Barium oxide, obtained by calcining witherite

Endpoint summary

Description of key information

Repeated Dose 90-day Oral Toxicity Study (NTP, 1990): NOAEL (rat) = 65 mg/kg bw/day, NOAEL (mouse) = 100 mg/kg bw/day, test substance BaCl2*2H2O

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

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.

Reason / purpose for cross-reference:

reference to same study

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

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

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.

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.

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

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.

Dose descriptor:

NOAEL

Effect level:

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

Based on:

other: drinking water consumption

Sex:

male

Dose descriptor:

NOAEL

Effect level:

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

Based on:

other: drinking water consumption

Sex:

female

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.

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.

Critical effects observed:

not specified

see attached document

 

 

 

 

 

 

 

 

 

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.

Endpoint conclusion

Dose descriptor:

NOAEL

65 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

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, is well documented and both rats and mice were tested.

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

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. Several repeated dose toxicity studies are available for BaCl₂.

Animal data:

 A set of studies sponsored by NTP assessed barium toxicity upon administration of 0, 125, 500, 1000, 2000, or 4000 ppm barium chloride dihydrate in the drinking water to both rats and mice. Toxicity was tested in a 15-day rangefinder study, a 90-day study conducted equivalent to OECD TG 408 and a 2-year cancer study similar to OECD TG 451 (for summary of the cancer data, please refer to chapter 7.7).

In the 15-day study, rats were dosed with up to 2000 ppm, mice with up to 692 ppm barium chloride dihydrate in drinking water. No adverse effects were observed at any dose level tested.

In the 90-day study, administration of 4000 ppm barium chloride dihydrate resulted in nephropathy and increased mortality, paired with decreased body weights in both rats in mice. At 2000 ppm, both male and female rats did not show increased mortality or clinical signs of toxicity. Changes were still observed in the absolute and relative kidney weights in females, however without histopathological findings. Therefore, the NOAEL for barium chlorid dihydrate was set at 1000 ppm in rats, corresponding to 65 mg/kg bw/day based on average drinking water consumption. In mice dosed with 2000 ppm, no increased mortality or nephropathy were observed, however the liver and thymus weights were reduced, therefore also in mice the NOAEL for barium chloride dihydrate was set at 1000 ppm, corresponding to 100 mg/kg bw/day. 

Another study exposed both mice and rats to the same concentrations of barium chloride for 92 days (Dietz et al., 1992). The study was conducted similar to OECD TG 408, however the data reporting is incomplete. The authors of this publication also found that exposure of animals to 4000 ppm barium chloride led to increased mortality and nephropathy. In accordance with the NTP study, female rats receiving 2000 ppm test substance showed increased kidney weights without histopathological findings. In mice, females dosed with 2000 ppm barium chloride had decreased liver weights at necropsy, which did not correlate with histopathological lesions. Therefore, the NOAEL for barium chloride was determined at 1000 ppm. Since drinking water consumption of the animals strongly decreased throughout the course of the study, the absolute concentration of barium consumed cannot be deducted from the data at hand.

A third study tested 10, 50, and 250 mg barium/L as BaCl₂, given in the drinking water for 13 weeks to Charles River rats. None of the dose levels resulted in significant chemical-related changes upon necropsy.

Since barium is most likely the toxophore in both barium chloride dihydrate and barium oxide and since barium chloride dihydrate has an about ten times higher solubility in water, it can be assumed that the LOAEL for barium oxide in terms of barium toxicity would be equal or higher. For details on comparability of barium oxide and barium chloride dihydrate, please refer to the weight-of-evidence justification.

Human data:

One systematic repeated dose study exists in which 18 welders were exposed to barium fumes from arc welding of barium-containing metals for one week. The group with the highest exposure showed average barium fume levels of 4.4 mg/m3 barium in the breathing air. Continuous biomonitoring showed that plasma and urine barium levels peaked at the end of a shift, whereas they were decreased again the next morning. The baseline plasma and urine barium levels increased over the course of one week, but were again in the range of the baseline values after a free weekend (2 days without barium exposure). The symptoms recorded throughout the study time could all be traced back to pre-existing conditions and were not related to barium exposure. Thus, levels of 4.4 mg/m³with intermittent peaks in barium fume exposure were well tolerated and did not lead to signs of barium intoxication.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Study with design similar to OECD TG 408. Robust study summary available.

Justification for classification or non-classification

The present data on repeated dose toxicity do not fulfill the criteria laid down in Regulation (EC) 1272/2008 (CLP), and therefore a non-classification is warranted.