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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:
1974
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Methods described clearly and results reported in sufficient detail to consider this a reliable study. Non-GLP study. Klimisch 2 reliability has also been assigned in accordance with (ECHA Practical Guide #6) due to the read-across purpose of this study (tested substance is a major constituent).

Data source

Reference
Reference Type:
publication
Title:
The absorption, distribution and excretion of linalool in the rat.
Author:
Parke, D.V., Quddusur Rahman, K.H.M., Walker, R.
Year:
1974
Bibliographic source:
Biochemical Society Transactions 2: 612-615.

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
1,2[14C]linalool was administered in male Wistar rats intragastricly and intraperitoneally in this study.

Experiment 1: After intragastric administration of 500 mg/kg bw, urine, faeces and expired air were collected and measured at several intervals over a 72 hours period. Radioactivity was determined. At the end of the experiment, residual radioactivity in brain, lung, liver, heart, spleen, gastro-intestinal tract, kidney, skin and skeletal muscle was determined.

Experiment 2: In this experiment intraperitoneal administration was used to determine if biliary excretion occurred. Bile was collected at several intervals after exposure of 2 rats and radioactivity was determined.

Experiment 3: In this experiment one rat was intraperitoneally exposed. Bile from this treated animal was introduced into the duodenum of a second animal. Bile of this animal was then collected. Presence of radioactivity was indicative of enterohepatic circulation.
GLP compliance:
no

Test material

Constituent 1
Chemical structure
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.
- Substance type: Oxygenated monoterpenes / tertiary alcolhol.
- Physical state: Liquid.
- Locations of the label (if radiolabelling): C14 positions 1 and 2 (synthesized by the method of Filip & Movarek (1959).
- Specific activity (if radiolabelling): Experiment 1: 10 µCi, Experiment 2 & 3: 1 µCi.
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 12 weeks.
- Individual metabolism cages: yes (Metabowls, Jencom Ltd).

Administration / exposure

Route of administration:
other: intragastric (gavage) and intraperitioneal
Vehicle:
polyethylene glycol
Details on exposure:
VEHICLE
- Concentration in vehicle: Exp 1: 25% w/w Exp 2&3: 10% w/w
Duration and frequency of treatment / exposure:
Single exposure.
Doses / concentrations
Remarks:
Doses / Concentrations:
Experiment 1: 500 mg/kg bw.
Experiment 2 & 3: 20 mg/animal.
No. of animals per sex per dose / concentration:
Experiment 1: male animals, number not specified.
Experiment 2 & 3: 2 male animals.
Control animals:
no
Positive control reference chemical:
Not applicable.
Details on study design:
Not applicable.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
Experiment 1:
- Tissues and body fluids sampled: urine, faeces, expired air.
- Time and frequency of sampling: collected at intervals over a 72h period.
- Tissues and body fluids sampled at end of experiment (distribution): brain, lung, liver, heart, spleen, gastro-intestinal tract, kidney, skin and skeletal muscle.

Experiment 2:
- Tissues and body fluids sampled: bile.
- Time and frequency of sampling: at intervals over a 6h and 11h period (1 animal for each period).

Experiment 3:
- Tissues and body fluids sampled: bile (from one of the two animals).

METABOLITE CHARACTERISATION STUDIES
Experiment 2:
- Tissues and body fluids sampled: bile.
- Time and frequency of sampling: at intervals over a 6h and 11h period (1 animal for each period).

Experiment 3:
- Tissues and body fluids sampled: faeces, bile.
- Time and frequency of sampling: at intervals over a 12h period.
- From how many animals: 1
Statistics:
Not applicable

Results and discussion

Preliminary studies:
Not applicable.
Main ADME resultsopen allclose all
Type:
absorption
Results:
At least 85% based on appearance in tissues and excretion in urine and exhaled air
Type:
excretion
Results:
97% after 72 hours in exhaled air, urine and faeces
Type:
distribution
Results:
3.1% in liver, gut, skin, skeletal muscle and other organs (e.g. kidney)

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Linalool appears to be rapidly absorbed from the gut as extensive and rapid urinary excretion of radioactivity over the first 36 hours occurs with no significant delay between dosing and appearance of radioactivity in urine. At least 85% appears to be absorbed as this is excreted via urine and exhaled air and found in tissues (approximately 15% is found in faeces).
Details on distribution in tissues:
In Experiment 1, in total 3.1% of the radioactivity remained in the tissue at the end of 72h period following intragastric administration:
- Liver: 0.5%.
- Gut: 0.6%.
- Skin: 0.8%.
- Skeletal muscle: 1.2%.
- Other organs including kidney: insignificant amounts of radioactivity.
Details on excretion:
Experiment 1: approx. 97% of the administered dose is excreted (expired air, urine and faeces) after 72 hours.
- Expired air: 23%.
- Urine: approx. 60%.
- Faeces: approx. 15% (delayed, possible biliary excretion).

Experiment 2:
- Bilary excretion takes place: more than 25% of the ip dose detected after 6-11 hours.

Experiment 3:
- Bile: 2.5% of ip dose detected in second rat after 12 hours (peak at 7-9h).

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
In Experiment 2 (common bile duct): No free linalool being detectable. Polar conjugates were detected, the conjugates were partitially hydrolysed by beta-glucuronidase and to a greater extent by a mixture of beta-glucuronidase and sulphatase.

Any other information on results incl. tables

Experiment 3: Assuming 25% of the ip dose appeared in bile of first animal and also that 25% of conjugates appeared in bile of second animal, it was calculated that 40% of the biliary conjugates are hydrolysed and reabsorbed on the first pass. Therefore extensive enterohepatic circulation is possible, and may partly expain the delayed fecal excretion. Evidence of hydrolysis of biliary conjugates in the gut is provided by the presence of non-polar ether-extractable metabolites in faeces that were absent from bile.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: Complete absorption, no bioaccumulation, rapid excretion, glucuronide- and sulfate conjugates, enterohepatic recirculation
Under the conditions of this study, linalool (500 mg/kg bw) was rapidly absorbed from the gut after oral (gavage) administration. After 72h, 3% of the dose remained in tissues. Intraperitoneal administration (20 mg/animal) showed that more than 25% of the dose is excreted in bile (faeces).
Biliary conjugates and non-polar ether-extractable metabolites (in faeces) are formed. These are glucuronide- and sulfate conjugates. Extensive enterohepatic circulation is possible. Within 72 h, 97% of the dose is excreted with ca. 80% after 36h and 95% after 48h. 60% of administered radioactivity occured in urine, 15% in faeces and 25% in expired air.

At least 85% of linalool has been found systemically available as it was excreted via exhaled air or urine, or present in body tissues. The other 15% is excreted via faeces, but due to the observed (extensive) enterohepatic circulation it is assumed that this amount was also initially absorbed. Bioavailability from an oral dose would therefore be approximately 100%.
Executive summary:

14C labeled linalool was administered to male 12 week old Wistar rats intragastric (500 mg/kg bw) and intraperitoneal (20mg/animal).

In the first experiment, linalool was administered orally (galvage). Urine, faeces and expired air were collected at intervals. After 72h animals were killed and examined for residual radioactivity in brain, lung, liver, heart, spleen, gastro-intestinal tract, kidney, skin and skeletal muscle.

In the second experiment, biliary excretion and enterohepathic circulation was determined using two rats. A cannula was inserted into the common bile duct. Bile was collected at intervals up to 6 hours for the first anumal, and up to 12 hours for the second animal.

In the third experiment, bile from the first animal was introduced into the duodenum of the second animal. Enterohepathic circulation was determined by presence of radioactivity in the bile of the second animal.

Under the conditions of this study, linalool (500 mg/kg bw) was rapidly absorbed from the gut after oral (gavage) administration. After 72h, 3% of the dose remained in tissues. Intraperitoneal administration (20 mg/animal) showed that more than 25% of the dose is excreted in bile (faeces). Biliary conjugates and non-polar ether-extractable metabolites (in faeces) are formed. These are glucuronide- and sulfate conjugates. Extensive enterohepatic circulation is possible. Within 72 h, 97% of the dose is excreted with ca. 80% after 36h and 95% after 48h. 60% of administered radioactivity occured in urine, 15% in faeces and 25% in expired air.

At least 85% of linalool has been found systemically available as it was excreted via exhaled air or urine, or present in body tissues. The other 15% is excreted via faeces, but due to the observed (extensive) enterohepatic circulation it is assumed that this amount was also initially absorbed. Bioavailability from an oral dose would therefore be approximately 100%.