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Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
114 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

Read-across BaCl2to Ba(OH)2

Repeated dose toxicity, oral

There are no reliable studies for the repeated dose toxicity via the oral route conducted with Ba(OH)2available. However,the toxicity of barium hydroxide 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. 263 g/L at pH ca. 6.5 (and 510.4 g/L at pH 1.5). Also the water solubility of barium hydroxide is high (37.4 g/L at pH > 13). Hence, any read across from barium chloride to barium hydroxide is considered to be justified and will lead to rather equal effect levels.It is noted; although Ba(OH)2is a strong base (pH 13 for a 10% solution) it will be neutralised within thegastrointestinal tract (pH approx. 1.5 - 2).

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 ratsand 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 114 mg/kg bw/d for barium hydroxide.

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. 77 mg Ba(OH)2/ 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

According to regulation (EC) 1907/2006 Annex XI (weight of evidence) and Annex VIII column 2 (repeated dose toxicity), testing for sub-chronic dermal toxicity is not considered to be required, for the following reasons:

-                     Repeated dose toxicity study via dermal route does not need to be performed since the physico-chemical and toxicological properties do not suggest potential for a significant rate of absorption through the skin.

-                     The substance is classified as corrosive to skin. Due to animal welfare reasons testing is not allowed. A qualitative approach for hazard assessment was chosen.

Repeated dose Toxicity, inhalation

According to the regulation (EC) 1907/2006 testing on long term inhalation toxicity is considered not being scientifically justified. Barium hydroxide is classified as corrosive by worst case. Therefore, the assumption has to be made that the substance is also corrosive to the respiratory tract. Due to animal welfare testing is not foreseen. However, for risk assessment purposes a DNEL for acute inhalation toxicity, local effects is used based on the available IOEL of 0.5 mg Ba2+/m3for soluble barium compounds. A STEL (15 min) was also calculated based on the IOEL (0.5 mg Ba2+/m3). In conclusion, there is no need to initiate testing on long term inhalation toxicity and derogation is considered to be justified.


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

Justification for classification or non-classification

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 114 mg Ba(OH)2/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