3,5,5-trimethylhexan-1-ol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

(Q)SAR

Adequacy of study:

other information

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Remarks:

Secondary source, review article

Justification for type of information:

QSAR prediction

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

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

3,5,5-trimethylhexan-1-ol

EC Number:

222-376-7

EC Name:

3,5,5-trimethylhexan-1-ol

Cas Number:

3452-97-9

Molecular formula:

C9H20O

IUPAC Name:

3,5,5-trimethylhexan-1-ol

Details on test material:

There are no data specifically on 3, 5, 5-trimethylhexan-1-ol, but on several other struturally related saturated aliphatic branched-chain primary alcohols

Radiolabelling:

no

Results and discussion

Metabolite characterisation studies

Metabolites identified:

no

Any other information on results incl. tables

Absorption

In general, branched-chain aliphatic acyclic alcohols, aldehydes and acids are rapidly absorbed from the gastrointestinal tract (Semino 1998; references Gaillard &Derache, 1965; Dawson et al., 1964).

Biotransformation

(1) Oxidation

(a) Alcohol dehydrogenase pathway

Like other long chain saturated primary alcohols, 3, 5,5-trimethylhexan-1-ol undergoes oxidation by alcohol dehydrogenase (ADH) to isononanal, followed by further oxidation by aldehyde dehydrogenase (AlDH) to isononanoic acid. The acid undergoes degradation via ß-oxidation and citrate cycle.

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).

(b) ß-oxidation and further usage in the citrate cycle proceeds easily for linear alcohols and branched alcohols bearing a methyl group at even positions. Methyl groups at uneven positions, or a 2 -ethyl group, inhibit ß-oxidation, which favors alternative metabolic pathways (Semino, 1998).

(2) 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 (w- or w-1 oxidation) result inpolyolswhich may be further oxidized to carbonic or dicarbonic acids, orketoacids, etc.

(3) 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).

The attached figure 1, Metabolism of 2 -EH, outlines the described reactions.

 

Applicant's summary and conclusion

Conclusions:

Expectedly, isononanol will be rapidly absorbed from the GI-tract. Biotransformation will probably be governed by chain oxidation reactions and conjugation reactions, followed by urinary and biliary excretion. Oxidation by ADH will occur at a low rate, but the 3-methyl group inhibits ß-oxidation and further usage in the citrate cycle.

Executive summary:

Given the background information on saturated long chain primary alcohols, the following is expected for3, 5, 5,-trimethylhexan-1-ol:

Absorption: isononanol is rapidly absorbed from the gastro-intestinal tract, whereas dermal absorption is expected to be slow.

Biotransformation: isononanol is expected to be a poor substrate for ADH and AlDH, and ß-oxidation is hindered by the methyl group in the uneven 3 -position, which prevents further degradation in the citrate cycle. Therefore, significant chain hydroxylation and conjugation reactions of the unchanged isononanol 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).