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Effects on fertility

Description of key information

No toxicity data on adverse effects on sexual function and fertility with zirconium, acetate lactate oxo ammonium complexes are available, thus the reproductive toxicity will be addressed with existing data on the assessment entities zirconium, acetate, lactate and ammonium.

Zirconium, acetate lactate oxo ammonium complexes is not expected to show effects on reproduction, since the individual moieties zirconium, acetate, lactate and ammonium have not shown toxicity to the reproduction. Moreover, acetate, lactate and ammonium are used in medical and food products, and thus increased toxicity is not expected.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No toxicity data on adverse effects on sexual function and fertility with zirconium, acetate lactate oxo ammonium complexes are available, thus the reproductive toxicity will be addressed with existing data on the individual moieties zirconium, acetate, lactate and ammonium.

 

Zirconium

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 effects on reproduction or development were observed in any dose group or in pups. Therefore, on the basis of the results obtained in the study, the No Observed Adverse Effect Level (NOAEL) for reproductive toxicity and for developmental toxicity was considered to be >=1000 mg/kg bw/day (expressed as zirconium acetate anhydrous).

Acetate

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:

Acetic acid, calcium acetate, and sodium diacetate have a well-established history of use in food where they are considered safe at any concentration level, consistent with their intended physical, nutritional or other technical effect. They are also widely used in human and veterinary medicine, cosmetics, as plant protection agents and in a variety of household products as buffering agents or because of their anti-microbial properties. 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. 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)

 

It is also noteworthy that acetic acid is known to be a part in many biochemical reactions such as protein, carbohydrate and lipid metabolism. Coenzyme A (CoA) is acetylated to acetyl-CoA by the breakdown of carbohydrates through glycolysis and by the breakdown of fatty acids through β-oxidation. Acetyl-CoA then enters the citric acid cycle, where the acetyl group is oxidized to carbon dioxide and water, and the energy released captured in the form of 11 ATP and one GTP per acetyl group. Thus, acetyl-CoA is required for ATP generation necessary for all viable cells and processes.

As reported in the Cosmetic Ingredient Review (2012) no maternal or neonatal effects were observed in mice exposed to 1000 mg/kg of sodium acetate on gestation days 8-12. Additionally, sodium acetate was also determined to be nonteratogenic to chick embryos.

Supporting developmental toxicity studies conducted with apple cider vinegar containing 5% acetic acid showed no maternal or developmental effects in rats, rabbits and mice. Pregnant rabbits, mice and rats were administered for 10-13 consecutive days with up to 1600 mg/kg bw of apple cider vinegar. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls. Thus, the NOAEL for maternal and developmental toxicity can be expected above the highest dose of 1600 mg/kg body weight apple cider vinegar (5 % acetic acid) in these studies.

Based on the long history of use and the fact that 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 as well as the crucial role of acetic acid in cellular processes such as the citric acid and the non-genotoxic effects of acetic acid salts indicate that acetic acid has no reproductive effects. All cells in every organism are highly dependent on acetic acid maintaining their functionality and viability. Thus, it appears highly unlikely that acetic acid exerts any reproductive effect and further testing is not necessary.

 

Lactate

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 effects on reproduction are expected.

As reported in the final report on the safety assessment of lactic acid and other substances (CIR, 1998) sodium lactate, 5 mM, was added to B&F1 mice pre-embryo cultures to examine its effect on the development of these cells over a 72-h period; a control group was cultured in medium alone (Moley et al., 1994). No significant difference was observed in the overall rate of development between embryos cultured in the presence of Sodium Lactate as compared to those cultured in medium alone. No difference was found in the distribution of pre-embryo growth stages.

Rats were fed stock diet supplemented with 2.5 or 5% Lactic Acid or untreated stock diet to determine the effect of Lactic Acid on the sex ratio in rats (D‘Amour, 1934). The sex ratio of rats was not affected by oral administration of Lactic Acid.

“In a developmental toxicity study, lactic acid was neither toxic to dams or offspring when administered orally to pregnant CD-1 mice via gavage at doses of 0 or 570 mg/kg bw/day during days 6-15 of gestation. The NOAEL for maternal and developmental toxicity was 570 mg/kg bw” (OECD SIPA, 2011).

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

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.

As reported by the OECD SIDS for ammonium chloride (2003) for humans, there is no restriction to medication to a pregnant woman according to the appending document of the medical drugs using ammonium chloride in Japan. Moreover, it is also used as medical drug and classified into Category A in Australia. Category A means that it is a medicine which has been used for many pregnant women and women of conceiving age, and that there is no proof of increase in the frequency of deformation and the frequency of direct or indirect detrimental action to the embryo.

The teratogenicity was tested using Sprague-Dawley rats (10 female) [Goldman and Yakovac, 1964]. Rats were administered by gavage once a day at 1 mL/kg b.w. of 1/6 M (equivalent to 8.9 mg/kg bw/day) solution on days 7 to 10 of gestation. The fetuses were obtained by Cesarean section and examined on day 20 of gestation. Maternal effect was supposedly to be acidosis, no teratogenic toxicity was found. The effects of ammonium chloride on fetal growth noted were considered a consequence of maternal acidosis. No fetus with malformations was observed in the substance-treated group. Ammonium chloride has no teratogenicity at this dose level.

Diammonium phosphate did not produce teratogenic effects in vivo, and the highest dose tested was 1500 mg/kg/day Diammonium Phosphate (in rats) for 35 days (CIR, 2016).

Based on these results and the long history of use as well as the fact that it is considered in the U.S. as Generally Recognized As Safe (GRAS), 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

As the assessment entities of zirconium, acetate lactate oxo ammonium complexes do not impair sexual function, fertility or the development of the offspring, zirconium, acetate lactate oxo ammonium complexes can safely be assumed to also be void of reproductive toxic effects.

Information on the individual moieties zirconium, acetate, lactate and ammonium will be used for the hazard assessment and, when applicable, for the risk characterisation of zirconium, acetate lactate oxo ammonium complexes.

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). In case of zirconium in zirconium, acetate lactate oxo ammonium complexes, the NOAEL of 279 mg/kgbw/day for repeated dose toxicity will be used.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the available data for reproductive toxicity, zirconium, acetate lactate oxo ammonium complexes does not impair sexual function or fertility. Based on the limited data set, a classification for reproductive toxicity does appear unjustified, however a definitive decision is to be made after appropriate higher-tier studies become available.

Additional information

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