Barium bis(2-ethylhexanoate)

Endpoint summary

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:

other: rat and mice

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

Introduction

A comprehensive data gap analysis was conducted for the entire substance portfolio of the Metal carboxylates REACH Consortium (MCRC), covering 10 metal carboxylates in total. This literature screening effort included:

 

• all available proprietary studies from the Metal carboxylates REACH Consortium (MCRC)
• detailed literature searches in online databases
• screening of human health review articles
• rigorous quality and reliability screening according to Klimisch criteria, where those criteria apply

 

During the literature search and data gap analysis it became obvious that the overall database on substance-specific human health hazard data for the metal carboxylates is too scant to cover all REACH endpoints. Therefore, the remaining data gaps had to be covered by either experimental testing or read-across from similar substances.

 

Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the organic acid counterion and the metal (or one of its readily soluble salts). This way forward is acceptable, since metal carboxylates dissociate to the organic anion and the metal cation upon dissolution in aqueous media. No indications of complexation or masking of the metal ion through the organic acid were apparent during the water solubility tests (please refer to the water solubility data in section of the IUCLID and chapter of the CSR). Once the individual constituents of the metal carboxylate become bioavailable (i.e. in the acidic environment in the gastric passage or after phagocytosis by pulmonary macrophages), the “overall” toxicity of the dissociated metal carboxylate can be described by the toxicity of the “individual” constituents. Since synergistic effects are not expected for this group of metal carboxylates, the human health hazard assessment consists of an individual assessment of the metal cation and the organic anion.

 

The hazard information of the individual constituents was obtained from existing REACH registration dossiers via a license-to-use obtained by the lead registrant. These registration dossiers were submitted to ECHA in 2010 as full registration dossiers, and are thus considered to contain relevant and reliable information for all human health endpoints. All lead-registrant dossiers were checked for completeness and accepted by ECHA, i.e. a registration number was assigned.

 

Barium bis(2-ethylhexanoate) is the barium metal salt of 2-ethylhexanoic acid, which readily dissociates to the corresponding metal barium cation and 2-ethylhexanoic anions. The barium cation and the 2-ethylhexanoic acid anion are considered to represent the overall toxicity of barium bis (2-ethylhexanoate) in a manner proportionate to the free acid and the metal (represented by one of its readily soluble salts). Based on the above information, unrestricted read-across is considered feasible and justified.

Although the term „constituent“ within the REACH context is defined as substance (also being part of a mixture), the term constituent within this hazard assessment is meant to describe either part of the metal carboxylate salt, i.e. anion or cation.

Repeated dose toxicity

No repeated dose toxicity study with barium bis(2-ethylhexanoate) is available, thus the repeated dose toxicity will be addressed with existing data on the dissociation products barium and 2-ethylhexanoic acid as detailed in the table below.

 

Table: Summary of repeated dose toxicity data of the barium bis(2-ethylhexanoate) and the individual constituents.

	BaCl2 (CAS# 10361-37-2)	2-ethylhexanoic acid (CAS# 149-57-5)	Barium bis(2-ethylhexanoate) (CAS# 2457-01-4)
Repeated dose oral toxicity	NOAEL(rat;90d)= 61.1 mg/kg bw/day (calculated as Ba2+)*	NOAEL(rat;90d)= 300 mg/kg bw/day   NOAEL(mice;90d)= 200 mg/kg bw/day	no data

* Identified as most sensitive endpoint in the registration dossier for barium, thus has been used for the DNEL derivation of this substance.

 

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 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 and 166 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 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.

 

2-Ethylhexanoic acid

In a 90-day repeated dose toxicity study in rats and mice with 2-ethylhexanoic acid, adiet containing 0.5% 2-ethylhexanoic acid caused no adverse effect in rats in a 13 week feeding study (dose levels were 0, 0.1, 0.5, or 1.5%, calculated NOAEL ca. 300 mg/kg bw/day). No adverse effect was observed in mice receiving a diet containing 0.5 % 2-ethylhexanoic acid in a 13 week feeding study (dose levels were 0, 0.1, 0.5, or 1.5%). The NOAEL was calculated to be 200 mg/kg bw/day. Both NOAELs were based on reduced food consumption and a decreased rate of body weight gain in the high dose groups.For further information on the toxicity of 2-ethylhexanoic acid, please refer to the relevant sections in the IUCLID and CSR.

 

Barium bis(2-ethylhexanoate)

Since no repeated dose toxicity study is available specifically for barium bis(2-ethylhexanoate), information on the individual constituents barium and 2-ethylhexanoic acid will be used for the hazard assessment and when applicable for the risk characterisation of barium bis(2-ethylhexanoate). For the purpose of hazard assessment of barium bis(2-ethylhexanoate), the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation. In case of barium in barium bis(2-ethylhexanoate), the NOAEL of 61.1 mg/kg bw/day in repeated dose toxicity (90-day repeated dose toxicity study via oral route in rats) will be used.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Information from read-across substances:
animal data for barium: NOAEL(rat)=61.1mg Ba/kg bw/day
animal data for 2-ethylhexanoic acid: NOAEL(rat)=300mg/kg bw/day, NOAEL(mice)=200mg/kg bw/day

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys

Justification for classification or non-classification

Barium bis(2-ethylhexanoate) is not expected to induce specific target organ toxicity by repeated exposure, since its two moieties barium and 2-ethylhexanoic acid have not shown respective (severe) adverse effects and are not classified as specific target organ toxicant (STOT) - repeated. Thus, barium bis(2-ethylhexanoate) is not to be classified according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) - repeated. Furthermore, barium bis(2-ethylhexanoate) is not to be classified according to Directive 67/548 EEC for repeated dose toxicity.