Farnesol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

The study was not of guideline design including just two treatment groups and a control, and was not conducted to GLP

Data source

Reference

Reference Type:

publication

Title:

Modulation of hepatic and renal drug metabolising enzyme activities in rats by subchronic administration of farnesol

Author:

Horn TL, Long L, Cwik MJ,Morrissey RL, Kapetanovic IM, McCormick DL

Year:

2005

Bibliographic source:

Chemico-Biological Interactions, 152, 79-99

Materials and methods

Objective of study:

absorption

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The study design was similar to an OECD 407 28-day repeated dose toxicity study although only two treated groups were included together with a standard vehicle control group. The numbers of animals per group complied with guideline requirements for studies of this type along with the experimental conditions. Half the animals from each group were terminated after 28 days of oral dosing whilst the remaining animals were terminated after a further 28-day period without treatment to assess recovery from any toxicities. Blood samples were taken from all animals at termination for the determination of plasma farnesol levels.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Farnesol

EC Number:

225-004-1

EC Name:

Farnesol

Cas Number:

4602-84-0

Molecular formula:

C15H26O

IUPAC Name:

farnesol

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Rats were individually housed in stainless steel cages suspended over absorbent cage boards, and were held in a temperature-controlled room maintained on a 12 h light/dark cycle. Rats were permitted free access to drinking water (supplied by automatic watering system) at all times during the study; rats were also allowed free access to Purina Certified Rodent Diet 5002 (PMI Nutrition International Inc., Brentwood, MO) throughout the study, except during an overnight fast prior to scheduled necropsies.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
- Dose levels of 500 or 1000 mg/kg/day were selected on the basis of a previous pre-clinical 28-day toxicity study without recovery

VEHICLE
- Justification for use and choice of vehicle (if other than water): Not stated
- Concentration in vehicle: Not stated
- Amount of vehicle (if gavage): 5 mL/Kg
- Lot/batch no. (if required): Not stated
- Purity: Not stated

Duration and frequency of treatment / exposure:

28 days followed by a 28-day recovery period

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

100 other: mg/mL

Doses / concentrations 2

Dose / conc.:

200 other: mg/mL

No. of animals per sex per dose / concentration:

20 male and 20 female rats per group

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dose levels of 500 and 1000 mg/kg/day were selected by the National Cancer Institute on the basis of a previous preclinical 28-day toxicity study
- Rationale for animal assignment (if not random): animals randomly assigned to groups
- Rationale for selecting satellite groups: not stated
- Post-exposure recovery period in satellite groups: 28-day recovery period

Details on dosing and sampling:

PHARMACOKINETIC STUDY
- Tissues and body fluids sampled: plasma
- Time and frequency of sampling: Blood samples taken from all animals killed at the end of 28-days of treatment
- Method type(s) for identification: Gas chromoatography/mass spectrometry
- Limits of detection and quantification: cis, cis-farnesol (0.233 umol/l); cis, trans-farnesol (0.527 umol/l); trans, cis-farnesol (0.516 umol/l); trans,
trans-farnesol (0.814 umol/l).

Results and discussion

Main ADME results

Type:

absorption

Results:

Plasma levels of total farnesol and individual farnesol isomers in rats receiving daily exposure to farnesol at doses of 500 or 1000 mg/kg/day

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Total plasma farnesol levels, and plasma levels of individual farnesol isomers in samples collected from study animals at approximately two hours post-dosing during the final week of farnesol administration are summarised in Table 1. As expected, plasma levels of total farnesol (all isomers) and individual farnesol isomers increased with increasing farnesol dose. Despite the fact that farnesol is an endogenous compound, plasma farnesol levels were not detectable in all animals in the vehicle control group (data not shown) as the levels were probably below the detection limit of the assay.

Any other information on results incl. tables

Table 1 - Plasma levels of total farnesol and individual farnesol isomers in rats receiving daily exposure to farnesol at doses of 500 or 1000 mg/kg/day

		Concentration (µmol/L)
		Male, 500^a	Male, 1000^a	Female, 500^a	Female, 1000^a
Total Farnesol	Mean±SD^b Range^c N^d	3.75±2.02 1.29-6.68 8	7.82±1.60 5.12-9.64 10	5.89±3.38 2.76-11.3 9	8.75±2.91 5.74-13.6 10
cis,cisFarnesol	Mean±SD^b Range^c N^d	0.676±0.267 0.283-0.931 5	1.09±0.393 0.603-1.57 10	0.485±0.178 0.234-0.729 5	0.929±0.336 0.576-1.57 10
cis,transFarnesol	Mean±SD^b Range^c N^d	0.801 0.801 1	1.28±0.714 0.553-2.17 4	2.01 2.01 1	1.01±0.183 0.881-1.14 2
trans,cisFarnesol	Mean±SD^b Range^c N^d	0.846±0.197 0.06-0.985 2	0.814±0.339 0.522-1.25 8	1.03±0.409 0.742-1.32 2	0.665±0.089 0.562-0.765 5
trans,transFarnesol	Mean±SD^b Range^c N^d	3.02±1.44 1.29-4.95 8	5.57±1.00 4.08-6.97 10	5.18±2.64 2.76-10.0 9	7.29±2.27 4.90-11.6 10

Blood samples were collected approximately 2h post-dosing during the fourth week of farnesol administration. Plasma farnesol levels in all samples collected from vehicle controls were not detectable

a Sex and dose (mg/kg/day)

b Mean concentration (+/- standard deviation) for animals with quantifiable levels within the group

c Concentration range among animals with quantifiable levels within the group

d Number of animals (out of 10) with quantifiable levels within the group

Applicant's summary and conclusion

Conclusions:

Plasma concentrations of farnesol and associated isomers increased with increasing dose concentration following oral exposure in rats.

Executive summary:

Male and female rats received daily exposure to farnesol at doses of 500 or 1000 mg/kg/day, alongside a vehicle control, for 28 days followed by a 28-day recovery period. Total plasma farnesol levels and plasma levels of individual farnesol isomers were analysed at approximately two hours post-dosing during the final week of farnesol administration. Plasma levels of total farnesol (all isomers) and individual farnesol isomers increased with increasing farnesol dose. This study is considered to be reliable with restriction (Klimisch 2) as it was a published study conducted similar to an OECD 407 28-day repeated dose toxicity study, with minor limitations in reporting.