Reaction product of adipic acid and sebacic acid and isotridecan-1-ol

Endpoint summary

Description of key information

Reaction product of adipic acid and sebacic acid and isotridecan-1-ol will be hydrolysed by esterases and cleaved into isotridecyl alcohol, adipic acid and sebacic acid. Isotridecyl alcohol wil be oxidized to the corresponding aldhyde and subsequently to the carboxylic acid.
Carboxylic acid will undergoe oxidation (beta and at other positions). beta-Oxidation products will  be subject to fatty acid degradation and ultimately enter the citric acid cycle. Due to its bulky branched structure, other metabolic transformations as alcohol oxidation and fatty acid beta-oxidation are expected play an impoartant role resulting in hydroxy acids, dialcohols and dicarboxylic acids. Conjugation of various metabolites is very likely in order to solubilise the highly hydrophobic sceletal structure.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

For reaction product of adipic acid and sebacic acid and isotridecan-1 -ol no data on toxicokinetics could be identified. Based on the structure basic information on properties of aliphatic carboxylic esters is used to characterise the substance.

In addition, toxicokinetic data of 2-ethylhexyl adipate are presented which are used for read across to validate the general information derived for the product.

Reaction product of adipic acid and sebacic acid and isotridecan-1 -ol

The substance is a diester of a dicarboxylic acid consisting of adipic acid (C6 carbon frame) or sebacic acid (C10 carbon frame) and isotridecan-1 -ol with a branched carbon chain (n=13). Accordingly the substance is expected to show the typical characteristics of an ester. In vivo, esters are hydrolysed by ubiquitous hydrolases to alcohol and carboxylic acid. In case of diesters, this operation will proceed in two steps resulting first in a monoester. Isotridecyl alcohol and adipic acid or sebacic acid, formed by hydrolysis of the substance, will then follow metabolic pathways typical for alcohols and carboxylic acids.

 

In principle given the background information on aliphatic saturated long chain esters, alcohols and acids, the following properties and metabolic pathways are expected for the test substance Reaction product of adipic acid and sebacic acid and isotridecan-1 -ol.

Absorption: Reaction product of adipic acid and sebacic acid and isotridecan-1 -ol and eventually isotridecan-1 -ol, sebacic acid and adipic acid are rapidly absorbed from the gastro-intestinal tract, whereas dermal absorption is expected to be slow.

Biotransformation: Reaction product of adipic acid and sebacic acid and isotridecan-1 -ol is expected to hydrolyse rapidly in vivo to isotridecan-1 -ol, sebacic acid and adipic acid. The alcohol will be oxidised by alcohol dehydrogenase and aldehyde dehydrogenase to the corresponding aldehyde and carboxylic acid. Isotridecan-1 -ol is not expected to be a good substrate for ADH and AlDH, due to its branched bulky structure. ß-Oxidation of the carboxylic acid may be hindered by methy/alkyl substituents at uneven positions, forcing oxidation at other positions. and preventing further degradation in the citrate cycle. Therefore, significant chain hydroxylation and conjugation reactions (e.g. glucuronides, sulfates) of the alcohol and of other metabolic oxidation products are expected to account for the majority of the biotransformation.

Excretion of polar metabolites and conjugates may occur via urine and bile and is estimated to be substantial. Expiration of CO2 is not expected to be important Entero-hepatic circulation of metabolites excreted via bile is likely to occur (Eisenbrand 2002).

 

Di-2-ethylhexyl adipate (DEHA)

Absorption, Distribution, Excretion

An ADME study was performed in mice, rats and monkeys (CMA, 1984). The data showed that after oral administration DEHA or its metabolites is readily absorbed, and distributed to various tissues (with highest levels recovered in blood and liver). From these data absorption rates of 67-98% were noted. The highest absorption rates were noted for the mice 98 -100%, in comparison with rats (75%) and monkeys (49-67%).

The excretion rates were also extensive (90-100%) and rapid. After 24 hours rats and monkeys showed lower elimination in urine (60-74%) and higher elimination in feces (app. 20 %).

Metabolism

Urine of mice, rats, and monkeys contained 2-ethylhexanoic acid (EHA), its glucuronic acid conjugate, a hydroxy acid (5-hydroxy-2-ethylhexanoic acid,5-OH EHA), and the diacid (2-ethyl-1,6-hexanedioic acid, DiEHA). In monkeys, glucuronides of the monoester, monoethylhexyladipate (MEHA), and the alcohol, ethylhexanol (EH) were also tentatively identified. In a human volunteers study, similar metabolites were found in urine and MEHA was found in fecal samples (Loftus, 1993).

The GI-tracts contained appreciable amounts of Diester (DEHA), monoester, and alcohol (EH). Hydrolysis to the alcohol through the monoester appears, therefore, to be the principal metabolic process.

Although the site of DEHA metabolism was not definitively determined, the data suggest that hydrolysis to the mono-ester occurs primarily in the GI tract. The absorbed 14C appears to be primarily the alcohol; the diester and monoester were detected in the liver only in small quantities.

Summary

Overall the data presented in the ADME studies indicate that orally administered 14C-DEHA was rapidly hydrolyzed in the GI tract before absorption and distribution to tissues. Hydrolysis of the monoester, MEHA, also appears to occur readily, leading to the low recovery of this metabolite in the hepatic tissue and urine. Low doses of' DEHA and/or its metabolites were absorbed rapidly and distributed to major organs and tissues. Absorption, however, was incomplete following a high dose of 14C-DEHA. The absorbed radioactivity is metabolized further in the liver before elimination in urine, expired air, and feces. Dose-dependent changes in absorption, tissue uptake, metabolism, and elimination were demonstrated in mice. Sex differences were also apparent in the hepatic uptake and metabolism of the absorbed radioactivity. The data indicate little, if any, prolonged retention of DEHA or its metabolites in blood and tissue following oral administration to mice, rats, and monkeys. From the results of the in vivo-study of Takahashi et al., 1981 it can be concluded that the elimination of radioactivity from tissues and organs is very rapid and there is no specific organ affinity under the experimental conditions. There was no evidence of the accumulation of radioactivity in any organs or tissues.