3,7-dimethylnona-1,6-dien-3-ol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

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

Adequacy of study:

key study

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study was not performed according to GLP. Study was similar to OECD 417, metabolisation and enzyme induction were studied. Ethyllinalool and linalool are structural homologues which differ only by a methyl-group. Their physical-chemical properties are comparable and available experimental data on same toxicological endpoints, showed identical toxicological properties. Therefore, it is assumed that all toxicological properties are as well comparable and thus read-across is justified.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Metabolism of geraniol and linalool in the rat and effects on liver and lung microsomal enzymes

Author:

Chadha, A., Madhava Madyastha, K.

Year:

1984

Bibliographic source:

Xenobiotica, 1984, vol 14, no 5, pp 365-374

Materials and methods

Objective of study:

other: metabolism and enzyme induction

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

yes

Remarks:

only metabolism was studied

Principles of method if other than guideline:

Metabolites in urine were determined, as well as enzyme activities in lung and liver microsomes

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Linalool

EC Number:

201-134-4

EC Name:

Linalool

Cas Number:

78-70-6

Molecular formula:

C10H18O

IUPAC Name:

3,7-dimethylocta-1,6-dien-3-ol

Details on test material:

- Name of test material (as cited in study report): linalool
- Analytical purity: >99.5%

Radiolabelling:

no

Test animals

Species:

rat

Strain:

other: IISC strain

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 160-200 g
- Housing: individually
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): free access to food
- Water (e.g. ad libitum): free access to water

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 1% methyl cellulose soln.

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Suspension in 1% methyl cellulose soln.

DIET PREPARATION

VEHICLE
- Amount of vehicle (if gavage): 4 ml/kg

HOMOGENEITY AND STABILITY OF TEST MATERIAL:
Suspension

Duration and frequency of treatment / exposure:

Induction study: once daily for six days
Identification of metabolites: once daily for 20 days

Doses / concentrations

Remarks:

Doses / Concentrations:
Induction study: 600 mg/kg bw
Identification of metabolites: 800 mg/kg bw

No. of animals per sex per dose / concentration:

Not specified

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

Not relevant

Details on study design:

No remarks

Details on dosing and sampling:

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: urine collected daily for 20 days following oral administration
- Method type(s) for identification: TLC on silica gel G-coated plates,GC, HPLC, and NMR

TREATMENT FOR CLEAVAGE OF CONJUGATES: Urine was acidified to pH 3-4 and extracted with ether. The aqueous portion containing conjugated metabolites was refluxed under acid conditions

Statistics:

No remarks

Results and discussion

Preliminary studies:

No remarks

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Not relevant

Details on distribution in tissues:

Not relevant

Details on excretion:

Not relevant

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The identified metabolites of linalool were 8-hydroxy linalool and 8-carboxy linalool (main metabolites). Several other (minor) metabolites could not be identified.

Any other information on results incl. tables

Administration of linalool to rats resulted in a statistically significant increase (~50%) in the concentration of cytochrome P-450 in the liver microsomes after three days of dosing. After six days, it had decreased to control values. No significant changes in the activities of cytochrome b5, NADPH-cytochrome c reductase and NADH-cytochrome c reductase in the liver microsomes were observed after six days, however, an increase (~20%) in cytochrome b5 was noticed after three days of treatment.

No effects were observed on the activity of measured enzymes in the lung microsomes.

Read across:

Ethyllinalool and linalool are structural homologues which differ only by a methyl-group. Their physical-chemical properties are comparable and available experimental data on same toxicological endpoints, showed identical toxicological properties. Therefore, it is assumed that all toxicological properties are as well comparable and thus read-across is justified. Toxicokinetic data were identified for linalool which was shown to be rapidly and completely absorbed and excreted upon oral administration. Although toxicokinetic data on ethyllinalool were not identified, it can be reasonably assumed that ethyllinalool is absorbed, distributed, metabolized and excreted via the same mechanisms as linalool. This assumption is supported by (i) comparable vapor pressure, water solubility and log Pow and (ii) in silico metabolism prediction for ethyllinalool using computational software METEOR version 12. It is predicted that ethyllinalool may be glucuronidated at the hydroxyl-group and / or hydroxylated at the allylic positions and at the terminal methyl-group with subsequent glucuronidation.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: Linalool is metabolised extensively
The metabolism of linalool after oral exposure to rats results in the metabolites 8-hydroxy linalool and 8-carboxy linalool, indicating that 8-hydroxylation (allylic hydroxylation) is the major pathway. Although liver-microsomal P450 enzymes were elevated after three days of treatment, it decreased to normal values after six days, therefore no conclusion can be drawn on the role of cytochrome P450 in the metabolism of linalool. Linalool did not affect any of the lung-microsomal parameters measured.

Executive summary:

In an induction experiment activities of lung- and liver-microsomal enzymes after six days of exposure to linalool (600 mg/kg bw/day) were measured.

The induction experiment showed that although liver-microsomal P450 enzymes were elevated after three days of treatment, it decreased to normal values after six days. Therefore no conclusion can be drawn on the role of cytochrome P450 in the metabolism of linalool. Furthermore, linalool did not affect any of the lung-microsomal parameters measured.

Metabolism was studied in urine obtained from male rats treated with 800 mg/kg bw/day for 20 days. In this experiment the metabolites 8-hydroxy linalool and 8-carboxy linalool were identified as major metabolites, indicating that 8-hydroxylation is the major pathway. In addition, several other metabolites were found, which could, however, not be identified.