]dihydroxydioxodizirconium

Endpoint summary

Description of key information

No experimental data is available on toxicokinetics for this substance. Therefore, a qualitative assessment of the absorption, distribution/accumulation, metabolism and elimination is performed on the basis of the physico-chemical properties of the substance and available information.

Key value for chemical safety assessment

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

10

Additional information

No reliable toxicokinetic data (animal or human studies) are currently available on zirconium basic carbonate, an insoluble zirconium compound. However, 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.

Generally it is 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 water-soluble metal-containing compounds with the same specific metal ion.Taking into account the concept of the more water-soluble the substance, the higher its potential for systemic bioavailability, it can be concluded that toxicity after exposure to an insoluble zirconium compound may be lower than after exposure to a water-soluble zirconium compound. Furthermore, at physiologically relevant pHs, water-soluble zirconium compounds appear to precipitate significantly from solution, showing a similar behavior as the insoluble salts and therefore a similar bioavailability. Based on the abovementioned considerations on solubility, data from other zirconium salts are described in this document to support the assessment.

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

 

Absorption

Oral/Gastro-intestinal (GI) absorption

Zirconium basic carbonate is a solid inorganic salt of zirconium. When present in compounds, zirconium mainly exists in its highest oxidation state (4+) as it is the most stable oxidation state. Generally solids have to dissolve before they can be absorbed. However zirconium basic carbonate is insoluble in water (< 85 µg/L at 20°C and pH 6; O'Connor (2010). Although release of free zirconium ions could be expected at pHs below 4 (e.g. acidic conditions in the stomach), at pH values above 6 (e.g. intestinal lumen), this process is negligible and the chemical equilibrium is clearly on the side of the insoluble zirconium carbonate. Based on this information, zirconium basic carbonate will not readily dissolve and therefore it will not pass through aqueous pores and will not be carried through the epithelial barrier by the bulk passage of water.

In general, absorption from the gastro-intestinal lumen can occur by two mechanisms: passive diffusion or by specialized transport system. With respect to absorption via 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). In addition zirconium basic carbonate is insoluble and therefore not ionized in the gastrointestinal lumen.

Relatively new information has become available on mechanisms of active transport and distribution of metals in the body. In particular, it has been reported that several metals can cross cell membranes by using 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⁺) does not exist in solution as it is insoluble under the gastrointestinal lumen conditions.

Based on the physicochemical properties of the zirconium basic carbonate (i.e. insolubility under the intestinal tract conditions and the anticipated hampered diffusion as ionized substance), very low absorption is expected.

As discussed previously, a qualitative assessment can be also performed based on the toxicological data available for zirconium basic carbonate, however only few data are available after oral exposure.

In a publication (Harrison, 1951), the acute oral toxicity of the zirconium basic carbonate (hydrated form) was evaluated in rats. Hydrated zirconium carbonate was mixed with cheese. No deaths occurred during either the preliminary test with the group of 20 adult male rats or the more extensive test with 50 younger adult male rats. All animals continued to grow at a normal rate and gross examination of the autopsied animals revealed nothing abnormal up to a dose of 47 850 mg/kg bw (based on test material). Based on the results, an LD50 = 47 850 mg/kg bw was derived (based on test material).

One study has been identified where rats were orally (administered via the diet) exposed to zirconium basic carbonate (hydrated form) for 17 weeks (Harrison,1951). There was no mortality and no clinical signs. Neither clinical chemistry nor histopathological evaluation was performed. The NOAEL for the tested material was calculated to be greater than 15 100 mg/kg bw/d. Despite the fact that no all relevant information was reported, it is clear that the substance can be considered to have a low toxicity and therefore to have a low bioavailability due to low absorption.

Relevant data after oral repeated exposure to other zirconium compounds are also available. These data are considered relevant to support this assessment, taking into account the concept of the more water soluble the substance is, the higher is its potential for systemic bioavailability. Indeed, in this case it could be assumed that systemic toxicity after repeated oral exposure to zirconium basic carbonate (an insoluble zirconium compound) may be even lower than after repeated oral exposure to water-soluble zirconium compounds (such as zirconium acetate).

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in Wistar rats, zirconium acetate was tested at 100, 300 and 1000 mg/kg bw/day (expressed as zirconium acetate). The NOAEL for systemic toxicity of the parent animals and reproduction/developmental toxicity was considered to be 1000 mg/kg bw/day. There was no 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 at 300 mg/kg bw/day and 1000 mg/kg bw/day. These changes were considered to be a local effect due to repeated gavage of the test item 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 (Rossiello, 2013). The results of this study show that the absorption after repeated oral exposure to zirconium acetate through the GI tract is not significant. It is assumed that the absorption of zirconium basic carbonate (an insoluble zirconium compound) will be even lower.

Following the same approach as per zirconium acetate, data on zirconium dichloride oxide (a highly soluble zirconium salt) in mouse and rat are used to support this assessment. These data showed oral absorption to be at levels of 0.01 to 0.05% of the administered dose (Delongeas, 1983). These results also support the assumption that zirconium basic carbonate, an insoluble zirconium compound, is very poorly absorbed.

Based on all abovementioned considerations (i.e. insolubility of zirconium basic carbonate under intestinal conditions and the toxicological data available after oral exposure to zirconium basic carbonate and other zirconium compounds), low absorption of zirconium basic carbonate is anticipated when administered orally. Therefore an oral absorption factor of 10% is proposed for risk assessment, as worst case scenario for an insoluble zirconium salt. The reason for setting these worst case absorption factors is the absence of experimental toxicokinetic data that are sufficiently reliable to allow lowering these values.

Respiratory absorption

No studies were available regarding the absorption of zirconium basic carbonate in humans or animals following inhalation exposure.

Low exposure to zirconium basic carbonate is expected based on the inherent properties of the substance. So, as the substance starts to decompose at relatively low temperature (between 25 and 50°C) and it is expected to show a low vapour pressure, it is not likely that zirconium basic carbonate is available for inhalation as a vapour.

Two in-house company studies on particle size have been conducted. In one study (Butler, 2010), the particle size distribution of zirconium basic carbonate was determined based on volumetric distribution, providing d10, d50 and d90 percentiles of 21.47 µm, 31.55 µm and 46.31 µm, respectively. In another study (Saint-Gobain, 2010), the particle size distribution was determined based on volumetric distribution, providing d10, d50 and d90 percentiles of 4.62 µm, 12.97 µm and 24.49 µm, respectively. Although few particles can be smaller than 10 µm (and then able to penetrate the alveoli), the mass median diameter reported were 31.55 µm and 12.969 µm, thus it is expected that they are efficiently filtered by the nasal.

Despite the fact that the exposure is considered not significant, the absorption of the potentially inhaled particles of zirconium basic carbonate 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 basic carbonate being insoluble, the potential dissolution will be hampered and absorption is expected to be minimal. Particles deposing 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.

Very limited experimental data on the toxicity of zirconium basic carbonate after inhalation exposure are available. In an acute inhalation study (Smith, 2013), rats were exposed to zirconium basic carbonate (hydrated form) according to OECD Guideline 436. The maximum mean achieved aerosol concentration was 4.74 mg/L (based on test material). Animals were exposed for 4 hours (nose-only exposure) and observed for 14 days. The 4-hour LC50 was calculated to be greater than 4.74 mg/L for male and female rats, based on test material as supplied (53.37% of anhydrous zirconium basic carbonate). No mortality or adverse effects were reported.

Based on the abovementioned considerations, an inhalation absorption factor of 10% is proposed.

Dermal absorption

Studies evaluating absorption following dermal exposure in humans or animals were not available.

Zirconium basic carbonate is not expected to cross the intact skin. This assumption is based on the qualitative assessment of the physico-chemical properties of the substance. Zirconium basic carbonate is a solid substance and dry particulates will have to dissolve into the surface moisture of the skin before uptake can begin. As zirconium basic carbonate is insoluble at pH 6, it is expected to be insoluble at physiologically relevant pH. Therefore, no significant uptake will occur through the skin.

The buffer potential of the skin is not expected to be overruled as the amount of compound absorbed is very low and therefore the solubility of the substance will not be increased.

Experimental animal data evaluating the toxicity of zirconium basic carbonate after dermal exposure is available. In a GLP study (BIBRA, 1986), performed according to OECD 404, zirconium basic carbonate was determined not to be irritating to New Zealand White rabbit shaved skin after 4 hours of exposure using a occlusive dressing. Furthermore, zirconium basic carbonate is considered not to be a skin sensitizer (weight of evidence of 2 studies: Chemicals Inspection and Testing Institute (1999) and Harrison et al. (1951)). No animal data is available for repeated dermal exposure to zirconium basic carbonate.

In the absence of data, the ECHA guidance (2012) suggests the assignment of either 10% or 100% default dermal absorption rates. However, there is available scientific evidence on dermal absorption of metals (e.g. Zn sulphate, Ni acetate; based on the experience from previous EU risk assessments) showing that values below the default value of 10 % are expected (HERAG, 2007). Nonetheless, in the absence of experimental toxicokinetic data, a dermal absorption factor of 10% is suggested for risk assessment purposes as a worst-case scenario.

 

Distribution and accumulation

No significant and even very low levels of bioavailable zirconium after exposure via oral, inhalation or dermal route are expected due to the low absorption rates. However, the distribution of the potentially available zirconium after exposure to zirconium basic carbonate is evaluated here below. In this perspective, all the data available on this substance are considered.

Reliable studies evaluating the distribution of bioavailable zirconium basic carbonate in humans or animals are not available. Although toxicity studies are available with zirconium basic carbonate, these data do not give any indication on the distribution pathway of zirconium after exposure to this substance or on a potential target organ.

Histopathological results in a combined repeated dose toxicity study (included in this dossier) with the reproduction/ developmental toxicity screening test in rats were limited to a treatment-related local effect on forestomach mucosa when treated with zirconium acetate, a water-soluble zirconium compound used as surrogate (Rosiello, 2013). No target organ was identified.

Olmedo (2002) studied the dissemination of zirconium dioxide (another ‘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 due to the inherent properties of zirconium dioxide (i.e. insoluble zirconium salt) as the substance was administered via intra-peritoneal injection and thus difficult to compare with the behavior after administration via the oral, dermal or inhalation route.

Based on available data, relevant parameters like 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 through 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 (Becket, 2007).

Reliable experimental data evaluating this ‘metabolism’ for zirconium as ion have not been found. However, zirconium basic carbonate was not mutagenic to bacteria in a reliable Ames test (BIBRA, 1996) and not clastogenic in a reliablein vitro Chromosome Aberration test in Chinese hamster ovary cells (Ciliutti, 2013), both in the presence and in the absence of metabolic activation.

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

Excretion

Because of the hampered absorption in the GI tract of zirconium basic carbonate, it is expected that a majority of the orally administered compound will be excreted via the faeces.

Potential bioavailable zirconium, as ion, is expected to be eliminated by urine.

References

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

BIBRA (1986). Acute Skin Irritation Study in the Rabbit with Ammonium Zirconium Carbonate, Zirconium Propionate and Superfine Zirconium Oxide. The British Industrial Biological Research Association. Technical report.

Butler (2010). Melting point of ZBC. Mel Chemicals. Technical report.

Butler (2010). Particle size distribution determination of ZBC. Mel chemicals. Technical report. Chemicals Inspection and Testing Institute, Japan (1999). Skin Sensitization Test of TZ-3Y on Guinea Pigs (Maximization Test).Technical report.

Delongeas (1983). Toxicité et pharmacocinétique de l'oxychlorure de zirconium chez la souris et chez le rat.J. Pharmacol., 14 (4): 437-447.

Harrison (1951). The acute, chronic and topical toxicity of zirconium carbonate.J Pharmacol Exp Ther; 102 (3): 179-84.

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.

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

O'Connor (2010). Zirconium Basic Carbonate : Determination of water solubility. Harlan laboratories Ltd. Technical report.

Olmedo (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.

Saint-Gobin (2010). Mastersizer 2000 - ZBC-1977. Saint-Gobain. Technical report.

Smith (2013). Zirconium basic carbonate: acute (four-hour) inhalation study in rats. Huntingdon Life Sciences. Technical report.