C18 (branched) fatty acids, esters with mono-, di-, and tri-glycerol

Endpoint summary

Description of key information

Based on the experimental data and the read-across consideration, no bioaccumulation is expected.
An in vitro encymatic Lipase Assay with the target substance is available.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The toxicokinetic and metabolism profile of C18 (branched) fatty acids, esters with mono-, di-, and tri-glycerol (syn. name Diglyceryl diisostearate) (target chemical) can reasonably be derived based on in-vitroexperimental data and on the read-across approach using Polyglycerin polyricinoleate (PGPR) as a source chemical.

The analogue approach using Polyclycerin polyricinoleate (PGPR) as source chemical is justified.

Both chemicals are of comparable structures and can be characterized as an ester of polyglycerols and fatty acid.

However, the two chemicals exhibit differences in chain length of the fatty acids which varies about C14 to C20. Although the length of the alkyl chain varies the metabolic pathway is tested to be the same.The metabolic fate of polyglycerol fatty acid esters after ingestion is extensively investigated (Howes et al., 1998; Michael and Coots, 1971) and can be summarized:

- After ingested orally, the compound is bioavailable only after ester bond cleavage in intestine, other wise fecal excretion occurs.

- The liberated polyglycerols are excreted unchanged. The lower glycerols (n= 2, 3) are more readily absorbed and are excreted in the urine, while the higher glycerols are less easily absorbed and are excreted in the feces.

- The liberated fatty acids are to be incorporated into the normal fatty acid metabolism.

 

The hydrolysis of the target chemical Diglyceryl diisostearate catalyzed by pancreas lipases is proven in an enzymatically in vitro test system (Hoeppner, 2013). It could be shown that target chemical is subject to fatty acid releasing hydrolysis by porcine pancreas lipase (PPL). These findings suggest that metabolism of the polyglycerol isosteric esters of the target chemical occur initially via enzymatic hydrolysis, leading to polyglycerols and the corresponding fatty acids.The isostearic acid (16-methylheptadecanoic acid) is a mixture of fatty acids consisting of mainly methyl branched isomers of octadecanoic acid.The liberated fatty acids will be incorporated into the fatty acid metabolism with a minor deviation to normal straight long-chain fatty acid metabolism.

Acyl coenzyme A synthetase of rat liver homogenate was found to activate lsostearic Acid (Lippel K., 1973). Iso-fatty acids are metabolized in a way similar to that of straight-chain fatty acids by the mitochondrial and microsomal fractions of rat-liver homogenate. In contrast, however, with the straight-chain fatty acids which are successively oxidized at the beta-carbon to yield two carbon fractions, the iso-fatty acids are also oxidized to a large extent at the omega-carbon to ultimately form three carbon dicarboxylic acids. The enzymes catalyzing the omega-hydroxylation are present in the mitochondrial and microsomal fractions of liver homogenate, whereas the enzymes catalyzing the further oxidation into carboxylic acids have been demonstrated in the soluble fraction (Bjorkhem I. and Danielson H., 1970).

 

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 a ”suitable with interpretation” analogue.(Wu et al.,2010).

 

Additionally studies are reported in the review from Wilson et al, 1998, were rats were fed for 30 an45 weeks on a purified diet containing 9 % PGPR (source chemical) plus 1 % groundnut oil. In the 30 week study it could be shown, that comparison of fat intake with fecal fat excretion corrected for endogenous fat excretion resulted in 98 % digestibility of PGPR. This is nearly equivalent to that of groundnut oil alone which was 99.8 % for the diet containing 10 % groundnut oil.

 

Furthermore, the source chemical PGPR is well assessed as food additive. Polyglycerol esters of fatty acids have been evaluated for acceptable daily intake by the Joint FAO/WHO Expert Committee on Food Additives in 1966. In its evaluation of PGPR in 1974, the Joint FAO/WHO Expert Committee on Food Addities (JECFA 17th report) considered that the rat reproduction study (Wilson R. and Smith M., 1998), with a dietary level of PGPR of 1.5%, should be used to estimate an acceptable daily intace (ADI) of PGPR for man since the study showed a no-effect level for liver enlargement. Accordingly, a rat intake equivalent to 750 mg PGPR/kg body weight was used to set the ADI for PGPR of 7.5 mg/kg body weight. This intake is more than maximum likely from the use of PGPR in tin-greasing emulsions or in block chocolate and chocolate couverture.

Taken these findings together, it is reasonable that the target substance after oral ingestion is resorbed in the gut and further metabolized distributed and excreted in the analogue manner investigated for the source chemical.