Zirconium, acetate lactate oxo ammonium complexes

Endpoint summary

Description of key information

No acute toxicity studies with zirconium, acetate lactate oxo ammonium complexes are available, thus the acute toxicity will be addressed with existing data on the dissociation products zirconium, acetate, lactate and ammonium.

Acute dermal toxicity of the substance zirconium, acetate lactate oxo ammonium complexes is not expected, since the individual moieties zirconium, acetate, lactate and ammonium have not shown overt toxicity upon dermal exposure in experimental animal testing and in exposure related information in humans (for e.g. use in cosmetics). All dermal LD50 values available were found to be greater than 2000 mg/kg bw.

The assessment entities zirconium, lactate and acetate have not shown adverse effects in experimental animal testing (all LD50 >2000 mg/kg bw). Additionally, lactate and acetate are found in physiological processes and are used in food products. Ammonium chloride, as representative of ammonium, oral LD50 values of 1410 mg/kg bw and 1300 mg/kg bw were determined for rats and male mice, respectively. Further, ammonium chloride has a legal classification for acute oral toxicity category 4 (Regulation (EC) No.1272/2008; Index No.: 017-015-00-8).

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

No acute toxicity studies with zirconium, acetate lactate oxo ammonium complexes are available, thus the acute toxicity will be addressed with existing data on the dissociation products zirconium, acetate, lactate and ammonium.

Zirconium

Acute oral toxicity

One key study was identified (Klimisch 1). Acute toxicity was determined via the acute class method (OECD Guideline 423 and EU Method B1 tris) in female Sprague-Dawley rats. The LD50 -value was > 5000 mg/kg. Three supporting studies were identified (Klimisch 2) which studied the acute oral toxicity via a standard acute test in Crj: CD (SD) IGS male and female rats. The LD50 -values determined in these studies were > 2000 mg/kg.

Acute dermal toxicity

In the absence of measured data on dermal absorption, current guidance suggests the assignment of either 10 % or 100 % default dermal absorption rates. In contrast, the currently available scientific evidence on dermal absorption of metals yields substantially lower figures, which can be summarised briefly as follows: Measured dermal absorption values for metals or metal compounds in studies corresponding to the most recent OECD test guidelines are typically 1 % or even less. Therefore, the use of a 10 % default absorption factor is not scientifically supported for metals. This is corroborated by conclusions from previous EU risk assessments (Ni, Cd, Zn) and current metal risk assessments under REACH, which have derived dermal absorption rates of 2 % or far less (but with considerable methodical deviations from existing OECD methods) from liquid media. However, considering that under industrial circumstances many applications involve handling of dry powders, substances and materials, and since dissolution is a key prerequisite for any percutaneous absorption, a factor 10 lower default absorption factor may be assigned to such “dry” scenarios where handling of the product does not entail use of aqueous or other liquid media. This approach was taken in the in the EU RA on zinc. A reasoning for this is described in detail elsewhere (Cherrie and Robertson, 1995), based on the argument that dermal uptake is dependent on the concentration of the material on the skin surface rather than its mass. The following default dermal absorption factors for metal cations are therefore proposed (reflective of full-shift exposure, i.e. 8 hours): From exposure to liquid/wet media: 1.0 % From dry (dust) exposure: 0.1 % This approach is consistent with the methodology proposed in HERAG guidance for metals (HERAG fact sheet - assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal compounds; EBRC Consulting GmbH / Hannover /Germany; August 2007).

Acetate

Acute oral toxicity

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.

Immediate toxic effects of glacial acetic acid observed in experimental studies are due to its corrosive acid action and to dehydration of tissues with which it comes into contact. Ingestion results in severe pain and the formation of white plaques and ulcers of mucosal surfaces, and may be followed by haematemesis (Martindale, 1972). Thus, pH adjustment before experimental testing is required. However, those pH effects are not considered necessary for the substance subject to registration since the substance is not prepared by using glacial acetic acid.

The study conducted by Woodard reported the results of the acute oral toxicity testing in rats and mice. Acetic acid was adjusted to sodium hydroxide to a range of pH between 6 and 7 before being administered to groups of 10 fasted albino rats or 5 male and 5 female albino mice. Both species received 10 mL of solution per kg of body weight orally by gavage. The LD50 was calculated to be 3310 mg/kg bw in rats and 4960 mf/kg in mice.

Smyth et al. administered a single dose of acetic acid to rats and observed all animals 14 days postdosing. Further information were not given, due to lack of full report. The reported LD50 was 3530 mg/kg bw in rats, signs of toxicity were not tabulated. 

According to SCOEL document for acetic acid, the oral LD50 for acetic acid was 3310 and 4960 mg/kg bw in rats and mice, respectively.

As reported in the Cosmetic Ingredient Review, published in 2012, salts of acetate, such as calcium-, sodium-, magnesium and potassium acetate displayed low acute oral toxicity. The reported LD50 values for these salts were above 3000 mg/kg bw.

These in vivo data clearly demonstrate that the salts of acetate are not acutely toxic via the oral route and further testing is considered no necessary.

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 cycle and the above mentioned acute oral toxicity in vivo data with pH adjusted acetic acid indicate that acetic acid is not acutely toxic via the oral route. Therefore, no further testing is required.

Acute dermal toxicity

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 Voluntary Cosmetic Registration Program (VCRP) administered by the US Food and Drug Administration (FDA) indicates the total number of uses in cosmetic formulations in 2010 for sodium acetate, calcium acetate and a variety of other substances. For instance, in 2010 sodium acetate had 88 reported uses in cosmetic formulations. The reported percentage range in cosmetic products for sodium acetate is 0.0002-0.5%, for potassium acetate 3% and magnesium acetate 0.02-0.03%. All these cosmetic products are intended for direct dermal application and were proven to be safe.

Additionally, acetate and its salts are permitted for direct addition to food for human consumption for flavoring purposes and are generally recognized as safe (GRAS) according to the FDA.

As reported in the Cosmetic Ingredient Review (2012) the subcutaneous administration of sodium acetate in mouse induced no adverse effects. The reported LD50 value for sodium acetate was 3200 mg/kg bw.

Overall, the fact that the salts of acetic acid are used for cosmetic formulations and most of these substances are listed as GRAS-substances according to the FDA clearly demonstrate that the salts of acetic acid are not acutely toxic via the dermal route and further testing is considered not necessary.

Lactate

Acute oral toxicity

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:

As reported in the final report on the safety assessment of lactic acid and other substances (CIR, 1998) the oral LD50 of L-Lactic Acid for rats was 3730 mg/kg (Smyth et al., 1941). The oral LD50 of a 12% Ammonium Lactate lotion, pH 5.0-5.5, for both rats and mice was >15 mL/kg (FDA, 1988). Rats have been stated to survive 2000-4000 mg/kg body-weight administered s.c. Mice were killed by doses of 2000-4000 mg/kg body-weight whether or not alkalosis was present (Fürth & Engel, 1930). A skin cream containing 0.6% of 85% aq. Lactic Acid, pH 7.50, had an oral LD50 of > 15,000 mg/kg and was classified as “practically nontoxic” when given undiluted to rats (Avon Products, Inc., 1995b).

The oral LD50 for rats of a stone remover formulation containing 6.0% Lactic Acid dark (44%) was >4640 mg/kg (Stauffer Chemical Co., 1971). The animals were necropsied 14 days after dosing, and no gross lesions were observed. The oral LD50 of Lactic Acid for mice was 4875 mg/kg (FAO/WHO, 1967).

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

Acute dermal toxicity

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:

“The acute dermal LD50 value in male and female New Zealand white rabbits is > 2000 mg/kg bw following 2 hour exposure of L(+)-lactic acid to clipped, abraded skin. No mortality or clinical signs of toxicity were seen. Severe erythema and edema were observed at the application sites of all animals on day 1. Both erythema and edema decreased in severity by observation day 14” (OECD SIAP, 2011).

However, local effects of Zirconium, acetate lactate oxo ammonium complexes are not addressed in the read across approach and tested on a substance-specific basis.

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

Ammonium

Acute oral toxicity

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:

As reported by the OECD SIDS for ammonium chloride (2003) Wistar rats (10 animal/group/sex) were administered by gavage at 681, 1,000, 1,470, 1,780 and 2,150 mg/kg bw. Dead male and female animals were observed in those given a dose of 1,470 mg/kg bw or higher and 1,000 mg/kg bw or higher within 1 day after administration. Dyspnea, apathy, abnormal position and staggering were observed at a dose of 1,000 mg/kg bw or higher. In necropsy findings, no abnormalities were detected in surviving animals. The LD50 for males, females and overall were 1,630, 1,220 and 1,410 mg/kg bw.

Additionally, CD-1 mice (10 male/group) were administered at 0 (control), 800, 1,000, 1,200, 1,400, 1,700 and 2,100 mg/kg bw through a stomach tube. Dead animals were observed in those dose groups given 1,200 mg/kg bw or higher. Diarrhoea, cyanosis and ataxic gait were observed. At necropsy, swelling and whitening of kidney and hemorrhage in brain were observed. The LD50 was 1,300 mg/kg bw in male mice. Both studies were considered to be most reliable and identified as key studies. Based on these results the oral LD50 in rats was 1410 mg/kg bw and in male mice 1300 mg/kg bw.

The oral LD50 for the ammonium salts of phosphoric acid in studies involving rats ranged from 3250 mg/kg (Ammonium Phosphate) to > 25,100 mg/kg (Diammonium Phosphate) (CIR, 2016).

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

 

Acute dermal toxicity

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:

The acute dermal toxicity of ammonium carbonate was evaluated in accordance with OECD Guideline 402 using 10 (5 male, 5 female) rats of the CRL:(WI) strain.31 The test substance (200 mg/kg body weight) was applied to 10% of the total body surface for 24 h. The application site was covered with a gauze pad that was secured with a semi-occlusive plastic wrap. Dosing was followed by a 14-day observation period, after which necropsy was performed. None of the animals died and there were no clinical signs of toxicity. Additionally, there were no effects on body weight. It was concluded that the LD50 was > 2000 mg/kg body weight (CIR, 2017).

For ammonium salts of phosphoric acid, the reported LD50 was > 5000 mg/kg (rats) and ranged from > 7940 mg/kg to > 10,000 mg/kg (rabbits) (CIR, 2016).

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

 

Zirconium, acetate lactate oxo ammonium complexes

Signs of acute dermal toxicity are not expected for zirconium, acetate lactate oxo ammonium complexes, since the individual moieties zirconium, acetate, lactate and ammonium have not shown signs of acute dermal toxicity in reliable experimental testing (LD50 > 2000mg/kg) or show only low dermal absorption.

The moieties zirconium, lactate and acetate have not shown signs of acute oral toxicity in experimental testing (LD50 > 2000mg/kg). An acute oral toxicity study with the moiety ammonium, as represented by ammonium chloride, resulted in an LD50 value of 1300 mg/kg bw. The LD50 value is accordance with the legally binding classification for ammonium chloride, is legally binding classified for acute oral toxicity category 4 (Regulation (EC) No.1272/2008; Index No.: 017-015-00-8). Thus, the substance zirconium, acetate lactate oxo ammonium complexes will be self-classified for acute oral toxicity category 4 accordingly.

A study for acute toxicity via inhalation was not conducted with zirconium, acetate lactate oxo ammonium complexes, since it is produced and placed on the market in a form in which no inhalation hazard is anticipated, thus acute toxic effects are not likely to occur during manufacture and handling of that substance.

For further information on the toxicity of the assessment entities, please refer to the relevant sections in the IUCLID and CSR.

Justification for classification or non-classification

The assessment entities zirconium, acetate and lactate are void of any acute oral toxicity. According to the classification of ammonium chloride (Regulation (EC) No.1272/2008; Index No.: 017-015-00-8), the substance zirconium, acetate lactate oxo ammonium complexes is self-classified for acute oral toxicity category 4 (H302: Harmful if swallowed). No acute dermal toxicity has been observed for the individual assessment entities of the substance zirconium, acetate lactate oxo ammonium complexes. Thus, the substance does not have to be classified for acute dermal toxicity according to the criteria of regulation (EC) No.1272/2008.

No adverse effects are reported or assumed for the acute oral or dermal toxicity studies with the assessment entities zirconium, acetate, lactate or ammonium that would justify a classification for specific target organ toxicity-single exposure.