Registration Dossier

Administrative data

Link to relevant study record(s)

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 physicochemical properties of the substance and other available (toxicological) information (including information from other zirconium substances).

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 (animal or human studies) are currently available on zirconium basic sulfate, which is an insoluble zirconium compound. However, a qualitative toxicokinetics 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 that the more water soluble the substance is, the higher is 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 pH, water soluble zirconium compounds appear to precipitate significantly from solution, showing a similar behavior as the insoluble zirconium compounds and therefore a similar bioavailability. Based on the abovementioned considerations on solubility, data from other zirconium compounds are described in this document to support the assessment. It should be noted that the toxicokinetic behaviour of the ziconium counterpart is not evaluated.

 

Absorption

Oral/Gastro-intestinal (GI) absorption

Zirconium basic sulfate is a solid inorganic zirconium compound. 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 sulfate is insoluble in water (< 0.004 mg/L at 20°C and pH 4; Sydney, 2015). Although release of free zirconium ions could be expected in the stomach due to the acidic conditions, at pH levels above 6 (e.g. in the intestinal lumen), this process is negligible and the chemical equilibrium is clearly on the side of the insoluble zirconium basic sulfate. Based on this information, it can be concluded that zirconium basic sulfate 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 of substances from the gastro-intestinal lumen can occur by passive diffusion or by specialized transport systems. Regarding 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 et al., 2007). In addition, zirconium basic sulfate is insoluble and therefore not ionized in the gastrointestinal lumen. Regarding the possible absorption through specialized transport systems, it has been reported that absorption mechanisms for some essential metal ions sometimes serve to transfer non-essential metals into the body as well (Beckett et al., 2007). There is no specific information on the zirconium ion available but it is not expected that the zirconium cation is transported through the membrane as it is insoluble under gastrointestinal lumen conditions.

The available toxicological data on zirconium basic sulfate and other zirconium compounds (including 'water soluble' zirconium compounds) support the conclusion of extremely low oral absorption potential of zirconium in general.

Not many data are available for zirconium basic sulfate, but the acute oral toxicity study (Cuthbert and Jackson, 1992a), in which the toxicity of zirconium basic sulfate was evaluated in rats (limit test) according to OECD 401, did not report any adverse effects and yielded a LD50 > 5000 mg/kg.

For several other zirconium compounds, additional toxicological data are available. Oral repeated dose toxicity data for instance are available for zirconium basic carbonate, a similar insoluble zirconium compound, as well as for zirconium acetate, which is a 'water soluble' zirconium compound. In the study of Harrisson et al. (1951), rats were orally (via the diet) exposed to zirconium basic carbonate (hydrated form) for 17 weeks. There was no mortality or clinical signs. Neither clinical chemistry nor histopathological evaluation was performed. The NOAEL for the tested material was calculated to be > 15100 mg/kg bw/day. Despite the fact that not all relevant information was reported, it is clear that the substance can be considered to be of low toxicity, supporting the expectation that zirconium has a very low bioavailability in the intestinal lumen and is very poorly absorbed.

The other oral repeated dose toxicity study (Rossiello, 2013) is an OECD 422 study performed with zirconium acetate, which is a 'water soluble' zirconium compound. This study was added to the repeated dose toxicity endpoint as well as to this toxicokinetics assessment as a worst case, taking into account the concept that the more water soluble the substance is, the higher is its potential for systemic bioavailability. In this combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in Wistar rats (OECD 422), zirconium acetate was tested at 100, 300 and 1000 mg/kg bw/day (expressed as zirconium acetate, anhydrous). The NOAEL (No Observed Adverse Effect Level) for systemic toxicity of the parent animals and reproduction/developmental toxicity was considered to be >= 1000 mg/kg bw/day. 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. Histopathological evaluation showed a treatment-related effect on the forestomach of the rat at 300 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. The results of this study do not provide reasons to deviate from the assumption that absorption of zirconium acetate through the GI tract is not significant. It can be assumed that absorption of zirconium from insoluble compounds such as zirconium basic sulfate and zirconium basic carbonate is even lower, if any.

Following the same approach as for zirconium acetate, data on zirconium dichloride oxide (a 'water soluble' zirconium compound) 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 et al., 1983). These results also support the assumption of very limited oral absorption of zirconium from both 'water soluble' and less soluble zirconium compounds.

Based on all abovementioned considerations, low absorption of zirconium basic sulfate is anticipated when administered orally. Therefore an oral absorption factor of 10% is proposed for risk assessment, as worst case scenario. The reason for setting this worst case absorption factor is the absence of experimental toxicokinetic data that are sufficiently reliable to allow lowering this value.

 

Respiratory absorption

No studies are available regarding absorption of zirconium basic sulfate in humans or animals following inhalation exposure. Low exposure to zirconium basic sulfate is expected based on the inherent properties of the substance. As the substance is expected to show a low vapour pressure (endpoint waived based on decomposition before melting, i.e. test technically not feasible), it is not likely that zirconium basic sulfate is available for inhalation as a vapour. Further, no particle size distribution test has been performed with zirconium basic sulfate as the substance is marketed as a paste. Therefore, the human exposure potential by the inhalation route is expected not to be significant. Should any particles be released from the moist paste, the particles can be expected to be efficiently filtered by the nasal passages, deposited in the upper respiratory tract and not to be able to penetrate the alveoli of the lungs.

 

Despite the fact that the exposure is considered not significant, the absorption of the potentially inhaled particles of zirconium basic sulfate 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 sulfate being insoluble in aqueous media at physiologically relevant pH, the potential dissolution will be hampered and absorption 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.

There are no experimental data available on the toxicity of zirconium basic sulfate after inhalation exposure and due to the irrelevance of the inhalation route of exposure, no data from read across substances are included in the dossier. For the toxicokinetics assessment it is however relevant to mention the acute inhalation study (Smith, 2013) in rats with the read across substance zirconium basic carbonate. In this study, rats were exposed to zirconium basic carbonate (hydrated form) according to OECD Guideline 436. The maximum 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-h LC50 was calculated to be > 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 all abovementioned considerations, an inhalation absorption factor of 10% is proposed. Similar as for oral absorption, this is a worst case value set in the absence of experimental toxicokinetic data that are sufficiently reliable to allow further lowering this value.

 

Dermal absorption

Studies evaluating absorption following dermal exposure in humans or animals are not available. Zirconium basic sulfate is not expected to cross the intact skin. This assumption is based on the qualitative assessment of the physicochemical properties of the substance. Zirconium basic sulfate is a paste and it will have to dissolve into the surface moisture of the skin before uptake can take place. As zirconium basic sulfate is insoluble at physiologically relevant pH, no significant uptake through the skin is expected to occur.

 

Zirconium basic sulfate was found not to be irritant to the skin in two in vivo studies (Cuthbert and Jackson, 1992b; Clouzeau, 1994). No other tests evaluating the toxicological potential of zirconium basic sulfate after dermal administration are available. As similar behavior at physiologically relevant pH is expected for the ‘water soluble’ compound zirconium acetate, information on this compound is used to further support this assessment.

 

In an acute dermal toxicity study (Longobardi, 2013), 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 no deaths, no signs of toxicity (clinical observations) nor abnormalities at necropsy. The absence of systemic signs of toxicity after acute dermal exposure to zirconium acetate supports the expectation that the substance is poorly absorbed and / or essentially non-toxic.

 

No toxicological information is available for animals after repeated exposure to zirconium basic sulfate or other zirconium compounds via the dermal route.

 

In the absence of measured data on dermal absorption, the ECHA guidance suggests the assignment of a default dermal absorption rate of 50%. However, the currently available scientific evidence on dermal absorption of metals (predominantly based on the experience from previous EU risk assessments) yields substantially lower figures (even << 10%) (HERAG, 2007).Based on all abovementioned considerations, no significant dermal absorption is expected. A dermal absorption factor of 10% is therefore suggested for risk assessment purposes as a worst case scenario.

 

Distribution and accumulation                                        

Studies evaluating the distribution of zirconium basic sulfate in humans or animals are not available. Due to the low absorption rates, no significant or very low levels of zirconium are expected to be taken up in the body after exposure via oral, inhalation or dermal route. Nevertheless, the distribution of the potentially absorbed zirconium after exposure to zirconium basic sulfate is evaluated here below. Since there is no reliable experimental information available on the distribution of zirconium from zirconium basic sulfate, data on other zirconium compounds is considered below.

 

Toxicological studies can sometimes give an indication of the distribution pathway after exposure to a substance, especially when a specific target organ is identified. For zirconium acetate (a 'water soluble' zirconium compound), experimental data after repeated oral exposure are available (OECD 422, Rossiello, 2013). However, no significant toxicity was observed and the histopathological results 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. No target organ was identified in this study.

 

Olmedo et al. (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 as the test substance was administered via intraperitoneal injection, which is of limited relevance for the behaviour of the substance after administration via the oral, dermal or inhalation route.

 

Based on the 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 zirconium from zirconium basic sulfate through 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 of zirconium in the gastrointestinal tract, it is expected that the majority of the orally administered compound will be excreted via the faeces.

 

References

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

Clouzeau (1994). Irritation cutanée aigue chez le lapin. Centre International de Toxicologie (CIT). Technical report.

Cuthbert and Jackson (1992a). Zirconium basic sulphate: acute oral toxicity (limit) test in rats. Inveresk Research International. Technical report no. 8592.

Cuthbert and Jackson (1992b). Zirconium basic sulphate: acute dermal corrosivity test in rabbits. Inveresk Research International. Technical report no. 8593.

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.

Harrisson et al. (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.

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

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

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

Sydney (2015). Zirconium basic sulphate relative density and water solubility. Huntingdon Life Sciences, Technical report no. BOB0001.