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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:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: secondary literature

Data source

Reference
Reference Type:
publication
Title:
A toxicologic and dermatologic assessment of linalool and related esters when used as fragrance ingredients
Author:
Bickers D., Calow P., Greim H., Hanifin J.M., Rogers A.E., Saurat J.H., Sipes I.G., Smith R.L. and Tagami H.
Year:
2003
Bibliographic source:
Food and Chemical Toxicology 41:919-942

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline required
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Radiolabelling:
no

Test animals

Species:
other: Not relevant
Strain:
other: Not relevant
Details on species / strain selection:
Not relevant
Sex:
not specified
Details on test animals and environmental conditions:
Not relevant

Administration / exposure

Route of administration:
other: Not relevant
Vehicle:
other: Not relevant
Details on exposure:
Not relevant
Duration and frequency of treatment / exposure:
Not relevant
No. of animals per sex per dose:
Not relevant
Positive control:
Not relevant
Details on study design:
Not relevant
Details on dosing and sampling:
Not relevant
Statistics:
Not relevant

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Not relevant
Details on distribution in tissues:
Groups of 4 mice were exposed to an atmosphere containing 5 mg/L lavender oil (which contained 37.3% linalool and 41.6% linalyl acetate). After lavender oil inhalation, the serum linalool levels were 3 ng/mL and the serum linalyl acetate levels were 11 ng/mL. The addition of b-glucuronidase to these one hour samples resulted in an increase of serum linalool to 4 ng/mL after lavender oil inhalation.
Details on excretion:
Tertiary alcohols such as linalool are excreted in the urine and to a lesser extent feces.
Biliary excretion of conjugated linalool was determined in male rats that received a single intraperitoneal dose of 20 mg linalool. More than 25% of the dose appeared exclusively in the form of polar conjugates in the bile within 6–11 h,principally in the first 4 h; no free linalool was detected.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
In general, esters are hydrolyzed to their corresponding alcohol and carboxylic acid. Hydrolysis is catalyzed by carboxylesterases or esterases. Linalyl esters are expected to be hydrolyzed in humans to yield linalool and the corresponding carboxylic acid. Linalyl acetate hydrolyzes in gastric juice to yield linalool which, to some extent, is rapidly ring closed to yield alpha-terpineol. Both linalool and alpha-terpineol may then be either conjugated and excreted or oxidized to more polar excretable metabolites.

The metabolic fate of linalool has been studied in mammals. Tertiary alcohols such as linalool are metabolized primarily through conjugation with glucuronic acid. In rats, the majority (55%) of an orally administered 14C-labelled dose of 500 mg/kg linalool was excreted in the urine as the glucuronic acid conjugate,while 23% of the dose was excreted in expired air,and 15% was excreted in the feces within 72 h of dose administration. Only 3% was detected in tissues after 72 h,with 0.5% in the liver,0 .6% in the gut, 0.8% in the skin and 1.2% in the skeletal muscle. Linalool and its P-450 derived metabolites are converted to glucuronide conjugate by rat liver homogenates.

Bioaccessibility

Bioaccessibility testing results:
Not relevant

Applicant's summary and conclusion

Executive summary:

Groups of 4 mice were exposed to an atmosphere containing 5 mg/L lavender oil (which contained 37.3% linalool and 41.6% linalyl acetate). After lavender oil inhalation, the serum linalool levels were 3 ng/mL and the serum linalyl acetate levels were 11 ng/mL. The addition of b-glucuronidase to these one hour samples resulted in an increase of serum linalool to 4 ng/mL after lavender oil inhalation.

In general, esters are hydrolyzed to their corresponding alcohol and carboxylic acid. Hydrolysis is catalyzed by carboxylesterases or esterases. Linalyl esters are expected to be hydrolyzed in humans to yield linalool and the corresponding carboxylic acid. Linalyl acetate hydrolyzes in gastric juice to yield linalool which, to some extent, is rapidly ring closed to yield alpha-terpineol. Both linalool and alpha-terpineol may then be either conjugated and excreted or oxidized to more polar excretable metabolites.

The metabolic fate of linalool has been studied in mammals. Tertiary alcohols such as linalool are metabolized primarily through conjugation with glucuronic acid. In rats, the majority (55%) of an orally administered 14C-labelled dose of 500 mg/kg linalool was excreted in the urine as the glucuronic acid conjugate,while 23% of the dose was excreted in expired air,and 15% was excreted in the feces within 72 h of dose administration. Only 3% was detected in tissues after 72 h, with 0.5% in the liver, 0.6% in the gut, 0.8% in the skin and 1.2% in the skeletal muscle. Linalool and its P-450 derived metabolites are converted to glucuronide conjugate by rat liver homogenates.

Tertiary alcohols such as linalool are excreted in the urine and to a lesser extent feces. Biliary excretion of conjugated linalool was determined in male rats that received a single intraperitoneal dose of 20 mg linalool. More than 25% of the dose appeared exclusively in the form of polar conjugates in the bile within 6-11 h, principally in the first 4 h; no free linalool was detected.