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Repeated dose toxicity: oral
Dietz (1992) performed a repeated dose toxicity study with the read-across susbtance barium chloride dihydrate. The substance was administered to rats in drinking water. Male and females rats were continuously exposed up to 92 days. A NOEL of 61.1 mg Ba/kg bw/day was derived (116.3 mg Ba nitrate/kg bw/day).

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
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.
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
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 old
- Housing: five per cage in drawer-type polycarbonate cages. The shelves supporting the cages were covered with filter sheets.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: The animals were quarantined for 10 to 11 days after arrival, and representatives were necropsied to verify that they were grossly free of disease.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 24°C
- Air changes (per hr): 13.5 room vol/hour
- Photoperiod (hrs dark / hrs light): 12 hours on (from 06h30 to 18h30) and 12 hours off

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:
The test substance was analyzed by EDTA titration. Dosage analyses 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 theoretical concentration.
Duration of treatment / exposure:
92 days
Frequency of treatment:
Exposures were continuous.
Dose / conc.:
0 ppm
Remarks:
BaCl2.H2O, nominal in water
Dose / conc.:
125 ppm
Remarks:
BaCl2.H2O, nominal in water
Dose / conc.:
500 ppm
Remarks:
BaCl2.H2O, nominal in water
Dose / conc.:
1 000 ppm
Remarks:
BaCl2.H2O, nominal in water
Dose / conc.:
2 000 ppm
Remarks:
BaCl2.H2O, nominal in water
Dose / conc.:
4 000 ppm
Remarks:
BaCl2.H2O, nominal in water
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
Animals were randomly assigned to groups of 10 per dose level after weight-sorting them by sex.
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- All animals were observed twice daily for clinical signs of toxicity.

BODY WEIGHT: Yes
- Body weights were determined weekly

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Water consumptions were measured twice weekly.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: Yes
- Serum electrolyte determination: Blood for serum electrolyte determinations was taken by heart puncture from sodium pentobarbital-anesthetized rats before they were terminated for necropsy. Serium sodium and potassium were measured by flame ion emission using a Coleman Ca-51 fmale photometer. Calcium and phosphorus were measured using a Germeni miniature centrifugal analyzer in conjunction with a Gemeni loader.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- The behavioral test battery consisted of (1) undifferentiated motor activity, (2) forelimb and hindlimb grip strengths, (3) thermal sensitivity to a 55°C water bath, (4) startle response to acoustic and air-puff stimuli, and (5) hindlimb foot splay. These tests were performed on each animal at 0, 45 to 48, and 91 days of exposure and were performed sequentially in the above mentioned order. For the activity measurements, the movements of each animal were monitored electronically for 30 min. Grip strength and foot splay results were averaged after three trials while thermal sensitivity and startle response tests were conducted one time. The startle response test was repeated up to two times if no response was attained on the first trial.

OTHER:
Reproductive and fertility assessment are discussed in IUCLID section 7.8.1 Toxicity to reproduction.


Sacrifice and pathology:
GROSS PATHOLOGY: Yes
All animals were examined for gross lesions.
HISTOPATHOLOGY: Yes
The tissues of the animals were fixed in neutral-buffered 10% formalin. The brain, liver, right kidney, lung, thymus, right testis, heart, and adrenals were weighed before fixation. Complete histologic exams were performed on 30 or more tissues from animals of the 4000 ppm and the control groups. Tissues were trimmed, embedded in paraffin, sectioned to 6 µm thickness and stained with hematoxylin and eosin for microscopic examination.
Because histopathologic changes were observed in several tissues (thymus, spleen, kidneys, and lymph nodes) from rats in the 4000 ppm group, these tissues were examined from lower dose animals to determine a no-effect level.
Statistics:
Each parameter for which individual values were available was subjected to a linear least 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 deviations or standard errors were calculated from continuous variables. The multiple comparison procedure of Dunnett 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. Temporal and dose-related variations were evaluated using a repeated measures analysis of variance. When a collection of measurements was made on each animal, a multivariate analysis of variance was used to test for simultaneous equality of measurements across dose levels.
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 examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
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.

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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Water consumption was decreased in rats at some dose levels. Rats consumed approximately 70%.

NEUROBEHAVIOUR
Compared to their controls, rats exposed to 2000 ppm BaCl2 or lower did not show any consistent changes in behavioral indices (motor activity, fore-and hindlimb grip strength, and thermal sensitivity). Marginal although significant behavioral 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 behavioral effects observed at 4000 ppm level are as follows: decreased undifferentiated motor activity 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.

ORGAN WEIGHTS
Treatment-related depressed liver weights were observed among rats drinking 4000 ppm barium chloride. Absolute kidney weights were elevated in the 1000 and 4000 ppm female rats. Relative kidney weights were elevated among treated rats (males, 4000 ppm; females, 1000 ppm or greater) and mice (4000 ppm). Thymus weights were depressed among high-dose (4000 ppm) female rats who became moribund or died early in the study.

HISTOPATHOLOGY: NON-NEOPLASTIC
Treatment-related lesions associated with the barium chloride toxicity were present in the kidneys. The kidney changes were limited to a few foci of dilated tubules in the outer medulla or medullary rays. Tubular cell regeneration, 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. In one female rat administered 4000 ppm BaCl2, there was moderate degeneration of the myocardium. This lesion was not clearly related to treatment; the morphologic features were similar to those seen in the spontaneously occurring cardiomyopathy (minimal to mild severity) which was present in most treated and control male and female rats in this study.
Dose descriptor:
NOEL
Effect level:
2 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: depressed body weight gains and chemically related lesions in the kidney and lymphoid tissue
Dose descriptor:
NOEL
Effect level:
61.1 mg/kg bw/day (nominal)
Based on:
other: Calculated as Ba2+
Sex:
male
Basis for effect level:
other: Individual effects observed at 2000 ppm barium chloride in drinking water (corresponding to the final barium dose of 61.1 mg Ba/kg bw/day to male rats) were regarded as not treatment-related and this dose levels represents the NOEL.
Dose descriptor:
NOEL
Effect level:
80.9 mg/kg bw/day (nominal)
Based on:
other: calculated as Ba2+
Sex:
female
Basis for effect level:
other: Individual effects observed at 2000 ppm barium chloride in drinking water (corresponding to the final barium dose of 80.9 mg Ba/kg bw/day to female rats respectively) were regarded as not treatment-related and this dose levels represents the NOEL.
Critical effects observed:
not specified
Conclusions:
The no effect level for barium toxicity in this study based on depressed body weight gains and chemically related lesions in the kidney and lymphoid tissue was 2000 ppm BaCl2.2H2O (corresponding to the final barium dose of 61.1 and 80.9 mg Ba/kg bw/day (116.27 and 153.95 mg Ba nitrate/kg/day ) to male and female rats respectively) in the drinking water.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
116.3 mg/kg bw/day
Study duration:
subchronic
Species:
rat

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

Repeated dose toxicity oral - subacute (28-days):

A short-term toxicity study (28 days) does not need to be conducted if a reliable sub-chronic (90 days) or chronic toxicity study is available, provided that an appropriate species, dosage, solvent and route of administration were used (column 2 of Annex VIII of the REACH Regulation, section 8.6.1). As appropriate long-term toxicity information (>=90 days) is available with the read-across substance barium dichloride dihydrate, no short-term toxicity study should be performed with barium nitrate. The read across justification is added in Section 13 of IUCLID.


Repeated dose toxicity oral - Annex IX testing:

A subchronic study was performed by Dietz (1992) in Fischer 344 rats. Males and females (10 per sex and per dose) were exposed to the read-across substance barium chloride dihydrate up to 92 days. The test substance was administered continuously in the drinking water at dose levels of 0, 125, 500, 1000, 2000 and 4000 ppm BaCl2.H2O. The no effect level for barium toxicity in this study based on depressed body weight gains and chemically related lesions in the kidney and lymphoid tissue was 2000 ppm BaCl2.2H2O (corresponding to the final barium dose of 61.1 and 80.9 mg Ba/kg bw/day to male and female rats respectively) in the drinking water.

This study was considered reliable with restrictions (K2) to reflect the read-across status.The read across justification is added in Section 13 of IUCLID.


Other supportive studies:

Borzelleca (1988) performed a short-term study in rats by oral gavage with the read-across substance barium dichloride. In this study was concluded that exposure to barium dichloride up to 209 mg/kg bw produces no significant adverse health effects.

In addition, Tardiff (1980) exposed rats to the read-across substance barium chloride for 4, 8 and 13 weeks. Male and females rats were administered in the drinking water. The no effect level in this study was 250 ppm barium dichloride in the drinking water (38.1 mg/kg bw/day for males and 45.7 mg/kg bw/day for females).

A subchronic study was performed by Dietz (1992) in B6C3F1 mice.

Male and females (10 per sex and per dose) were exposed to the read-across substance barium chloride dihydrate up to 92 days. The test substance was administered continuously in the drinking water at dose levels of 0, 125, 500, 1000, 2000 and 4000 ppm BaCl2.H2O. The no effect level for barium toxicity in this study based on depressed body weight gains and chemically related lesions in the kidney and lymphoid tissue was 2000 ppm BaCl2.2H2O (corresponding to the final barium dose of 164.7 and 165.8 mg Ba/kg bw/day to male and female mice, respectively) in the drinking water

Repeated dose toxicity inhalation: A key study is available for the oral route of exposure. According to the REACH Regulation, only one route of exposure should be tested for repeated dose toxicity (column 2, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the inhalation route of exposure.

Repeated dose toxicity dermal: A key study is available for the oral route of exposure. According to the REACH Regulation, only one route of exposure should be tested for repeated dose toxicity (column 2, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the dermal route of exposure.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

No study available with barium nitrate. The selected study is the most reliable study with read-across substance barium chloride dihydrate assessing oral subchronic exposure.


Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

A key study is available for the oral route of exposure. According to the REACH Regulation, only one route of exposure should be tested for repeated dose toxicity (column 2, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the inhalation route of exposure.


Justification for selection of repeated dose toxicity inhalation - local effects endpoint:

A key study is available for the oral route of exposure. According to the REACH Regulation, only one route of exposure should be tested for repeated dose toxicity (column 2, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the inhalation route of exposure.


Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

A key study is available for the oral route of exposure. According to the REACH Regulation, only one route of exposure should be tested for repeated dose toxicity (column 2, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the dermal route of exposure.


Justification for selection of repeated dose toxicity dermal - local effects endpoint:

A key study is available for the oral route of exposure. According to the REACH Regulation, only one route of exposure should be tested for repeated dose toxicity (column 2, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the dermal route of exposure.

Justification for classification or non-classification

Based on the available data on the read-across substance barium chloride dihydrate and according to the criteria of the CLP Regulation, barium nitrate should not be classified for STOT repeated exposure via the oral route.