Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
in silico
Type of information:
(Q)SAR
Adequacy of study:
other information
Study period:
1998
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Remarks:
Secondary source, compilation of data on toxicokinetics and metabolism of saturated aliphatic alicyclic branched-chain alcohols, aldehydes and acids
Justification for type of information:
QSAR prediction: migrated from IUCLID 5.6

Data source

Reference
Reference Type:
review article or handbook
Title:
Unnamed
Year:
1998
Report date:
1998

Materials and methods

Principles of method if other than guideline:
no guideline required
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
3,5,5-trimethylhexanoic acid
EC Number:
221-975-0
EC Name:
3,5,5-trimethylhexanoic acid
Cas Number:
3302-10-1
Molecular formula:
C9H18O2
IUPAC Name:
3,5,5-trimethylhexanoic acid
Details on test material:
No substance-specific data are available, but on other saturated aliphatic branched-chain alcohols, aldehydes and acids.

Test animals

Species:
other: summary of in vivo studies and in vitro studies with liver extracts
Strain:
not specified
Sex:
not specified

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
not specified
Control animals:
other: not required

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Aliphatic, alicyclic branched-chain alcohols, aldehydes and acids are in general rapidly absorbed after oral uptake.
Details on excretion:
Metabolites of aliphatic, alicyclic branched-chain alcohols, aldehydes and acids are expected to be excreted as conjugates (glucuronides, sulfates) into the urine.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
As 3,5,5-trimethylhexanol is expected to be poor substrate for alcohol dehydrogenase, the formation of 3,5,5-trimethylhexanal and subsequently of 3,5,5-trimethylhexanoic acid seems to be a minor pathway of metabolism of the alcohol.

3,5,5-trimethylhexanoic acid with an uneven position of methylsubstitution does not undergo ß-oxidation. Alternative pathways (w- or w1-oxidation) therefore gain in importance for the three substances, resulting in the formation of diols, hydroxy acids, keto acids and dicarbonic acids. These metabolites may be conjugated to glucuronides or sulfates, which can be excreted into the urine or bile or cleaved in the gut with the possibility of reabsorption (entero-hepatic circulation).

Any other information on results incl. tables

ß-oxidation and further usage in the citrate cycle proceeds easily only for linear alcohols and branched alcohols bearing a methyl group at even positions. Methyl groups at uneven positions (as in the case of 3,5,5 -trimethylhexanoic acid), or a 2 -ethyl group, inhibit ß-oxidation, which favors alternative metabolic pathways.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: conclusion on formation of 3,5,5-trimethylhexanoic acid from 3,5,5-trimethylhexanol
The formation of 3,5,5-trimethylhexanoic acid from the corresponding alcohol is expected to be a minor metabolism pathway. For this reason, toxicological data from the latter substances cannot be used in risk assessment of the 3,5,5-trimethylhexanoic acid.
Executive summary:

3,5,5-trimethylhexanoic acid is expected to be rapidly absorbed after oral uptake. To all appearances it does not undergo ß-oxidation due to an un-even methyl substitution. The metabolism is suspected to occur via w- or w1-chain hydroxylation and subsequent formation of various ketoacids or dicarbonic acids, which are excreted into bile or urine or cleaved in the gut and undergo entero-hepatoc circulation.

No noteworthy formation of 3,5,5-trimethylhexanoic acid is expected from the corresponding alcohol. Therefore, data from this substance are not relevant for the risk assessment of 3,5,5 -trimethylhexanoic acid (Semino, 1998).