Barium carbonate

Endpoint summary

Description of key information

Reliable studies via the oral route are available for the analogue substance barium dichloride. The main adverse effect caused by barium dichloride was the nephrotoxicity in rats and mice of both sexes. No information via the dermal and inhalation route is available for barium dichloride and other soluble barium substances.

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:

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: 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 quanities 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.

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

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:

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 of Barium carbonate is is ≥ 87.8 mg/kg bw/day

Executive summary:

Read across BaCl2 to BaCO3:

There are no reliable studies for the repeaded dose toxicity via the oral route conducted with BaCO3. However, due to the fact that BaCO3 is soluble in HCl and HNO3 (ATSDR, 2007) solutions (pH value of the gastrointestinal tract pH2) and the toxicity of the substance is dependent on the Ba2+ concentration, read-across to BaCl2 is possible.

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.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

88 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

Read across BaCl2 to BaCO3:

The toxicity of barium substances such as barium carbonate can reasonably assumed to be determined by the availability of barium ions in solution. This was investigated for barium carbonate experimentally in a test for comparative bio-accessibility with barium carbonate and barium chloride in artificial gastric juice (HCl, pH=1.5): an excess of each test item was added to a freshly prepared HCl solutions (pH=1.5) to obtain saturation (for details, please refer to IUCLID section 4.20 “pH” of this dossier). It could be shown that the solubility of barium carbonate in acidic media at 37°C is 3.7 g/L, whereas 510.4 g/L of barium chloride could be dissolved under equal conditions. In consequence, the solubility of barium carbonate under these conditions is more than two orders of magnitude less than that of barium chloride and therefore Ba2+ ions are more bioavailable if barium chloride is adminstered as if barium carbonate. Hence, read-across to barium carbonate based on worst case consideration is justified and will likely lead to rather conservative no-effec levels. Further information on the read-across justification is included as attachment in Section 13.

Repeated dose toxicity, oral

Comparing the results of the different oral studies it becomes obvious that the findings of the studies are not contradictory. The studies conducted by NTP (1994) and Dietz and co-workers (1992) in rats and mice found similar targets of toxicity; although some differences in sensitivity were found. The main adverse effect caused by barium chloride was the nephrotoxicity in rats and mice of both sexes.

The available data in laboratory animals suggest that the toxicity of ingested barium is similar across species. The lowest NOAEL for nephrotoxic effects in rats or mice were identified from the 13-week drinking water study by Dietz et al. (1992) as the NOAEL of 61 mg Ba/kg bw/d in male rats and 81 mg/kg bw/d in female rats and of about 165 mg Ba/kg bw/d in male mice and166 mg Ba/kg bw/d in female mice.

The no-observable-effect concentration of the 13-weeks NTP study (1994) conducted with barium chloride was estimated to be 2000 ppm as based on changes of the final mean body weights, mean body weight gains, mortality, and renal toxicity at 4000 ppm in both species (LOAEL). The dose of 2,000 ppm represents the NOAEL value of this study corresponding to 110 and 115 mg Ba/kg bw/d in male and female rats, respectively, and 205 and 200 mg Ba/kg bw/d in male and female mice, respectively. Thus, the dose of 110 mg Ba/kg bw/d in male rats and 115 mg Ba/kg bw/d in female rats can be regarded as relevant NOAEL for chronic barium toxicity in this 13-week study.

Taken the results for male and female rats from both studies (NTP and Dietz et.al) into consideration, an average NOAEL could safely be calculated at 91 mg Ba/kg bw/d, which results in a re-calculated value of 131 mg/kg bw/d for barium carbonate.

It is explicitly noted that according to the precautionary principle the “worst case value” of 61 mg Ba/kg bw/d (in male rats according to Dietz et al.) is used for the derivation of DNELs. This value refers to approx. 88 mg BaCO3/kg bw/d. However, for classification and labelling purposes it appears appropriate to consider all relevant data on repeated dose oral toxicity. As already mentioned above, the results of the NTP study (1994) and the study performed by Dietz et al. (1992) are not contradictory, and in both investigations similar target organs of toxicity were found and no differences in susceptibility of gender was seen. Therefore, it could safely be stated that the calculation of an average value, using the NOAELs for male and female rats coming from the NTP and the Dietz studies, is considered to be a valid approach for the classification and labelling discussion.

Repeated dose toxicity, dermal

Taking into consideration the physico-chemical properties of the barium compounds under consideration (especially dissociation of the highly soluble compound), the toxicokinetic behaviour (very limited penetration into the upper epithelial layers of the epidermis) and the negative in vitro genotoxicity test results (see section 7.6 of this technical dossier) it may be concluded that there will be no systemic risks to humans with respect to dermal exposure to barium chloride. In addition, applying HERAG (HERAG fact sheet - assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal compounds; EBRC Consulting GmbH / Hannover /Germany; August 2007) methodology, one may assume a conservative default of 1% for dermal absorption of barium ions, leading to the anticipation of a negligible toxicity via the dermal route.

Repeated dose toxicity, inhalation

According to regulation (EC) 1907/2006 Annex XI (weight of evidence) testing on sub-chronic inhalation toxicity is not considered being required. BaCl₂ is highly soluble at a (≥ 375 g/L) pH around 6.5. Therefore, no pH-related local effects need to be assumed upon contact with respiratory tract epithelia, and any lung overload associated with inert particles can obviously be excluded. In consequence, local effects are not anticipated for this substance and only a derivation of a DNEL for long term systemic effects via inhalation is necessary for BaCl₂ (section 7 of the technical dossier).

In accordance to the ECHA guidance on information requirements and chemical safety assessment-chapter R.8: characterisation of dose [concentration]-response for human health, May 2008, a DNEL for systemic effects could be derived by route to route extrapolation. For BaCl₂ a 90-day toxicity study, oral in rats was performed and used for the derivation of a long-term DNEL for systemic effects. This leads to the conclusion that the initiation of a long term inhalation study in rats in not considered to be required.

Justification for classification or non-classification

Repeated dose toxicity, oral:

The results of the NTP study (1994) and the study performed by Dietz et al. (1992) are not contradictory, and in both investigations similar target organs of toxicity were found and no differences in susceptibility of gender was seen. Therefore, it could safely be stated that the calculation of an average value, using the NOAELs for male and female rats coming from the NTP and the Dietz studies, is considered to be a valid approach for the classification and labelling discussion. The results are as follows:

(i) Dietz et al. (1992): NOAEL of 61 mg Ba/kg bw/d in male rats and 81 mg/kg bw/d in female rats

(ii) NTP (1994): NOAEL of 110 mg Ba/kg bw/d in male rats and 115 mg Ba/kg bw/d in female rats

No classification and labelling of barium chloride according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – repeated exposure, oral is necessary, since the guidance value for a Category 1 classification of C ≤ 10 mg BaCl₂/kg bw/day, and the guidance value for a Category 2 classification of 10 < C ≤ 100 mg BaCl₂/kg bw/day are not met. Based on a “weight of evidence” approach the mean NOAEL for sub-chronic toxicity is 131 mg BaCO₃/kg bw/d.

Furthermore, no classification and labelling according to regulation (EC) 1272/2008 are expected for long term oral, dermal and inhalation are expected