Barium bis(2-ethylhexanoate)

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

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.

Toxicity for reproduction– effects on fertility

No toxicity data on adverse effects on sexual function and fertility with bariumbis(2-ethylhexanoate)are available, thus the reproductive toxicity will be addressed with existing data on the dissociation products as detailed in the table below. Further details on the reproductive toxicity of the individual constituents are given below.

 

Table: Summary of toxicity data on adverse effects on sexual function and fertility of bariumbis(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)
Screening for repro./dev. toxicity (OECD 421/422)	NOAEL(rat; P) = 4000 ppm NOAEL(rat; F1) = 100 mg/kg bw/day	No data	No data
Two-generation reproductive toxicity study	Test proposal	NOAEL(rat; F1) = 100 mg/kg bw/day NOAEL(rat; P) = 300mg/kg bw/day   not classified	No data   not classified

 

Barium

Only two studies (NTP and Dietz) exist in which a dose-response relationship of different adverse effects after oral administration of barium chloride was investigated. Thus, the studies which were published in peer-reviewed journals were examined with respect to their adequacy for the derivation of NOAEL/LOAEL values for fertility impairment.

Based on these limited investigations with barium chloride as described above, a lack of adequate, guideline conform data must be noted. Tentatively, the premating study by Dietz et al. (1992) on rats and mice may be considered as the only acceptable study for the derivation of a preliminary NOAEL for fertility effects of soluble barium compounds. This study investigated the occurrence of different adverse effects in male and female rats and mice and their offspring related to barium chloride exposure via drinking water. A tentative NOAEL for fertility impairment of 4,000ppm in rats and 2,000 ppm in mice can be derived.

 

2-Ethylhexanoic acid

2-Ethylhexanoic acid was administered via drinking water to an unspecified number of male and female rats at 0, 100, 300, or 600 mg/kg bw/day. There were no deaths. The relative epididymal weights in high-dose males were significantly increased, but no histological changes were noted. A slight, but not statistically significant increase in the number of abnormal sperm was noted in the highest two dose groups; however, the incidence per animal was not provided. Treated groups required more time to successfully complete mating, and the mean litter size in high-dose pregnant females was significantly reduced. The mean pup weights in the high-dose group were significantly lower on postnatal day 7 and 14. Mean fetal weight per litter and mean placental weights were significantly reduced in the mid- and high-dose groups. Clubfoot was the only skeletal malformation; changes in skeletal variations were also noted (wavy ribs, reduced cranial ossification, and twisted hind legs). Corrected maternal body weights at termination and weight gains of high-dose females were significantly reduced. Physical development of the eyes, teeth and hair appeared to be slightly later in the pups from the high-dose groups; the significance of this finding is unclear since no data were presented on the length of gestation in treated and control dams. The high-dose of 600 mg/kg bw/day significantly reduced overall water consumption and body weights in female animals. The NOAEL for reproductive effects in parental animals was 300 mg/kg bw/day; this effect occurred in the presence of maternal toxicity. The NOAEL for F1 offspring was 100 mg/kg bw/day. Based on these results, 2-ethylhexanoic acid is not likely to cause effects on fertility but is likely to be a developmental toxicant. The developmental toxicity of 2-ethylhexanoic acid is at least partially related to disruption of Zn metabolism and distribution in the mother, and that higher zinc levels in the mothers leads to lower developmental toxicity in offspring.

 

Barium bis(2-ethylhexanoate)

Since notoxicity data on adverse effects on sexual function and fertilityis available 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.

 

No information for barium on adverse effects on sexual function and fertility is available, adequate for risk assessment and classification and labelling purposes. A test proposal was issued by the lead registrant for a readily bioavailable barium substance.Upon availability of the testing results for barium chloride, the registrant ensures that the dossier for barium bis(2-ethylhexanoate) and the risk assessment will be updated without undue delay.

Short description of key information:
A testing proposal for a two generation study was issued by the lead registrant for a readily bioavailable barium substance. The dossier for barium bis(2-ethylhexanoate) will be updated, when the testing result for barium chloride is available.

Justification for selection of Effect on fertility via oral route:
Information from read-across substances:
No data available for barium: a testing proposal for a two-generation study is included in the reference dossier.
Animal data for 2-ethylhexanoic acid: NOAEL(rat, P)=300mg/kg bw/day

Effects on developmental toxicity

Description of key information

A testing proposal for a developmental toxicity study was issued by the lead registrant for a readily bioavailable barium substance. The dossier for barium bis(2-ethylhexanoate) will be updated, when the testing result for barium chloride is available.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

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.

Toxicity for reproduction – developmental toxicity

No toxicity data on adverse effects on development of the offspring with bariumbis(2-ethylhexanoate)are available, thus the reproductive toxicity will be addressed with existing data on the dissociation products as detailed in the table below. Further details on the reproductive toxicity of the individual constituents are given below.

 

Table: Summary of toxicity data on adverse effects on development of the offspring of the bariumbis(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)
Screening for repro./dev. toxicity (OECD 421/422)	NOAEL(rat; P) = 4000 ppm NOAEL(rat; F1) = 100 mg/kg bw/day	No data	No data
Pre-natal developmental toxicity study	Test proposal	NOAEL(rat; mat.)= 250 mg/kg   NOAEL(rat; dev)= 100 mg/kg*   Category 2, H361d (CLP) Category 3, R63 (DSD)	no data   self-classified, Category 2, H361d (CLP) Category 3, R63 (DSD)
Two-generation reproductive toxicity study	Test proposal	NOAEL(rat; F1) = 100 mg/kg bw/day NOAEL(rat; P) = 300mg/kg bw/day   not classified	No data   not classified

* Identified as most sensitive endpoint in the registration dossier for 2-ethylhexanoic acid, i.e. has been used for the DNEL derivation of this substance.

 

Barium

Guideline-conform prenatal developmental toxicity studies (according to OECD TG 414) via the oral route in any species are not available.

Tentative NOAEL values for developmental toxicity of 4,000 ppm and 2,000 ppm for rats and mice, respectively, are reported in the study by Dietz et al. (1992). However, these NOAELs are of limited value to evaluate the potential for barium to induce developmental effects because the study design did not include prenatal exposure of the female animals to barium chloride. Therefore, this study has to be considered as inadequate for the assessment of the potential to induce developmental toxicity and cannot be used in a regulatory context.

 

2-Ethylhexanoic acid

2-Ethylhexanoic acid was administered via drinking water to an unspecified number of male and female rats at 0, 100, 300, or 600 mg/kg bw/day. There were no deaths. The relative epididymal weights in high-dose males were significantly increased, but no histological changes were noted. A slight, but not statistically significant increase in the number of abnormal sperm was noted in the highest two dose groups; however, the incidence per animal was not provided. Treated groups required more time to successfully complete mating, and the mean litter size in high-dose pregnant females was significantly reduced. The mean pup weights in the high-dose group were significantly lower on postnatal day 7 and 14. Mean fetal weight per litter and mean placental weights were significantly reduced in the mid- and high-dose groups. Clubfoot was the only skeletal malformation; changes in skeletal variations were also noted (wavy ribs, reduced cranial ossification, and twisted hind legs). Corrected maternal body weights at termination and weight gains of high-dose females were significantly reduced. Physical development of the eyes, teeth and hair appeared to be slightly later in the pups from the high-dose groups; the significance of this finding is unclear since no data were presented on the length of gestation in treated and control dams. The high-dose of 600 mg/kg bw/day significantly reduced overall water consumption and body weights in female animals. The NOAEL for reproductive effects in parental animals was 300 mg/kg bw/day; this effect occurred in the presence of maternal toxicity. The NOAEL for F1 offspring was 100 mg/kg bw/day. Based on these results, 2-ethylhexanoic acid is not likely to cause effects on fertility but is likely to be a developmental toxicant. The developmental toxicity of 2-ethylhexanoic acid is at least partially related to disruption of Zn metabolism and distribution in the mother, and that higher zinc levels in the mothers leads to lower developmental toxicity in offspring.

 

Barium bis(2-ethylhexanoate)

Since notoxicity data on adverse effects on development of the offspringis available 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.

 

No information for barium on adverse effects on development of the offspring is available, adequate for risk assessment and classification and labelling purposes. A test proposal was issued by the lead registrant for a readily bioavailable barium substance.Upon availability of the testing results for barium chloride, the registrant ensures that the dossier for barium bis(2-ethylhexanoate) and the risk assessment will be updated without undue delay.

 

Considering the read-across principles as detailed above for barium bis(2-ethylhexanoate) based on the toxicological assessment of the individual constituents, the harmonised legally binding classification of 2-ethylhexanoic acid for reproductive toxicity is read-across to barium bis(2-ethylhexanoate). Thus, barium bis(2-ethylhexanoate is self-classified for reproductive toxicity in category 2 H361d (Suspected of damaging the unborn child) and according to Regulation 67/548/EEC in category 3 R63 (Possible risk of harm to the unborn child). 

Justification for selection of Effect on developmental toxicity: via oral route:
Information from read-across substances:
No data available for barium: a testing proposal for a prenatal developmental toxicity study is included in the reference dossier.
Animal data for 2-ethylhexanoic acid: NOAEL(rat, F1)=100mg/kg bw/day

Justification for classification or non-classification

No information for barium on adverse effects on sexual function and fertility is available, adequate for risk assessment and classification and labelling purposes.

Considering the read-across principles as detailed above for barium bis(2-ethylhexanoate) based on the toxicological assessment of the individual constituents, the harmonised legally binding classification of 2-ethylhexanoic acid for reproductive toxicity is read-across to barium bis(2-ethylhexanoate). Thus, barium bis(2-ethylhexanoate is self-classified for reproductive toxicity in category 2 H361d (Suspected of damaging the unborn child) and according to Regulation 67/548/EEC in category 3 R63 (Possible risk of harm to the unborn child).