Hydroxido potassium zirconium carbonate, where there are 0, 1 or 2 hydroxide groups and 2, 3 or 4 potassium atoms and 2, 3 or 4 carbonate groups.

Endpoint summary

Additional information

Toxicokinetic assessment

No human data or specific animal data studies investigating the toxicokinetic behaviour of KZC are available.

Absorption through the intact skin is assumed to be minimal. This is supported by the acute dermal toxicity study where no toxic effects were reported after treatment with 2000 mg/kg of the surrogate substance. Further, within a M&K sensitization test no systemically effects were seen when guinea pigs were treated with KZC although, due to the study design, the test substance is brought through the skin barrier by intra cutaneous (i.c.) injection. Oral treatment of rats with AZC for a period of 45 days (OECD 422 study) does not result in any systemic toxicity effects. No information about distribution or excretion is available based on this study type.

Summary of gastric hydrolysis data with respect to support of a read-across approach

Studies aimed to determine the behaviour of KZC and the structurally related substance AZC 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 CO2released 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 ZrO2basis (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 thein vivogenotoxicity 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.