Barium sulfate

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

104 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

Repeated dose toxicity, oral:

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 level therefore represents the NOAEL.

Read-across from BaCl₂to BaSO₄

The toxicity of barium sulfate and barium chloride may reasonably be considered to be determined by availability of Ba²⁺cations. As a first surrogate for bioavailability, the water solubility of a test substance may be used. Barium chloride is highly water soluble with ca. 375 g/L at pH ca. 6.5 (pH of artificial sweat solution), whereas barium sulfate is poorly soluble (3.1 mg/L at pH 9). Hence, any read across from barium chloride to BaSO₄is inherently very conservative.

Repeated dose toxicity, dermal:

Taking into consideration the physico-chemical properties of the barium compounds under consideration (especially the low water solubility of the substance), 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 is concluded that there will be no systemic risks to humans with respect to dermal exposure to barium sulfate. 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:

The available inhalation studies only provide tentative information on the health effects of barium because all studies have a number of limitations and deficiencies. Inhalation exposure of rats to 40 mg/m³barium sulfate for 2 months resulted in an increased barium content in lungs and bone tissue. In addition, changes of the bronchiolar epithelium and proliferation of alveolar macrophages were observed (Holusa et al., 1973). A diffuse thickening of the interalveolar septa of the lungs and a marked reaction of the lymphoid tissue of the bronchi, with hypertrophy and hyperplasia of the peribronchial tissue and lymph nodes, were reported after inhalation of 250-300 mg/m³barium sulfate or baryte dusts for 6 months (Rumyantsev, 1963).

Nevertheless, the studies only investigated selected endpoints of chronic toxicity after exposure for time periods between two and 6 months. None of these studies established concentration-response relationships of the adverse effects, thus the determination of a concentration without effect (no-observed-adverse-effect concentration, NOAEC) in order to provide a basis for quantitative risk assessment purposes was not possible.

However, five reports of occupational exposure to barium sulfate have been identified. In one study (Doig 1976) a benign pneumoconiosis was observed in several workers exposed to barium sulfate, in other studies (i.e. Seaton et al. 1986) no barium-related alterations in the respiratory tract of workers exposed to barium sulfate could be observed.

It is explicitly noted that due to that exposure to barium sulfate via inhalation may cause baritosis in humans, but only when exposed to high concentrations. Baritosis does not produce any abnormal physical signs, incapacity for work, interference with lung function or any liability to develop pulmonary or bronchial infection or any other thoracic disease. Therefore, and in accordance with regulation (EC) 1907/2006 Annex XI, neither a testing proposal for a sub-chronic nor a chronic repeated dose toxicity study is included in the registration dossier of barium sulfate since the available data are sufficient to evaluate the toxic potential of the substance registered.

Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: lymph nodes; urogenital: kidneys

Justification for classification or non-classification

Repeated dose toxicity, oral:

The reference Dietz (1992) is considered as the key study for repeated dose toxicity via oral application and will be used for classification. Rats were dosed at 61.1 and 80.9 mg Ba2+ /kg bw/day to male and female rats via feed for 90 days. The values refer to 104 and 138 mg/kg bw/day. 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. Individual effects observed were regarded as non treatment-related.

 

The classification criteria according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – repeated exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and the no observed adverse effect level (NOAEL) via oral application is above the guidance value for a Category 1 classification of 10 mg BaSO4/kg bw/day and above the guidance value for a Category 2 classification of 100 mg BaSO4/kg bw/day. For the reasons presented above, no classification for specific target organ toxicant (STOT) – repeated exposure, oral is required.

 

Repeated dose toxicity, dermal:

According to Annex VIII, point 8.6.1, column 2 of Regulation No 1907/2006, information on sub-chronic toxicity testing via the dermal route shall be provided if (1) inhalation of the substance is unlikely; and (2) skin contact in production and/or use is likely; and (3) the physicochemical and toxicological properties suggest potential for a significant rate of absorption through the skin.

For barium sulfate, inhalation can be anticipated. Therefore, provision (1) of Annex VIII, point 8.6.1 is not fulfilled. Testing of sub-chronic toxicity testing via the dermal route is therefore not required.

Furthermore, following the HERAG guidance for metals and metal salts (see section 7.1.2), a dermal absorption rate in the range of maximally 0.1-1.0 % can be anticipated. Dermal absorption in this order of magnitude is not considered to be “significant”. Therefore, also provision (3) of Annex VIII, point 8.6.1 is not fulfilled.

In conclusion, testing for sub-chronic toxicity testing via barium sulfate via the dermal route is not required according the criteria laid down in Annex VIII, point 8.6.1. It can safely be anticipated that there will be no systemic risk in case of dermal long-term exposure to barium sulfate. Additional toxicity studies are not expected to provide further information, thus there is no need for any further repeated dose testing.

For the reasons presented above, no classification for specific target organ toxicant (STOT) – repeated exposure, dermal is required.

 

Repeated dose toxicity, inhalation:

The rat is uniquely sensitive to lung damage when exposed under conditions of particle overload to poorly soluble low-toxicity particles such as barium sulfate or others. Although particle overload is observed in other experimental species such as the mouse, it is only in the rat that a sequence of events is initiated that may lead to fibroproliferative disease, septal fibrosis, hyperplasia and eventually lung tumours. However, similar pathological changes are not observed in exposed humans, and detailed epidemiological investigations have shown no causative link between barium sulfate exposure and the risk of non-malignant respiratory disease in humans.

 

According to regulation (EC) 1272/2008, a classification for specific target organ toxicity – repeated exposure shall be taken into account only when reliable evidence associating repeated exposure to the substance with a consistent and identifiable toxic effect demonstrates support for the classification. These adverse health effects include consistent and identifiable toxic effects in humans, or, in experimental animals, toxicologically significant changes which have affected the function or morphology of a tissue/organ, or have produced serious changes to the biochemistry or haematology of the organism and these changes are relevant for human health.

 

In this context, the following observations have been made in experimental animals and in human epidemiological studies:

(i)     No systemic toxicity was shown to result from long term inhalation exposure in humans to high concentrations of barium sulfate

(ii) Particle overload is observed for insoluble particles such as barium sulfate, whereby the rat is the most sensitive species studied, and species-specific differences are demonstrated in various mechanistic animal studies (Oberdörster, 1996). It has been demonstrated with reasonable certainty that lung overload conditions are not relevant for human health and, therefore, results based on these data do not justify classification.