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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
02 November 1988 to 12 May 1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Fully GLP and test guideline compliant study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report Date:
1990

Materials and methods

Objective of study:
absorption
distribution
excretion
Test guideline
Qualifier:
according to
Guideline:
EPA OPP 85-1 (Metabolism and Pharmacokinetics)
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): CGA185072 (company code)

[14C]- cloquintocet-mexyl
Radiochem. purity:
Specific activity:> 96%. Determined by TLC.
Specific Activity 1940 kBq/mg (52.51 uCi/mg)
For the treatment the test material was diluted with non-labelled material to a specific activity of
1847 kBq/mg (49.93 uCi/mg) - Group B
1501 kBq/mg (40.58 uCi/mg) - Group C
35.3 kBq/mg (0.953 uCi/mg) - Group D
1733 kBq/mg (46.84 uCi/mg) - Group E
34.2 kBq/mg (0.924 uCi/mg) - Group F





Radiolabelling:
yes
Remarks:
[14C]- cloquintocet-mexyl

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 6 to 10 weeks
- Weight at study initiation: 160 - 250 g
- Individual metabolism cages: yes for collection of volatiles and expired air
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days

IN-LIFE DATES: From: 02 November 1988 To: 12 May 1989

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Polyethylene glycol 200/ ethanol/ water 45/25/30 (v/v)
Details on exposure:
Dosing groups for pharmacokinetic study with cloquintocet-mexyl - see table below
Duration and frequency of treatment / exposure:
Single or repeat
Doses / concentrations
Remarks:
Doses / Concentrations:
0.5, 100mg/kg
No. of animals per sex per dose:
Groups B-D five males and five females
Groups E and F three males and three females
Control animals:
no
Details on dosing and sampling:
In Groups B to D, urine and faeces were collected 6, 12 and 24 hours after dosing and thereafter at 24 hours intervals over 7 days. At the end of the collection period, cages were rinsed with methanol/water and the cage wash solution was sampled. Volatiles and expired air were collected after 6, 12 and 24 hours. At sacrifice, blood was collected and the following tissues and organs were taken: Adrenals, bone, bone marrow, brain, fat (abdominal), gonads, heart, kidneys, liver, lung, uterus, skeletal muscle, spleen, thymus, thyroid, residual carcass.

In the biliary excretion groups E and F, the rats were canulated and allowed to recover for 24 hours before administration of the test substance. Urine and faeces were collected after 24 and 48 hours and bile was collected after 1, 2, 4, 8, 24 and 48 hours

Radioactivity was measured by scintillation counting using standard methods and scintillation mixes. In addition, pooled samples from urine, faeces (and bile in groups E and F) were sent to the sponsor for chromatographic characterization of the metabolite profile.
Statistics:
Not specified

Results and discussion

Preliminary studies:
Clinical assessment of Groups B to F
During the observation period in Groups B, C and D there were no signs of toxicity. Among the bile canulated animals, all three high dose (Group F) females died between 12 and 48 hours after the administration. The cases were attributed to stress and are not considered to be a toxic effect of the test article.
Main ADME resultsopen allclose all
Type:
absorption
Results:
Radioactivity in urine and bile accounted for at least 40% of the dose.
Type:
distribution
Results:
Seven days after treatment with 0.5 mg/kg or 100 mg/kg cloquintocet-mexyl residues were below the detection limit in all tissues. Also pretreatment with the non-labelled test material did not lead to detectable residues in individual organs
Type:
excretion
Results:
No radioactivity was detected in expired air. Approximately 30% of the dose was excreted in urine with the remainder in faeces. Biliary secretion accounted for approximately 15% of the dose. The route and rate of excretion was independant of the dose.

Metabolite characterisation studies

Metabolites identified:
no

Any other information on results incl. tables

Excretion kinetics in rats after oral gavage of 14C-CGA 185072 (Excretion of radioactivity in % of the administered dose)

Group

B

C

D

Dose mg/kg bw

0.53

0.51

0.50

0.50

99.2

99.2

Sex

 Males

Females

Males

Females

Males

Females

Urine
  0 -   24 hrs
24 - 168 hrs

Subtotal


19.8
0.6
20.4


24.6
0.7
25.4


25.4
2.5
28.0


20.5
0.5
21.1


29.7
0.7
30.6


35.8
0.8
36.6

Faeces

 0 -  24 hrs
24 - 168 hrs

Subtotal

55.0
6.7
61.7


58.8
1.4
60.3


38.5
7.5
46.0


59.9
2.1
62.0


50.2
7.9
58.2


45.6
8.8
54.3

Expired air

ND

ND

ND

ND

ND

ND

Tissues + carcass

0.4

ND

0.1

ND

0.1

ND

Cage wash

5.6

8.5

14.3

5.5

4.6

7.6

Total Excretion

87.6

94.3

88.3

88.6

93.4

98.5

Total Recovery

88.0

94.3

88.3

88.6

93.4

98.5

Biliary excretion in rats after oral gavage of 14C-CGA 185072 (Excretion of radioactivity in % of the administered dose)

 

Group

 

E

F

Dose mg/kg bw

0.52

0.55

99.1

93.5

 

 

Sex

 Males

Females

Males

Females

 

 

Bile
1-8 hrs
8 - 48 hrs
Subtotal


8.3
6.9
15.2


10.1
5.1
15.2


10.3
5.2
15.7


6.7
2.8
9.3

 

Urine
Subtotal (48 hrs)


21.8


36.0


36.9


10.6

 

Faeces

Subtotal (48 hrs)


44.8


27.5


34.4


6.7

 

Tissues + carcass

0.5

2.3

1.1

57.1

 

Cage wash

4.4

4.3

7.0

1.6

 

Total Excretion

82.3

83.3

94.0

28.2

 

Total Recovery

86.7

85.6

95.1

85.3

 

The apparently low excretion in the females is due to the premature death of all three individuals

 

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
The test compound was rapidly absorbed and excreted. The main portion of the radioactivity was excreted within 24 hours after the dosing with urine and faeces. Urinary and biliary excretion revealed that at least 50% of the orally administered test material were absorbed from the intestinal tract in both sexes. The compound did not accumulate in any tissue or organ.
Executive summary:

Radiolablled test material was administered to groups of rats as a single or repeated oral administration or to bile-cannulated animals in five separate assays, in accordance with EPA test methods. Samples were collected for determination of excretion via expired air, urine and faeces and biliary excretion. Radioactivity recovery and tissue absorption values were determined. Blood, tissues, organs and residual carcass were analysed for absorption and distribution. There were no signs of systemic toxicity. Deaths among the bile-cannulation groups were attributed to procedural stress rather than toxic effects of treatment. The test compound was rapidly absorbed and excreted. The main portion of the radioactivity was excreted within 24 hours after the dosing with urine and faeces. Urinary and biliary excretion revealed that at least 40% of the orally administered test material were absorbed from the intestinal tract in both sexes. The compound did not accumulate in any tissue or organ. Calculated from urinary and biliary excretion and tissue residues, around 50% of an orally administered dose were absorbed into general circulation by both sexes and at both dose levels. Excretion was essentially complete within 48 hours. Independent from sex or dose around 60% of the administered radioactivity were found in the faeces and 40% in the urine. Biliary excretion amounted to 15%. No radioactivity was detected in the expired air, indicating that the quinoline ring of the molecule was not broken down during metabolization. Pretreatment with non-labelled test material did not alter the kinetics of cloquintocet-mexyl.