Diammonium bis[carbonato-O]dihydroxyzirconate

Endpoint summary

Additional information

No specific studies investigating the toxicokinetic are available; however, toxicological studies suggest that ammonium zirconium carbonate is likely to be minimally absorbed following oral and dermal exposures.

The acute oral LD50 was calculated to be approximately 2900 mg/kg and in a fully compliant OECD 422 oral gavage study, no clinical signs and no effect on any of the several parameters examined was observed up to and including the limit dose of 1000 mg/kg bw/day. No target organ was identified and the NOEL for systemic toxicity was set at the highest dose tested, 1000 mg/kg bw/day, the limit dose. Accumulation is therefore not expected to occur.

No signs of systemic toxicity were observed in an acute dermal toxicity study, and the LD50 resulted to be greater than 2000 mg/kg bw. Although evoking some signs of irritation in one of the two available primary skin irritation studies, these were not observed in the key study and were not enough severe to trigger for classification. In addition, no evidence of any skin sensitisation potential was detected in a Maximization test in which 100% was used for the challenge topical exposure.

Evidence of exposure was obtained in a mouse micronucleus test, where dosages of 250, 500 and 1000 mg/kg bw were injected intraperitoneum, in order to allow maximum delivery of the test substance to the animal system. The treated animals showed clinical sign and significant decreases in the PCE/NCE ratio were also observed. This study reassured on the lack of any genotoxic potential, because doubtful results were previously obtained in an in vitro chromosome aberration assay using CHO cells, while all other in vitro studies (i.e. Ames test and Mouse Lymphoma TK locus assay) were also clearly negative. Summary of gastric hydrolysis data with respect to support of a read-across approach Studies aimed to determine the behaviour of AZC and the structurally related substance KZC under simulated gastric conditions (i.e. pH 2 and 4) were performed, in line with OECD guideline 111 (hydrolysis as a function of pH). The aim of this work was to demonstrate that the two substances behave similarly in the acidic conditions of the stomach. Similar results would suggest similar behaviour of the substances in the event that they are ingested and would support the argument that read-across between the two substances for certain toxicological endpoints would be valid. Gas absorption on sodium hydroxide (on a support material) was used to determine the cleavable amount of carbon dioxide from each substance in acidic solution at pH values of 2 and 4. Hydrolysis is observed via effervescence during addition of the acidic buffer solution. For both substances, the preliminary studies showed that evolution of carbon dioxide occurred immediately when the acidic solution was added. Therefore, it was not possible to obtain kinetic information.    In the main experiments, the CO2 released during the hydrolysis reaction was determined to correspond to the carbonate content of each substance (i.e. 42.6% ± 0.1 in KZC and 17.0% ± 0.4 in AZC, compared to values of 44.89% for KZC and 17% for AZC given by the supplier). Based on the results of these studies, it was concluded that both KZC and AZC undergo complete degradation to carbon dioxide and zirconium compounds (not identified) under acidic conditions within a few minutes. As pH 2-4 is that naturally occurring in the stomach, this implies that both substances would behave in the same manner following ingestion (the only difference between AZC and KZC would be the liberation of potassium ions vs ammonium ions). This is supported by results of the acute toxicity oral studies, which gave similar calculated LD50values between AZC and KZC, where the number of mortalities was essentially the same at the same dosage level of 5000 mg/kg calculated on a ZrO2 basis (i.e. the tested 1000 mg/kg dose level for AZC, containing 20% ZrO2, and the tested 5000 mg/kg dose level for the pure solid KZC). These data also indicate that KZC, as well as AZC, are minimally absorbed following oral administration. Results for KZC and AZC were similar also in irritancy and skin sensitisation studies. The skin and eye irritation studies with KZC were performed using the registered substance in solution, because it was considered that the lower pH of the solution would represent the worst-case scenario than testing the pure solid KZC. As AZC exists only as a solution and KZC in solution showed the same irritating/sensitisation properties, reading-across from AZC for acute dermal toxicity is also considered appropriate; not least because dermal absorption is considered minimal and neither material is toxic via the oral route. Genotoxicity data on both KZC and AZC also confirm the similarity of the 2 substances, and that the same technical difficulties were encountered in testing both substances in the mouse lymphoma assay. As it is expected that behaviour of the two substances would also be similar under less acidic conditions (e.g. pH 7), reading-across from AZC for the in vivo genotoxicity endpoint is considered appropriate; sincethe ammonium ions and zirconium ions presenting to systemic circulation did not produce a positive result in the study with AZC, there is no plausible rationale why substituting the ammonium ion for the potassium (an endogenous mammalian cation) in KZC will result in a different result. Given the similarity of the two substances in acute and genotoxicity testing, and on complete degradation of both substances under simulating gastric conditions, it is considered that reading-across from AZC to KZC for the repeat-dose toxicity and screening reproductive / developmental toxicity endpoints is appropriate. Not least because mole for mole, the ammonium ion presenting on ingestion would be considered toxicologically more relevant than the potassium ion. As the NOEL of the study was 1000 mg/kg/day based on tested AZC as a 50% solution in water, reading-across from this study results in a NOAEL for pure KZC of 500 mg/kg/day.