(R)-2,2,3-trimethylcyclopent-3-ene-1-acetaldehyde

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

Not stated

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: A non-GLP study performed to sound scientific principles with a sufficient level of detail to assess the quality of the submitted data.

Data source

Reference

Reference Type:

publication

Title:

Terpenoid biotransformation in mammals. V. Metabolism of (+)-citronellal, (±)-7-hydroxycitronellal, citral, (-)-perillaldehyde, (-)-myrtenal, cuminaldehyde, thujone and (±)carvone in rabbits

Author:

Ishida, T., Toyota, M. and Asakawa, Y.

Year:

1989

Bibliographic source:

Xenobiotica Vol. 19, No. 8, 843-855

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

In this study, the metabolism of several terpenoids were investigated. Six male rabbits per group were administered with a 20 mL dose containing 2 g of the test material. Urine was collected in metabolism cages over a period of three days, and the identity of metabolites and the relevant pathways were defined by TLC.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

(-)-perillaldehyde

IUPAC Name:

(-)-perillaldehyde

Constituent 2

Reference substance name:

(-)-myrtenal

IUPAC Name:

(-)-myrtenal

Radiolabelling:

no

Test animals

Species:

rabbit

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 2.5-3.0 kg
- Fasting period before study: 1 day
- Housing: metabolism cages
- Metabolism cages: yes
- Diet (e.g. ad libitum): rabbit food ad libitum
- Water (e.g. ad libitum): ad libitum

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

other: 100 mL water with 0.02g Tween-80 at 5ºC

Details on exposure:

20 mL of the aqueous solution containing about 2 g of sample, followed by 20 mL water

Duration and frequency of treatment / exposure:

A single dose

Doses / concentrations

Remarks:

Doses / Concentrations:
2 g per animal

No. of animals per sex per dose / concentration:

6 males

Control animals:

not specified

Details on dosing and sampling:

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: daily for 3 days at room temperature
- Method type(s) for identification: urine pH was adjusted to 6.0 with phosphate buffer and incubated with ß-glucuronidase/arylsulphatase for 48 hours at 37ºC and ether-extracted for 48 hours. The ether later was washed with 0.5M Na2CO3 and 1.25M NaOH successively and separated into three fractions to give acidic, phenolic and neutral portions. The neutral portion was purified by silica gel chromatography with n-hexane-ethyl acetate (4:1 v/v). The acidic and phenolic fractions were combined and esterified with methyl iodide in acetone and K2CO3 and purified as in the case of the neutral fraction.

TLC plates of silica gel F254 were used with n-hexane-ethyl acetate as solvent and materials were detected by UV (254 nm) and iodine vapour.

UV spectra were recorded with double-beam spectrometers. 1H- and 13C-NMR were also recorded. Optical rotation was measured with a polarimeter. GC-MS conditions were: column packed with silicone oil (1%) with oven temperature of 50-250ºC, 250ºC for injector and detector and helium at 30 mL/minute. Ionization voltage was 70 eV. GC equipped with hydrogen-FID and a thermal conductivity detector was used with 5% silicone oil column with the following conditions: 100-250ºC oven temperature, 250ºC for injection and detector, nitrogen at 40 mL/minute.

Results and discussion

Main ADME results

Main ADME results 1

Type:

metabolism

Results:

After administration of (-)-perillaldehyde, neutral (0.83) and acidic metabolites (4.65 g after methylation) were identified, a total of four metabolites were identified

Main ADME results 2

Type:

metabolism

Results:

After administration of (-)-myrtenal, neutral (0.64) and acidic metabolites (2.878 g after methylation) were identified, two neutral and two esters were identified

Main ADME results 3

Type:

metabolism

Results:

The following metabolites were identified from the administration of (-)-myrtenal: myrentol (55 %), cis-10-pinanol (44 %), myrtenic acid as methyl ester (76 %) and perillic acid as methyl ester (m/z %)

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

(-)-PERILLALDEHYDE
The two main compounds were identified as a perillyl alcohol and a shisool. The perillyl alcohol represented 46% of the neutral metabolites by GC whereas the shisool represented 39%. Perillic acid as methyl ester represented 57% of the acidic metabolites. p-Isopropyl benzoic acid as methyl ester was also identified.

(-)-MYRTENAL
Myrtenol represented 55% of the neutral metabolites by GLC and cis-10-pinanol represented 44%. Myrtemic acid as methyl ester represented 76% of the neutral metabolites. Perillic acid as methyl ester was also identified.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
Under the conditions of the study, the metabolism of (-)-perillaldehyde and (-)-myrtenal occurs via both oxidation and reduction pathways.

Executive summary:

Under the conditions of the study, the metabolism of (-)-perillaldehyde and (-)-myrtenal occurs via both oxidation and reduction pathways.