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Description of key information

Repeated dose toxicity - oral route:
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 systemic dose-related adverse effects were reported in this study. This study was scored as Klimisch 2 study (reliable with restrictions) because it is included for read across purposes in this dossier.
In the second study, no adverse effects were reported after oral administration of zirconium basic carbonate (hydrated form) to rats during 17 weeks. The NOAEL for the tested material was >= 15100 mg hydrated zirconium carbonate/kg bw/day (Harrisson et al., 1951).
Repeated dose toxicity - dermal route:
No data are available for repeated dose toxicity, dermal route of exposure.
Repeated dose toxicity - inhalation route:
No data are available for repeated dose toxicity, inhalation 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
Study duration:
subacute
Species:
rat

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 route

Because there was no relevant and reliable information available on repeated dose toxicity of zirconium basic sulfate, read across was performed using a study on zirconium acetate (a 'water soluble' zirconium compound) and a study on zirconium basic carbonate (an insoluble zirconium compound).

The read across justification is added in Section 13 of IUCLID.

The systemic toxic effects of zirconium acetate solution (containing 40.7% of the active ingredient zirconium acetate) after repeated dosing, 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 observed 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. 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 could be considered >= 1000 mg/kg bw/day for both males and females. This Klimisch 1 study was assigned a Klimisch 2 score (reliable with restrictions) because it is used for read across purposes in this dossier.

The second study in the weight of evidence approach is the study of Harrisson et al. (1951). In this non-GLP study, conducted according to a method equivalent to the OECD 408 guideline, no adverse effects were observed after oral (dietary) administration of hydrated zirconium carbonate to rats during 17 weeks. The actual daily consumption of zirconium basic carbonate (hydrated form) during the test period was 0, 300 to 130, 3300 to 1300 and 33900 to 15100 mg/kg bw/day (two calculations performed, one for week 1 and one for week 15, respectively). The NOAEL for the tested material was considered to be >= 15100 mg hydrated zirconium carbonate/kg bw/day. This study was assigned a Klimisch 2 score (reliable with restrictions) because there were no data reported on test conditions and preparation of animals, because no data were reported for individual animals, and because no histopathology observations were done.

Repeated dose toxicity - dermal route

Studies performed with the read across substances zirconium acetate and zirconium basic carbonate are 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.

Repeated dose toxicity - inhalation route

Studies performed with the read across substances zirconium acetate and zirconium basic carbonate are 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 inhalation route of exposure.

Annex IX further testing:

On the basis of the results observed in the OECD 422 test (Rossiello, 2013) performed with the read across substance zirconium acetate (NOAEL >= 1000 mg/kg bw/d; no systemic toxicity observed at the highest dose), as well as the results from the 17-week oral repeated dose toxicity study performed with the read across substance zirconium basic carbonate (NOAEL >= 15100 mg hydrated zirconium carbonate/kg bw/day; Harrisson et al., 1951), no adverse effects need to be addressed by a subchronic test. In addition, based on the toxicokinetics assessment, low absorption of zirconium basic sulfate is expected via oral, dermal and inhalation administration. Therefore, and in accordance with the REACH Regulation (Annex IX, section 8.6.2, column 2), an additional test is scientifically unjustified and a test proposal for a 90-day study is not included for zirconium basic sulfate.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The endpoint is covered using a weight of evidence approach, including an OECD 422 test performed with zirconium acetate, a 'water soluble' zirconium compound (Rossiello, 2013), and a 17-week oral repeated dose toxicity study performed with zirconium basic carbonate, which is an insoluble zirconium compound (Harrisson et al., 1951).

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Studies performed with the read across substances zirconium acetate and zirconium basic carbonate are 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 inhalation route of exposure.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Studies performed with the read across substances zirconium acetate and zirconium basic carbonate are 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 inhalation route of exposure.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Studies performed with the read across substances zirconium acetate and zirconium basic carbonate are 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.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Studies performed with the read across substances zirconium acetate and zirconium basic carbonate are 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.

Justification for classification or non-classification

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