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Diss Factsheets

Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Qualitative judgement on the toxicokinetic behaviour based on physico-chemical and toxicological characteristics.
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The toxicokinetics assessment is based on the physicochemical characteristics of the substance as well as on available reliable toxicological data for both zirconium dioxide and other zirconium substances (see read across justification document). 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.

Data source

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Guideline:
other:
Principles of method if other than guideline:
This qualitative assessment of the toxicokinetic behaviour of zirconium dioxide is based on physico-chemical properties as well as on the available toxicological data for both zirconium dioxide and other zirconium substances (see read across justification document). Literature data on toxicokinetics, which are on their own however not of sufficient quality for endpoint coverage, are used as supporting information in this evaluation. The assessment follows the recommendations of ECHA (ECHA Endpoint specific guidance, Chapter R.7c; section R.7.12.2.1).
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Zirconium dioxide
EC Number:
215-227-2
EC Name:
Zirconium dioxide
Cas Number:
1314-23-4
Molecular formula:
O2Zr
IUPAC Name:
zirconium dioxide

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Oral
Generally solids have to dissolve before they can be absorbed. Based on the extremely low water solubility of zirconium dioxide (< 55 µg/L) however, significant absorption via passive diffusion is not expected. It may be possible however for small particles to be taken up by pinocytosis. Based on this, and in the absence of reliable experimental data, a worst case oral absorption factor of 10% is proposed. However, since no effects were observed in rats after oral exposure to (single) high doses of zirconium dioxide, absorption via the gastrointestinal tract can be expected to be extremely limited, and elimination can be expected to occur mainly via the faeces.

Inhalation
The particle size distribution of zirconium dioxide is dependent on the production process of the material as well as on the anticipated use. As a result, particle size distributions vary widely with D50 values between roughly 3 and 100 µm. It can therefore be concluded that at least some zirconium dioxide materials contain particles that can reach the alveolar region of the respiratory tract (50% of the particles with an aerodynamic diameter of 4 µm are assumed to belong to the respirable fraction, i.e., the fraction that reaches the alveoli). The rate at which the particles dissolve into the mucus will limit the amount that can be absorbed directly. Due to the extremely low water solubility, particles depositing in the alveolar region would 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. Based on this, and in the absence of reliable experimental data, a worst case inhalation absorption factor of 10% is proposed.

Dermal
Zirconium dioxide is a solid substance with an extremely low water solubility and has thus no potential for dermal absorption. Based on this, and in the absence of reliable experimental data, a worst case dermal absorption factor of 10% is proposed.

The absorption factors proposed in this assessment should be considered default values to be used for substances having an expected low potential for absorption. This is in conformity with the lowest proposed default dermal absorption factor of 10% based on physical/chemical properties (ECHA Endpoint specific guidance, Chapter R.7c; section R.7.12.2.1, Dermal absorption). Although the ECHA guidance does not specify a lowest proposed oral and inhalation absorption factor, 10% is also considered a default value for these exposure routes and hence considered still defendable based on the limited physical/chemical data that can be applied for inorganic substances.

It is recognised that the actual absorption factors for zirconium dioxide will be much lower. 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, see read across justification) 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.
Details on distribution in tissues:
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.
Olmedo et al. (2002) studied the dissemination ot 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 different zirconium coumpounds 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 Lanthanum: 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.
Details on excretion:
Only very limited amounts of zirconium dioxide will be absorbed. Based on available data it is difficult to predict whether the main route of excretion (after absorption) will be via the kidneys or bile. Data on zirconium dichloride oxide (a 'water soluble' zirconium compound which is instantaneously converted to zirconium dioxide or other insoluble zirconium species in aqueous solutions at physiologically relevant pH levels) suggest that absorbed zirconium will be excreted via the kidneys (Delongeas et al., 1983). Following oral intake, non-absorbed zirconium can be expected to be excreted via the faeces as zirconium dioxide or other insoluble zirconium complexes.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no data
A qualitative assessment of the toxicokinetic behaviour was performed based on physico-chemical properties as well as on toxicological data available for both zirconium dioxide and other zirconium compounds. No data are available from toxicokinetics experiments which can be considered sufficiently reliable for endpoint coverage, however, some available literature data are used as supporting information. All together, there are indications for absorption of zirconium to be extremely limited following all exposure routes. Nevertheless, in the absence of reliable experimental data on toxicokinetics, worst case absorption factors of 10% are proposed for oral, inhalation and dermal absorption.

After intraperitoneal administration of zirconium dioxide in rats, histological analysis revealed the presence of abundant intracellular aggregates of metallic particles of zirconium in peritoneum, liver, lung and spleen (Olmedo et al., 2002). Additional data show distribution of several different zirconium coumpounds through the body with main presence in bone and liver, but also in spleen, kidney and lungs (Spiegl et al., 1956; Hamilton, 1948; Dobson et al., 1948). 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.

Data on zirconium dichloride oxide suggest that absorbed zirconium will be excreted via the kidneys (Delongeas et al., 1983). Following oral intake, non-absorbed zirconium (which is expected to be the largest fraction) can be expected to be excreted via the faeces as zirconium dioxide or other insoluble zirconium complexes.