Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Based on the experimental data and the read-across consideration, no bioaccumulation is expected.
In-vitro study (sorbitan caprylate)
- sorbitan caprylate is hydrolyzed to fatty acid by PPL.
In-vivo studies (sorbitan stearate)
- sorbitan stearate was mainly hadrolyzed to fatty acid and anhydrides of sorbitol, which was largely excreted into the urine before completely oxidized to CO2
- sorbitan stearate was not deposited or accumulated in the fat stores

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

The toxicokinetic and metabolism profile of sorbitan caprylate can reasonably be derived based on in-vitro experimental data and on the read-across approach using sorbitan stearate as a source chemical.

The analogue approach using sorbitan stearate as source chemical is justified:

Both chemicals are of comparable structures with minor deviations and can be characterized as an ester of sorbitan and a fatty acid. Compared to the source chemical, the target chemical has a shorter alkyl chains that affect its physicochemical properties. But based on the kinetic / metabolic investigations on both chemicals, the length of the alkyl chain is not considered to have significant impact on the metabolic pathway or toxicological mode of action. Oral gavage studies in rats administered C14 labeled sorbitan stearate in oil solutions have demonstrated that about 90% of the substance was absorbed and hydrolyzed to stearic acid and sorbitan. The metabolic fate of sorbitan caprylate was investigated using a lipase assay. The hydrolysis mediated by porcine pancreas lipase was quantitatively determined. The target chemical sorbitan caprylate is proved to be hydrolyzed and caprylic acid was formed . These findings suggest that metabolism of the sorbitan occur initially via enzymatic hydrolysis, leading to sorbitan and the corresponding natural acids.

Based on the above mentioned information, it is reasonable to consider that these two substances are comparable in their metabolic fate and thereby toxicological profiles. Hence, the source chemical is considered as “suitable with interpretation” analog.

According to the available toxicity studies, the findings are also comparable for target and source chemicals:

·        The findings in acute toxicity studies are comparable. Both chemicals are of no acute toxicity.

·        The findings in subacute dose toxicity studies are comparable. No treatment effects were observed in 28-day repeated toxicity studies in Wistar rats. The same NOEL of 1000 mg/kg bw/d was derived for both chemicals.

·        The findings in genetic toxicity are comparable. Both chemicals did not induce gene mutations in Ames tests, but induced structural chromosomal aberrations in cell lines of Chinese Hamster.

·        The findings in reproduction / developmental toxicity studies are comparable.

The metabolism and kinetic of soribtan caprylat was evaluated by a Lipase Assay. Lipases (EC number 3.1.1.3) are esterases that catalyze the hydrolytic cleavage of triglycerides, fats and oils into glycerol and free fatty acids.The resultsindicated that sorbitan caprylate is subject to fatty acid releasing hydrolysis by PPL, the mean turnover rate for sorbitan caprylate being approximately 236.5 % of the rate obtained for olive oil. Under the chosen experimental conditions, sorbitan caprylate is broken down at an even greater rate as the representative substrate olive oil.

The metabolism of kinetic of sorbitan stearate was investigated in rats. Radioactive sorbitan monostearate has been fed to rats and the fate of the C14 has been studied. The distribution of the C14 shows that at least 90% of the labeled substance, when fed in oil solution, was hydrolyzed to stearic acid and the anhydrides of sorbitol. The anhydrides of sorbitol which were liberated by the hydrolysis were largely excreted into the urine before they could be completely oxidized to CO2. The amount of C14 found in the tissues 48 hours after feeding of polyol labeled sorbitan monostearate in oil was 5 to 7% of the administered C14. Fractionation of the crude fat extract of the tissues (excluding the intestinal tract) indicated that less than 0.1% of the fed C14 may represent sorbitans derived from fed sorbitan monostearate or sorbitan esters synthesized from circulating sorbitan.

The deposition and accumulation of sorbitan stearate were investigated in rats which were fed for 28 days a synthetic diet containing 0.1% sorbitan stearate radioactively labeled with carbon-14 in the polyol moiety, and their fat stores were then annalyzed for residual radioactivity. The results demonstrated that sorbitan stearate not deposited or accumulated the fat stores.

Based on these studies, the metabolism of sorbitan caprylate was considered to occur initially via enzymatic hydrolysis mediated by lipases, leading to caprylic acid and sorbitan which would be expected to be metabolized further to either smaller and more polar water-soluble metabolites excretable in the urine or as carbon dioxide exhaled in the lungs. No deposition or accumulation was expected in body fat stores.