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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Deficiencies: missing: purity of substance, number of animals used, statistical methods applied for data analysis

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1988

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The present work describes the isolation and characterization of several metabolites from the urine of rats treated with L-Menthol.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Radiolabelling:
no

Test animals

Species:
rat
Strain:
other: IISC
Sex:
male
Details on test animals and environmental conditions:
Adult male rats (IISc. strain, body weight 180-200 g) were used in these studies. For the isolation of metabolites, L-menthol (800 mg/kg bw/day) was administered orally by gastric intubation as a suspension in 1 % methyl cellulose solution (2 ml) for 20 days.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 1 % methyl cellulose solution (2 ml)
Details on exposure:
no data
Duration and frequency of treatment / exposure:
daily up to 10 days
Doses / concentrations
Dose / conc.:
800 mg/kg bw/day
No. of animals per sex per dose:
no data
Control animals:
yes, concurrent vehicle
Positive control:
Not set
Details on study design:
no data
Details on dosing and sampling:
Urine was collected in bottles maintained at 0-4°C.
Statistics:
no data

Results and discussion

Preliminary studies:
Irrelevant
Main ADME results
Type:
metabolism
Results:
In vivo, the major urinary metabolites were the compounds p-menthane-3,8-diol and 3,8-dihydroxy-p- menthane-7-carboxylic acid. Further metabolites were p-menthane-3,9-diol and 3,8-oxy-p-menthane-7-carboxylic acid.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
No data
Details on distribution in tissues:
no data
Details on excretion:
the four mentioned metabolites were identified in rat urine after oral L Menthol administration

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Metabolites isolated and characterized from the urine of rats after oral administration of L-Menthol were the following: p-menthane-3,8 -diol, p-menthane-3,9 -diol, 3,8 -oxy-p-menthane-7 -carboxylic acid, and 3,8 -dihydroxy-p-menthane-7 -carboxylic acid.

Any other information on results incl. tables

Neutral Metabolites.

The neutral fraction on TLC analysis (system 2) showed the presence of one major (RF 0.46) and two minor (RF 0.64 and 0.3) metabolites. The compound with RF 0.64 was found to be L-menthol. The compound with RF 0.3 (120 mg) was assigned the structure of p-methane-3,9-diol.

Acidic Metabolites.

Examination of the methyl esters of the acidic fraction by TLC (system 2) showed two major (RF 0.58

and 0.31) and one minor (RF 0.72) metabolites.

The compound (85 mg) with RF 0.72 was tentatively assigned as the methyl ester of 3,8-oxy-p-menthane-7-carboxylic acid;

The fraction with RF 0.58 could not be purified further to yield any compound for characterization;

The most polar methyl ester (RF 0.31; 570 mg) was identified as the methyl ester of 3,8-dihycroxy-p-menthane-7-carboxylic acid.

The other compounds present in this fraction could not be identified.

Applicant's summary and conclusion

Conclusions:
Interpretation of results: no bioaccumulation potential based on study results L Menthol has the ability to induce the hepatic microsomal cytochrome P-450 system and NADPH-cytochrome c (P-450) reductase by nearly 80% after oral administration to rats for 3 days.
4 different metabolites of L-menthol were identified in rat urine. L-Menthol has the ability to induce the hepatic microsomal P-450 and NADPH-cytochrome c (P-450) reductase in rats.
Executive summary:

Metabolism in rats was investigated. Metabolites isolated and characterized from the urine of rats after oral administration of L-Menthol were the following: p-menthane-3,8 -diol, p-menthane-3,9 -diol, 3,8 -oxy-p-menthane-7 -carboxylic acid, and 3,8 -dihydroxy-p-menthane-7 -carboxylic acid. Repeated oral administration of L-Menthol to rats for three days resulted in the increase of both liver microsomal cytochrome P-450 content and NADPH-cytochrome c reductase activity by nearly 80%.