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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Test procedure in accordance with generally accepted scientific standard and described in sufficient detail. Data and rating according to the SIDS 2005 on barium carbonate.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Subchronic Toxicity of Barium Chloride Dihydrate Administered to Rats and Mice in the Drinking Water
Author:
Dietz, D.D. et al.
Year:
1992
Bibliographic source:
Fundamental and Applied Toxicology 19, 527-537
Report Date:
1992

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Barium chloride dihydrate (BaCl2 * 2H2O) was given for 92 days to Fischer 344/N rats in their drinking water at levels of 0, 125, 500, 1000, 2000 and 4000 ppm.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Barium chloride dihydrate
- EC number: 233-788-1
- Analytical purity: 99.5 % pure
- Lot No.: 123120

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Simonsen Laboratories (Gilroy, CA)
- Age at study initiation: 32 days
- Housing: The animals were housed five per cage in drawer type polycarbonate cages. The shelves supporting the cages were covered with filter sheets. The bedding was (Ab-Sorb-Dri, Lab Products, Rochelle Park, NJ)
- Diet (ad libitum): NIH-07 pellets (Ziegler Brothers, Gardners, PA)
- Water (ad libitum): dosed with test substance or undosed water
-Quarantine period: 10 to 11 days after arrival, and representatives were necropsied to verify that they were grossly free of disease.

ENVIRONMENTAL CONDITIONS
- Temperature: 21 to 24 °C
- Air changes (per hr): Filtered fresh air (13.5 room vol/hr) was supplied directly and removed from the animal room.
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:Solutions were made weekly in 19-liter quantities by dissolving weighed portions of the chemical in glass-distilled water.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dosage analyses were performed on all levels before and after use, and at the beginning and midway through the test period, indicated that the concentrations were within 1 to 6 % of the theroretical concentrations.
Duration of treatment / exposure:
92 consecutive days
Frequency of treatment:
Dosed water on an ad libitum basis during treatment.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
4000 ppm BaCl2 * 2H20
Basis:
nominal in water
Remarks:
Doses / Concentrations:
2000 ppm BaCl2 * 2H20
Basis:
nominal in water
Remarks:
Doses / Concentrations:
1000 ppm BaCl2 * 2H20
Basis:
nominal in water
Remarks:
Doses / Concentrations:
500 ppm BaCl2 * 2H20
Basis:
nominal in water
Remarks:
Doses / Concentrations:
125 ppm BaCl2 * 2H20
Basis:
nominal in water
No. of animals per sex per dose:
Groups of 10 per dose level after weight-sorting them by sex.
Control animals:
yes, concurrent vehicle
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- twice daily for clinical signs

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

WATER CONSUMPTION (if drinking water study): Yes
- Time schedule for examinations: twice weekly

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: no data
- Animals fasted: No data
- How many animals: 7-10 animals
- Parameters checked in table: serum sodium potassium, calcium, phosphorus

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: on each animal at 0, 45 to 48, and 91 days of exposure
- Dose groups that were examined: all
- Battery of functions tested: undifferentiated motor activity, forelimb and hindlimp grip strengths, thermal sensitivity to a 55°C water bath, startle response to acoustic and air-puff stimuli, and hindlimb foot splay.

DETAILED CLINICAL OBSERVATIONS: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

URINALYSIS: No data



Sacrifice and pathology:
GROSS PATHOLOGY: Yes
All animals were examined for gross lesions. The brain, liver, right kidney, lung, thymus, right testis, heart, and adrenals were weighed before fixation
HISTOPATHOLOGY: Yes
Complete histologic exams were performed on 30 or more tissues from animals of 4000 ppm and the control groups. Because histopathological changes were observed in several tissues (thymus, spleen, kidneys, and lymph nodes) from rats in the 4000 ppm group, these tissues were examined from the lower dose animals to determine a no-effect level.
Other examinations:
none
Statistics:
Each parameter for which individual values were available was subjected to a linaer lesat squares regression over the dose levels and the direction of the slope and the p value indicating the significance of the deviation of the slope from 0 was determined. Group means and standard deviation or standard errors were calcualted for continuous variables. the multiple comparison procedure of Dunnett (1955) was employed for pairwise comparisons of these variables between dosed groups and controls. Fisher's exact test was used to make pairwise comparisons of discrete variables between dosed groups and controls and the Cochran-Armitage test was used to assess the significance of dose-related trends (Armitage, 1971; Gart et al., 1979). Temporal and dose-related variations were evaluated using a repeated measures analysis of variance (Winter, 1971). When a collection of measurements were made on each animal, a multivariate analysis of variance (Morrison, 1976) was used to test for the simultaneous equality of measurements across dose levels.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
Three of 10 male and 1 of 10 female rats in the 4000 ppm groups died during the last week of the study. No clinical signs were oberved.

BODY WEIGHT AND WEIGHT GAIN
Body weights of both sexes in the 4000 ppm groups were significantly (p< 0.05) lower than the controls. Signs of weight loss were observed.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Rats in the 4000 ppm groups consumed 70 % of water consumed by controls. It is not clear whether the effcets are toxicity related or due to palatobility

CLINICAL CHEMISTRY
In the male rats, there was a significant elevation in phosphorous in the 1000, 2000, and 4000 ppm groups compared with the controls. In the female rats, a significant elevation in phosphorous was seen in the 500, 1000, 2000, and 4000 ppm groups. The biological significance of the changes in females are reagrded as marginal due to lower than expected control values.

ORGAN WEIGHTS
The liver weights of the rats received 4000 ppm were depressed. The absolute kidney weights were elevated in the 1000 and 4000 ppm females, and the relative kidney weights were elevated in 4000 ppm to males and 1000 ppm or greater to females. These changes were variable and were probably related to treatment-depressed body weights rather than kidney toxicity. Tymus weights were depressed in the high dose female rats.

GROSS PATHOLOGY/HISTOPATHOLOGY
The kidney changes in rats were limited to few foci of dilated tubules in the outer medulla or meduallary rays. Tubular cell regression, casts, and crystals were not a feature of the renal lesions in rats. Lymphoid depletion was also present in the spleen and thymus of the early death rats.
There were no treatment-related histopathologic effects in the brain or other tissues of rats.

NEUROBEHAVIOUR
Compared to their controls, rats exposed to 2000 ppm Ba Cl2 or lower did not show any consistent changes in behavoioural indices (motor activity, fore- and hindlimp grip strength, and thermal sensitivity). Marginal although significant behavioural effects were noted at the 4000 ppm level in rats. these changes were probably a result of the overall BaCl2 toxicity observed at the 4000 ppm dose level.The behavioural effects observed at the 4000 ppm are as follows: Decreased undifferentiated motor acivity in female rats on day 91. No significant or dose-related effects were seen in the startle response to acoustic and air-puff stimuli or the hindlimb foot splay.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
2 000 ppm
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOAEL
Effect level:
80.9 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: calculated as Ba2+
Dose descriptor:
NOAEL
Effect level:
61.1 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: calculated as Ba2+

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The NOAEL of barium titanium trioxide is ≥ 103 mg/kg bw/day (calculated from the molecular weight of Barium titanium trioxide based on the NOAEL of 61.1 mg Ba2+/kg bw/day for male rats).



Executive summary:

Based on read-across:

The NOAEL for barium toxicity in this study is based on depressed body weight gains, elevated phosphorus levels, neurobhavioural effects and chemically related lesions in the kidney and lympoid tissue at the highest dose level of 4000 pm. Individual effects observed at 2000 ppm barium chloride in drinking water (corresponding to the final barium dose of 61.1 and 80.9 mg Ba/kg bw/day to male and female rats respectively) were regarded as not treatment-related and this dose levels represents the NOAEL.

 

The toxicity of barium titanium trioxide and barium chloride is based on the cation Ba2 + and on the water solubility (dependent on the Ba2+ concentration). Barium chloride is a well water soluble substance whereas barium carbonate is low soluble in water. The NOAEL of Barium chloride dihydrate is 2000 ppm which corresponds to a NOAEL of 80.9 mg Ba2+/kg bw/day for females and a NOAEL of 61.1 mg Ba2+/kg bw/day for males. As a worst case assumption it can be concluded that the NOAEL for barium titanium trioxide is ≥ 103 mg/kg bw/day based on the nominal test item application.