Fatty acids, C14-18 and C16-18-unsatd., barium salts

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 fatty acids, C14-18 and C16-18, unsatd. barium salts is available, thus the repeated dose toxicity will be addressed with existing data on the dissociation products barium and fatty acids, C14-18 and C16-18 -unsatd as detailed in the table below.

 

Table: Summary of repeated dose toxicity data of the fatty acids, C14-18 and C16-18, unsatd. barium salts and the individual constituents.

 

	BaCl2 (CAS# 10361-37-2)	Fatty acids, C14-18 and C16-18-unsatd. (CAS#67701-06-8)	Fatty acids, C14-18 and C16-18, unsatd. barium salts (CAS# 95465-85-3)
Repeated dose oral toxicity	NOAEL(rat;90d)= 61.1 mg/kg bw/day (calculated as Ba2and)*	not toxic to humans over a lifetime exposure	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.

 

Fatty acids, C14-18 and C16-18-unsatd.

(1) A large part of human nutrition consists of oils and fats of vegetable and animal origin. The oils and fats contain a mixture of fatty acids with a chainlength distribution of C6-C24 (vegetable sources) and C4-C22 (animal origin). The oleic acid (C18:1) content of widely used oils and fats makes up to: 36-44% (palm oil), 45.8% (beef fat), 26.6% (cow milk), 45.1% (bacon fat) (Beare-Rogers J,2001)

 

(2) The Scientific Committee on GRAS Substances (SCOGS) of the U.S. FDA concluded on oleic acid: “There is no evidence in the available information on coconut oil, peanut oil, and oleic acid that demonstrates, or suggests reasonable grounds to suspect, a hazard to the public as they are now used in paper and cotton packaging material for food at levels now current or as they might reasonably be expected to be used for such purposes in the future. There is no evidence in the available information on linoleic acid that demonstrates, or suggests reasonable grounds to suspect, a hazard to the public when it is used as a nutrient or dietary supplement at levels now current or that might reasonably be expected in the future.” (SCOGS, 1975)

 

(3) Exposure of breast-fed babies to oleic acid via mother milk: A breast-fed of 3 months age has an average weight of 6.5 kg (WHO 2013) and the infant ingests approx. 180mL/kg bw of milk per day (Riordan 2001), being 1170 mL for a baby at an age of 3 months. The fat content of mother milk is approx. 4.2% (United Nations 1996), with a content of oleic acid of approx. 32% (total content of C18 fatty acids: C18:0, C18:1, C18:2 and C18:3 = 58.2%) (Finley et al. 1985). This results in a total “exposure” for a 3 month old baby of 15.7 g oleic acid per day, being 2400 mg/kg bw/day.

 

(4) Substances obtained from natural sources are exempt from the obligation to register (in accordance with Annex V, Section 9). Sincefatty acids, C14-18 and C16-18, unsatdis a substance obtained from natural sources (see point 1 above), thus the chemically unmodified substance is exempt from registration.

 

Based on the above given arguments, one may safely assume that human exposure towardsfatty acids, C14-18 and C16-18, unsatdexerts any adverse effects of toxicological relevance after acute or chronic exposure is grossly implausible.

 

Fatty acids, C14-18 and C16-18, unsatd. barium salts

Since no repeated dose toxicity study is available specifically for fatty acids, C14-18 and C16-18, unsatd. barium salts, information on the individual constituents barium and fatty acids, C14-18 and C16-18, unsatdwill be used for the hazard assessment and when applicable for the risk characterisation of fatty acids, C14-18 and C16-18, unsatd. barium salts. For the purpose of hazard assessment of fatty acids, C14-18 and C16-18, unsatd. barium salts, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation. In case of barium in fatty acids, C14-18 and C16-18, unsatd. barium salts, 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

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

Justification for classification or non-classification

Substance Fatty acids, C14-18 and C16-18, unsatd., barium salts is not expected to induce specific target organ toxicity by repeated exposure, since its two moieties barium and Fatty acids, C14-18 and C16-18, unsatd., have not shown respective (severe) adverse effects and are not classified as specific target organ toxicant (STOT) - repeated.

Thus, substance Fatty acids, C14-18 and C16-18, unsatd., barium salts is not to be classified according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) - repeated. Furthermore, substance Fatty acids, C14-18 and C16-18, unsatd., barium salts is not to be classified according to Directive 67/548 EEC for repeated dose toxicity.