3,5,5-trimethylcyclohex-2-enone

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no data

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

publication

Title:

Transformations metaboliques de la trimethyl-3,5,5, cyclohexene-2, one-1 (isophorone)

Author:

Dutertre Catella H, Lich NP, Quan DQ and Truhaut R

Year:

1978

Bibliographic source:

Toxicol. Europ. Res. 1, 209-216

Report date:

1978

Materials and methods

Objective of study:

metabolism

Principles of method if other than guideline:

other: metabolism study; method see reference

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

3,5,5-trimethylcyclohex-2-enone

EC Number:

201-126-0

EC Name:

3,5,5-trimethylcyclohex-2-enone

Cas Number:

78-59-1

Molecular formula:

C9H14O

IUPAC Name:

3,5,5-trimethylcyclohex-2-enone

Constituent 2

Reference substance name:

Isophorone

IUPAC Name:

Isophorone

Details on test material:

origin: Ugine-Kuhlmann ; purity > 99%
ca. 91.5 % alpha-isophorone, CAS-78-59-1
ca. 8.5 % beta-isophorone, CAS 471-01-2
traces 3,3,5-trimethylcyclohexanone, CAS 873-94-9

Remark: No distincion was made between alpha-isophorone, CAS-78-59-1 and  beta-isophorone, CAS 471-01-2

Radiolabelling:

no

Test animals

Species:

other: rabbits and rats

Strain:

other: rabbit: New Zealand White; rat: Wistar

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ORGANISMS
- Rabbits, New Zealand White
-Rats, Wistar
- Weight at study initiation:    rabbits ca. 2.5 kg; rats ca. 250 g
- Number of animals: not reported

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: rabbits: pure substance followed by ca. 20 ml water; rats: olive oil

Details on exposure:

ADMINISTRATION / EXPOSURE 
- Duration of test/exposure: single dose
- Type of exposure: gavage
- Post exposure period:    Air sampling for 6 hours after dosing; Urine sampling 24 and 48 hours after dosing  
- Vehicle:    rabbits: pure substance followed by ca. 20 ml water   rats: olive oil
- Concentration in vehicle: 0.2 g/ml (rats)
- Total volume applied: 1 ml/200 g bw (rats)
- Doses: 1000 mg/kg bw
SAMPLING
- Exhaled air (part of the animals): absorption on charcoal
- Urine sampling for 48 hours

Duration and frequency of treatment / exposure:

single dose

Doses / concentrations

Remarks:

Doses / Concentrations:
1000 mg/kg bw

No. of animals per sex per dose / concentration:

not reported

Control animals:

no

Positive control reference chemical:

no positive control

Details on study design:

ANALYSIS
Urine: Enzymatic hydrolysis by beta-glucuronidase (buffered at pH 4.7, 37  °C), extraction, gas chromatography, identification using Kovats index
Charcoal: Elution with dichloromethane, gas chromatography,  identification using Kovats index

Details on dosing and sampling:

no details

Statistics:

not reported

Results and discussion

Preliminary studies:

not reported

Toxicokinetic / pharmacokinetic studies

Details on absorption:

not applicable

Details on distribution in tissues:

not applicable

Details on excretion:

Following oral administration of isophorone to rats and rabbits, the substance was partly eliminated unchanged in expired air and urine. The
remainder was metabolized to: see below

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Urine:  The following substances were identified both in rabbits and rats urine,  however in varying ratios:
- Unreacted isophorone
- 3,5,5-trimethylcyclohexan-1-one (dihydroisophorone - mainly in rats)
- 3,5,5-trimethyl-2-cyclohexen-1-ol (isophorol - mainly in rabbits)  eliminated as glucuronide
- 3,5,5-trimethylcyclohexan-1-ol (CAS 116-02-9), cis (933-48-2) and trans  (767-54-4) isomers. 
These compounds were identified only via GC and correlation to Kovats  indices.  Further compounds were seen, but could not be identified.

5,5-dimethyl-2-cyclohexen-1-one-3-carboxylic acid was extracted, isolated  and identified (GC, IR) in the urine of rabbits.
Expired air of rats and rabbits: unreacted isophorone

Any other information on results incl. tables

Fig. 1 Metabolic scheme for isophorone: see atteched document

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: while part of the absorbed isophorone is excreted unchanged via urine and exhaled air, metabolites are mainly excreted as glucuronides
The main metabolite of rabbits after isophorone administration is  5,5-dimethyl-2-cyclohexene-1-one-3-carboxylic acid found as glucuronide  
conjugate in the urine (after 48 hours). Further detoxifications occur in rabbit and rat was hydrogenation of the 1-one-, the 2-ene- and both  
positions.

Executive summary:

Following oral administration of isophorone to rats and rabbits, the substance was partly eliminated unchanged in expired air and urine; the remainder was metabolized (see attached document) to:

a) 5,5 -dimethyl-cyclohex-1-en-3 -one-1-carboxylic acid (i), derived from isophorone by methyl-oxidation;

b) isophorol (3,5,5 -trimethyl-cyclohex-2 -en-1 -ol) (ii), formed by the reduction of the ketonic group to a secondary alcohol and eliminated as a glucuronide;

c) dihydroisophorone (3,5,5 -trimethyl-cyclohexanone) (iii), proceeding from the hydrogenation of the cyclohexene ring; and

d) cis- and trans-3,5,5 -trimethyl-cyclohexanol-1 (iv), likely to have formed from dihydroisophorone.

The amounts of the identified metabolites as a proportion of the administered dose were not reported. The metabolites were detected in the urine of rats and rabbits 24 and 48 hours after the administration. The expired air contained unchanged isophorone 6 hours after dosing.