Barium m-toluate

Endpoint summary

Description of key information

No repeated dose toxicity study with barium m-toluate is available, thus the repeated dose toxicity will be addressed with existing data on the entities formed upon dissolution of barium m-toluate, namely barium and m-toluate. The hazard assessment will be conducted taking into account the toxicological information for barium and m-toluic acid reported below.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

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

Barium

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 62.0 and 65.3 mg Ba/kg bw/d in male and female rats, respectively. Thus, the dose of 62.0mg Ba/kg bw/d in male rats and 65.3 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 61.5 mg Ba/kg bw/d, which results in a re-calculated value of 93.3 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. 92.5 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.

 

m-toluate

In a combined repeated dose/ reproductive and developmental toxicity test according to OECD guideline 422, 10 male and 10 female SD rats were exposed orally via gavage to 0, 30, 100, 300 and 1000 mg/kg bw/day m-toluic acid for 41 to 45 days.

No deaths were observed in male and female animals in each group.

In males of the 1000 mg/kg bw/day dose group, the following effects were observed: slightly decreased locomotor activity, increased prothrombin time and increased aspartate aminotransferase values. The statistical significantly increased prothrombin time (14.3 sec) is, although being statistical significant, still within the historical control range for that rat strain (13.3 - 16.5 sec, Lee et al. 2012), thus should be regarded as incidental finding with no biological relevance. The slightly decreased locomotor activity is regarded as transient finding, in the absence of further interrelated clinical or pathological findings should be regarded as not biological relevant. The increased aspartate aminotransferase (AST, 77 ±13 IU/L) might indicate a correlation with the histopathological findings in the liver in the female animals, however the value is still well within the historical control range of that rat strain (48.9-122.7 IU/L). Thus, an NOAEL of 1000 mg/kg bw/day was identified for male animals.

In females of the 1000 mg/kg bw/day dose group, the following effects were observed: significant increase of absolute and relative liver weights and periportal hepatocellular vacuolar degeneration. In females of the 300 mg/kg bw/day dose group, periportal hepatocellular vacuolar degeneration was observed with a grading of minimal to moderate severity. Vacuolar degeneration, also termed cell swelling, characterises a reversible cell injury, occurs in most types of acute injury (Ed.: Haschek, WM et al. 2007 Fundamentals in toxicologic pathology, AP; p. 13). In combination with increased liver weight, this is a common finding in animals being exposed to high doses of xenobiotics and commonly reverses if the injurious stimulus is removed (Ed.: Haschek, WM et al. 2007 Fundamentals in toxicologic pathology, AP; p. 201f). In the absence of degenerative cell lesions, such as necrosis or apoptosis, and based on the minimal to mild manifestation of that injury, this finding is considered a very mild adverse effect. Based on the increased relative and absolute liver weight and the periportal hepatocyte vacuolar swelling, the NOAEL for females was considered at 100 mg/kg bw/day.

 

Barium m-toluate

Since no repeated dose toxicity study is available specifically for barium m-toluate, information on the individual moieties barium and m-toluic acid will be used for the hazard assessment and when applicable for the risk characterisation of barium m-toluate. For the purpose of hazard assessment of barium m-toluate, the point of departure for the most sensitive endpoint of each moiety will be used for the DNEL derivation. In case of m-toluic acid in barium m-toluate, the NOAEL of 100 mg/kg bw/day for repeated dose toxicity will be used. In case of barium, the NOAEL of 61 mg/kg bw/day for repeated dose toxicity will be used.

Justification for classification or non-classification

As the two moieties of substance barium m-toluate do not induce adverse effects leading to a STOT RE classification, barium m-toluate in all probability has also no potential for systemic toxicity leading to a classification.

According to the criteria of REGULATION (EC) No 1272/2008 and its subsequent adaptations, barium m-toluate does not have to be classified and has no obligatory labelling requirement for Specific target organ toxicity by repeated exposure (STOT-RE).