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Basic toxicokinetics

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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

Constituent 1
Chemical structure
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 resultsopen allclose all
Type:
distribution
Results:
Tissue residues were low; liver, kidney and carcass contained <0.3% of dose after 3 days.
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.