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Description of key information

No repeated dose toxicity study with zirconium, acetate lactate oxo ammonium complexes is available, thus the repeated dose toxicity will be addressed with existing data on the individual moieties zirconium, acetate, lactate and ammonium.

In relevant and reliable repeated dose toxicity studies as well as supporting studies for the moieties of zirconium, acetate lactate oxo ammonium complexes, there were no toxicological findings reported that would justify a classification. Moreover, acetate, lactate and ammonium are used in medical and food products, and thus increased toxicity is not expected.

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 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

No repeated dose toxicity study with zirconium, acetate lactate oxo ammonium complexes is available, thus the repeated dose toxicity will be addressed with existing data on the individual moieties zirconium, acetate, lactate and ammonium.

Zirconium

Repeated dose toxicity, oral

No effects were reported after oral administration to rats during 17 weeks of hydrated basic carbonate in form of moist paste containing 20.9% zirconium dioxide from a reliable study (Klimisch 2). The total intake of ZrO2 during the test period is 0, 0.9, 9 and 103.5 g. The equivalent NOAEL for ZrO2 is > 3150 mg/kg bw/day.

A similar study was performed on kittens, but the reported information from that study is limited and thus is provided for information porposes only.

In a combined repeated dose toxicity study with the reproduction and developmental toxicity screening test, Sprague Dawley rats were administered zirconium acetate at 0, 100, 300 and 1000 mg/kg bw/day via gavage. The required amount of zirconium acetate solution (containing 40.7% of zirconium acetate anhydrous) was dissolved in the vehicle (purified water). 10 males per group were treated two weeks prior to pairing, throughout pairing and thereafter through the day before scheduled sacrifice (32 days of dosing). 10 females were treated two weeks prior to pairing, throughout pairing until day 3 post partum or the day before scheduled sacrifice (up to 50 days of dosing). No systemic toxicity could be observed. Therefore, on the basis of the results obtained in the study, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity after sub-acute exposure was considered to be >=1000 mg/kg bw/day (expressed as zirconium acetate anhydrous).

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. The 60 days study didn't observe effects after repeated inhalation exposure. Therefore the 60 days study is used to cover the 90 days study requirement.

 

Acetate

Repeated dose toxicity, oral

A registration dossier shall contain information on the human health hazard assessment (regulation 1907/2006, Art.10). However, it is considered that the information requirements for acetate as laid down in annex VII to IX can be fulfilled by adaptation of the standard testing regime according to Annex XI, points 1.2. and 1.3. as presented in the following:

The EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) concluded “Acetic acid, sodium diacetate, and calcium acetate are permitted food additives that may be added directly to food intended for human consumption without any limitation. This authorisation followed the assessment of safety by JECFA (1974, 1998) and the EU Scientific Committee on Food (SCF, 1990). JECFA considered acetic acid, calcium acetate, and sodium diacetate separately although data on acetic acid were primarily considered in each evaluation as no specific studies on sodium diacetate and calcium acetate were identified at that time. JECFA allocated an ADI of “not limited” (i.e., “not specified”) to acetic acid and its calcium salt in 1974 and this conclusion was retained when JECFA evaluated a group of saturated linear primary alcohols, aldehydes, and acids that included acetic acid in 1998.” (EFSA 2012).

Based on the above information, one can therefore safely assume that the acetate anion in the zirconium complex does not contribute to the overall toxicity.

 

Lactate

Repeated dose toxicity, oral

A registration dossier shall contain information on the human health hazard assessment (regulation 1907/2006, Art.10). However, it is considered that the information requirements for lactate/lactic acid as laid down in annex VII to IX can be fulfilled by adaptation of the standard testing regime according to Annex XI, points 1.1. and 1.2. as presented in the following:

Beside the fact that lactic acid is produced endogenously and is a known intermediate of various processes, it is also a naturally occurring part of the human diet and therefore administered orally. Lactic acid is found primarily in sour milk products, such as yogurt, kefir, and some cottage cheeses. On top of that, it is an approved food additive in the EU and used as food preservative, curing agent and flavouring agent. It is an ingredient in processed foods and is used as a decontaminant during meat processing. Lactic Acid, Calcium Lactate, Potassium Lactate, and Sodium Lactate have been approved for use as direct food additives with generally recognized as safe (GRAS) status for use beyond infancy at concentrations that do not exceed good manufacturing practices (GMP) (FDA, 1980). Based on this and the long history of use, no long-term effects are expected.

As reported in the final report on the safety assessment of lactic acid and other substances (CIR, 1998) a group of white rats was fed 10% Lactic Acid at a dose of 4 mL/20 g of meal and a control group was given untreated feed (Wysokinska, 1952). No differences in appearance, gross observations at necropsy, or organ weights were observed between the test and control animals. Changes in blood carbon dioxide were slight. No overt toxic effects were observed in pigs given approximately 3.6-18 g/kg Lactic Acid in feed or water for up to 5 months (Lamb and Eward, 1919; Kershaw et al., 1966). Groups of 15 Syrian hamsters, 8 males and 7 females per group, were dosed with Lactic Acid by adding 0.057 mL Lactic Acid (80%) to 100 g of feed or by adding 0.050 mL Lactic Acid (80%) to 100 mL distilled water for 100 days; the amount of Lactic Acid added to the feed and water provided the same daily ingested dose for the two groups (Granados et al., 1949). A third group was given untreated feed and water. All animals were killed for necropsy at study termination. No differences in appearance or growth rate were noted between the groups, and no gross changes were observed at necropsy. Various degrees of alveolar resorption were reported for several animals, but no significant difference was observed between the groups.

Five groups of 10 F344 rats, five per sex, were dosed with 0.3-5.0% Calcium Lactate in the drinking water for 13 weeks and fed basic diet ad libitum; a control group was given untreated drinking water (Matsushima et al., 1989). All animals survived until study termination. A ~10% decrease in body weight gains were observed for all treated groups. Some hematological and biochemical parameters changed in the treated groups, but no severe lesions were found at microscopic examination.

In conclusion, the conduct of any further toxicity studies with chronic exposure in animals would not contribute any new information and is therefore not considered to be required.

 

Ammonium

Repeated dose toxicity, oral

A registration dossier shall contain information on the human health hazard assessment (regulation 1907/2006, Art.10). However, it is considered that the information requirements for ammonium as laid down in annex VII to IX can be fulfilled by adaptation of the standard testing regime according to Annex XI, points 1.1. and 1.2. as presented in the following:

Ammonium chloride has been ingested for a long time by humans. It can be added directly to human food and is considered in the U.S. as Generally Recognized As Safe (GRAS) [US FDA]. This substance is approved as a drug in several countries for electrolyte replenishment or expectorants and as food additive (fermentation and blowing agent) without usage restrictions in Japan. It is also used as food additive (flavors) in Germany and has been available as a therapeutic agent in Canada since its introduction in 1925. It has been used as a mild diuretic, an expectorant, a weight-reducing agent and as in the case, a urine-acidifying agent. The toxicity of ammonium chloride depends on ammonia which enters the living organism and thence the cell. This substance is readily absorbed by the gastrointestinal tract and utilized in the liver to form amino acids and proteins.

As reported by the OECD SIDS for ammonium chloride (2003) Sprague-Dawley rats (10 males/group) were fed a diet containing this substance at 12,300 ppm (equivalent to 684 mg/kg bw/day) for 70 days [Arnold et al. 1997]. This substance had no effect on clinical signs, body weights, food consumption or necropsy findings. The urine pH was approximately 6.0 compared with a pH of 7.56 or greater in the control group, and the concentration of urinary calcium increased. However, the crystals in urine were not found. The other urinary chemistries (the concentration of magnesium, creatinine, phosphate, protein, and osmolality) were unchanged. Histopathological examination was conducted on stomach kidneys and bladder. The study is consistent with the result of a study conducted in similar dose duration and method (580 mg/kg bw/day, 58 days, with histopathology of bladder) [Shibata, et al 1989], revealing no adverse effect. No histopathological changes ascribable to this substance were found. The NOAEL for repeat dose toxicity is considered to be 12,300 ppm (equivalent to 684 mg/kg bw/day). This study by Arnold et al. (1997) was considered to be the most reliable and identified as the key study.

In conclusion, the conduct of any further toxicity studies with chronic exposure in animals would not contribute any new information and is therefore not considered to be required.

 

Zirconium, acetate lactate oxo ammonium complexes

Since the assessment entities of zirconium, acetate lactate oxo ammonium complexes do not induce adverse effects in any relevant and reliable repeated dose toxicity studies, zirconium, acetate lactate oxo ammonium complexes is assumed to also show no potential to induce adverse effects after repeated exposure.

For the purpose of hazard assessment of zirconium, acetate lactate oxo ammonium complexes, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation. In case of ammonium in zirconium, acetate lactate oxo ammonium complexes, the NOAEL of 230.7mg/kg bw/day for repeated dose toxicity will be used. The NOAEL for ammonium is calculated, based on molecular weights, from the NOAEL of ClNH4(NOAEL of 684 mg/kg bw/day). 

Justification for classification or non-classification

In relevant and reliable repeated dose toxicity studies as well as supporting information for the assessment entities of zirconium, acetate lactate oxo ammonium complexes, there were no toxicological findings reported that would justify a classification for specific target organ toxicity-repeated exposure (oral route).

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