Fatty acids, C18-(unsaturated) dimers and their monoesters and diesters with 2-ethylhexanol

Endpoint summary

Description of key information

No experimental studies with the UVCB substance 400160 are available. Published data for the alcoholic component (2-EH) and fatty acids were used to derive an assessment on the toxicokinetic behaviour of 400160. 
Based on the molecular weight and physicochemical properties of all constituents of 400160 it can be expected that they can be absorbed or are able to penetrate human skin. An extensive metabolisation and excretion is expected for the components of 400160.  

Additional information

Based on the molecular weight and physicochemical properties all constituents of 400160 are expected absorbable after oral or dermal exposure. Subsequent to absorption, the esters may become hydrolysed to the corresponding dicarboxylic acid and 2-ethylhexanol (2 -EH).

For the alcoholic component (2-EH) in vivo data on toxicokinetics after oral or dermal administration is available. 2-EH is rapidly absorbed following oral administration, but is only slowly absorbed following dermal application (Deisinger et al. 1994). Systemic 2-EH is subjected to extensive oxidative metabolism and glucuronidation followed by rapid excretion, primarily in the urine. Only at very high dosages some evidence of metabolic saturation was observed, but repeated dosing with 2-EH at 50 mg/kg produced no evidence of metabolic induction (Deisinger et al. 1994).

In rats 2-EH was efficiently absorbed following oral administration and rapidly excreted mainly in the urine (80 -82%); minor fractions were excreted via the lungs (6 -7%) and feces (8 -9%). Elimination was essentially complete by 28 h. The major urinary metabolite of 2-EH in the rat was shown to be 2-ethylhexanoic acid through acid extraction of urine. This metabolite can undergo partial β-oxidation and decarboxylation to produce ¹⁴CO₂ in the lung and 2- and 4-heptanone in the kidneys. Other urinary metabolites of 2-EH were identified as 2-ethyl-5-hydroxyhexanoic acid, 2-ethyl-5-ketohexanoic acid, and 2-ethyl-1,6-hexanedioic acid. Approximately 3% of the parent compound was excreted unchanged (WHO; Environ Health Criteria Number 32: Toxicological Evaluation of Certain Food Additives and Contaminants. p. 35 (1993)).

An in vitro dermal absorption study of 2-EH was conducted with full thickness rat skin and human stratum corneum. The ratio of the rate of absorption of 2-EH through rat and human skin (rat/human) was reported to be 5.8, indicating that rat skin is more permeable to 2-EH than human skin (WHO; Environ Health Criteria Number 32: Toxicological Evaluation of Certain Food Additives and Contaminants. p. 36 (1993)).

As commonly known for long-chain fatty acids also the dicarboxylic acid is subjected to β-oxidation, leading finally to C2-moieties that enter the citric acid cycle for endoxidation.

Fatty acids are usually ingested as triglycerides, which cannot be absorbed by the intestine. Therefore, fatty acids are emulsified by bile salts from the gall bladder and form micelles. In the small intestine the enzyme pancreatic lipase degrades the triglycerides into fatty acids and monoglycerides.

Together with apoproteins and cholesterol the triacylglycerols form blood-soluble complexes (chylomicrons) which are able to move across the blood vessel membrane. Chylomicrons are transported via the bloodstream to fat cells (adipocytes) or muscle fibers, where they are either stored or oxidized for energy supply. For storage of fat in adipocytes, the triacylglycerol is cleaved by lipoprotein lipase into fatty acids and glycerol and are able to pass the membrane of adipocytes. Then they can be released and transported to myocytes by serum albumin. For energy utilization in muscle cells (myocytes) fatty acids undergo β-oxidation. This process finally releases carbon dioxide and ATP via the citric acid cycle.

It has been generally well established that the length of carbon chain determines the intestinal absorption pathway of fatty acids (Bernard and Carlier, 1991). The shorter the chain length the better is the absorption into blood, and unsaturated fatty acids can be better resorbed than saturated fatty acids. The differences might partial be related to the differences in the fatty acid hydrosolubility (Bernard and Carlier, 1991).

In general the components of 400160 are expected to be absorbed and undergo extensive oxidative metabolisation.