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

Endpoint summary

Description of key information

Repeated dose toxicity oral calculated from read across substance barium chloride:
• key study, subchronic (90 d), oral, Fischer 344 rats; NOAEL ≥ 104 mg/kg bw/d (no guideline followed, Dietz et al., 1992)
• supporting study, subchronic (90 d), oral, Fischer 344 rats; NOAEL ≥ 188 mg/kg bw/d (no guideline followed, Anonymous, NTP 1994)
Repeated dose toxicity inhalation:
no data
Repeated dose toxicity dermal:
no data

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. Data and rating according to the SIDS 2005 on barium carbonate.

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

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.

Remarks:

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

Remarks:

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

Remarks:

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

Remarks:

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

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

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.

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.

Dose descriptor:

NOAEL

Effect level:

2 000 ppm

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Dose descriptor:

NOAEL

Effect level:

80.9 mg/kg bw/day (nominal)

Sex:

female

Basis for effect level:

other: calculated as Ba2+

Dose descriptor:

NOAEL

Effect level:

61.1 mg/kg bw/day (nominal)

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, 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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

104 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

There are reliable in vivo studies available to assess the potential of the analogous test substance barium dichloride dihydrate for repeated dose toxicity after oral administration.

For read-across barium chloride is adopted as it is also an inorganic barium salt whose relevant eco-/toxicological nature depends on the common cation barium whereas the toxicological nature of the anion is negligible. The substances differ in solubility. Barium chloride is soluble while barium titanium trioxide is slightly soluble. But this difference is considered as negligible as it is supported by the absence of any adverse findings in acute toxicity for the analogue substance. In conclusion, read-across for the endpoint repeated dose toxicity is justified.

 

Repeated dose toxicity oral:

In a non guideline conform study the potential of the analogous test substance barium dichloride dihydrate (purity: >99.5 weight-%) to assess repeated dose toxicity after oral ingestion was carried out using 10 Fischer 344 rats per sex and dose level (Dietz et al., 1992). The test substance was given for 92 days to the rats in their drinking water in the following concentrations: 0, 125, 500, 1000, 2000 and 4000 ppm. No clinical signs were observed. Three of 10 male and 1 of 10 female rats in the 4000 ppm groups died during the last week of the study. Body weights of both sexes in the highest dose group (4000 ppm) were significantly (p< 0.05) lower than the controls. Rats in the 4000 ppm groups consumed 70 % of water related to controls. It is not clear whether the effects are toxicity related or due to palatability. Liver weights of the rats received from the highest dose group (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 of males and 1000 ppm or greater of 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.

In the male rats, there was a significant elevation in phosphorous in the dose group 1000, ppm and higher compared to the controls. In the female rats, a significant elevation in phosphorous was seen in the 500 ppm dose groups and higher. The biological significance of the changes in females is regarded as marginal due to lower as expected control values.

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 histopathological effects in the brain or other tissues of rats.

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 hind limp 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 dose group 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 hind limb foot splay.

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

According to the results of the present study, the NOAEL of the test substance barium dichloride dihydrate can be derived to be 2000 ppm barium dichloride dehydrate (corresponding to the final barium dose of 61.1 and 80.9 mg Ba2+/kg bw/day to male and female rats respectively) under the experimental conditions chosen here. Therefore, based on the NOAEL of 61.1 mg Ba2+/kg bw/day for male rats, the NOAEL of barium calcium zirconium titanate is ≥ 104 mg/kg bw/day (calculated from its molecular weight).

 

In another non guideline conform study the potential of the analogous test substance barium dichloride dihydrate (purity: >99 weight-%) to assess repeated dose toxicity after oral ingestion was carried out using 10 Fischer 344 rats per sex and dose level (Anonymous, NTP 1994).

The test substance was given for 91 days (13 weeks) to the rats in their drinking at concentrations of 0, 125, 500, 1000, 2000 and 4000 ppm corresponding to average daily doses of 10, 30, 65, 110 or 200 mg barium/kg body weight to males and 10, 35, 65, 115 or 180 mg barium/kg body weight to females. No chemical-related clinical findings of toxicity were noted.

Three males and one female that received 4,000 ppm died during the last week of the study. The cause of these deaths was not apparent histological, but deaths were considered to be chemical-related. The final mean body weights and mean body weight gains of male and female rats receiving 4,000 ppm were significantly lower than those of the controls (final mean body weights: 13% and 8% lower; mean body weight gains: 18% and 24% lower).

Water consumption by male and female rats that received 4,000 ppm was lower than that of controls; these groups consumed approximately 70% of that consumed by the controls.

Serum phosphorus levels in males receiving 2,000 ppm and more and in females receiving 500 ppm and more were significantly higher than those in controls. Elevations in serum phosphorus levels may have been caused by renal tubule damage. However, due to the minimal to mild severity of this lesion, it is more likely that the elevated values were due to an artefact from haemolysis of collected blood samples. Significantly decreased sodium levels in 4,000 ppm male rats and calcium levels in 1,000 ppm males did not occur in a dose-related manner and thus were not considered to be clearly related to barium chloride dihydrate exposure.

A slight but significant decrease in undifferentiated motor activity in rats that received 4,000 ppm was observed at day 90 of the study. A marginal decrease in this parameter was observed at day 90 of the study in all other exposed groups of rats except in 1,000 ppm females.

The absolute and relative kidney weights of females that received 2,000 and 4,000 ppm and the relative kidney weight of males that received 4,000 ppm were significantly greater than those of the controls and were associated with chemical-induced renal lesions. The differences in the absolute and/or relative weights in other organs could be attributed to the decrease in mean body weights observed in 4,000 ppm male and female rats.

Chemical-related kidney lesions occurred in three male and three female rats receiving 4,000 ppm. None were observed in the controls or in any of the remaining exposure groups.

Microscopically, 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. The tubule epithelial cells were usually low cuboidal cells with a decreased cytoplasmic volume, yet they contained a nucleus of typical size. Tubule dilatation observed in this study was different from the common spontaneous lesions observed in the kidney of rats. In this study, early lesions of nephropathy were observed in virtually all males and in small numbers of females in all treatment groups as well as the controls.

Based on the final mean body weights, mean body weight gains, decreased water consumption, mortality, and renal toxicity the NOAEL for barium dichloride dihydrate in drinking water for rats was estimated to approximately 2000 ppm. The dose of 2000 ppm corresponds to NOAEL values of 110 and 115 mg Ba/kg bw/d to male and female rats, respectively.

Therefore, based on the NOAEL of 110 mg Ba2+/kg bw/day for male rats, the NOAEL of barium calcium zirconium titanate is ≥ 188 mg/kg bw/day (calculated from its molecular weight).

 

In conclusion barium calcium zirconium titanate is considered not to be toxic after repeated dose in subchronic oral repeated dose toxicity studies with rats.

Repeated dose toxicity - inhalation:

We propose a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) as we also propose a developmental toxicity study. This study would be appropriate to conduct to reduce the number of animals.

Repeated dose toxicity - dermal:

The study to test dermal repeated dose toxicity does not need to be conducted as dermal absorption is not the relevant route. Skin contact in production and/or use is unlikely and the physicochemical and toxicological properties suggest no potential for a significant rate of absorption through the skin.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; neurologic: behaviour; urogenital: kidneys

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008:

Based on the results, the classification of the test substance for repeated dose toxicity under Regulation 1272/2008 is not warranted.