Registration Dossier

Administrative data

Description of key information

Reliable studies via the oral route are available for 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

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
139 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

Repeated dose toxicity, oral, rat

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 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 ratsand 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 139 mg/kg bw/d for barium chloride.

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. 94 mg BaCl2/ 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 (see below).

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, rat

According to regulation (EC) 1907/2006 Annex XI (weight of evidence)testing on sub-chronic inhalation toxicity is not considered being required. BaCl2is 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 BaCl2a 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 selection of repeated dose toxicity via oral route - systemic effects endpoint:
The results of the study performed by Dietz et al (1992) and NTP (1994) using barium dichloride dihydrate as test substance are not contradictory, and in both investigations similar target organs of toxicity were found and no differences in susceptibility of gender was seen. Both studies (RL1 and RL2, respectively) were used in a weight of evidence approach.

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 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 139 mg BaCl2/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