Propanoic acid, 2-[4-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenoxy]-, (2R)-

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1980-07 - 1980-12

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP study, sufficient documentation

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1981

Report date:

1981

Materials and methods

Principles of method if other than guideline:

Investigative study, based on OECD TG 417 (with three subjects per sex per group used instead of four, but this is considered not to have affected the integrity of this study).

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

(RS)-2-[4-(5-Trifluoromethyl-2-pyridyloxy)phenoxy]propionic

EC Number:

614-949-9

Cas Number:

69335-91-7

Molecular formula:

C15H12F3NO4

IUPAC Name:

(RS)-2-[4-(5-Trifluoromethyl-2-pyridyloxy)phenoxy]propionic

Constituent 2

Reference substance name:

2-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenoxy)propanoic acid

IUPAC Name:

2-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenoxy)propanoic acid

Details on test material:

The test substance contains [14-C] 2-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenoxy)propanoic acid (uniformly labelled in the phenyl ring) together with unlabelled 2-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenoxy)propanoic acid.
The test substance is the racemate 2-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenoxy)propanoic acid (CAS# 69335-91-7). It is a 1:1 mixture of the two enantiomers (2R)-2-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenoxy)propanoic acid (CAS# 83066-88-0; the substance defined in section 1) and (2S)-2-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenoxy)propanoic acid (CAS# 95977-30-3).

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

other: Alderley Park strain (Wistar derived)

Sex:

male/female

Details on test animals or test system and environmental conditions:

specific pathogen free strain

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Duration and frequency of treatment / exposure:

single oral dose

Doses / concentrations

Remarks:

Doses / Concentrations:
1.1 mg/kg bw 2-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenoxy)propanoic acid (corresponding radioactivity: 64.2 μCi/kg bw)

No. of animals per sex per dose / concentration:

3 male + 3 female adult rats (163 - 168 g bw)

Control animals:

no

Details on study design:

A single oral dose in corn oil was administered to 3 male and 3 female rats. They were housed individually in metabolism cages from which urine and faeces were collected at daily intervals. The study was terminated 7 days after dosing, when representative samples of tissues were removed and analysed for residual radioactivity.

Details on dosing and sampling:

single oral dose

Results and discussion

Any other information on results incl. tables

Remark: some of the results are expressed in equivalents of butyl (2R)-2-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenoxy)propanoate (molar mass: 383.4 g/mol) instead of the test substance (2-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenoxy)propanoic acid; molar mass: 327.3 g/mol) itself.

The results for the excretion and tissue distribution of administered radioactivity by the 3 male and female rats are presented in Tables 1 and 2 respectively.

Over 7 days, males excreted a mean of 79% of the dose, with 45% excreted in urine and 33% in faeces. Over the same time, females excreted 104% of the dose. The urinary route of excretion predominated in females, accounting for over 101% of the dose. The rate of urinary excretion was much faster in females, which eliminated over 96% of the dose in urine within 24 hours of dosing. Accordingly, faecal excretion was much lower in females accounting for less than 3% of the dose. Excretion was incomplete in males after 7 days with over 20% of administered radioactivity still present in tissues, whilst the rate of excretion was rapid in females with approximately 99% of the dose eliminated within 24 hours of dosing.

 

At the termination of the experiment, the highest concentration of residual radioactivity was present in the fat of both males and females, representing means of 0.99 and 0.04 μg equivalents of butyl 2-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenoxy)propanoate/g respectively. Lower concentrations were present in all other tissues, with female residues being much lower than males. In male rats all other residues were lower than the concentration in blood (0.59 μg equivalents/g). The mean concentrations in the residual carcasses accounted for 0.61 and <0.01 μg equivalents/g in males and females (18% of the dose), much of this being attributed to residues in fat depots.

 

A single oral dose of 1.1 mg/kg bw was almost quantitatively absorbed by the female rat. The extent of absorption by male rats cannot be accurately determined from the data presented in this report, but accounted for at least 66% of the administered dose.

 

Table 1: Mean percentage recoveries of administered radioactivity over 7 days after a single oral dose of 1.1 mg/kg bw (mean of 3 rats)

Sample	Males	Females
Urine	45.1	101.1
Faeces	33.4	2.9
Tissues (Including carcass)	20.8	4.1
Total	99.3	108.1

Table 2: Mean tissue concentrations (as equivalents of butyl 2-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenoxy)propanoate in μg/g) of radioactivity, 7 days after a single oral dose of 1.1 mg/kg bw test substance (mean of 3 rats)

Tissue	Males	Females
Kidneys	0.36	<0.01
Liver	0.49	<0.01
Fat               (abdominal)	0.99	0.04
Blood	0.59	<0.01
Residual Carcass	0.61	Not determined

 

Chromatographic analysis of urine showed that most of the radioactivity extracted corresponded to the test substance (2-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenoxy)propanoic acid). Small amounts of the taurine conjugate of the test substance were detected in female urine and in male faeces.