Octanoic acid, esters with anhydrosorbitol and dianhydrosorbitol

Carcinogenicity

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

chronic

Species:

rat

Quality of whole database:

reliable and robust, 2 chronic studies on source chemical sorbitan stearate

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Sorbitan caprylate does not have to be classified for carcinogenicity according to the criteria laid down in the EU Dangerous Substances Directive (67/548/EEC) and in the EU Classification Labelling and Packaging Regulation (1272/2008/EC) because it has not genotoxic properties (results from studies performed with sorbitan caprylate and its structural analogue) and carcinogenicity properties (based on the analogue approach)

Additional information

The carcinogenicity of sorbitan caprylate was assessed based on the analogue approach using sorbitan stearate as a read-across supporting substance.

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.

In one long-term study, Wistar rats (25 groups consisting of 12 males and 20 females/dose; F0 generation) were administered with sorbitan monostearate in the diet at 0, 5, 10 or 20% (~ 0, 2500, 5000 or 10,000 mg/kg-bw/day) for two years (spanning four generations). During the courseof the study, observations were made of physical appearance, behavior, reproduction, and lactation through three successive generations, and gross and histologic evaluations were made at termination. The test item caused no carcinogenic at any dose level.

In another long-term study, sorbitan stearate was given to groups of 48 male and 48 female mice at dose levels of 0 (control), 0.5, 2.0 or 4.0% of the diet for 80 weeks. There was also no evidence of carcinogenic activity at any of these dose levels.