Magnesium zirconium oxide

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

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.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Justification for type of information:

The read across study from Spiegl et al. (1956) performed using zirconium dioxide as well as the expert evaluation of the toxicokinetic behaviour of zirconium dioxide contribute to the toxicokinetics assessment of magnesium zirconium oxide. The read across justification document is attached in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Type:

other: Qualitative assessment of ADME of magnesium zirconium oxide based on information for ZrO2 and MgO.

Results:

The ADME of magnesium zirconium oxide was evaluated qualitatively based on information for ZrO2 and MgO.

Reference 3

Endpoint:

basic toxicokinetics in vivo

Remarks:

Qualitative judgement

Type of information:

other: Qualitative judgement

Adequacy of study:

weight of evidence

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

Principles of method if other than guideline:

This qualitative assessment of the toxicokinetic behaviour of zirconium dioxide is based on physicochemical properties as well as on the available toxicological data for both zirconium dioxide and other zirconium substances. 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

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 (< 55 µg/L), 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 absorption:
The particle size distribution of zirconium dioxide is dependent on the production process of the material as well as on the anticipated use. For magnesium zirconium oxide (magnesia stabilised zirconia, with minimally 90% w/w zirconium dioxide in the crystal lattice), particle size distribution varied widely with D50 values roughly between 0.58 and 12.66 µm. It can therefore be concluded that at least some grades 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 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 for zirconium dioxide in magnesium zirconium oxide.

Dermal absorption:
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.

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) 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 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 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 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.

Conclusions:

A qualitative assessment of the toxicokinetic behaviour of zirconium dioxide was performed based on physicochemical 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.

Description of key information

No experimental data is available on toxicokinetics for magnesium zirconium oxide. Therefore, the toxicokinetic behaviour of the substance is assessed through expert judgement. The main component of magnesia 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, some information on magnesium, relevant for the toxicokinetics assessment of the substance, is included in this endpoint summary. 

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 magnesium

The focus of the toxicokinetics assessment for magnesium oxide is on magnesium, since in aqueous media, magnesium oxide dissociates, forming magnesium 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 magnesium (Mg2+) is considered in the assessment.

Due to its ubiquitous occurrence in the environment and its function as an essential mineral for human nutrition, magnesium is among the most extensively investigated elements with respect to physiological behaviour. Magnesium is the fourth most abundant cation in the mammalian body and the second most abundant cation in intracellular fluid. It is essential to living organisms and deficiency symptoms may occur when intake is not sufficient. Magnesium is a cofactor in hundreds of enzymatic reactions, many of which involve energy metabolism. For example, ATP (adenosine triphosphate), the main source of energy in cells, must be bound to a magnesium ion in order to be biologically active. Magnesium also plays an important role in protein and nucleic acid synthesis and has a stabilising and protecting effect on membranes. Finally, magnesium is also considered essential in maintaining Ca, K and Na homeostasis.

Several facts relevant to this toxicokinetics assessment are given below (Scientific Committee on Food, 2001):

- Enteral absorption of magnesium is highly variable and depends on the magnesium content of the food, with normal absorption levels of 30-40% and absorption levels of up to 80% at low dietary magnesium intake. Most likely an active transport system is involved.

- Magnesium turnover differs individually, depending for example on age, growth, physical activity, etc.

- Magnesium excretion via the kidneys is also very variable and upon low magnesium intake a magnesium sparing mechanism decreases magnesium excretion and guarantees magnesium homeostasis as much as possible.

- Overall, an Acceptable Range of Intake for Adults is determined of 150-500 mg/day.

- Distribution: Of the body’s magnesium, 30-40% is found in muscles and soft tissues, 1% is found in extracellular fluid, and the remainder (50-60%) is in the skeleton, where it accounts for up to 1% of bone ash (Heaton, 1976; Webster, 1987).

In conclusion, due to its function as an essential element, distribution of magnesium is actively regulated according to the body's requirements. Magnesium levels in the body are subject to homeostasis.

 

3. Conclusion on magnesium zirconium oxide

Magnesium zirconium oxide or magnesia 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. Additional information relevant to the toxicokinetics assessment was added for magnesium in this endpoint summary. Magnesium oxide, as an individual substance, is rapidly transformed to magnesium hydroxide, which dissociates to magnesium 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 magnesium. Magnesium however, being an essential nutrient for living organisms, is actively regulated and subject to homeostasis. Some facts concerning absorption, distribution and excretion of magnesium are given above. As observed by Eidam (2015, 2016), only limited amounts of magnesium are released from magnesium zirconium oxide when in contact with aqueous media. Any magnesium released from the substance can be considered to behave similar to what is described in this additional assessment for magnesium (oxide).