2,6-dimethyloct-7-en-2-ol

Basic toxicokinetics

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: An essentially well conducted study using accepted procedures of the time. Predates GLP requirements.

Data source

Reference

Reference Type:

publication

Title:

The Absorption, Distribution and Excretion of Linalool in the Rat

Author:

Parke, D.V., Quddusur Rahman, KH.M. and Walker, R.

Year:

1974

Bibliographic source:

Biochemical Society Transactions Vol. 2, pp. 612-615, 547th Meeting, London

Materials and methods

Objective of study:

absorption

distribution

excretion

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The rate and route of excretion of linalool was investigated in the rat after intragastric and intraperitoneal administrations. The extent of enterohepatic circulation after biliary excretion was determined.

GLP compliance:

no

Test material

Reference

Name:

Unnamed

Type:

Constituent

Details on test material:

Linalool, labelled with 14C in positions 1 and 2, was synthesized by the method of Filip and Moravek (1959).

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals and environmental conditions:

Male, 12-week old rats.

Administration / exposure

Route of administration:

other: intragastric and intraperitoneal

Vehicle:

propylene glycol

Details on exposure:

Labelled linalool (10 microCi) was administered by stomach tube to rats as a 25% (w/v) solution in propylene glycol at a dose of 500 mg/kg bwt.

The animals were individually caged in Metabowls (Jencon Ltd.) and urine and feces were collected over a period of 72 hours. Expired air was passed through traps containing ethanol:ethanolamine (2:1, v/v) and samples were collected from the traps over the same period.

Two rats with indwelling common bile duct cannulas were administered labelled linalool (1 microCi, 20 mg) intraperitoneally as a 10% solution in propylene glycol and bile collected at intervals over a period of 6 hours in one animal and 11 hours in the other.

In a separate experiment, two rats with bile ducts cannulated were treated as follows: a cannula from the bile duct of the first animal was inserted into the duodenal end of the bile duct cannula of the second animal; another cannula was inserted into the hepatic end of the bile duct of the second animal and the bile duct was ligated between the cannulae. Thus, bile from the first animal was introduced into the duodenum of the second while bile was collected from the second animal. The presence of radioactivity in this bile after intraperitoneal injection to the first animal was indicative of enterohepatic circulation.

At the end of the experiment, animals were killed and residual radioactivity in brain, lung, liver, heart, spleen, gastro-intestinal tract, kidney, skin and skeletal muscle was counted after digestion with hyamine.

Duration and frequency of treatment / exposure:

Single administration

Doses / concentrations

Remarks:

Doses / Concentrations:
As indicated above

No. of animals per sex per dose:

As indicated above

Control animals:

no

Positive control:

None

Details on dosing and sampling:

See description above

Results and discussion

Main ADME results

Type:

other: DT50

Results:

Approximately 50% of the total administered dose was excreted within 18 hours.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Linalool is rapidly absorbed from the gut as evidenced by extensive and rapid urinary excretion of radioactivity over the first 36 hours with no significant delay between dosing and the appearance of radioactivity in the urine.

Details on distribution in tissues:

At the end of the 72 hour period following intragastric administration, only about 3% of the radioactivity remained in the tissues and this was located mainly in the liver (0.5%), gut (0.6%), skin (0.8%) and skeletal muscle (1.2%). Other organs including the kidney contained insignificant amounts of radioactivity.

Details on excretion:

Following intragastric intubation, nearly complete elimination (est. 97%) of linalool occurred by 72 hours. The majority of this was in urine (est. 58%) with 23% in expired air, primarily as 14^CO2 and not as exhaled linalool or other metabolites. Fecal excretion was delayed; occurring primarily between 36 and 48 hours and suggesting biliary excretion was involved. Approximately 50% of the administered total dose was excreted within 18 hours.

In bile duct cannulated rats, more than 25% of the intraperitoneal dose was excreted by this route in 6-11 hours (principally in the first 4 hours) and appearing as polar conjugates. The conjugates were partially hydrolyzed by beta-glucuronidase and more fully by a mixture of beta-glucuronidase and sulphatase. In the cross-over experiment with cannulated rats in which bile from a first rat was introduced into the duodenum of a second rat, radioactivity equivalent to 2.5% of the original dose appeared in the bile of the second rat over a 12 hour period with peak excretion at 7 to 9 hours.

Assuming that 25% of the original dose appears in the bile of the first animal over the period studies, and also that 25% of the conjugates that were hydrolyzed and reabsorbed by the second animal, it can be calculated that 40% of the biliary conjugates are hydrolyzed and reabsorbed in the first pass. This extensive enterohepatic circulation may account in part for the delayed fecal excretion.

Applicant's summary and conclusion

Conclusions:

The study suggests that large doses of linalool may be metabolized in the rat by conjugation and excretion in the urine and bile while a substantial amount of the dose may enter intermediary metabolism with eventual excretion as carbon dioxide. The rapid and complete excretion of linalool and its metabolites suggests no long-term hazard from tissue accumulation.