Didocosyl sebacate

Endpoint summary

Additional information

Toxicokinetics

A reliable key toxicokinetic study with Didocosyl sebacate (CAS 42233-75-0) is available and was performed according to OECD TG 417 and in compliance with GLP (Bernard, F., 2013). The absorption, distribution, excretion and metabolism properties of Didocosyl sebacate were assessed in four Wistar rats of each sex after a single [14C] labeled fatty alcohol dose of 30 mg/kg bw via oral gavage. The concentration of radioactivity in urine, feces, expired air, blood, tissues, organs and in the remaining carcass was determined. About 6.85% and 7.96% of the dose for male and female rats, respectively, were absorbed from the gastrointestinal tract into systemic circulation. The absorbed radioactivity was predominately excreted with the expired air, accounting for 5.2% and 6.9% for male and female rats, respectively. Very low amounts of the absorbed radioactivity were excreted with the urine, accounting for less than 0.3% for male and female rats. Almost all absorbed radioactivity was detected in expired air in male and female rats (5.2% and 6.9%, respectively). The major part of the radioactivity (approximately 94% of administered dose) was excreted with the feces for male and female rats. Within 48 hours after administration, over 90% of the dose was totally excreted. After 7 days almost the complete dose was excreted, accounting totally for 99.7% and 101.3% of the dose in male and female rats, respectively. Between 1.1% and 0.7% of the dose was found in the remaining carcass and tissues of male and female rats, respectively, seven days after dosing. Residual radioactivity was found in all tissues and organs at higher concentrations than in blood (0.074 μg/g and 0.092 μg/g for males and females, respectively), except for the brain. The highest residual radioactivity was found in the adrenals, epididymis, white fat, liver, ovaries, pancreas, spleen and thyroids. Total recoveries were calculated to be 100.8 and 102.1%. Due to the low concentration (< 0.3%) the metabolite profiling in urine was not performed. The investigation of the metabolite pattern in feces revealed that the test material was left unchanged for both sexes.

 

From the available toxicokinetic data and literature the following metabolic fate is anticipated. In general, dicarboxylic acid esters, such as Didocosyl sebacate are expected to have the same metabolic fate as aliphatic acid esters, which are rapidly hydrolyzed to the corresponding alcohol and fatty acid by esterases (Fukami and Yokoi, 2012; Lehninger, 1970). However, also for both cleavage products, it is anticipated that they are absorbed in the gastro-intestinal tract. In case of alcohols with long carbon chains (e.g. C22) and thus relatively low water solubility absorption will take place by micellar solubilisation (Ramirez et al., 2001). Small and water soluble cleavage products dissolve into the gastrointestinal fluids (ECHA, 2012c). Alcohol metabolism proceeds by oxidation to the corresponding carboxylic acids, followed by a stepwise elimination of C2-units in the mitochondrial β-oxidation process (OECD SIDS, 2006) resulting in excretion ofcarbon dioxide via the expired air. Depending on the carbon chain length dicarboxylic acids are either predominantly excreted unchanged via urine or metabolized via peroxisomal and mitochondrial β-oxidation (Passi et al., 1983). The products of β-oxidation of even-chain dicarboxylic acids (e.g. sebacic acid) produce acetyl-CoA and succinyl-CoA, which is a gluconeogenesis precursor (Grego and Mingrone, 1994). Further oxidation of the C2-untis (acetyl-CoA) via the citric acid cycle leads to the formation of H2O and CO2(Lehninger, 1970; Stryer, 1996).

The excretion of 5.2% and 6.9% of the absorbed radioactivity (male and female rats, respectively) with the expired air indicates that to a certain extend hydrolysis of Didocosyl sebacate into the[14C] labeled fatty alcohol (1-docosanol) and sebacic acid takes place. Both, sebacic acid and 1-docosanol feed into the physiological process of fatty acid oxidation and subsequent metabolic pathways. Therefore,It can be assumed that1-docosanol undergoes β-oxidation resulting in excretion of[14C] labeled carbon dioxide via the expired air. Metabolization of sebacic acid is predicted to follow the same route since even-chain dicarboxic acids are degraded toH2O and CO2in a final step. In summary, oral administration of Didocosyl sebacate at a nominal dose level of 30 mg/kg bw showed low absorption potential and rapid excretion mainly via feces. Absorbed Didocosyl sebacate is assumed to be physiological metabolized via fatty acid metabolism (β-oxidation) and excreted with expired air. Male and female blood kinetic was considered to be similar with a maximum concentration of radioactivity in blood found at sampling time point 4 hours and 8 hours for males and females, respectively. A Cmax of 0.701 and 0.733 μg Didocosyl sebacateeq/g was reached for males and females, respectively. Terminal half-life was calculated to be approximately 71.4 hours for males and 63.0 hours for females. AUC0-t in blood was calculated to be 32.9 and 43.0 μg.h/g for males and females, respectively.