Zirconium, acetate lactate oxo ammonium complexes

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Zirconium Dioxide is an inorganic substance and thus some physico-chemical characteristics (like the octanol/water partition coefficient) are not defined. This limits the reliability of the qualitative judgement.

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Guideline:

other:

Principles of method if other than guideline:

This qualitative judgement on the toxicokinetic behaviour based on physico-chemical characteristics follows the recommendations of ECHA (ECHA Endpoint specific guidance, Chapter R.7c; section R.7.12.2.1).

GLP compliance:

no

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral
Generally solids have to dissolve before they can be absorbed. Based on the very low water solubility of Zirconium Dioxide (< 55 ug/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, an oral absorption factor of 10% is proposed. Furthermore, since no effect were observed after oral exposure with high level (level to be added) of zirconium oxide, we could expect low absorption via the gastrointestinal tract and elimination 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 at least between 0.3 and 100 um. It can therefore be concluded that particles below 15 ¿m can be present in Zirconium Dioxide material and thus particles can reach the alveolar region of the respiratory tract. The rate at which the particles dissolve into the mucus will limit the amount that can be absorbed directly. Due to the 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 mucocilliary 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, an inhalation absorption factor of 10% is proposed.

Dermal
Zirconium Dioxide is a solid substance with a very low water solubility and has thus no potential for dermal absorption. Based on this, a 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 very 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 JL et al., Toxicité et pharmacocinétique de l'oxychlorure de zirconium chez la souris et chez le rat; J. Pharmacol (Paris) 1983, 14, 4, 437-447). This well water soluble compound could be regarded as a reference for Zirconium dioxde as it will instantaneously be converted to Zirconium dioxide in aqueous solution.

The available toxicological data provide no reason to deviate from the above absorption factors, but might even indicate significantly lower absorption factors than proposed as the substance has no eye and skin irritating potential, is not a skin sensitizer and is of low acute toxicity. In addition the available repeated dose studies show no systemic effects at the highest dose tested.

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. 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, D., M.B. Guglielmotti and R.L. Cabrini. An experimental study of the dissemination of Titanium and Zirconium in the body; Journal of Materials Science: Materials in Medicine, Volume 13, Number 8, 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 (Hamilton, J.G. The Metabolic Properties of the Fission Products and Actinide Elements, University of California, Radioation Laboratory, W-7405-eng-48A-I, 1948) and Dobson et al., 1948 (Dobson, E.L. et al., 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, Radioation Laboratory, W-7405-eng-48A, 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.

Details on excretion:

Only very low amounts of Zirconium Dioxide will be absorbed. Based on available data it is difficult to predict whether the main route of excretion will be via the kidneys or bile. Data on Zirconium dichloride oxide suggest that absorbed Zirconium will be excreted via the kidneys (Delongeas et al., 1983).

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no data
A qualitative judgement on the toxicokinetic behaviour was performed based on physico-chemical characteristics. Zirconium Dioxide is an inorganic substance of low water solubility (< 55 ug/L) and thus some physico-chemical characteristics (like the octanol/water partition coefficient) are not defined, limiting the possibilities of a qualitative assessment. Absorption factors of 10% are proposed for oral, inhalation and dermal absorption, representing default values of what is considered still defendable based on the limited physical/chemical data that can be applied for inorganic substances. These values might be too high in the light of available information on other zirconium compouds and following the absence of toxicological effects seen in the available database.
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, D., M.B. Guglielmotti and R.L. Cabrini. An experimental study of the dissemination of Titanium and Zirconium in the body; Journal of Materials Science: Materials in Medicine, Volume 13, Number 8, 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 (Hamilton, J.G. The Metabolic Properties of the Fission Products and Actinide Elements, University of California, Radioation Laboratory, W-7405-eng-48A-I, 1948) and Dobson et al., 1948 (Dobson, E.L. et al., 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, Radioation Laboratory, W-7405-eng-48A, 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).