Registration Dossier

Administrative data

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 individual moieties barium and dodecylphenolate.

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

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.

 

Dodecylphenolate

 

In accordance with the SIDS Initial Assessment Profile (SIAP), “this substance causes adverse effects on organs and tissues in rats at dose levels that cause reductions in body weight gain. The NOAEL for repeated-dose toxicity in rodents is 5 mg/kg/day, as adrenal cortical hypertrophy was observed at doses of 20 mg/kg/day and above. It is noteworthy that similar changes were not observed in dogs administered up to 4000 ppm in the diet for 13 weeks. The repeated-dose oral toxicity of two different commercial samples of tetrapropenyl phenol has been evaluated in tests in rats in two 28-day studies in accordance with OECD Test Guideline 407.28-day oral (gavage) toxicity study in rats (Harriman 2004): A commercial sample of tetrapropenyl phenol was evaluated in a 28-day oral gavage study in rats (OECD Guideline 407). The dose levels were 0, 5, 20, 60, 180, and 300 mg/kg/day. This study is considered to be reliable without restriction (Klimisch Code = 1).

Mean liver weights were significantly increased at 300 mg/kg/day in males and females, and this finding was accompanied by centrilobular hepatocellular hypertrophy. Centrilobular hepatocellular hypertrophy was also observed at 180 mg/kg/day in males and females and at 60 mg/kg/day in males. Mean adrenal gland weights were significantly increased at 180 and 300 mg/kg/day in males, and this finding was accompanied by cortical hypertrophy, which was also observed at 20 and 60 mg/kg/day in males and 300 mg/kg/day in females. Follicular cell hypertrophy in the thyroid was observed in males at all dose levels. Mean testes weights were significantly decreased at 300 mg/kg/day, and this finding was accompanied by microscopic changes in this tissue. Mean weights of the epidydimides, seminal vesicles, and prostate were also significantly decreased at 180 and 300 mg/kg/day. Mean ovary weights were significantly decreased at 180 and 300 mg/kg/day, and this finding was accompanied by a decrease in the number of corpora lutea.

Overall, the LOELs for this study were 5 mg/kg/day in males (based on thyroid follicular cell hypertrophy) and 60 mg/kg/day in females (based on urogenital staining); and the NOELs were <5mg/kg/day in males and 20 mg/kg/day in females. However, it should be noted when deriving an overall NOAEL for repeated dose toxicity, that the microscopic follicular cell hypertrophy in the thyroids of male rats did not repeat in the one-generation reproductive toxicity study and are of questionable significance for human health (Capin 2001), and the microscopic effects on the liver at 60 mg/kg/day are considered adaptive responses. Because only the reproductive organ weight and/or microscopic findings persisted to the recovery necropsy, the Study Director considered the NOAEL to be 60 mg/kg/day for males and females.” (SIAP, 2006)

 

References:

SIAP (2006): SIDS Initial Assessment Profile for Phenol, (tetrapropenyl) derivates; Tetrapropenyl phenol and Phenol, dodecyl-, branched; SIAM 22, 18-21 April 2006)

 

Barium 4-dodecylphenolate

Since no repeated dose toxicity study is available specifically for barium 4-dodecylphenolate, information on the individual moieties barium and dodecylphenolate will be used for the hazard assessment and when applicable for the risk characterisation of barium 4-dodecylphenolate. For the purpose of hazard assessment of barium 4-dodecylphenolate, the point of departure for the most sensitive endpoint of each moiety will be used for the DNEL derivation. In case of barium 4-dodecylphenolate, the NOAEL of 5 mg/kg bw/day for reproductive toxicity will be used. For repeated dose toxicity, a NOAEL of 60 mg/kg bw/day was identified.

 

Barium 4-dodecylphenolate is not classified according to regulation (EC) 1272/2008 for repeated dose toxicity. Further testing is not required. For further information on the toxicity of the individual moieties, please refer to the relevant sections in the IUCLID and CSR.

Justification for classification or non-classification

Since no repeated dose toxicity study is available specifically for barium 4-dodecylphenolate, information on the individual moieties barium and dodecylphenolate will be used for the hazard assessment and when applicable for the risk characterisation of barium 4-dodecylphenolate.

Barium 4-dodecylphenolate does not require a classification, sinceboth moieties are not classified for the repeated oral toxicity endpoint.