[μ-[carbonato(2-)-O:O']]dihydroxydioxodizirconium

Endpoint summary

Description of key information

Repeated dose toxicity: oral
Two studies are used in a 'weight-of-evidence' approach.
In the first study, 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 was derived. No adverse effects were reported in this study. This study was scored as K2 study (reliable with restrictions) because of read-across purposes. The read-across justification is included in the Section 13 of IUCLID.
In the second 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 NOAEL for the tested material was greater than 15100 mg hydrated zirconium carbonate/kg bw/day (Harrison et al., 1951).
Repeated dose toxicity: dermal
No data were available for repeated dose toxicity, inhalation route of exposure.
Repeated dose toxicity: dermal
No reliable data were available for repeated dose toxicity, dermal route of exposure.

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 study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

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

Two studies are used in a 'weight-of-evidence' approach.

In the first study (Harrison et al., 1951), no effects were reported after oral (diet) 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 (Klimisch 2) . The daily consumption of zirconium basic carbonate (hydrated form) during the test period was 0, 300 to 130 mg/kg bw/day, 3300 to 1300 mg/kg bw/day and 33900 to 15100 mg/kg bw/day. The NOAEL for the tested material was greater than 15100 mg hydrated zirconium carbonate/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 (Harrison et al., 1951).

The study in rats by Harrison et al. (1951) was a non-GLP study conducted according to a method equivalent to the OECD 408 guideline with deviations: no data on test conditions and preparation of animals were reported; follow-up of body weight was done weekly; no individual animal data were reported; no histopathology observations were done. Therefore read-across is performed to a combined repeated dose toxicity study with reproduction/developmental toxicity screening via oral route in rats with zirconium acetate. In this study (Rossiello, 2013) the systemic toxic effects of the read-across substance zirconium acetate solution (containing 40.7% of the active ingredient zirconium acetate) after repeated dose, as well as any toxic effects on reproduction and development were investigated in Sprague Dawley rats up to early lactation (day 4 postpartum). The study was performed according to OECD 422 guideline and in compliance with 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 thereafter during pairing, gestation and lactation periods until day 3 postpartum. 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, 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 forestomach or structure analogous to forestomach, it is not considered of toxicological relevance. In addition, no abnormalities were found at the evaluation of the spermatogenic cycle. No effects were noted on reproduction and development at any dose.

 

On the basis of the results obtained in the study, the NOAEL (No Observed Adverse Effect Level) for systemic toxicity and reproduction/developmental toxicity was considered to be >= 1000 mg/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 basic carbonate (an insoluble zirconium compound) may be even lower than after repeated oral exposure to zirconium acetate (a water-soluble zirconium compound). This study was considered reliable with restrictions (K2) to reflect the read across status. The read across justification is included in Section 13 of IUCLID.

Repeated dose toxicity: inhalation

Information is available for the oral route of exposure ('weight-of-evidence' approach). 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 inhalation route of exposure. In addition, there is sufficient evidence available indicating that zirconium is barely absorbed after inhalation exposure to zirconium basic carbonate (see section 7.1). Therefore, and for animal welfare reasons, testing after repeated inhalation exposure is not performed.

Repeated dose toxicity: dermal

Information is available for the oral route of exposure. 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 .In addition, the dermal route is not the most appropriate route as exposure via inhalation is more likely and there is no indication from the physicochemical properties of significant absorption through the skin.

Annex IX further testing:

There is sufficient evidence available indicating that zirconium is barely absorbed after oral, dermal and inhalation exposure (see section 7.1) and is therefore of low bioavailability. In addition, no adverse effects have been reported neither after repeated oral exposure of females during 50 days to the read-across substance zirconium acetate nor after repeated oral exposure of test animals during 17 weeks to zirconium basic carbonate (see above). Based on this information it is unlikely to expect any toxicity after a period of 90 days of repeated exposure. As no adverse effect needs to be addressed, a test proposal for a 90-day study is not scientifically justified. Furthermore, the substance can be considered as insoluble (water solubility < 85 µg/L). 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:
No study has been selected as 'weight-of-evidence' approach is used to cover this endpoint. See description of key information.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Information is available for the oral route of exposure ('weight-of-evidence' approach). 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 inhalation route of exposure. In addition, there is sufficient evidence available indicating that zirconium is barely absorbed after inhalation exposure to zirconium basic carbonate (see section 7.1). Therefore, and for animal welfare reasons, testing after repeated inhalation exposure is not performed.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Information is available for the oral route of exposure ('weight-of-evidence' approach). 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 inhalation route of exposure. In addition, there is sufficient evidence available indicating that zirconium is barely absorbed after inhalation exposure to zirconium basic carbonate (see section 7.1). Therefore, and for animal welfare reasons, testing after repeated inhalation exposure is not performed.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Infomation is available for the oral route of exposure. 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 .In addition, the dermal route is not the most appropriate route as exposure via inhalation is more likely and there is no indication from the physicochemical properties of significant absorption through the skin.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Infomation is available for the oral route of exposure. 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 .In addition, the dermal route is not the most appropriate route as exposure via inhalation is more likely and there is no indication from the physicochemical properties of significant absorption through the skin.

Justification for classification or non-classification

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