Eucalyptus globulus, ext.

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1986

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

In vivo metabolism study, following oral (gavage) administration in rats.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Cineole

EC Number:

207-431-5

EC Name:

Cineole

Cas Number:

470-82-6

Molecular formula:

C10H18O

IUPAC Name:

1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane

Test material form:

not specified

Details on test material:

- Name of test material (as cited in study report): Cineole
- Analytical purity: 99 % (GLC analysis)

Radiolabelling:

no

Test animals

Species:

rat

Strain:

not specified

Sex:

male

Administration / exposure

Route of administration:

other: oral - gastric intubation

Vehicle:

other: 1 % methyl cellulose

Duration and frequency of treatment / exposure:

Once daily for 20 days

Doses / concentrations

Remarks:

Doses / Concentrations:
800 mg/kg bw/day

No. of animals per sex per dose / concentration:

No data

Control animals:

yes, concurrent vehicle

Results and discussion

Main ADME results

Type:

metabolism

Results:

hydroxylated derivatives of Cineol such as 2-hydroxy cineole and 3-hydroxy cineole are excreted as conjugates

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Not applicable

Details on distribution in tissues:

Not applicable

Details on excretion:

Not applicable

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

- The acid methyl esters (250 mg) were subjected to TLC which showed the presence of one major compound i.e., methyl ester of 1,8-dihydroxy -10-carboxy p-methane and three minor compounds. The TLC analysis of the neutral fraction (200 mg) showed the presence of one major i.e., 2-hydroxy cineole and two minor metabolites. The neutral fraction (500 mg) obtained from hydrolysed urine on TLC analysis revealed the presence of two major (similar to 2-hydroxy cineole and 3-hydroxy cineole) and two minor metabolites.
- Based on the results, it is rather difficult to predict the sequence of reactions taking place during the biotransformation of cineole. However, one can envisage the formation of 1,8-dihydroxy-10-carboxy-p-methane through the intermediary of p-methane 1,8-diol and further metabolism is possibly initiated by the oxygenation of the C-10 methyl group resulting in the formation of p-methane-1,8,10-triol which undergoes stepwise oxidation to the corresponding aldehydes and then to an acid.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

Not applicable

Any other information on results incl. tables

None

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: hydroxylated derivatives of Cineol such as 2-hydroxy cineole and 3-hydroxy cineole are excreted as conjugates
Cineole was metabolised to hydroxylated derivatives such as 2-hydroxy cineole and 3-hydroxy cineole in rats and are excreted as conjugates.

Executive summary:

In an in vivo metabolism study, 1,8-Cineole was administered by oral route (via gastric intubation) to male albino rats at the dose of 800 mg/kg bw/day once daily for 20 days as a suspension in 1 % methyl cellulose solution. Control rats were given only with vehicle (4 mL/kg bw/day). Urine samples collected daily for 20 days, were adjusted to pH 3-4 and extracted with ether. The aqueous portion containing conjugated metabolites was then subjected to acid hydrolysis and extracted with ether (Chadha and Madyastha 1984). Both the ether extracts were separated into neutral and acidic fractions. The total acidic fraction was methylated using diazomethane (Chadha and Madyastha 1984). Thin-layer chromatographic (TLC) analyses (silica gel G) of the metabolites were carried out using hexane-ethyl acetate. Separation and purification of the metabolites were accomplished by using a silica gel column and hexane-ethyl acetate as the eluent.

The acid methyl esters (250 mg) were subjected to TLC which showed the presence of one major compound i.e., methyl ester of 1,8-dihydroxy -10-carboxy p-methane and three minor compounds. The TLC analysis of the neutral fraction (200 mg) showed the presence of one major i.e., 2-hydroxy cineole and two minor metabolites. The neutral fraction (500 mg) obtained from hydrolysed urine on TLC analysis revealed the presence of two major (similar to 2-hydroxy cineole and 3-hydroxy cineole) and two minor metabolites. Based on the results, it is rather difficult to predict the sequence of reactions taking place during the biotransformation of cineole. However, one can envisage the formation of1,8-dihydroxy-10-carboxy-p-methane through the intermediary of p-methane 1,8-diol and further metabolism is possibly initiated by the oxygenation of the C-10 methyl group resulting in the formation of p-methane-1,8,10-triol which undergoes stepwise oxidation to the corresponding aldehydes and then to an acid. The opening of the ether bridge in cineole could result in the formation of a p-menthanoid cation with a positive charge either at C-1 or C-8 which further gets readily neutralized by the attack of a hydroxide ion to yield p- methane-1, 8-diol. The 2- and 3-hydroxy derivatives from cineole have been reported in bacterial (MacRae et al. 1979) and fungal systems (Nishimura et al. 1982) respectively. So it appears that the microbial systems are more specific while carrying out the hydroxylation of cineole unlike the mammalian system which hydroxylates at C-2 as well as C-3 position. Both these hydroxylated derivatives are excreted as conjugates.

 

1,8-Cineole was metabolised to hydroxylated derivatives such as 2-hydroxy cineole and 3-hydroxy cineole in rats and are excreted as conjugates.