Zirconium dinitrate oxide

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 physicochemical 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 dinitrate oxide (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 for the remaining toxicokinetic data. 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.

 

It should be noted that the toxicokinetic behaviour of the counter ion (nitrate in this case) is not evaluated.

 

Absorption

Oral: Gastrointestinal (GI) absorption

Zirconium dinitrate oxide is registered as a solid inorganic zirconium compound. When present in compounds, zirconium mainly exists in its highest oxidation state (+IV) as it is the most stable oxidation state. Zirconium dinitrate oxide is soluble in water (115 g/L) at 20°C and low pH (pH = 0.48). This solubility is however influenced by the pH of the medium: when adjusting pH to pH 4, 7 or 9, no measurable dissolved zirconium levels could be observed anymore (Bauer, 2015). Based on this information, it is expected that zirconium dinitrate oxide will readily dissolve into the gastric fluid (low pH conditions). Once in the intestines however, 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: passive diffusion and/or specialised transport systems. With respect to absorption by passive diffusion, the lipid solubility and the ionisation are important. However, inorganic metal compounds are usually not lipid soluble and are thus poorly absorbed by passive diffusion (Beckett, 2007). Although no specific information is available on this for inorganic zirconium compounds, it is not expected that the metal ion Zr4+ readily diffuses across biological membranes. In addition, as mentioned above, zirconium will be mainly precipitated in the intestinal lumen.

 

It has also 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 clear 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 dinitrate oxide (i.e. decreased solubility in the intestinal tract and the anticipated hampered diffusion as ionised substance), low oral absorption is expected.

 

Limited reliable toxicological data are available for zirconium dinitrate oxide from studies in which the material is administered orally. In a publication (Cochran et al., 1950), the acute oral toxicity of a 50% aqueous solution of zirconium dinitrate oxide was evaluated in rats and an LD50 of 2500 mg/kg bw was obtained. In a more recent study (Matting, 2015a), performed according to OECD guideline 423 (acute toxic class method), the LD50 in rats was found to be > 300 and < 2000 mg/kg bw (based on anhydrous zirconium dinitrate oxide). Indications of adverse local effects in the stomach were observed in 2 out of 3 animals found dead (red coloration of the glandular stomach mucosa). These observations were considered to be potentially test item-related, however, in the absence of histopathological examination, definitive attribution of this change to the test item could not be made. Nevertheless, these findings are in line with the expectations based on the physicochemical properties of zirconium dinitrate oxide and are also in line with other toxicological findings, resulting in a toxicological profile driven by the potential to cause local adverse effects due to its pH reducing capacity, which results from the presence of nitrate (acid residue or nitric acid) in the compound, not from zirconium.

 

As indicated previously, comparison of the water solubility can be used as surrogate to assess the bioavailability of metals, metal compounds and other inorganics compounds. Therefore information on other ‘water-soluble’ zirconium compounds such as zirconium acetate or zirconium dichloride oxide is used to estimate the absorption and bioavailability of the common metal ion Zr4+.

 

In a combined oral repeated dose toxicity study with reproduction/developmental toxicity screening, performed with the read across substance zirconium acetate, a 'water-soluble' compound with similar behaviour as zirconium dinitrate oxide (Rossiello, 2013), 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. The results of this study are supportive of the expected low absorption in the gastrointestinal tract.

 

Further, in the registration dossier of zirconium dichloride oxide there is some supporting evidence (scored Klimisch 3 for endpoint coverage) 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.

 

In conclusion, the physicochemical properties of zirconium dinitrate oxide and the available toxicological information on this zirconium compound and on the read across substances zirconium dichloride oxide and zirconium aceteate (both also ‘water-soluble’ zirconium compounds) confirm that zirconium from zirconium dinitrate oxide is most likely barely absorbed after oral exposure. Taking into consideration all abovementioned information, and in the absence of direct experimental evidence for zirconium dinitrate itself, the oral absorption factor for zirconium dinitrate oxide is estimated to be 10% for risk assessment purposes.

 

Respiratory absorption

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

 

Regarding the physicochemical properties of zirconium dinitrate oxide, in a melting point study (Younis, 2015b), endothermic events were observed starting between 88.16 and 114.57°C, representing consecutive dehydration steps. As a result, zirconium dinitrate oxide did not present true melting during the study. Further heating is predicted to result in final decomposition and transformation into 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 dinitrate oxide and thus it is unlikely that zirconium dinitrate oxide 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 potential of zirconium dinitrate oxide after inhalation exposure is assessed here below.

 

In general, solubilised substances will rapidly diffuse into the epithelial lining of the lungs 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 dinitrate oxide is a ‘water-soluble’ zirconium compound but the solubility markably 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 (about 6.6 in healthy individuals) and absorption from the lungs to the circulatory system is expected to be minimal.

 

Particles or precipitates 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. Solid material which settles in the tracheobronchial region would mainly be cleared from the lungs by the mucociliary mechanism and swallowed. However, a small amount of particles/precipitates may be taken up by phagocytosis and temporarily stored in the lymph nodes associated with the respiratory system.

 

Based on abovementioned information, low absorption after inhalation exposure to zirconium dinitrate oxide is expected. Although there are no toxicological data after acute or repeated inhalation exposure to zirconium dinitrate oxide, 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 Zr4+.

 

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 is barely absorbed following inhalation exposure.

 

Based on the physicochemical properties of zirconium dinitrate oxide 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 direct experimental evidence.

 

Dermal absorption

 

Studies evaluating absorption of zirconium following dermal exposure to zirconium dinitrate oxide in humans or animals are not available. Therefore a qualitative assessment of the toxicokinetic behaviour based on the physicochemical properties of zirconium dinitrate oxide is performed, taking 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 dinitrate oxide. This assumption is based on the qualitative assessment of the physicochemical properties of zirconium dinitrate oxide: as its solubility rapidly decreases when pH increases (generally pH of the skin ranges from pH 4.0 to 7.0), no significant uptake by the intact skin is expected.

 

In an acute dermal toxicity study with zirconium oxynitrate hydrate (CAS 14985-18-3), the hydrated form of the reference substance zirconium dinitrate oxide (Bioassay, 2018), rats were dermally exposed to a single dose of 2000 mg/kg bw. The animals were observed for 14 days. 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 oxynitrate hydrate supports the assumption that zirconium is poorly absorbed (low bioavailability) after dermal exposure.

No repeated dose dermal toxicity studies have been performed yet with zirconium dinitrate oxide.

 

Further, zirconium dinitrate oxide (solid form) was neither found to be a skin irritant (Matting, 2015b) nor a skin sensitiser (Totok Batho, 2015) in an in vivo skin irritation study and an in vivo skin sensitisation study (GPMT), respectively. Because the skin irritation potential was only investigated using solid zirconium dinitrate oxide, and the fact that aqueous solutions of zirconium dinitrate oxide, due to their acidity, may result in adverse local effects in skin, it is not excluded that such local adverse effects might enhance dermal penetration.

 

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).

 

Nonetheless, because of the possibility that aqueous solutions of zirconium dinitrate oxide might cause local adverse effects in skin which might enhance dermal penetration of zirconium, lower figures than 10% for dermal absorption are not proposed for zirconium dinitrate oxide.

 

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 extremely low levels of absorbed zirconium are expected after exposure via oral, inhalation or dermal route. However, the distribution of potentially absorbed zirconium is evaluated here below. In this perspective, all the data available on this substance and other ‘water-soluble’ zirconium compounds are considered.

 

Reliable studies evaluating the distribution of bioavailable zirconium dinitrate oxide in humans or animals are not available. Toxicological studies can sometimes give an indication of the distribution pathway after exposure to a substance or may inform on a potential target organ. However, based on the reliable toxicological information (including that obtained with read across substances) included in this registration dossier for zirconium dinitrate oxide, no information on distribution could be obtained and no target organ could be identified.

 

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).

 

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. It is worth mentioning that zirconium dinitrate oxide was not mutagenic to bacteria in a reliable Ames test (Hargitai, 2015), and zirconium oxynitrate hydrate (CAS 14985-18-3), the hydrated form of the reference substance zirconium dinitrate oxide, was not clastogenic in a reliable in vitro Mammalian Cell Micronucleus test in human lymphocytes (Envigo, 2018) and not mutagenic in a reliable in vitro Mammalian Cell Gene Mutation Test (HPRT Locus Assay) in Chinese hamster ovary cells (BASF SE, 2018). Nevertheless, this only informs on the fact that no genotoxic zirconium forms are expected to be formed in living organisms.

 

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

 

Excretion

Because of the hampered absorption in the gastrointestinal tract, it is expected that a majority of the orally administered compound is excreted via the faeces.

 

Potentially absorbed 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. 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

BASF SE (2018). Zirconium oxynitrate hydrate - In vitro gene mutation test in CHO cells (HPRT Locus Assay). Report no. 50M0479/17M243.

Bauer (2015). "Zirconium dinitrate oxide". Determination of the water solubility. Seibersdorf Labor GmbH. Report CTL53.

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

Bioassay (2018). Zirconium oxynitrate hydrate - Acute dermal toxicity study in rats. Report no. 17-BF-DT127.

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).

Envigo (2018). Zirconium oxynitrate hydrate: Micronucleus Test In Human Lymphocytes In Vitro. Report no. 50M0479/17M243.

Hargitai (2015). Zirconium dinitrate oxide: bacterial reverse mutation assay. CitoxLab Hungary Ltd. Report no. 14/347-007M.

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.

Matting (2015a). Zirconium dinitrate oxide: acute oral toxicity study in rats. CitoxLab Hungary Ltd. Report no. 14/347-001P.

Matting (2015b). Zirconium dinitrate oxide: acute skin irritation study in rabbits. CitoxLab Hungary Ltd. Report no. 14/347-006N.

Rossiello (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.

Totok-Batho (2015). Zirconium dinitrate oxide: a skin sensitization study in the guinea pig using the Magnusson and Kligman method. CitoxLab Hungary Ltd. Report no. 14/347-104T.

Younis (2015b). Melting point on a sample of zirconium dinitrate oxide. Chilworth Technology Ltd. Report GLP1122442R1V1/2014.