Registration Dossier

Administrative data

Description of key information

According to the data requirements as outlined in section 8.6, column 2, Annexes VIII-IX, of Regulation (EC) 1907/2006 a repeated dose toxicity study shall be performed via the most appropriate route of administration, having regard to the likely route of human exposure. However, in case of barium sulfide the inhalation route AND the oral route are considered as the relevant routes of exposures. Adequate repeated dose toxicity studies are available for inhalation of hydrogen sulfide and oral intake of barium chloride dihydrate (see discussion).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
75.5 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
552 mg/m³
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
69.5 mg/m³
Study duration:
subchronic
Species:
rat

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 CONCEPT

Valid toxicological data on sub-acute or sub-chronic exposure specifically for barium sulfide from animal studies are not available. Therefore, because of the lack of appropriate experimental data, read-across from studies with H2S and BaCl2is proposed based on the following reasoning:

 

Read-across to H2S:

The readily water-soluble compound barium sulfide will initially dissociate upon dissolution in water and/or relevant physiological media into barium and sulfide ions.

 

However, sulfide anions will react with water in a pH-dependant reverse dissociation to form hydrogensulfide anions (HS-) or H2S, respectively, according to the following equation:

 

H2S  ↔  H+  +  HS-  ↔  2H+  +  S2-

 

The dissociation behaviour is presented in the Hägg graph reported under IUCLID section 5.1.2 Hydrolysis.

 

The pKa values for the first and second dissociation steps of H2S are 7.0 and 12.9 (for details, refer to the IUCLID section on dissociation constant), respectively. Therefore, at neutral physiological pH values, hydrogen sulfide in the non-dissociated form (H2S) and the hydrogen sulfide anion (HS-) will be present in almost equimolar proportion, whereas only very small amounts of the sulfide anion (S2-) will be present. Conversely, at gastric pH (pH 1-2), non-dissociated H2S will be the predominant species.

 

In conclusion, under physiological conditions, inorganic sulfides or hydrogensulfides as well as H2S will dissociate to the respective species relevant to the pH of the physiological medium, irrespective of the nature of the “sulfide”, which is why read-across between these substances and H2S is considered to be appropriate without any restrictions for the purpose of hazard and risk assessment of barium sulfide.

 

 

Read-across to Ba(OH)2 and BaCl2, respectively:

 

Upon dissolution in water and/or physiological media, dissociation of barium sulfide to release Ba2+ions may initially be expected.

 

However, based on the established fact that barium ions may form poorly soluble species for example with physiologically present carbonate ions, the bioaccessibility/bioavailability may vary between different physiological conditions. Notwithstanding this limitation, it is considered justified to read-across from available data either on barium hydroxide (similar water solubility) and/or barium chloride (higher water solubility), the latter representing a conservative approach). In this context, the water solubility of a substance is used as a first approximation of bioavailability:

 

- barium chloride is highly water soluble with ca. 375 g/L at 20 °C/pH ca. 6.5 (510.4 g/L at pH 1.5)

- barium hydroxide is also highly water soluble (37.4 g/L at 20 °C/pH > 13).

 

In comparison, the water solubility of barium sulfide is 73.5 g/L at 20 °C (pH 13.7; saturated solution).

 

In conclusion, read across from barium chloride and barium hydroxide to barium sulfide is considered as justified since the toxicity of these substances may reasonably be considered to be determined by the availability of barium cations. It is noted that although BaS is a strong base, substantial neutralisation in the gastrointestinal tract at pH-levels of approx. 1.5 – 2 may nevertheless be anticipated.

Repeated dose toxicity, oral

Data - barium:

Comparing the results of the different oral studies it becomes obvious that the findings of all these 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 of61 mg Ba/kg bw/d in male rats and 81 mg/kg bw/d in female ratsand 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 ratscan 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 112 mg BaS/kg bw/d.

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. 75 mg BaS/ 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.

Conclusion - sulfides:

According to the data requirements as outlined in section 8.6, column 2, Annexes VIII-IX, of Regulation (EC) 1907/2006 a repeated dose toxicity study shall be performed via the most appropriate route of administration, having regard to the likely route of human exposure. The inhalation route is considered the most appropriate route for exposure, and repeated dose toxicity studies are available for this route.

The toxicity of sulfide has preferably been assessed for the inhalation route of exposure (by read-across from hydrogen sulfide). Barium sulfide is produced and handled only in industrial settings and the oral exposure route is not considered relevant for workers. Furthermore, there are no professional or consumer uses for barium sulfide that are relevant for Regulation (EC) 1272/2008 (see IUCLID section 3.5). Furthermore, the substance is not present in consumer products (barium sulfide will only be used as intermediate for preparation of tooth paste) and is not released to the environment. Since the oral route of exposure is primarily relevant for the general population and any exposure of general population to barium sulfide is negligible for the above mentioned reasons, the conduct of any new animal studies for repeated dose toxicity by oral route is not required.

Repeated dose Toxicity, inhalation

Conclusion - barium:

According to the regulation (EC) 1907/2006 testing on long term inhalation toxicity is considered not being scientifically justified, since barium sulfide is classified as corrosive to skin and eye based on pH effect (10% solution results in pH 12.4). Therefore, the assumption has to be made that the substance is also corrosive to the respiratory tract.

Nevertheless, relevant DNELs for long term inhalation toxicity for local AND systemic effects were derived based on studies conducted with barium compounds (see “toxicological information”).

Data - sulfides:

The 90-day inhalation study by Dorman et al. (2004) in Fischer 344 rats, Sprague-Dawley rats and B6C3F1 mice is considered to represent the most reliable study for the derivation of NOAEC values. This study, performed in conformity with GLP regulations, is considered to be of an adequate test design and quality. Different toxicological endpoints were evaluated in rats and mice of both sexes following exposure to hydrogen sulfide without signs of systemic toxicity. When comparing the results of the reliable sub-chronic studies in rats and mice, it becomes obvious that the findings of these inhalation studies are not contradictory. Brennemann et al. (2000), Moulin et al. (2002) and Dorman et al.(2004) found similar targets of toxicity.

 

Taken into consideration the key study, an NOAEC of 10 ppm H2S (~14 mg/m3 air) for local effects was derived, which is based on an increased incidence of olfactory neuronal loss (ONL) at 30 and 80 ppm of hydrogen sulfide. Regarding systemic toxicity, some minor effects on food consumption and body weight were observed, but exposure did not result in toxicologically relevant alterations in haematological indices, serum chemistry or gross pathology. Therefore, the concentration of 80 ppm H2S (111 mg/m3 air) can be considered as NOAEC for systemic effects that is re-calculated to 552 mg BaS/m3 air.

Repeated dose toxicity, dermal

Conclusion - barium sulfide:

Repeated dose toxicity testing via the dermal route is not required for barium sulfide since the physico-chemical and toxicokinetic properties do not suggest any potential for a significant rate of absorption through the skin. It can safely be anticipated that there will be no systemic risk in case of dermal short-term exposure to barium sulfide.

Taking into consideration the physico-chemical properties of barium sulfide (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 sulfide. 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 sulfide, leading to the anticipation of a negligible toxicity via the dermal route (see IUCLID section 7.1 of this technical dossier).

According to Regulation (EC) 1907/2006, the repeated dose toxicity study, dermal shall be performed only if inhalation of the substance is unlikely, skin contact in production and/use is likely and the phys. -chem. and toxicological properties suggest potential for a significant rate of absorption through the skin. Barium sulfide is not used in consumer products (barium sulfide will only be used as intermediate for preparation of tooth paste) and due to the fact that the substance is classified as corrosive (pH 12.4; 10 % solution), the worker have to use adequate gloves and protection equipment (see IUCLID section 11 “guidance on safe use”). Thus, since skin contact essentially needs to be minimised because of the protection against corrosivity, quantitatively relevant exposure and absorption through skin are not expected under conditions of normal handling and use, so that no chronic dermal toxicity study is required. Furthermore, based on the corrosive action of barium sulfide on skin, testing on intact skin is not feasible for obvious reasons.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Relevant studies (Dietz, 1992 and NTP, 1994) for repeated dose toxicity, oral route performed with barium chloride dihydrate are available that results in an NOAEL of 61 mg Ba/kg bw/d.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
The 90-day inhalation toxicity studies with exposure of rats and mice to hydrogen sulfide (Dorman et al., 2004) results in no toxicologically relevant alterations in haematological indices, serum chemistries, or gross pathology. Therefore, the highest concentration of 80 ppm H2S may be considered as NOAEC for systemic effects.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
When comparing the results of the available sub-chronic studies in rats and mice, it becomes obvious that the findings of these inhalation studies are not contradictory. Brennemann et al. (2000), Moulin et al. (2002) and Dorman et al. (2004) found similar targets of toxicity. The main adverse effect caused by 30 and 80 ppm hydrogen sulfide was an exposure-related increased incidence of olfactory neuronal loss (ONL). Thus, the concentration of 10 ppm H2S represents an NOAEC for local effects in the olfactory system.

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 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 hydroxide 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 Ba(OH)2/kg bw/day, and the guidance value for a Category 2 classification of 10 <C <100 mg Ba(OH)2/kg bw/day are not met. Based on a “weight of evidence” approach the mean NOAEL for sub-chronic toxicity is 75.5 mg BaS/kg bw/d.

Repeated dose toxicity, dermal

(i) Based on physico-chemical properties of barium sulfide and the toxicokinetic behaviour (very limited penetration into the upper epithelial layers of the epidermis) there is no systemic risks to humans with respect to dermal exposure to sodium sulfide.

(ii) One may assume a conservative default of 1% for dermal absorption of barium sulfide, leading to the anticipation of a negligible toxicity via the dermal route.

(iii) No risk is expected for workers due to the fact that the substance is classified as corrosive (pH 12.4; 10 % solution) and risk management measures are in place (worker have to use sufficient gloves and protection equipment, see IUCLID section 11 “guidance on safe use”). Thus, skin contact is unlikely and therefore absorption through skin, if any, is only possible in case of an accident.

Thus, it may be concluded that there will be no systemic risks to humans with respect to dermal exposure to barium sulfide, and no classification for specific target organ toxicant (STOT) – repeated exposure, dermal is required.

Repeated dose toxicity, inhalation

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.

Since classification as corrosive to respiratory tract is proposed for barium sulfide and due to the lack of substance specific data for barium sulfide (animal welfare -- corrosive substance) no further classification for specific target organ toxicant (STOT) – repeated exposure, inhalation is required for barium sulfide.