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Description of key information

Repeated dose toxicity data are not available for barium di(acetate). However, studies conducted with soluble barium substances were included in the dossier resulting in an NOAEL for barium of 61 mg/kg bw/day that is used for the hazard assessment of barium di(acetate).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
113.5 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The results of the study performed by Dietz et al (1992) and NTP (1994) using barium dichloride dihydrate as test substance are not contradictory, and in both investigations similar target organs of toxicity were found and no differences in susceptibility of gender was seen. Both studies (RL1 and RL2, respectively) were used in a weight of evidence approach.
System:
other: cardiovascular / hematological: lymph nodes; urogenital: kidneys
Organ:
kidney
lymph node

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

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

Read-across concept:

Repeated dose toxicological data specifically for barium di(acetate) are not available. Instead, read-across from sub-chronic toxicity data on barium dichloride dihydrate is 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 performedand considered to be very conservativewith regard to systemic toxicity.

There are reliable studies addressing the long-term toxicity of barium dichloride. The DNEL calculation is based on the toxicity effects of barium cation only, since 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).

 

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.

However, comparing the results of the different oral studies it becomes obvious that the findings of all these studies are not contradictory. The studies conducted by NTP (1994) and Dietz and co-workers (1992) in rats and mice found similar targets of toxicity; although some differences in sensitivity were found. The main adverse effect caused by barium chloride was the nephrotoxicity in rats and mice of both sexes.

The available data in laboratory animals suggest that the toxicity of ingested barium is similar across species. The lowest NOAEL for nephrotoxic effects in rats or mice were identified from the 13-week drinking water study by Dietz et al. (1992) as the NOAEL of 61 mg Ba/kg bw/d in male rats and 81 mg/kg bw/d in female rats and of about 165 mg Ba/kg bw/d in male mice and166 mg Ba/kg bw/d in female mice.

The no-observable-effect concentration of the 13-weeks NTP study (1994) conducted with barium chloride was estimated to be 2000 ppm as based on changes of the final mean body weights, mean body weight gains, mortality, and renal toxicity at 4000 ppm in both species (LOAEL). The dose of 2,000 ppm represents the NOAEL value of this study corresponding to 62.0 and 65.3 mg Ba/kg bw/d in male and female rats, respectively. Thus, the dose of 62.0mg Ba/kg bw/d in male rats and 65.3 mg Ba/kg bw/d in female rats can be regarded as relevant NOAEL for chronic barium toxicity in this 13-week study.

Taken the results for male and female rats from both studies (NTP and Dietz et.al) into consideration, an average NOAEL could safely be calculated at 61.5 mg Ba/kg bw/d, which results in a re-calculated value of 93.3 mg/kg bw/d for barium chloride.

It is explicitly noted that according to the precautionary principle the “worst case value” of 61 mg Ba/kg bw/d (in male rats according to Dietz et al.) is used for the derivation of DNELs. This value refers to approx. 92.5 mg BaCl2/ kg bw/d. However, for classification and labelling purposes it appears appropriate to consider all relevant data on repeated dose oral toxicity. As already mentioned above, the results of the NTP study (1994) and the study performed by Dietz et al. (1992) are not contradictory, and in both investigations similar target organs of toxicity were found and no differences in susceptibility of gender was seen. Therefore, it could safely be stated that the calculation of an average value, using the NOAELs for male and female rats coming from the NTP and the Dietz studies, is considered to be a valid approach for the classification and labelling discussion.

 

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

Repeated dose toxicity, oral:

The results of the NTP study (1994) and the study performed by Dietz et al. (1992) are not contradictory, and in both investigations similar target organs of toxicity were found and no differences in susceptibility of gender was seen. Therefore, it could safely be stated that the calculation of an average value, using the NOAELs for male and female rats coming from the NTP and the Dietz studies, is considered to be a valid approach for the classification and labelling discussion. The results are as follows:

(i) Dietz et al. (1992): NOAEL of 61 mg Ba/kg bw/d in male rats and 81 mg/kg bw/d in female rats

(ii) NTP (1994): NOAEL of 62 mg Ba/kg bw/d in male rats and 65.3 mg Ba/kg bw/d in female rats

No classification and labelling of barium di(acetate) according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – repeated exposure, oral is necessary, since the guidance value for a Category 1 classification of C<10 mg Barium di(acetate)/kg bw/day, and the guidance value for a Category 2 classification of 10 <C <100 mg Barium di(acetate)/kg bw/day are not met. The lowest NOAEL re-calculated to barium di(acetate) is 113.5 mg/kg bw/day.

Furthermore, no classification and labelling according to regulation (EC) 1272/2008 are expected for long term oral, dermal and inhalation are expected