Registration Dossier

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: Only very short publication available, but experimental result consistent with good scientific knowledge.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
The absorption, distribution and excretion of linalool in the rat
Author:
DV Parke, KHM Quddusar Rahman and R Walker
Year:
1974
Bibliographic source:
Biochemical Society Transactions 2:612–615

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
number and sex of animals is not specified
Principles of method if other than guideline:
1,2[14C]linalool was administered in male Wistar rats intragastrically 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

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Linalool
- Substance type: Tertiary alcohol
- Locations of the label (if radiolabelling): Positions 1 and 2 of linalool
- Specific activity (if radiolabelling):
Experiment 1: 10 uCi
Experiment 2 & 3: 1 uCi
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 12 weeks
- Individual metabolism cages: yes

Administration / exposure

Route of administration:
other: intragastric (exp. 1) and intraperitoneal (exp. 2 & 3)
Vehicle:
propylene glycol
Details on exposure:
VEHICLE
- Concentration in vehicle:
Experiment 1: 25% (w/v)
Experiment 2 & 3: 10% (w/v)
Duration and frequency of treatment / exposure:
Single administration
Doses / concentrations
Remarks:
Doses / Concentrations:
Experiment 1: 500 mg/kg bw
Experiment 2 & 3: 20 mg/animal
No. of animals per sex per dose:
Experiment 1: Not indicated
Experiment 2 & 3: 2 male animals
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 relevant

Results and discussion

Preliminary studies:
Not relevant

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Experiment 1: at least 85% of linalool is absorbed (detected in urine and expired air) after 72 hours
Details on distribution in tissues:
Experiment 1 (in total: 3% of dose) after 72 hours:
- Liver: 0.5%
- Gut: 0.6%
- Skin: 0.8%
- Skeletal muscle: 1.2%
- Other organs: insignificant amounts of radioactivity
Details on excretion:
Experiment 1: approx. 100% of the administered dose is excreted (urine, faeces, expired gas) after 72 hours.
- Expired air: 23%
- Urine: approx. 60%
- Faeces: approx. 15% (delayed, possible biliary excretion)

Experiment 2:
- Bile: more than 25% of the ip dose detected after 11 hours

Experiment 3:
- Bile: 2.5% of ip dose detected in second rat after 12 hours

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Experiment 2: No free linalool, but only polar conjugates were detectable in bile (partially hydrolysed by beta-glucuronidase and to a greater extent by a mixture of beta-glucuronidase and sulphatase).

Experiment 3: Biliary conjugates detected in bile, non-polar ether-extractable metabolites (5% of dose) detected in faeces.

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. Extensive enterohepatic circulation is therefore possible. Part of the absorbed linalool is thus excreted by faeces.

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 and completely absorbed in rats after oral (gavage) administration. After 72h, 3% of the dose remained in tissues. Intraperitoneal administration (20 mg/animal) showed that at least 25% of the dose is excreted in bile (faeces). Enterohepatic circulation was detected and biliary conjugates and non-polar ether-extractable metabolites (in faeces) are formed. These are glucuronide- and sulfate conjugates. Within 72 h, 97% are excreted with the majority (ca. 80%) after 36h and 95% after 48h. 60% of administered radioactivity occured in urine, 15% in faeces and 25% in expired air.
Executive summary:

14C labelled linalool was administered orally (gavage) and intraperitoneally to male Wistar rats in this study. For the first exposure route a dose of 500 mg/kg bw was used, for the second route this was 20 mg/animal.

Experiment 1: After intragastric administration, 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 up to 11 hours after exposure of 2 rats and radioactivity was determined.

Experiment 3: In this experiment one rat was intraperitoneally exposed. Bile from a 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.

Under the conditions of this study, linalool (500 mg/kg bw) was rapidly and completely absorbed in rats after oral (gavage) administration. After 72 h, 3% of the dose could be detected in tissues. Intraperitoneal administration (20 mg/animal) showed that ca. 25% of the dose is excreted in bile (faeces). Enterohepatic circulation is possible and that biliary conjugates and non-polar ether-extractable metabolites (faeces) are formed. These are likely glucuronide and sulfate conjugates. Excretion is rapid; within 36h 80% of radioactivity and within 48h 95% of radioactivity had been excreted. After 72h, majority was excreted via urine (60% of administered radioactivity), faeces (15%), expired air (23%).