Calcium zirconium oxide

Endpoint summary

Description of key information

No experimental data is available on toxicokinetics for calcium zirconium oxide. Therefore, the toxicokinetic behaviour of the substance is assessed through expert judgement. The main component of calcia stabilised zirconia being zirconium dioxide, the toxicokinetic behaviour of the substance is considered to be very similar to that described in a qualitative assessment of the toxicokinetic behaviour of zirconium dioxide. Additionally, an assessment of the toxicokinetic behaviour of calcium is included. Any calcium that may be released from calcium zirconium oxide can be expected to behave as described in this assessment. Calcium being an essential nutrient however is internally regulated in living organisms and is (contrary to zirconium dioxide) not considered as a xenobiotic.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

1. Information on zirconium dioxide

A qualitative judgement on the toxicokinetic behaviour was performed based on the physicochemical characteristics of the substance as well as on available reliable toxicological data for both zirconium dioxide and other zirconium substances. However, because there are no experimental toxicokinetics data available that are reliable enough for endpoint coverage (only supporting information available), this qualitative judgement is to be considered as reliable with restrictions.

Absorption

Although the available data suggest extremely limited absorption of zirconium via all exposure routes, worst case absorption factors of 10% are proposed for oral, inhalation and dermal absorption. The reason for setting these worst case absorption factors is the absence of experimental toxicokinetics data that are sufficiently reliable to allow lowering these values. Supporting information on toxicokinetics however suggests much more limited absorption. Data on zirconium dichloride oxide in mouse and rat show oral absorption to be at levels of 0.01 to 0.05% of the administered dose (Delongeas et al. (1983), Toxicité et pharmacocinétique de l'oxychlorure de zirconium chez la souris et chez le rat, Journal de Pharmacologie (Paris) 14, 437-447). This 'water soluble' zirconium compound could be regarded as a reference for zirconium dioxide as it will instantaneously be converted to zirconium dioxide in aqueous solutions at physiologically relevant pH levels. The results of the available toxicological data (both on zirconium dioxide and other zirconium compounds) are supportive of the low absorption factors and even suggest much more limited absorption, as none of the available studies revealed any adverse effects up to and including the highest test doses or at least the agreed limit test doses via the different exposure routes, both after single and repeated exposure. However, in the absence of results from reliable toxicokinetics experiments, the worst case absorption factors of 10% are not lowered.

Distribution

Based on available physicochemical 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. Olmedo et al. (2002) studied the dissemination of zirconium dioxide 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 (Olmedo et al. (2002). An experimental study of the dissemination of titanium and zirconium in the body. Journal of Materials Science: Materials in Medicine 13, 793-796). Additional data show distribution of several zirconium compounds through the body with main presence in bone and liver, but also in spleen, kidney and lungs (Spiegl et al., 1956; Hamilton, 1948 (The Metabolic Properties of the Fission Products and Actinide Elements, University of California, Radiation Laboratory, W-7405-eng-48A-I); Dobson et al., 1948 (Studies with Colloids Containing Radioisotopes of Yttrium, Zirconium, Columbium and Lanthaum: 2. The Controlled Selective Localization of Radioisotopes of Yttrium, Zirconium, Columbium in the Bone Marrow, Liver and Spleen, University of California, Radiation Laboratory, W-7405-eng-48A). These data should be treated with care as substances were mainly administered via injection and thus not only the chemical but also the physical form which becomes systemically available might be different compared to administration via the oral, dermal or inhalation route.

Excretion

Based on available physicochemical data it is difficult to predict whether the main route of elimination (after absorption) will be via the kidneys or bile. Data on zirconium dichloride oxide, a 'water soluble' zirconium compound, suggest that absorbed zirconium will be excreted via the kidneys (Delongeas et al., 1983). Following oral intake, non-absorbed zirconium (which can be assumed to be the largest fraction) can be expected to be excreted via the faeces, either as zirconium dioxide or other insoluble zirconium complexes.

2. Information on calcium oxide

Due to its ubiquitous occurrence in the environment and its function as an essential mineral for human nutrition, calcium is among the most extensively investigated elements with respect to physiological behaviour. In the human body, calcium serves as a structural element in bone. It is the fifth most abundant element by mass in the human body (1.5%). Calcium is a common cellular ionic messenger with a broad range of functions. Further functions of calcium include e.g. its involvement in neurotransmitter release and in muscle contraction. The focus of the toxicokinetics assessment for calcium oxide is on calcium, since in aqueous media, calcium oxide dissociates, forming calcium cations and hydroxyl anions. Dissociation in water is accompanied by generation of heat. Neither the alkaline reaction nor the generation of heat is of concern regarding systemic effects. Thus, only calcium (Ca2+) is considered in the assessment.

Absorption

Net oral absorption, as is known from calcium-containing dietary supplements, amounts to 30%. The oral absorption rate is independent of the solubility of the calcium compound and is therefore applicable to calcium contained in calcium oxide. For dermal absorption, following an approach consistent with the methodology proposed in the HERAG guidance for metals (2007), the default dermal absorption factors for calcium present in calcium oxide are considered to be 1.0% for exposure to liquid/wet media and 0.1% for dry (dust) exposure. The estimates for inhalation absorption are composed of 100% absorption for material deposited in the pulmonary region, plus material deposited in the tracheobronchial and the head region (transported to the pharynx and swallowed), corrected for intestinal absorption (30% for Ca). As a result, total inhalation absorption of calcium after calcium oxide exposure is 19.0% for powder <= 0.2 mm and 18.1% for coarse grained material > 10 mm.

Distribution

Over 99% of the total calcium of the body is located in the bones, where it accounts for 39% of the total body bone mineral content, and in the teeth, mostly as hydroxyapatite. Bone mineral provides structure and strength to the body, and very importantly, a reservoir of calcium that helps maintain a constant concentration of blood calcium. Less than 1% of the total body calcium is found in soft tissues and body fluids. Calcium in the extracellular fluid and the blood are kept constant via cell surface calcium-sensing receptors in parathyroid, kidney, intestine, lung, brain, skin, bone marrow, osteoblasts and other organs. Calcium is present in blood in three different forms: as free Ca2+ ions, bound to protein (about 45%), and complexed to citrate, phosphate, sulphate and carbonate (about 10%). Ionised calcium is maintained within narrow limits by the action of hormones. Extracellular calcium serves as a source for the skeleton and participates in blood clotting and intercellular adhesion. Intracellular calcium varies widely between tissues and is predominantly bound to intracellular membrane structures of the nucleus, mitochondria, endoplasmatic reticulum or contained in special storage vesicles. Intracellular calcium rises in response to stimuli interacting with the cell surface receptor. The increase of intracellular calcium comes from influx of extracellular calcium or from release of intracellular calcium stores. This activates specific responses like hormone or neurotransmitter release, muscle contraction, cellular differentiation and many others. Therefore, due to its function as an essential element, distribution of calcium is actively regulated according to the body's requirements. Calcium levels in the body are subject to homeostasis.

Excretion

Absorbed calcium is predominantly excreted via urine, and to a minor degree via faeces and sweat. Renal calcium excretion is the result of glomerular filtration an tubular re-absorption.

3. Conclusion on calcium zirconium oxide

Calcium zirconium oxide or calcia stabilised zirconia consists mainly of zirconium dioxide (≥ 90% w/w) and therefore the toxicokinetic behaviour can be considered largely the same as described for zirconium dioxide. Additionally, a toxicokinetics assessment was added for calcium oxide (which is present at maximally 10% w/w in the crystal lattice). Calcium oxide, as an individual substance, is rapidly transformed to calcium hydroxide, which dissociates to calcium and hydroxyl ions in physiologically relevant media. Since the release of hydroxyl anions is not considered relevant in view of the evaluation of potential systemic effects, the assessment was focused on calcium. Calcium however, being an essential nutrient for living organisms, is actively regulated and subject to homeostasis. A rough overview of absorption, distribution and excretion of calcium is given above. As observed by Eidam (2014, 2015), only limited amounts of calcium are released from calcium zirconium oxide when in water. Any calcium released from the substance can be considered to behave similar to what is described in this additional assessment for calcium (oxide).