Barium oxide, obtained by calcining witherite

Repeated dose toxicity: oral

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: see 'Remark'

Remarks:

BaO rapidly hydrolyzes to Ba(OH)2, a strongly alkaline substance, upon contact with water. Barium chloride dihydrate as well soluble barium salt was used to assess the potential of BaO to cause barium toxicity. The study was performed similar to OECD TG 408 and a detailed study report is available.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1994

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

10326-27-9

EC Number:

600-412-6

Cas Number:

10326-27-9

IUPAC Name:

10326-27-9

Constituent 2

Reference substance name:

barium chloride dihydrate

IUPAC Name:

barium chloride dihydrate

Details on test material:

- Name of test material (as cited in study report): barium chloride dihydrate
- Molecular formula (if other than submission substance): BaCl2*2H2O
- Molecular weight (if other than submission substance): 244.28
- Physical state: white crystalline granule or powder
- Analytical purity: >99%
- Lot/batch No.: 123120 (material was obtained from JT Baker Chemical Company)
- Stability under test conditions: at least 3 weeks, test material was prepared weekly
- Storage condition of test material: in the dark at 25°C

Test animals

Species:

rat

Strain:

other: F344/N

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Simonsen Laboratories Inc. (Gilroy, CA)
- Age at study initiation: 43 days
- Weight at study initiation: 356 +/- 8 g (males), 194 +/- 3 g (females)
- Fasting period before study: none
- Housing: 5 animals per cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 11 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-24°C
- Humidity (%): 40-62%
- Air changes (per hr): 13.5 changes/hour
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Remarks:

distilled drinking water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: weekly

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Dose formulations were analytically tested twice, once at initiation and once mid-way through the study. The test substance content of the drinking water was within 1% of the target concentration at initiation of the study. Analytical testing midway through the study revealed 1-6% variation of the test substance concentration from the target concentration, increasing with prolonged storage. The maximum variation of 6% from target concentration was observed 1 week after substance preparation.

Duration of treatment / exposure:

The animals were treated with drinking water containing the test substance for 90 days, 7 days a week.

Doses / concentrations

Remarks:

Doses / Concentrations:
125, 500, 1000, 2000, 4000 ppm
Basis:
nominal in water

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: A preliminary study with rats receiving 2000 ppm for 15 days in the drinking water revealed no significant toxicological effect, therefore the doses for the 13 week-study were set at 4000 ppm, 2000 ppm, 1000 ppm, 500 ppm, 125 ppm and 0 ppm. These doses were estimated to deliver 200, 110, 65, 30, and 10 mg/kg bw to males and 180, 115, 65, 35, and 10 mg/kg bw to females.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: weekly, by cage

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at necropsy
- How many animals: all
- Parameters examined: hematocrit, hemoglobin, erythrocytes, mean erythrocyte volume, mean erythrocyte hemoglobin, mean erythrocyte hemoglobin concentration, platelets, nucleated erythrocytes, and leukocyte count and differential

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at necropsy
- Animals fasted: No data
- How many animals: all
- Parameters examined: barium, sodium, potassium, calcium, and phosphorus

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: 0, 45, 90 days
- Dose groups that were examined: all
- Battery of functions tested: sensory activity / grip strength / motor activity / other: thermal sensitivity / acoustic and air-puff startle response / hindlimb foot splay

OTHER:

CARDIOVASCULAR STUDIES:
- Time schedule for examinations: 0, 45, 90 days
- Dose groups that were examined: all
- Parameters examined: heart rate / systolic arterial pressure measurements / analysis of electrocardiogram recordings.

Sacrifice and pathology:

GROSS PATHOLOGY: organ weights

HISTOPATHOLOGY (only 4000 ppm group): adrenal gland, brain, epididymis, esophagus, heart, kidney, large intestine (cecum, colon, rectum), liver, lung, mammary gland, mandibular lymph node, mesenteric lymph node, nose, ovary, pancreas, parathyroid gland, pituitary gland, prostate gland, salivary gland, seminal vesicle, skin, small intestine, spleen, sternebrae (including marrow), stomach, testis, thyroid gland, trachea, thymus, urinary bladder, and uterus.
2000 ppm group all animals: kidney, liver, spleen, and thymus
2000 ppm group (females): in addition adrenal gland, heart, and salivary gland

Results and discussion

Results of examinations

Details on results:

All treated animals showed a slight decrease in undifferentiated motor activity at day 90, which was not dose-responsive. The authors reported findings of early kidney lesions in "virtally all males and in small number of females" in all treatment groups, including controls.

Animals in 4000 ppm group showed increased mortality (30% in males and 10% in females), reduced water consumption and reduced body weight increase combined with significant organ weight changes and histopathological signs of nephropathy. Clinical chemistry showed increased phosphorus levels at d90, however the authors conclude that this finding is most likely due to hemolysis of collected blood samples. Decreased serum sodium levels were observed in the 4000 ppm group and decreased serum calcium was measured in the 1000 ppm treatment group. These findings did not occur in a dose related manner; they were thus not considered to be treatment-related. Three male and three female animals in the high dose group showed chemical-induced lesions in the kidney, paired with increased relative and absoulte kidney weights: "the kidney lesions appeared as a minimal to mild, focal to multifocal dilatation of the proximal convoluted tubules in the outer medulla and the renal cortex". Small numbers of male and female animals also showed mild atrophy of the spleen and/or thymus.

Animals in 2000 ppm group did not show any clinical signs of toxicity or increased mortality. Water consumption and body weight increase were comparable to control animals. Clinical chemistry showed increased serum phosphorus levels at d90, however these alterations were not dose responsive and the authors concluded that they are most likely due to hemolysis of collected blood samples. Although female animals did show changes in relative and absolute kidney weight in these treatment groups, these findings could not be supported by histopathological analysis.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

65 mg/kg bw/day (actual dose received)

Based on:

other: drinking water consumption

Sex:

male

2

Dose descriptor:

NOAEL

Effect level:

65 mg/kg bw/day (actual dose received)

Based on:

other: drinking water consumption

Sex:

female

3

Dose descriptor:

LOAEL

Effect level:

110 mg/kg bw/day (actual dose received)

Based on:

other: drinking water consumption

Sex:

male

Basis for effect level:

other: Adrenal gland weights are slightly reduced and serum phosphorus levels are increased.

4

Dose descriptor:

LOAEL

Effect level:

115 mg/kg bw/day (actual dose received)

Based on:

other: drinking water consumption

Sex:

female

Basis for effect level:

other: Absolute and relative kidney weights increased without histopathological lesions. Serum phosphorus levels are increased.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

see attached document

 

 

 

 

 

 

 

 

 

Applicant's summary and conclusion

Executive summary:

BaCl2 shows nephrotoxic effects in a rat 90-day-study at daily intake doses of 180-200 mg barium/kg bw/day in both males and females. Female animals also showed increased kidney weights at 115 mg/kg bw/day, however these data could not be corroborated by histopathological findings. Therefore, a dose of 65 mg/kg bw/day represents the NOAEL for Barium in a 90-day study. The solubility and consequently most likely also the bioavailibility of BaO is lower than that of BaCl₂, therefore it can be assumed that the NOAEL for barium toxicity is equal or greater.