heptan-2-yl [(5-chloroquinolin-8-yl)oxy]acetate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

20 July 1987 to 14 November 1987

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1989

Report date:

1989

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

according to guideline

Guideline:

EPA OPP 85-1 (Metabolism and Pharmacokinetics)

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

heptan-2-yl [(5-chloroquinolin-8-yl)oxy]acetate

EC Number:

619-447-3

Cas Number:

99607-70-2

Molecular formula:

C18H22ClNO3

IUPAC Name:

heptan-2-yl [(5-chloroquinolin-8-yl)oxy]acetate

Details on test material:

- Name of test material (as cited in study report): CGA185072 (company code)
See details given in attached word file

Radiolabelling:

yes

Remarks:

[3-14C] quinoline-CGA 185072

Test animals

Species:

rat

Strain:

other: Tif RAIf (SPF), Sprague-Dawley derived

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 6-8 weeks
- Weight at study initiation: circa 200g

- Individual metabolism cages: yes

- Acclimation period: 4 days

IN-LIFE DATES: From: 20 July 1987 To: 14 November 1987

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: PEG200/ethanol/water (4/3/2 v/v)

Details on exposure:

The test material was dissolved in PEG200/ethanol/water (4/3/2 v/v) yielding solutions of 11.42 mg/ml (males) and 11.64 mg/ml (females) respectively. A single dose of 0.9 ml was administered by gastric intubation. The stability of the dosing emulsion was checked by TLC at the time of dosing. This dose was equivalent to about 50 mg/kg bw.
A total of 5 male and 5 female rats were treated. Urine and faeces were collected at 24 hour intervals for three days. At sacrifice, kidneys, liver and the residual carcass were sampled.
See details of exposure given in tables below.

Duration and frequency of treatment / exposure:

Single

Doses / concentrations

Dose / conc.:

50 mg/kg bw/day

No. of animals per sex per dose / concentration:

A total of 5 male and 5 female rats were treated. Urine and faeces were collected at 24 hour intervals for three days. At sacrifice, kidneys, liver and the residual carcass were sampled.

Control animals:

no

Details on study design:

The test material was dissolved in PEG200/ethanol/water (4/3/2 v/v) yielding solutions of 11.42 mg/ml (males) and 11.64 mg/ml (females) respectively. A single dose of 0.9 ml was administered by gastric intubation. The stability of the dosing emulsion was checked by TLC at the time of dosing. This dose was equivalent to about 50 mg/kg bw

Five male andfive females were dosed at 50 or 52 mg/kg bw the dose of labelled material (KBq/rat) was 7610 or 7470 respectively.

The pattern of radioactivity was determined using TLC methods. Separation and purification of samples was done by LC, HPLC and HVE to separate and purify individual metabolites.
The main metabolite was identified by co-chromatography with reference substances and finally, the structure was confirmed by NMR and mass spectroscopy.

Results and discussion

Main ADME results

Main ADME results 1

Type:

distribution

Results:

Tissue residues were low; liver, kidney and carcass contained <0.3% of dose after 3 days.

Main ADME results 2

Type:

excretion

Results:

38.9 and 34.5% in urine and 59.4 and 59.7% in males and females respectively.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Urine and faeces contained only one major metabolite fraction accounting for around 95% of the recovered radioactivity. No significant differences were observed between males and females. The structure was identified as the acid residue of cloquintocet-mexyl after cleavage of the ester bond (see attached metabolic pathway).

Any other information on results incl. tables

Balance of radioactivity in male rats after oral gavage of ¹⁴ C-CGA 185072 (Radioactivity in % of the administered dose)

	Males	Females
Dose mg/kg bw	50 mg/kg bw	52 mg/kg bw
Urine   0 - 24 hrs 24 - 48 hrs 48 - 72 hrs Subtotal	38.9 1.1 0.2 40.2	34.5 0.9 0.2 35.6
Faeces   0 - 24 hrs 24 - 48 hrs 48 - 72 hrs Subtotal	59.4 2.8 0.1 62.3	59.7 2.0 0.2 61.9
Tissue Residues                 Liver                 Kidney                 Carcass Subtotal	0.03 0.01 0.13 0.16	0.01 0.01 0.25 0.26
Total Recovery	102.7	97.8

The metabolism of [3-¹⁴C] quinoline-CGA 185072 in the rat after oral administration of a single dose of 50 mg/kg bw revealed only one major metabolite CGA 153433, which accounted for around 95% of the recovered radioactivity in urine and faeces. No significant differences were observed between males and females.

Applicant's summary and conclusion

Conclusions:

The metabolism of [3-14C] quinoline labelled substance in the rat after oral administration of a single dose of 50 mg/kg bw revealed only one major metabolite, which accounted for 95% of the recovered radioactivity in urine and faeces. No significant differences were observed between males and females.

Executive summary:

The metabolism of cloquintocet-mexyl in the rat, following a single oral dose of 50 mg/kg bw/day of [3-14C] quinoline-labelled substance, was studied under GLP to EPA OPP methods. The metabolites in urine, faeces and bile were separated and the main metabolites were identified by co-chromatography with reference substances. In all samples the metabolite profile was dominated by one single metabolite which was identified by co-chromatography as the acid residue of cloquintocet-mexyl after cleavage of the ester bond. The major metabolite accounted for 95% of the recovered radioactivity. Few other metabolite fractions were detected, none of which exceeded 0.5% of the administered dose. The metabolite pattern was independent of sex or pretreatment.