barium(2+); oxygen(2-); titanium(4+); zirconium(4+) ;calcium (2+)

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

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.

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

Test material information

Constituent 1

Reference substance name:

10326-27-9

Cas Number:

10326-27-9

IUPAC Name:

10326-27-9

Constituent 2

Reference substance name:

Barium dichloride dihydrate

IUPAC Name:

Barium dichloride dihydrate

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 or test system 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 / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
4000 ppm BaCl2 * 2H20
Basis:
nominal in water

Doses / concentrations 2

Remarks:

Doses / Concentrations:
2000 ppm BaCl2 * 2H20
Basis:
nominal in water

Doses / concentrations 3

Remarks:

Doses / Concentrations:
1000 ppm BaCl2 * 2H20
Basis:
nominal in water

Doses / concentrations 4

Remarks:

Doses / Concentrations:
500 ppm BaCl2 * 2H20
Basis:
nominal in water

Doses / concentrations 5

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

1

Dose descriptor:

NOAEL

Effect level:

2 000 ppm

Sex:

male/female

Basis for effect level:

other: see 'Remark'

2

Dose descriptor:

NOAEL

Effect level:

80.9 mg/kg bw/day (nominal)

Sex:

female

Basis for effect level:

other: calculated as Ba2+

3

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 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.