Zirconium dioxide

Endpoint summary

Description of key information

Repeated dose toxicity: oral
Two studies were used in a weight of evidence approach.
Rossiello (2013) performed a combined repeated dose toxicity study with reproduction/developmental toxicity screening test via oral route in rats with the read-across substance zirconium acetate according to OECD guideline 422 (GLP). A NOAEL of >=1000 mg/kg bw/day (expressed as zirconium acetate anhydrous) was derived. No adverse effects were reported in this study.
No effects were reported after oral administration to rats during 17 weeks of zirconium basic carbonate (hydrated form) in the form of a moist paste containing 20.9% zirconium dioxide equivalent. The total intake of zirconium dioxide during the test period was 0, 0.9, 9 and 103.5 g. The equivalent NOAEL for zirconium dioxide was >= 3150-7080 mg/kg bw/day (Harrison et al., 1951).
Repeated dose toxicity: dermal
No reliable data were available for repeated dose toxicity, dermal route of exposure.
Repeated dose toxicity: inhalation
No effects were reported in any of the species studied (cat, dog, guinea pig, rabbit and rat) after inhalation of zirconium dioxide dust (NOAEC >= 100.8 mg ZrO2/m3 air in the 30 day study and NOAEC >= 15.4 mg ZrO2/m3 air in the 60 day study). The 30 and 60 days studies are used in a weight of evidence approach (Spiegl et al., 1956).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity: oral

No reliable information is available for zirconium dioxide after repeated oral exposure. Read across is proposed to repeated oral toxicity studies with zirconium acetate (a water-soluble zirconium compound) and zirconium basic carbonate (an insoluble zirconium compound as zirconium dioxide). These two studies are used in a weight of evidence approach and support each other in the fact that no oral toxicity was observed after repeated oral exposure. The read across justification is included in Section 13 of IUCLID.

No effects were reported after oral administration to rats during 17 weeks of zirconium hydrated basic carbonate in the form of a moist paste containing 20.9% zirconium dioxide in a reliable study (Klimish 2) (Harrison et al., 1951). The total intake of zirconium dioxide during the test period was 0, 0.9, 9 and 103.5 g. The equivalent NOAEL for zirconium dioxide was >= 3150-7080 mg/kg bw/day. A similar study was performed on kittens, but the reported information from that study is limited and thus is considered as supporting information.

The systemic toxic effects of zirconium acetate solution (containing 40.7% of the active ingredient zirconium acetate) after oral repeated exposure, as well as any toxic effects on reproduction and development were investigated in Sprague Dawley rats up to early lactation (day 4 post partum). The study (Rossiello, 2013) was performed according to OECD guideline 422 (GLP).

Three groups of 10 males and 10 females each received the test item, by oral gavage, at 100, 300 and 1000 mg/kg bw/day, expressed as zirconium acetate (anhydrous form). A similar constituted control group received the vehicle alone during the treatment period. The test item was diluted in purified water (vehicle) at concentrations of 10, 30 and 100 mg of zirconium acetate/mL. Chemical analyses of the formulated test item were performed during the study and the overall results were within the limits of acceptance. The overall dosing period was 32 days for males, which included 2 weeks before pairing and continuously thereafter up to the day before necropsy and up to 50 days for females including 2 weeks before pairing and thereafter during pairing, gestation and lactation periods until day 3 post partum.

 

The animals were followed for daily clinical signs, weekly body weight, food consumption, neurotoxicity assessment, oestrous cycle, mating performance, clinical pathology evaluation including haematology and clinical chemistry and offspring delivery. A detailed macroscopic examination, organ weights and histopathology including the spermatogenic cycle were performed.

 

No treatment-related findings were observed either during the in vivo phase or at post mortem examination. Microscopically, a treatment-related finding was seen in males receiving 300 and 1000 mg/kg bw/day consisting of minimal focal vacuolation of squamous epithelium (limiting ridge) of non-glandular region of the stomach. This change may be attributed to a local irritant effect of the compound administered by oral gavage and since humans do not have a forestomach or structure analogous to the forestomach, it is not considered of toxicological relevance.

 

No systemic adverse effects were therefore reported. On the basis of these results, the NOAEL (No Observed Adverse Effect Level) for systemic toxicity after repeated oral exposure was considered to be >= 1000 mg of zirconium acetate/kg bw/day for both males and females.

Taking into account the concept of the more water soluble is the substance the higher is its potential for systemic bioavailability, it could be concluded that systemic toxicity after repeated oral exposure to zirconium dioxide (an insoluble zirconium compound) may be even lower than after repeated oral exposure to zirconium acetate (a water-soluble zirconium compound).

Repeated dose toxicity: dermal

No reliable studies are available for repeated dose toxicity via the dermal route of exposure. Testing is waived based on the following justification: a short-term (30 days) and sub-chronic (60 days) study are available for the inhalation route of exposure. According to the REACH Regulation, only one route of exposure should be tested for repeated dose toxicity (Column 2 adaptation, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the dermal route of exposure.

Repeated dose toxicity: inhalation

Two reliable studies were available for this endpoint (Klimisch 2): a 30 day repeated dose inhalation test in dog, rabbit and rat and a 60 day repeated dose toxicity test in cat, dog, guinea pig, rabbit and rat. No effects were reported in any of the species studied after inhalation of ZrO2 dust (NOAEC >= 100.8 mg ZrO2/m3 air in the 30 day study and NOAEC >= 15.4 mg ZrO2/m3 air in the 60 day study). These studies are used in a weight of evidence approach and support each other in the fact that no inhalation toxicity was observed after repeated exposure. The 28 days study is covered by the 30 days test.

Annex IX testing:

There is sufficient evidence available indicating that zirconium is barely absorbed after exposure via inhalation (see section 7.1) and is therefore of low bioavailability. In addition, no adverse effects have been reported after repeated inhalation exposure of test animals during 30 or 60 days (see above). Based on this information it is unlikely to expect any toxicity after a period of 90 days of repeated exposure via inhalation. As no adverse effect needs to be addressed, a test proposal for a 90-day study is not scientifically justified. Therefore, and for animal welfare reasons, a testing proposal is not included.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
See description of key information.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
See description of key information.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
See description of key information.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
According to the REACH Regulation, only one route of exposure should be tested for repeated dose toxicity (column 2, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the dermal route of exposure.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
According to the REACH Regulation, only one route of exposure should be tested for repeated dose toxicity (column 2, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the dermal route of exposure.

Justification for classification or non-classification

Based on the available data for repeated dose toxicity via the oral and inhalation route and according to the CLP criteria, zirconium dioxide should not be classified for STOT - repeated exposure.