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Endpoint:
basic toxicokinetics in vivo
Remarks:
Qualitative judgement
Type of information:
other: Qualitative judgement
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Qualitative judgement.
Remarks:
This toxicokinetics assessment for zirconium dioxide 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.
Objective of study:
toxicokinetics
Guideline:
other:
Principles of method if other than guideline:
This qualitative assessment of the toxicokinetic behaviour of yttrium zirconium oxide is based on physicochemical properties as well as on the available toxicological data for zirconium dioxide and yttrium zirconium oxide. Some literature data on toxicokinetics for zirconium, 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
Details on absorption:
Oral absorption:
Generally, solids have to dissolve before they can be absorbed. Based on the extremely low water solubility of zirconium dioxide and the limited water solubility of yttrium oxide, significant absorption of zirconium or yttrium 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.

Since no effects were observed in rats after oral exposure to (single) high doses (limit test dose or higher) of zirconium dioxide or yttrium zirconium oxide, absorption via the gastrointestinal tract can be expected to be extremely limited, and elimination can be expected to occur mainly via the faeces. The absence of adverse effects in an oral repeated dose toxicity study with zirconium basic carbonate as well as an OECD 422 study with zirconium acetate further supports extremely limited absorption of zirconium via the gastrointestinal tract.

Inhalation absorption:
The particle size distribution of yttrium zirconium oxide is dependent on the production process of the material as well as on the anticipated use. Representative particle size distributions vary with D50 values between 0.249 and 2.679 µm. It can therefore be concluded that all yttrium zirconium oxide 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 limited water solubility of the substance, 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 for yttrium zirconium oxide.

Inhalation toxicity data are not available for yttrium zirconium oxide, however, the available studies for zirconium dioxide did not reveal any adverse effects. No acute adverse effects were observed in rats up to the maximum technically achievable concentration and no repeated dose effects were reported in repeated dose toxicity studies in dog, rabbit, rat, cat, and guinea pig up to the highest dose tested. This supports extremely limited absorption of zirconium after inhalation exposure.

Dermal absorption:
Yttrium zirconium oxide is a solid substance with a limited water solubility and has thus a very low 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.

There are indications that the actual absorption factors for yttrium zirconium oxide may 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 for zirconium dioxide and yttrium zirconium oxide are supportive of the low absorption factors and even suggest 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. For endpoints for which no reliable data are available on yttrium zirconium oxide, data on zirconium dioxide are included in the dossier. No data were included on yttrium oxide, but as is clear from the information on the ECHA dissemination website, no adverse effects have been observed in any of the available reliable toxicity studies either. Further, the limited water solubility of both zirconium dioxide and yttrium oxide as well as the similar known complexation behaviour of zirconium and rare earths such as yttrium (i.e., strong complexation with phosphate, pH-dependent hydroxide formation and carbonate complexation) strongly suggest a very similar behaviour of both elements in living organisms, with an extremely limited bioavailability for uptake to be expected at physiologically relevant pH levels. 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 such as 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 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.

Based on the information on the ECHA dissemination website as well as the similarities between zirconium and rare earths such as yttrium concerning behaviour in physiologically relevant media (strong phosphate complexation, pH-dependent formation of hydroxides and carbonate complexation, strongly reducing bioavailability of the substance for uptake and distribution), and the fact that both zirconium dioxide and yttrium oxide have a very limited water solubility, it is anticipated that under normal conditions of exposure, no systemic distribution of yttrium oxide is expected.
Details on excretion:
Only very limited amounts of yttrium zirconium oxide 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 eliminated via the faeces as zirconium dioxide or other insoluble zirconium complexes. A similar excretion pattern is expected for yttrium.
Conclusions:
A qualitative assessment of the toxicokinetic behaviour was performed based on physicochemical properties as well as on toxicological data available for yttrium zirconium oxide, 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.

Although no toxicological data on yttrium oxide are included in this dossier, taking into account the similar limited water solubility of yttrium oxide, the similar complexation behaviour of yttrium and zirconium (strong phosphate complexation, pH-dependent hydroxide formation and carbonate complexation), and the fact that none of the available reliable toxicity studies mentioned on the ECHA dissemination website revealed adverse effects for yttrium oxide, both yttrium oxide and zirconium oxide (and hence yttrium zirconium oxide) are expected to be extremely unavailable for uptake and distribution in living organisms.
Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
The read across study from Spiegl et al. (1956) performed using zirconium dioxide contributes as supporting study to the toxicokinetics assessment of yttrium zirconium oxide. The read across justification is attached to IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Type:
other: distribution, indirectly informing on absorption
Results:
In the study of Spiegl et al. (1956), the observed concentrations in the lung-associated lymph nodes appear to be more related to dissemination due to overload than true distribution. This study is considered relevant for yttrium zirconium oxide as well.
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
no data
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Insufficient information provided on methods or results to accurately evaluate the study. Only lung and pulmonary lymph node tissue concentrations of zirconium were examined.
Objective of study:
other: study of the toxicity of zirconium compounds after repeated exposure via inhalation
Qualifier:
no guideline followed
Principles of method if other than guideline:
Repeated dose toxicity study in which, next to toxicity, as well tissue concentrations of zirconium were examined in lung and pulmonary lymph node tissue following inhalation exposure to zirconium dioxide for 30 or 60 days.
GLP compliance:
no
Radiolabelling:
no
Species:
other: cat, dog, guinea pig, rabbit, rat
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
ENVIRONMENTAL CONDITIONS
- Temperature: 22 - 24 deg C
- Humidity (%): 47 +/- 6
Route of administration:
inhalation: dust
Vehicle:
unchanged (no vehicle)
Details on exposure:
TYPE OF INHALATION EXPOSURE: whole body


GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
- Exposure apparatus: Copper-lined chamber 6 x 8 x 6 ft high volume 288 cubic ft.
- Source and rate of air: test substance was ground twice in a Mikropulverizer to a mean bulk particle size of 1.5 u and fed into the inlet air stream by a Wright dust feed.
- Method of conditioning air: A centrally located duct in the ceiling of the chamber served as the inlet for exposure. Baffles below the inlet and two fans near the ceiling dispersed the test substance and distributed the test substance uniformly throughout the chamber. In the four bottom corners were outlets connected to an exhaust system. Air turnover during exposure was approximately 140 cfm, or one change every two minutes with no recycling.
- System of generating particulates/aerosols: Wright dust feed



TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: 30-day exposure: 1.5 microns; 60-day exposure: 1.6 microns
Duration and frequency of treatment / exposure:
6 hours/ day, 5 days/week
Method 1: 30 Days
Method 2: 60 Days
Dose / conc.:
100.8 mg/m³ air
Remarks:
Method 1 (eq. to 75 mg Zr/m3)
Dose / conc.:
15.4 mg/m³ air
Remarks:
Method 2 (eq. to 11 mg Zr/m3)
No. of animals per sex per dose / concentration:
30-day exposure
2 dogs
10 rats
6 rabbits
60-day exposure
4 dogs
4 cats
10 rats
10 rabbits
18 guinea pigs
Control animals:
no
Positive control reference chemical:
no data
Details on distribution in tissues:
The values reported below are not the result of distribution in tissue but pattern of deposition after inhalation of 30 or 60 days.

75 mg/m3 dose - 30 days exposure
Mean Zr concentration
rats: 220 µg/g in the lung and 21 µg/g in the pulmonary lymph node
dogs: 129 µg/g in the lung and 362 µg/g in the pulmonary lymph node
rabbits: 24 µg/g in the lung

11 mg/m3 dose - 60 days exposure
Mean Zr concentration
rats: 158 µg/g in the lung and 17 µg/g in the pulmonary lymph node
dogs: 73 µg/g in the lung and 731 µg/g in the pulmonary lymph node
rabbits: 16 µg/g in the lung
cats: 20 µg/g in the lung
guinea pigs: 71 µg/g in the lung
Metabolites identified:
not measured
Conclusions:
The deposition of zirconium dioxide in the lung is typical of insoluble material. The concentration indicated in the lymph nodes appears to be more related to dissemination due to overload than true distribution.

Description of key information

No experimental data are available on toxicokinetics for this substance. Therefore, a qualitative assessment of the toxicokinetic behaviour is performed on the basis of its physicochemical and toxicological properties, supported by information on the physicochemical and toxicological properties of zirconium dioxide and other zirconium substances of relevance. For further support, it was checked on the ECHA dissemination site whether or not the available toxicological data on yttrium oxide support the outcome of the assessment, which is the case. 

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

A qualitative judgement on the toxicokinetic behaviour is based on the physicochemical characteristics of the substance as well as on available reliable toxicological data for zirconium dioxide and yttrium zirconium oxide. Data on other zirconium substances (see read across justification document) are also used. Since yttrium zirconium oxide is an inorganic substance some physicochemical characteristics (e.g., the octanol/water partition coefficient) are not defined, limiting the possibilities of a qualitative assessment.

Absorption

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 and following 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). It is anticipated that the actual absorption factors for yttrium zirconium oxide 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 for zirconium dioxide and yttrium zirconium oxide are supportive of the low absorption factors and even suggest 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. For endpoints for which no reliable data are available on yttrium zirconium oxide, data on zirconium dioxide are included in the dossier. No data were included on yttrium oxide, but as is clear from the information on the ECHA dissemination website, no adverse effects have been observed in any of the available reliable toxicity studies either. Further, the limited water solubility of both zirconium dioxide and yttrium oxide as well as the similar known complexation behaviour of zirconium and rare earths such as yttrium (i.e., strong complexation with phosphate, pH-dependent hydroxide formation and carbonate complexation) strongly suggest a very similar behaviour of both elements in living organisms, with an extremely limited bioavailability for uptake to be expected at physiologically relevant pH levels. However, in the absence of results from reliable toxicokinetics experiments, the worst case absorption factors of 10% are not lowered.

Distribution

Based on 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 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 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.

Based on the information on the ECHA dissemination website as well as the similarities between zirconium and rare earths such as yttrium concerning behaviour in physiologically relevant media (strong phosphate complexation, pH-dependent formation of hydroxides and carbonate complexation, strongly reducing bioavailability of the substance for uptake and distribution), and the fact that both zirconium dioxide and yttrium oxide have a very limited water solubility, it is anticipated that under normal conditions of exposure, no systemic distribution of yttrium oxide is expected.

 

Excretion

Only very limited amounts of yttrium zirconium oxide 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 eliminated via the faeces as zirconium dioxide or other insoluble zirconium complexes. A similar excretion pattern is expected for yttrium.