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Description of key information

No reliable toxicokinetic data (human or animal studies) and only limited information on toxicity in animals is available for zirconium sulfate. 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 (%):
Absorption rate - dermal (%):
Absorption rate - inhalation (%):

Additional information

No toxicokinetic data (human or animal studies) are available on zirconium sulfate (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.

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.

Zirconium sulfate 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 (here, no evidence is presented in the water solubility study, but observations in aquatic ecotoxicity studies confirm that the behaviour in water is similar to that of other 'water soluble' zirconium compounds such as zirconium acetate and zirconium dichloride oxide - no dissolved zirconium could be obtained in aquatic test media at levels above the LOQ).

No vapour pressure is reported for zirconium sulfate 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 as these concepts do not apply for inorganic substances. The D50 values for particle size are roughly in the range of 20 to 90 μm, depending on the production batches (Coustet, 2011, 2012). The substance is however also brought on the market as aqueous solution.

It should be noted that the toxicokinetic behaviour of the counter ion (sulfate) 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 (acid release).



Oral/Gastrointestinal (GI) absorption

Studies evaluating the absorption of zirconium sulfate following oral exposure in animals and/or humans are not available.

Very limited data (Klimisch 3) on the absorption of zirconium dichloride oxide (another 'water soluble' zirconium compound) following oral exposure in animals are available. 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 (maximal absorption was between 0.007 and 0.05% of the administered dose after 6 h for both species).

Zirconium sulfate is highly soluble in pure water (669 mg/L) at 20°C and low pH (1.1-1.2) (Fox, 2013). 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 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. approximately 20 µg Zr/L) in any of the test solutions, including 100% v/v saturated solutions (Harris, 2014a,b; Vryenhoef and Mullee, 2014). Based on this information, it is expected that zirconium sulfate 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.

The assessment of the physicochemical properties of zirconium sulfate clearly supports the assumption of low oral absorption of zirconium. The expected limited absorption of zirconium after oral exposure is confirmed by the extremely low toxicity of zirconium substances after both acute and repeated exposure.

For zirconium sulfate specifically, a publication (Cochran et al., 1950) indicates that the LD50 of the substance is 3500 mg/kg bw for rats. Similar results were obtained with other zirconium substances (whether 'water soluble' or not, see the read across justification attached to IUCLID Section 13). No oral repeated dose toxicity data are available for zirconium sulfate, but an OECD 422 study (combined oral repeated dose toxicity study with reproduction/developmental toxicity screening) performed with zirconium acetate (another 'water soluble' zirconium compound) 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 (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 (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 sulfate and the available toxicological information on this substance and on other 'water soluble' zirconium compounds such as zirconium acetate and zirconium dichloride oxide support the assumption that zirconium sulfate is barely absorbed after oral exposure. Taking into consideration all abovemention information, the oral absorption factor for zirconium sulfate is estimated to be 10% for risk assessment purposes.

Respiratory absorption

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

No vapour pressure is reported for zirconium sulfate as the test was considered technically not feasible (decomposition). As a result, it is considered unlikely that zirconium sulfate is available for inhalation as a vapour.

As the D50 values are roughly in the range of 20 to 90 μm, depending on the production batches (Coustet, 2011, 2012), it is expected that they are efficiently filtered by nasal passage and do not penetrate down to the alveoli of the lungs. The substance is also brought on the market as 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 healthy individuals. Therefore, in the case of zirconium sulfate, 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 sulfate is expected. Although there are no toxicological data after acute or repeated inhalation exposure to zirconium sulfate, 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 sulfate 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 behaviour based on zirconium sulfate 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 sulfate. 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 solid zirconium sulfate 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 sulfate 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 zirconium acetate (another 'water soluble' zirconium compound), 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 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 sulfate 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). Due to the corrosive properties, 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

Due to the low absorption rates, no significant or very low amounts 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 zirconium (sulfate) in humans or animals are not available. There are three publications containing relevant information (de Bartolo et al., 2000; Berry et al., 1990; Schroeder et al., 1968) but due to the lack of quality, the results of these studies are not considered reliable.

Although there is no reliable in vivo information on zirconium sulfate, there is some information available on other zirconium compounds.

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 (another 'water soluble' zirconium compound), 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).

Olmedo et al. (2002) studied the dissemination of zirconium dioxide (an 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 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.

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 (a 'water soluble' zirconium compound). 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).

A 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 performed for the distribution of the substance throughout the body.



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.



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, 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.


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

Berry et al. (1990). Subcellular localization of zirconium in nodular lymphatic cells after administration of soluble salts. Study by electron microprobe. Toxicology 62, 239-246.

Cochran et al. (1950). Acute toxicity of Zirconium, Columbium, Strontium, Lanthanum, Cesium, Tantalum, and Yttrium. Industrial Hygiene and Occupational Medicine 1: 637-650.

Coustet (2011, 2012). CE diameter report - volume distribution. Saint Gobain. Internal technical report.

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

de Bartolo et al. (2000). Determination of biokinetic parameters for ingestion of radionuclides of zirconium in animals using stable tracers. Radiat. Environ. Biophys 39: 53 -58.

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

Fox (2013). Zirconium Sulfate: Determination of 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.

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.

Schroeder et al. (1968). Zirconium, Niobium, Antimony and Fluorine in mice: effects on growth, survaival and tissue levels. J. Nutrition 95: 95 -101.

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.