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EC number: 205-249-0 | CAS number: 136-51-6
Endpoint summary
Administrative data
Description of key information
No repeated dose toxicity study with calcium bis(2-ethylhexanoate) is available, thus the repeated dose toxicity will be addressed with existing data on the individual dissociation products calcium and 2‑ethylhexanoic acid.
In relevant and reliable repeated dose toxicity studies for both dissociation products of calcium bis(2-ethylhexanoate), there were no toxicological findings reported that would justify a classification.
Key value for chemical safety assessment
Additional information
Read-across approach
Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the metal cation and the organic acid anion. This way forward is acceptable, since metal carboxylates are shown to 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 and dissociation tests (please refer to the water solubility and dissociation in sections 4.8 and 4.21 of IUCLID). Once the individual transformation products 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 a combination of the toxicity of these transformation products, i.e. the metal cation and carboxylate anion according to an additivity approach.
Calcium bis(2-ethylhexanoate) is the calcium salt of 2-ethylhexanoic acid, which readily dissociates to the corresponding divalent calcium cation and monovalent 2-ethylhexanoate anions. The calcium cation and the 2-ethylhexanoate anion are considered to represent the overall toxicity of calcium bis(2-ethylhexanoate) in a manner proportionate to the free acid and the metal (represented by one of its readily soluble salts).
A detailed justification for the read-across approach is added as a separate document in section 13 of IUCLID.
Repeated dose toxicity
No repeated dose toxicity study with calcium bis(2 -ethylhexanoate) is available, thus the repeated dose toxicity will be addressed with existing data on the dissociation products calcium and 2-ethylhexanoic acid as detailed in the table below.
Table: Summary of repeated dose toxicity data of the calcium bis(2 -ethylhexanoate) and the individual constituents.
| calcium substances | 2-ethylhexanoic acid (CAS# 149-57-5) | Calcium bis(2 -ethylhexanoate) (CAS# 136-53-8) |
Repeated dose | NOAEL(human data) = 36 mg Ca/kg bw/day* | 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 calcium, thus has been used for the DNEL derivation of this substance.
Calcium
Guideline-compliant repeated-dose toxicity studies in rodents with oral administration of the various calcium compounds (28-day study acc. to OECD TG 407 or 90-day study acc. OECD TG 408) are not available. None of the five animal studies available for various calcium salts allow the derivation of a NOAEL or LOAEL value for quantitative risk assessment purposes.
However, assessment of potential systemic risks after prolonged oral exposure of humans to calcium is considered feasible on the basis of the comprehensive evaluation of all available human data on calcium as published in the Opinion of the Scientific Committee on Food (EFSA 2006), WHO report on mineral requirements in human nutrition (WHO 2004) and the report of the German BGVV on the toxicological evaluation of minerals in food (BGVV 2002).
In the most recent risk assessment document, the SCF decided to base the derivation of a tolerable upper intake level (UL) for calcium on the evidence of different interventional studies of long duration in adults, some of which were placebo-controlled and in which total daily calcium intakes of 2500 mg from both the diet and supplements were tolerated without any adverse effects (EFSA 2006). With regard to the data base, the evaluation by the SCF is considered to fulfil the criteria of to Annex XI, point 1.1.3. A detailed evaluation of the underlying single studies is not provided here, in order to avoid unnecessary duplication of the work already performed by an EU-nominated expert body. Based on the findings evaluated in the SCF document, an UL of 2500 mg of calcium per day for calcium intake from all sources is proposed for adults, which corresponds to a dose of approximately 36 mg calcium/kg bw/day taking into account an average body weight of 70 kg/person.
The UL derived by the SCF is considered as sufficient and adequate for risk characterisation. In conclusion, the conduct of any further repeated-dose toxicity studies in animals would not contribute any new information and is therefore not considered to be required.
2-Ethylhexanoic acid
In a 90-day repeated dose toxicity study in rats and mice with 2-ethylhexanoic acid, a diet 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.
Calcium bis(2 -ethylhexanoate)
Since no repeated dose toxicity study is available specifically for calcium bis(2 -ethylhexanoate), information on the individual constituents calcium and 2-ethylhexanoic acid will be used for the hazard assessment and when applicable for the risk characterisation of calcium bis(2 -ethylhexanoate). For the purpose of hazard assessment of calcium 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 calcium in calcium bis(2 -ethylhexanoate), the NOAEL of 36 mg/kg bw/day in repeated dose toxicity (human data) will be used.
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Information from read-across substances:
human data for calcium: NOAEL = 36 mg Ca/kg bw/day
animal data for 2-ethylhexanoic acid: NOAEL(rat) = 300mg/kg bw/day, NOAEL(mice) = 200mg/kg bw/day
Justification for classification or non-classification
According to the criteria of REGULATION (EC) No 1272/2008 and its subsequent adaptions, calcium bis(2-ethylhexanoate) does not have to be classified and has no obligatory labelling requirement for repeated oral toxicity.
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