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

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Secondary sources assessed to provide reliable background information related to chemical groups/classes

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Data source

Reference

Reference 1

Reference Type:

review article or handbook

Title:

Unnamed

Year:

1998

Report date:

1998

Reference 2

Reference Type:

review article or handbook

Title:

Alkohole, Ether, Ester

Author:

Eisenbrand G, Metzler M

Year:

2002

Bibliographic source:

Toxikologie für Naturwissenschaftler und Mediziner. Wiley-VCH, Weinheim, Germany, 2002

Report date:

2002

Materials and methods

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Compilation of accepted pharmacological and toxicological principles for the substance classes of esters, alcohols, and acids

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Diisotridecyl adipate

EC Number:

247-660-8

EC Name:

Diisotridecyl adipate

Cas Number:

26401-35-4

IUPAC Name:

bis(11-methyldodecyl) adipate

Details on test material:

There are no data specifically on diisotridecyl adipate, but on saturated aliphatic branched-chain primary alcohols, acids and esters

Results and discussion

Any other information on results incl. tables

Absorption

In general, branched-chain aliphatic acyclic esters, alcohols, aldehydes and acids are rapidly absorbed from the gastrointestinal tract (Semino 1998a, b).

 

Biotransformation

Esters

Esters are rapidly hydrolysed in vivo in various organs by ubiquitous esterases. Hydrolysis occurs already in the gastrointestinal tract and proceeds in blood, liver, and other organs (Semino 1998a). Diisotridecyl adipate is cleaved into isotridecyl alcohol and adipic acid.

Alcohols

Alcohol dehydrogenase pathway

Like other long chain saturated primary alcohols, isotridecyl alcohol undergoes oxidation by alcohol dehydrogenase (ADH) to the corresponding aldehyde followed by further oxidation by aldehyde dehrogenase (AlDH) to tridecanoic acid. The oxidation rate depends on the Michaelis constant (Km) of the alcohol for the reaction catalyzed by ADH. The Km values depend on the chain length (Km: C2< C1, C3<C4<C5<C6<C7<C8<C9<C10 etc.) and possibly also on steric hindrance due to bulky side chains (Eisenbrand & Metzler, 2002).

Alternative pathways

The proportion of alternative pathways increases with decreasing affinity to ADH (and, therefore, low reaction rates), and increasing dose, chain length and branch grade. Then, chain oxidations (omega- or omega-1oxidation) result in polyols which may be further oxidized to carbonic or dicarbonic acids, or keto acids, etc. For isotridecyl alcohol, this pathway is considered to be of importance due to its branched structure.

Acids

Branched carboxylic acids can undergoes degradation via ß-oxidation preferably in the longer chain to yield shorter fragments. These can be further metabolised in the fatty acid pathway and the citrate cycle. ß-Oxidation and further usage in the citrate cycle proceeds easily for linear alcohols and branched alcohols bearing a methyl group/alkyl substituent at even positions. Methyl groups(alkyl substituents at uneven positions, inhibit ß-oxidation, which favours alternative metabolic pathways (oxidation at other positions) (Semino, 1998b). Due to its branched bulky structure, isotridecanoic acid is expected to show pronounce oxidation other than ß -oxidation.

 

Conjugation

(Hydroxy-) acids may be conjugated, e.g. glucuronidated or sulfated, and the resulting esters may subsequently be excreted via urine or bile. The conjugates may be cleaved in the gut, which opens the possibility of re-absorption of the more lipophilic alcohol moiety, distribution in the body etc. (entero-hepatic circulation). Due to the large hydrophobic alkyl carbon chain of isotridecyl carboxylic acid, it is estimated that conjugation will occur.

Applicant's summary and conclusion

Conclusions:

Expectedly, diisotridecyl adipate will be rapidly absorbed from the GI-tract either intact or already hydrolised into acid and alcohol. Biotransformation will be governed by hydrolysis as first step followed by oxidation reactions of the alcohol and subsequently the aldehyde and acid. In addition, oxidation at the alkyl fraim will occur. Conjugation is expected followed by urinary and biliary excretion. Oxidation by ADH will probably occur at a reduced rate as the branching of the isotridecyl alkyl group impedes ß-oxidation and further usage in the citrate cycle.

Executive summary:

Given the background information on saturated long chain primary esters, alcohols and acids, the following is expected for diisotridecyl adipate.

Absorption: diisotridecyl adipate is already hydrolysed in the gastro-instestinal tract and it is rapidly absorbed either as such or in form of the alcohol and acid. Dermal absorption is expected to be slow.

Biotransformation: diisotridecyl adipate is expected to be hydrolysed rapidly by ubiquitous esterases. Hydrolysis is followed by oxidation of the alcohol and the acid subsequently formed. Adipic acid will enter endogenous metabolic pathways. As alcohol oxidation and ß-oxidation of triisotridecyl alcohol may be hindered due to the bulky and branched structure of the substance, significant chain hydroxylation and conjugation reactions of the unchanged alcohol and hydroxylated and oxidized metabolites are expected to account for the majority of the biotransformation. Excretion of polar metabolites and conjugates may occur via urine and bile. Entero-hepatic circulation of metabolites excreted via bile is likely to occur (Eisenbrand 2002, Semino 1998).