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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
Objective of study:
metabolism
Qualifier:
according to guideline
Guideline:
EPA OPP 85-1 (Metabolism and Pharmacokinetics)
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Radiolabelling:
yes
Remarks:
[3-14C] quinoline-CGA 185072
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
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
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.
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.
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).

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.


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.

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:
guideline study
Objective of study:
absorption
distribution
excretion
Qualifier:
according to guideline
Guideline:
EPA OPP 85-1 (Metabolism and Pharmacokinetics)
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Radiolabelling:
yes
Remarks:
[14C]- cloquintocet-mexyl
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system 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
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
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
0.5 mg/kg bw/day (nominal)
No. of animals per sex per dose / concentration:
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:
Dosing groups for pharmacokinetic study with cloquintocet-mexyl:
- Group B: female and male rats receiving a single oral dose of radiolabelled substance of 0.5 mg/kg bw (0.162 MBq for females, 0.203 MBq for males)
- Group C: female and male rats receiving a dose of 0.5 mg/kg bw unlabelled substance and then one single dose of 0.5 mg/kg bw radiolabelled substance (0.146 MBq for females, 0.211 MBq for males)
- Group D: female and male rats receiving a single dose of radiolabelled substance of 99.2 mg/kg bw (0.593 MBq for females, 0.77 MBq for males)
- Group E: female and male bile-canulated rats receiving a single dose of radiolabelled substance of about 0.5 mg/kg bw (0.145 MBq for females, 0.16 MBq for males)
- Group F: female and male bile-canulated rats receiving a single dose of radiolabelled substance of about 100 mg/kg bw (0.459 MBq for females, 0.577 MBq for males)

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
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.
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 pre-treatment 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 independent of the dose.
Metabolites identified:
no

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

 

Conclusions:
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:

Radiolabelled test material was administered to groups of rats as a single dose or by repeated oral administration or to bile-cannulated animals in five separate assays under GLP, in accordance with EPA test methods. Samples were collected for determination of excretion via expired air, urine and faeces and bile. 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. 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.

Description of key information

In rats there was no sex difference in excretion, tissue residues or metabolism of cloquintocet-mexyl after oral administration of the substance. The major metabolite was identified as Acetic acid, 2-[(5-chloro-8-quinolinyl)oxy]-, the carboxylic acid of cloquintocet mexyl. Neither dose level nor repeated dosing had any effect on excretion, tissue residues or metabolism.

The in-vitro dermal absorption of [14C]-labelled cloquintocet-mexyl was determined using rat and human epidermis. Absorption was inversely proportional to dose. Absorption was higher through rat epidermis than human epidermis.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Rats

Male and female rats were given a single oral dose of 50 mg/kg [14C]-labelled cloquintocet-mexyl (Mathies, 1989). Samples of urine and faeces were collected for up to 3 days after dosing; liver, kidney and residual carcass were retained at necropsy on day 3. There was no sex difference in either excretion or tissue residues. Approximately 95% of the dose was excreted within 24 hours after dosing, about 60% in faeces and about 35-39% in urine. Residues in liver, kidney and carcass 3 days after dosing accounted for <0.3% of the dose. Metabolite profiles were determined in urine and faecal extracts. In both sexes, there was one major metabolite accounting for approximately 95% of the radioactivity and two minor additional metabolites. identified as the carboxylic acid of cloquintocet mexyl (Acetic acid, 2-[(5-chloro-8-quinolinyl)oxy]-, CAS number 88349-88-6).


Five groups of male and female rats were given single oral doses of 0.5 or 100 mg/kg bw [14C]-labelled cloquintocet-mexyl or 14 daily doses of 0.5 mg/kg unlabelled cloquintocet-mexyl followed by a single dose of 0.5 mg/kg [14C]-labelled cloquintocet-mexyl (Stewart, 1990). Furthermore, two groups of bile duct cannulated rats received a single dose of either 0.5 or 100 mg/kg [14C]-labelled cloquintocet-mexyl. Samples of urine, faeces, expired air/volatiles, bile, blood, tissues and residual carcasses were retained. Radioactivity in urine and bile samples indicated that at least 40% of the dose was absorbed. Approximately 30% of the dose was excreted in urine with the remainder in faeces; no radioactivity was detected in expired air/volatiles. Biliary secretion accounted for approximately 15% of the dose. The rate and route of excretion were unaffected by sex, dose level or repeated dosing.
Metabolite profiles were determined in urine, faeces and bile samples from the Stewart study (Mathies, 1990). There was no sex difference in the metabolite profiles; pre-treatment, dose level and biliary cannulation also had no effect on the observed metabolite profile. All samples contained one major metabolite accounting for between 82.7 and 94.6% of the radioactivity in the individual samples. Minor unidentified metabolites were present in urine and bile accounting for between 0.1 and 0.7% of the dose. The identity of the major metabolite was confirmed as the carboxylic acid of cloquintocet-mexyl using mass spectroscopy and NMR (Kriemler & Winkler, 1987).


Pre-treatment or co-administration with clodinafop-propargyl, an active substance used together with cloquintocet-mexyl, had no effect on the metabolism, excretion or tissue distribution of [14C]-labelled cloquintocet-mexyl in either sex.

Goats

Lactating goats were given 10 daily oral doses of [14C]-labelled cloquintocet-mexyl equivalent to 5 ppm in feed (Muller, 1992). Milk and excreta were collected daily and selected tissues were retained at necropsy 24 hours after the final dose. Radioactivity was recovered mostly in urine (62.04% of dose) and faeces (20.81% of dose), and to a small extent in milk (0.097% of dose) and tissues (0.075% of dose). 

No accumulation in milk occurred throughout the remainder of the study. Overall, low concentrations in plasma indicated rapid clearance of radioactivity from plasma with no accumulation throughout the 10-day dosing period. Urine contained the major metabolite Acetic acid, 2-[(5-chloro-8-quinolinyl)oxy]- (66%); the remainder of the radioactivity was separated into 5 unidentified radioactive fractions. The major metabolite present in kidney and milk was also identified as Acetic acid, 2-[(5-chloro-8-quinolinyl)oxy]-.

In a second study (Close et al., 2003), lactating goats were given a higher oral dose of [14C]-labelled cloquintocet-mexyl equivalent to 127 ppm in feed for 4 days; excreta, milk and tissue samples were analysed for radioactivity, which was recovered in urine (52.2%), faeces (12.3%) and gastrointestinal tract (22.8%), and to a lesser extent in milk and tissues (<0.4%). Greater than 72% of the radioactivity in urine, faeces and bile was present as the main metabolite and <1.1% was present as unchanged [14C]-labelled cloquintocet-mexyl. Additionally, two further metabolites were identified as the cyclic compound M2 (5.5%) and its glucuronic acid conjugate, M1 (12.2%). Compounds identified in milk and tissues were unchanged [14C]-labelled cloquintocet-mexyl (1.8-9.5%), the main metabolite (48.1-80.2%), M1 (0.8-11.1%) and M2 (2.2-4.8%).

Hens

Laying hens received 14 daily oral doses of [14C]-labelled cloquintocet-mexyl equivalent to 5 ppm in feed (Stewart, 1991). Eggs and excreta were collected daily; tissue samples were retained at necropsy 12 hours after the final dose. A mean of 88.4% of the administered radioactivity was recovered in excreta; <0.011% of the dose was transferred to eggs. The substance did not accumulate in organs or tissues. Concentrations of radioactivity in eggs were very low or less than the limit of detection (0.004 µg equivalents/g); the highest concentration detected was 0.004 µg equivalents/g in yolk.

Excreta, liver, kidney and egg white contained the major metabolite Acetic acid, 2-[(5-chloro-8-quinolinyl)oxy]- (Muller 1992).

In a second study in laying hens (Close et al., 2003), 12.5 mg [14C]-labelled cloquintocet-mexyl (7.4 mg/kg bodyweight equivalent to 95 ppm in feed) was given orally for 8 days. Radioactivity was detected in excreta (66%), liver (0.04%), muscle (0.02%), fat (0.02%); egg yolk and white contained <0.01% each. Detectable concentrations of radioactivity were found in muscle (0.010 ppm), fat (0.070 ppm), liver (0.146 ppm), egg white (0.024-0.042 ppm; highest on day 1) and egg yolk (0.002-0.018 ppm; highest on days 7-8).

No unchanged [14C]-cloquintocet-mexyl was detected; the carboxyl acid of cloquintocet-mexyl as the main metabolite accounted for the majority of the radioactivity in muscle (50.5%), liver (64.9%), fat (73.3%), egg white (78.0%) and egg yolk (50.5%). Additionally, the hydroxyl of the main metabolite was identified in liver accounting for 10.2% of the radioactivity present.

Discussion on absorption rate

In an in-vitro percutaneous absorption study (Mueller, 1996), a simulated WP formulation containing [14C]-labelled cloquintocet-mexyl was applied to rat and human epidermis (0.64 cm2). Doses of 0.01, 0.1 and 1 mg/cm2 test material were applied with exposure for 8 hours. For rat epidermis, 68, 32 and 2% of the dose was absorbed at 0.01, 0.1 and 1 mg/cm2, respectively; the corresponding absorption values for human epidermis were 6, 5 and 0.1% of the dose. Cloquintocet-mexyl remained unchanged while exposed to and after penetrating rat and human epidermis.

The dermal absorption of a 25 g/L formulation containing [14C]-labelled cloquintocet-mexyl was determined in-vitro using human epidermis (Hadfield, 2003). The formulation was applied either neat (25 g/L; 4 µL/cm2) or as a 1:167 v/v spray dilution (0.15 g/L; 6 µL/cm2); exposure was for up to 24 hours. Absorption values for the neat formulation were 0.83, 1.33, 1.93 and 7.15% after 6, 8, 10 and 24 hours, respectively; the corresponding absorption values for the spray dilution were 3.74, 5.46, 7.58 and 18.8%, respectively.