Barium di(acetate)

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No studies on reproduction toxicity are available for barium di(acetate). Since the acetate anion in barium di(acetate) does not contribute to the overall toxicity of barium di(acetate) (see additional information), it is concluded that only the effect of “barium” will further be considered in the human health hazard assessment of barium di(acetate). However, studies conducted with soluble barium substances were included in the dossier.

Nevertheless, only a screening test is performed with barium dichloride is available. Based on this study there are no indications of a substantial impairment of fertility in rats up to the highest dose tested. Thus, the NOAEL was 4000 ppm (to average doses of 201.5 and 179.5 mg Ba/kg bw/d to male and and female rats, respectively). No-observed-adverse-effect levels (NOAELs) on developmental toxicity for rats of 4000 ppm were derived. However, this NOAEL is of limited value to evaluate the potential for barium to induce developmental effects because there was no exposure of the females during gestation. Nevertheless, a decision on the registrant’s testing proposal for a study investigating the effects on fertility has not yet been taken by ECHA.

Additional information

Only two studies (NTP and Dietz) exist in which a dose-response relationship of different adverse effects on fertility after oral administration of barium chloride was investigated. These studies which were published in peer-reviewed journals were examined with respect to their adequacy for the derivation of NOAEL/LOAEL values for fertility impairment.

Based on these limited investigations with barium chloride, a lack of fully, guideline conform data must be noted. Tentatively, the premating study by Dietz et al. (1992) on rats and mice may be considered as the only acceptable study for the derivation of a preliminary NOAEL for fertility effects of soluble barium compounds. This study investigated the occurrence of different adverse effects in male and female rats and mice and their offspring related to barium chloride exposure via drinking water. A tentative NOAEL for fertility impairment of 4,000 ppm in rats and 2,000 ppm in mice can be derived.

 

For this reason, a testing proposal for a study investigating the effects on fertility was included into the registration dossier but a final decision has not yet been taken by ECHA.

Effects on developmental toxicity

Description of key information

Developmental toxicity: a NOAEL of >=105 mg Barium di(acetate)/kg was derived in an oral developmental toxicity study according to OECD 414 performed with barium dichloride dihydrate. Read-across to soluble barium substances are fully justified (see RAAF report attached to IUCLID section 0 "assessment entity).

Additional information

Developmental toxicity of barium chloride dihydrate was evaluated in a recent prenatal developmental toxicity study by daily administration of the test item at dose levels of 0, 10, 30 or 100 mg BaCl₂ * 2 H₂O/kg body weight to pregnant rats from gestation day 1 up to and including gestation day 20. No effects on body weights, food consumption and clinical signs were observed. Maternal toxicity was evidenced by the spontaneous deaths of two animals on gestation day 21 only and the conditional decline of another animal on gestation day 21 in the high dose group (100 mg BaCl₂ * 2 H₂O/kg bw).

No developmental toxicity or treatment-related observations, whatsoever in external, visceral and skeletal foetal examinations were observed in any dose level.

The NOAEL for maternal toxicity was therefore 30 mg/kg body weight barium chloride dihydrate (25.6 mg/kg bw barium chloride)). In absence of developmental effects, the NOAEL for prenatal developmental toxicity in the rat was ≥ 100 mg/kg body weight barium chloride dihydrate (≥105 mg/kg bw barium di(acetate)).

Furthermore, tentative NOAEL values for developmental toxicity of 4,000 ppm and 2,000 ppm for rats and mice, respectively, are also reported in the study by Dietz et al. (1992). However, these NOAELs are of limited value to evaluate the potential for barium to induce developmental effects because the study design did not include prenatal exposure of the female animals to barium dichloride dihydrate. Therefore, this study has to be considered as inadequate for the assessment of the potential to induce developmental toxicity and cannot be used in a regulatory context. A study in accordance with Read-across to soluble barium substances are considered to be fully justified (see RAAF report attached to IUCLID section 0 "assessment entity).

Toxicity to reproduction: other studies

Additional information

Read-across concept:

Reproduction toxicity studies specifically for barium di(acetate) are not available. Instead, read-across from studies performed with barium dichloride dihydrate and acetate are considered to be justified without restriction.

Barium di(acetate) completely dissolves upon contact with water to Ba2+and 2*CH3COO-. The water solubility (CRC handbook, 2008) of barium di(acetate) indicates a complete dissolution and a rapid formation of Ba2+and 2*CH3COO-(792 mg/L at 25°C). The pH of a saturated aqueous solution of barium di(acetate) is pH 7.9. Considering that systemic human health effects of barium di(acetate) are due the dissolved concentrations of Ba2+and CH3COO-in physiological solutions, read-across to soluble (i.e., > 10 g/L at room temperature) inorganic barium compounds and acetic acid and its salts (i.e., > 10 g/L at room temperature) is performed and considered to be very conservative with regard to systemic toxicity.

 

No reliable studies addressing the fertility are available for soluble barium substances. However, a testing proposal is added to the dossier of barium dichloride and will be used (if available for barium di(acetate). A study on developmental toxicity with barium dichloride dihydrate in accordance with OECD 414 was performed in 2014, resulting in an NOAEL of >= 100 mg/kg bw/day (re-calculated to barium di(acetate) >= 105 mg/kg bw/day). No developmental toxicity or treatment-related observations, whatsoever in external, visceral and skeletal foetal examinations were observed in any dose level.

Nevertheless, considering the data gap for studies with acetic acid and its salts, the registrant of barium di(acetate) is of the opinion that the toxicity of barium di(acetate) is driven by the barium moiety, and that the acetate anion does not contribute to the overall toxicity of the substance barium di(acetate) to any relevant extent. For completeness, the toxicological relevance of the counter-ion acetate is addressed below:

 

Acetate:

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. 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 barium di(acetate) does not contribute to the overall toxicity of barium di(acetate). It is concluded that only the effect of “barium” it further considered in the human health hazard assessment of barium di(acetate).

 

Note on barium(II):

Systemic effects observed for barium dichloride are considered to be very conservative compared with barium di(acetate). This is supported by the results of acute oral toxicity testing with barium dichloride and barium di(acetate). A study performed with barium dichloride resulting in an LD50 ≥ 100 till ≤ 300 mg/kg bw, whereas a study with barium di(acetate) (toxic if swallowed) resulting in an LD50 of 500 mg/kg bw. (harmful if swallowed). Based on test results barium dichloride is considered to be toxic if swallowed whereas barium di(acetate) requires classification as harmful via ingestion. In both studies systemic effects were observed.

 

References:

EFSA (2012) Scientific Opinion on the safety and efficacy of acetic acid, sodium diacetate and calcium acetate as preservatives for feed for all animal species, EFSA Journal 10(2):2571

 

Joint FAO/WHO Expert Committee On Food Additives (JECFA), 1974. Toxicological evaluation of some food additives including anticaking agents, antimicrobials, antioxidants, emulsifiers and thickening agents. WHO food additives series NO. 5. World Health Organisation, Geneva. Available at:http://www.inchem.org/documents/jecfa/jecmono/v05je01.htm

 

Joint FAO/WHO Expert Committee On Food Additives (JECFA), 1998. Safety Evaluation of Certain Food Additives and Contaminants. WHO Food Additives Series, No. 40. World Health Organisation, Geneva. Available at:http://www.inchem.org/documents/jecfa/jecmono/v040je01.htm

Justification for classification or non-classification

No classification is required based on the results of the prenatal developmental toxicity study. Further classification and labelling will be postponed till the results of the study investigating the effects on fertility of barium chloride are available.