Calcium 3,5,5-trimethylhexanoate

Endpoint summary

Description of key information

No repeated dose toxicity study with calcium 3,5,5-trimethylhexanoate is available, thus the repeated dose toxicity will be addressed with existing data on the individual dissociation products calcium and 3,5,5-trimethylhexanoic acid.

In relevant and reliable repeated dose toxicity studies for both dissociation products of calcium 3,5,5-trimethylhexanoate, there were no toxicological findings reported that would justify a classification.

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 3,5,5-trimethylhexanoate is the calcium salt of 3,5,5-trimethylhexanoic acid and readily dissociates to the corresponding divalent calcium cation and monovalent 3,5,5-trimethylhexanoate anions. The calcium cation and the 3,5,5-trimethylhexanoate anion are considered to represent the overall toxicity of calcium 3,5,5-trimethylhexanoate 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 3,5,5 -trimethylhexanoate is available, thus the repeated dose toxicity will be addressed with existing data on the dissociation products calcium and 3,5,5 -Trimethylhexanoic acid as detailed in the table below.

 

Table: Summary of repeated dose toxicity data of calcium isononanoate and the individual constituents.

	calcium substances	3,5,5-trimethylhexanoic acid (CAS# 3302-10-1)	Calcium 3,5,5 -trimethylhexanoate (CAS# 64216 -15 -5)
Repeated dose oral toxicity	NOAEL(human data)= 36 mg Ca/kg bw/day*	NOAEL(rat;28d)= 50 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.

 

3,5,5 -Trimethylhexanoic acid

In a 28 day guideline study the test substance (purity 94.9%) was administered to male and female Wistar rats by gavage for4 weeks at dose levels of 0 (vehicle control), 10, 50 and 200 mg/kg body weight/day as aqueous solution of 0.1% Cremophor EL. Control and high dose groups consisted of each 10 animals per sex, whereas low and mid dose groups consisted of each 5 animals per sex. 5 animals per sex of all dose groups were sacrificed at the end of exposure (main groups). The remaining 5 animals per sex of control and high dose groups were maintained for another 14 days without administration of the test substance (recovery groups).

 

Kidney effects were seen in males of all dose groups (dose-related effect). This was attributed to the sex and species-specific hydrocarbon-induced a2u globulin accumulation in the kidneys of male rats and regarded as not relevant for humans. No effects apart from nephrotoxicity in males no effects at all were seen in females at 10 mg/kg bw/d.

At 50 mg/kg bw/d, fatty infiltration of liver cells (4 out of 10 animals) as well as alterations in clinical chemistry parameters and increased kidney weights were observed in females.

At 200 mg/kg bw/d, peripheral fatty infiltration of liver cells was increased in females (all animals) and observed also in one male. In this dose group the following effects were observed additionally: decreased motor activity (females) and increased liver weights (both sexes) as well as alterations in clinical chemistry and urinalysis parameters (both sexes). Except the kidney lesions in male rats, no treatment-related effects were reported in the recovery group. Despite the effects observed in the 50 mg/kg dose group (fatty degeneration of the liver in female rats) this dose is considered to be the NOAEL:

The minimal liver effects in females at this dose are accompanied by signs of liver peroxisome proliferation, a species-specific effect in rodents. Moreover these effects were completely reversible. Increased kidney weights in females are also reversible and occurred without any histological alterations in the kidneys, even at the highest dose tested. Therefore, the NOAEL of this study (BASF, 2002) is considered to be 50 mg/kg bw/d. This well performed guideline study (OECD 407) is considered to be of high reliability (RL1).

 

Slight maternal effects were observed in a one-generation rat study (reproduction/developmental toxicity screening test), but at far higher doses (Exxon, 1998, see IUCLID section 7.8.1).

 

Calcium 3,5,5 -trimethylhexanoate

Since no repeated dose toxicity study is available specifically for calcium 3,5,5-trimethylhexanoate, information on the individual constituents calcium and 3,5,5-trimethylhexanoic acid will be used for the hazard assessment and when applicable for the risk characterisation of calcium 3,5,5-trimethylhexanoate. For the purpose of hazard assessment of calcium 3,5,5-trimethylhexanoate, 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 3,5,5-trimethylhexanoate, the NOAEL of 36 mg/kg bw/day in repeated dose toxicity (human data) will be used, while for 3,5,5-trimethylhexanoate, the NOAEL of 50 mg/kg bw/day of a repeated dose toxicity test with rats 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 3,5,5 -trimethylhexanoic acid: NOAEL(rat)=50mg/kg bw/day

Justification for classification or non-classification

According to the criteria of REGULATION (EC) No 1272/2008 and its subsequent adaptions, calcium 3,5,5-trimethylhexanoate does not have to be classified and has no obligatory labelling requirement for repeated oral toxicity.