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Administrative data

Description of key information

Acute oral toxicity: 300 mg/kg bw < LD50 < 2000 mg/kg bw (LD50 cut off value: 500 mg/kg bw) (OECD 423; GLP; female rats) ; test substance: barium di(acetate)

Acute inhalation toxicity: LC50 > 1 mg/L (OECD 403; GLP; female rats) (test substance: barium dichloride dihydrate recalculated to barium di(acetate)

Acute dermal toxicity: derogation statement included; according to SIAR 2008 an LD50 > 2000 mg/kg was stated in the NIAR report 2008 for barium dichloride. The LD50 for barium di(acetate) is > 2000 mg/kg (re-calculated).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2017-12-07 to 2017-12-28
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
2001-12-17
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
signed 2017-05-08
Test type:
acute toxic class method
Limit test:
no
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at +10°C to 25°C, stored in the tightly closed original container in and in a cool, dry and well-ventilated place
Species:
rat
Strain:
other: Crl: CD(SD)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approx. 8 weeks
- Weight at study initiation: 187 - 200 g
- Fasting period before study: feeding was discontinued approx. 16 hours before administration; only tap water was then available ad libitum.
- Housing: during the 14-day observation period the animals were kept in groups of 3 animals in MAKROLON cages (type III plus); bedding material: granulated textured wood (Granulat A2, J. Brandenburg, 49424 Goldenstedt, Germany)
- Diet: commercial diet, ssniff® R/M-H V1534 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany)
- Water (ad libitum): drinking water
- Acclimation period: at least 5 adaptation days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 °C ± 3 °C (maximum range)
- Relative humidity: 55 % ± 10 % (maximum range)
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: 0.8% aqueous hydroxypropylmethylcellulose
Details on oral exposure:
VEHICLE
- Justification for choice of vehicle: 0.8% aqueous hydroxypropylmethylcellulose was chosen as vehicle as it is known not to produce toxic effects.
- Batch no.: 16H 23-B02-333146 (supplier: Fagron GmbH & Co., 22885 Barsbüttel, Germany)

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

DOSAGE PREPARATION (if unusual):

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose:
Doses:
300 and 2000 mg/kg bw
No. of animals per sex per dose:
2000 mg/kg/bw: 3 female rats (3 animals/step)
300 mg/kg/bw: 6 female rats (3 animals/step)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations were performed before and immediately, 5, 15, 30 and 60 minutes, as well as 3, 6 and 24 hours after administration. During the follow-up period of two weeks,the surviving animals were observed at least once a day until all symptoms subsided, thereafter each working day. Observations on prematurely deceased animals were made at least once daily to minimize loss of animals during the study.
Individual body weights were recorded before administration of the test item and thereafter in weekly intervals up to the end of the study and at death. Changes in weight were calculated and recorded.
- Necropsy of survivors performed: yes, at the end of the experiments, all surviving animals were sacrificed, dissected and inspected macroscopically. All gross pathological changes were recorded. Autopsy and macroscopical inspection of animals which died prematurely were carried out as soon as possible after exitus.
Statistics:
No statistical analysis could be performed (the method used is not intended to allow a calculation of a precise LD50 value).
Preliminary study:
not applicable
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: LD50 (cut off value): 500 mg/kg bw
Mortality:
2000 mg/kg bw: all 3 animals died within 60 minutes after administration.
300 mg/kg bw: 1/6 animals died (animal with clinical signs as described in the field "clinical signs" below)
Clinical signs:
2000 mg/kg bw: slightly to moderately reduced motility, slight to moderate ataxia, slightly to moderately reduced muscle tone, slight to moderate dyspnoea, abdominal position, salivation and pilo-erection in all animals.
300 mg/kg bw: slightly reduced motility, slight ataxia, slightly reduced muscle tone and slight dyspnoea in 1/6 animals.
Body weight:
All surviving animals gained the expected body weight.
Gross pathology:
No findings were observed at necropsy.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
LD50 (female rats): 300 < LD50 < 2000 mg/kg bw (LD50 cut off value: 500 mg/kg bw)
According to the Regulation (EC) No 1272/2008 and subsequent adaptations, the substance is classified as acute toxic via the oral route (Cat.4; H302).
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
500 mg/kg bw
Quality of whole database:
GLP guideline test was performed with barium di(acetate)

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Quality of whole database:
GLP study performed with barium dichloride dihydrate was performed. Read-across is fully justified for barium di(acetate).

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Read-across – barium di(acetate)

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 conservative.

 

However, there are reliable data available on acute oral toxicity performed with barium dichloride resulting in an LD50 ≥ 100 till ≤ 300 mg/kg bw. To support read-across a study on acute oral toxicity was performed with barium di(acetate) resulting in an LD50 of 500 mg/kg bw. Based on test results barium dichloride is considered to be toxic if swallowed whereas barium di(acetate) requires classification as harmful via ingestion. Hence, read-across from barium dichloride to barium di(acetate) is very conservative and unrestricted read-across is fully justified with regard to systemic toxicity.

 

However, considering the toxicity of the counter ion “acetate” in barium di(acetate) the following can be concluded:

 

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 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).

 

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

 

Scientific Committee on Food (SCF), 1990. Food-science and techniques. First series of food additives of various technological functions. Reports of the Scientific Committee for Food, 25th series. Available at :http://ec.europa.eu/food/fs/sc/scf/reports/scf_reports_25.pdf

Justification for classification or non-classification

Acute oral toxicity

The substance is acutely harmul via the oral route based on an acute oral toxicity test (OECD 423) and does require classification according to Regulation (EC) No 1272/2008 and subsequent adaptations (Category 4; H302).

Acute inhalation toxicity

The substance is acutely harmful via the inhalation route based on an acute inhalation toxicity test (OECD 403) with barium dichloride dihydrate. Based on read-across barium di(acetate) does require classification according to Regulation (EC) No 1272/2008 and subsequent adaptations (Category 4; H332).

Acute dermal toxicity:

no study available. However, based on read-across no C&L for barium di(acetate) is required.