Barium sulfate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
Further information is included as attachment in Section 13.

Cross-reference

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

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.

Reason / purpose for cross-reference:

reference to same study

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

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
No further information on the test animals was stated.

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.
No further information on details on oral exposure was stated.

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.

Dose / conc.:

4 000 ppm

Remarks:

nominal in water

Dose / conc.:

2 000 ppm

Remarks:

nominal in water

Dose / conc.:

1 000 ppm

Remarks:

nominal in water

Dose / conc.:

500 ppm

Remarks:

nominal in water

Dose / conc.:

125 ppm

Remarks:

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

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

No further information on observations and examinations performed and frequency was stated.

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.
No further information on sacrifice and pathology were stated.

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.

Clinical signs:

no effects observed

Description (incidence and severity):

No clinical signs were oberved.

Mortality:

mortality observed, treatment-related

Description (incidence):

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 changes:

effects observed, treatment-related

Description (incidence and severity):

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.

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

Description (incidence and severity):

Rats in the 4000 ppm groups consumed 70% of in comparison to the controls. It is not clear whether the effects are toxicity related or due to palatability.

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

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.

Urinalysis findings:

not specified

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

Compared to their controls, rats exposed to 2000 ppm BaCl2 or lower did not show any consistent changes in behavioural 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.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

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. Thymus weights were depressed in the high dose female rats.

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

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.

Histopathological findings: neoplastic:

not specified

Dose descriptor:

NOAEL

Effect level:

2 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Dose descriptor:

NOAEL

Effect level:

80.9 mg/kg bw/day (nominal)

Based on:

element

Remarks:

as Barium

Sex:

female

Basis for effect level:

other: calculated as Ba2+

Dose descriptor:

NOAEL

Effect level:

61.1 mg/kg bw/day (nominal)

Based on:

element

Remarks:

as Barium

Sex:

male

Basis for effect level:

other: calculated as Ba2+

Critical effects observed:

not specified

Conclusions:

The NOAEL for barium toxicity in this study is based on depressed body weight gains, elevated phosphorus levels, neurobehavioural 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.

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Barium sulfate

EC Number:

231-784-4

EC Name:

Barium sulfate

Cas Number:

7727-43-7

Molecular formula:

BaO4S

IUPAC Name:

barium sulfate

Test material form:

solid: particulate/powder

Results and discussion

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

2 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: See 'remark'

2

Dose descriptor:

NOAEL

Effect level:

80.9 mg/kg bw/day (nominal)

Based on:

element

Remarks:

as Barium

Sex:

female

Basis for effect level:

other: The NOAEL for barium toxicity in this study is based on depressed body weight gains, elevated phosphorus levels, neurobehavioural effects and chemically related lesions in the kidney and lymphoid tissue at the highest dose level of 4000 ppm.

3

Dose descriptor:

NOAEL

Effect level:

61.1 mg/kg bw/day (nominal)

Based on:

element

Remarks:

as Barium

Sex:

male

Basis for effect level:

other: The NOAEL for barium toxicity in this study is based on depressed body weight gains, elevated phosphorus levels, neurobehavioural effects and chemically related lesions in the kidney and lymphoid tissue at the highest dose level of 4000 ppm.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Based on a read-across from barium chloride, the NOAEL of barium sulfate is ≥ 104 mg/kg bw/day

Executive summary:

The NOAEL for barium toxicity in this study is based on depressed body weight gains, elevated phosphorus levels, neurobehavioural effects and chemically related lesions in the kidney and lymphoid 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 sulfate 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 sulfate is ≥ 104 mg/kg bw/day based on the nominal test item application.