Chlorimuron ethyl

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1983

Report date:

1983

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

1985

Report date:

1985

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The studies were initiated to examine the tissue distribution, metabolism and excretion of the test substance administered by gavage to rats. Two radioactive forms of the test substance were included, one containing the radiolabel on the phenyl moiety of the test substance and the other containing the radiolabel on the pyrimidine moiety of the test substance.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

ethyl 2-({[(4-chloro-6-methoxypyrimidin-2-yl)carbamoyl]amino}sulfonyl)benzoate

EC Number:

618-690-2

Cas Number:

90982-32-4

Molecular formula:

C15H15ClN4O6S

IUPAC Name:

ethyl 2-({[(4-chloro-6-methoxypyrimidin-2-yl)carbamoyl]amino}sulfonyl)benzoate

Test material form:

solid

Remarks:

White

Details on test material:

95 to >99% purity

Specific details on test material used for the study:

Three different samples of the radiolabeled test substance were used in the study. One sample labeled in the phenyl ring, had a specific activity of 8.4 μCi/mg and a radiochemical purity greater than 99%. The second sample, labeled in the pyrimidine ring, had a specific activity of 8.2 μCi/mg and a radiochemical purity greater than 99%. The third sample was the unlabeled test substance which had a purity greater than 99%.

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

other: Charles River CD

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: Ethanol:Corn Oil (1:9)

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

16 mg/kg bw (total dose)

Remarks:

Phenyl-labeled moiety without preconditioning

Doses / concentrations 2

Dose / conc.:

16 mg/kg bw (total dose)

Remarks:

Pyrimidine-labeled moiety without preconditioning

Doses / concentrations 3

Dose / conc.:

16 mg/kg bw (total dose)

Remarks:

Phenyl-labeled moiety following 21 days preconditioning at 100 ppm dietary intake of unlabeled test material

Doses / concentrations 4

Dose / conc.:

3 020 mg/kg bw (total dose)

Remarks:

20 mg/kg of the Phenyl-labeled moiety and 3000 mg/kg of the unlabeled test material

No. of animals per sex per dose / concentration:

2 males and 2 females

Control animals:

no

Details on study design:

The studies were initiated to examine the tissue distribution, metabolism and excretion of the test substance administered by gavage to rats. Two radioactive forms of the test substance were included, one containing the radiolabel on the phenyl moiety of the test substance and the other containing the radiolabel on the pyrimidine moiety of the test substance.

Two male and two female Sprague-Dawley rats each received a single oral gavage dose of 4 mg of the 14C-phenyl-labelled test substance containing approximately 33 μCi of C-radioactivity. The rats were housed in separate glass metabolism chambers immediately after dosing and were maintained on house water and ground meal diet containing no test material.

Another group of two male and two female Sprague-Dawley rats was preconditioned by feeding for 3 weeks a diet containing 100 ppm of the unlabeled test substance. At the end of this pre-conditioning period, the rats were administered by gavage 4 mg of the 14C-phenyl-labelled test substance containing approximately 33 μCi of C-radioactivity. The rats were housed in separate glass metabolism chambers immediately after dosing and were maintained on house water and ground meal diet containing no test material.

Another group of two male and two female Sprague-Dawley rats was administered by gavage a single dose of a mixture of 750 mg of the unlabeled cold test substance and 5 mg of the 14C-phenyl-labelled test substance containing approximately 41 μCi of C-radioactivity. The rats were housed in separate glass metabolism chamber3 immediately after dosing and were maintained on house water and ground meal diet containing no test material.

Another group of two male and two female Sprague-Dawley rats each received a single oral gavage dose of 4 mg of the 14C-pyrimidine-labelled test substance containing approximately 33 μCi of C-radioactivity. The rats were housed in separate glass metabolism chambers immediately after dosing and were maintained on house water and ground meal diet containing no test material.

For all the groups of rats, urine and feces were separately collected 6, 24, 48 and 72 hours post-treatment. The rats were sacrificed 72 hours after dosing by exposure to chloroform. Blood was drawn at sacrifice by cardiac puncture. The following tissues were excised and weighed: heart, lungs, liver, spleen, kidneys, G. I. tract, testes or ovaries, brain and samples of skin, fat and muscle.

Results and discussion

Main ADME results

Main ADME results 1

Type:

metabolism

Results:

Radiolabeled test substance was extensively metabolized by male and female rats after three different dosing routines with the phenyl-radiolabled moiety and one dosing routine with the pyrimidine-radiolabeled moiety.

Main ADME results 2

Type:

excretion

Results:

Excretion of radioactivity in the urine and feces was rapid, with biological half-lives of approximately 50 hours under all dosing conditions.

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

Two metabolites, HPY and ODM, comprised more than half of the 2-3% radioactivity retained in organs and tissues of low-dose animals maintained for 168 hours post-dosing. In those animals, tissue radioactivity levels did not exceed 1 ppm equivalent test substance (except for the liver, where the level was 1.5 ppm). Tissue radioactivity levels were proportionally higher in the high-dose group compared to the two low-dose groups, reflecting the difference in dose levels (3020 mg/kg vs. 16 mg/kg).

Details on excretion:

Excretion of radioactivity in the urine and feces was rapid, with biological half-lives of approximately 50 hours under all dosing conditions. Typically
98% or more of the recovered radioactivity was excreted by 168 hours post-dosing.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The principal metabolites were hydroxylated analogs of the test substance, which included the 5-hydroxy pyrimidine analog (HPY), the demethylated analog (ODM), an analog with the chlorine replaced with a hydroxyl group (HOPY), a demethylated analog of HOPY (DI-HOPY), and a de-esterified analog of HOPY (FA-HOPY).

Any other information on results incl. tables

Table 1A

Recovery of radioactivity from Group 1* male rats (average of 2 animals) dosed with the 14C-phenyl-labeled test substance

 

Sample	Radioactivity	ppm (µg/g)	% of Dose
Urine, 6 hour	0.03 µCi	2.4	0.08
Urine, 24 hour	3.83 µCi	54.7	10.57
Urine, 48 hour	4.65 µCi	51.8	12.68
Urine, 72 hour	3.56 µCi	25.3	9.85
Total Urine	12.07 µCi		33.18
Feces, 6 hour	0.00 µCi	0.5	0.02
Feces, 24 hour	0.85 µCi	25.6	2.96
Feces, 48 hour	4.80 µCi	61.9	16.59
Feces, 72 hour	4.30 µCi	41.4	14.86
Total Feces	9.95 µCi		34.43
Organ and Tissues			26.27
Cage Wash			0.71
Total			94.59

 

Table 1B

Recovery of radioactivity from Group 1* female rats (average of 2 animals) dosed with the 14C-phenyl-labeled test substance

 

Sample	Radioactivity	ppm (µg/g)	% of Dose
Urine, 6 hour	0.25 µCi	7.1	0.70
Urine, 24 hour	5.38 µCi	38.3	14.85
Urine, 48 hour	6.42 µCi	51.6	17.75
Urine, 72 hour	3.43 µCi	25.9	9.98
Total Urine	15.48 µCi		43.28
Feces, 6 hour	0.01 µCi	3.8	0.04
Feces, 24 hour	0.33 µCi	19.7	1.13
Feces, 48 hour	5.00 µCi	48.1	17.27
Feces, 72 hour	4.17 µCi	56.8	13.90
Total Feces	9.51 µCi		32.34
Organ and Tissues			25.77
Cage Wash			1.33
Total			102.72

 

 

Table 2A

Recovery of radioactivity from Group 2A* single male rat dosed with the 14C-pyrimidine-labeled test substance

 

Sample	Radioactivity	ppm (µg/g)	% of Dose
Urine, 6 hour	0.29 µCi	35.4	0.86
Urine, 24 hour	4.30 µCi	62.4	12.77
Urine, 48 hour	3.37 µCi	47.4	10.00
Urine, 72 hour	2.15 µCi	34.0	6.38
Urine, 96 hour	1.76 µCi	20.0	5.22
Urine, 104.5 hour	0.44 µCi	11.9	1.32
Total Urine	12.31 µCi		36.55
Feces, 6 hour	No sample available	-----	-----
Feces, 24 hour	2.87µCi	54.4	8.53
Feces, 48 hour	8.15 µCi	64.9	24.20
Feces, 72 hour	3.23 µCi	30.8	9.59
Feces, 96 hour	1.76 µCi	26.7	5.23
Feces, 104.5 hour	0.43 µCi	12.3	1.29
Total Feces	16.44 µCi		48.84
Organ and Tissues			9.43
Cage Wash			0.43
Total			95.25

 

Table 2B

Recovery of radioactivity from Group 2A* single female rat dosed with the 14C-pyrimidine-labeled test substance

 

Sample	Radioactivity	ppm (µg/g)	% of Dose
Urine, 6 hour	0.21 µCi	11.2	0.62
Urine, 24 hour	5.29 µCi	50.9	15.72
Urine, 48 hour	4.02 µCi	27.3	11.94
Urine, 72 hour	2.36 µCi	11.6	7.00
Urine, 96 hour	1.66 µCi	8.1	4.93
Urine, 104.5 hour	0.24 µCi	5.0	0.71
Total Urine	13.78 µCi		40.92
Feces, 6 hour	< 0.01 µCi	0.6	0.01
Feces, 24 hour	2.89 µCi	47.0	8.60
Feces, 48 hour	2.81 µCi	55.2	8.33
Feces, 72 hour	3.27 µCi	42.1	9.72
Feces, 96 hour	1.98 µCi	18.5	5.88
Feces, 104.5 hour	0.18 µCi	9.8	0.54
Total Feces	11.13 µCi		33.08
Organ and Tissues			8.37
Cage Wash			0.78
Total			83.15

 

Table 3A

Recovery of radioactivity from Group 2* single male rat dosed with the 14C-pyrimidine-labeled test substance

 

 

Sample	Radioactivity	ppm (µg/g)	% of Dose
Urine, 6 hour	0.50 µCi	25.2	1.75
Urine, 24 hour	4.15 µCi	59.6	14.55
Urine, 48 hour	4.04 µCi	31.5	14.15
Urine, 72 hour	2.28 µCi	17.8	7.99
Urine, 96 hour	1.22 µCi	10.7	4.28
Urine, 120 hour	0.70 µCi	5.7	2.74
Urine, 144 hour	0.37 µCi	2.2	1.28
Urine, 168 hour	0.25 µCi	2.1	0.52
Total Urine	13.51 µCi		47.60
Feces, 6 hour	No sample available	-----	-----
Feces, 24 hour	1.07 µCi	29.1	3.75
Feces, 48 hour	4.70 µCi	52.2	16.46
Feces, 72 hour	3.59 µCi	32.9	12.59
Feces, 96 hour	1.74 µCi	21.9	6.11
Feces, 120 hour	1.20 µCi	12.3	4.22
Feces, 144 hour	0.48 µCi	5.9	1.69
Feces, 168 hour	0.29 µCi	3.7	1.01
Total Feces	13.07 µCi		45.83
Organ and Tissues			1.57
Cage Wash			0.63
Total			95.63

 

 

Table 3B

Recovery of radioactivity from Group 2* single female rat dosed with the 14C-pyrimidine-labeled test substance

 

 

Sample	Radioactivity	ppm (µg/g)	% of Dose
Urine, 6 hour	0.56 µCi	18.2	1.95
Urine, 24 hour	2.69 µCi	50.9	9.43
Urine, 48 hour	3.47 µCi	65.7	12.17
Urine, 72 hour	2.73 µCi	24.9	9.58
Urine, 96 hour	1.84 µCi	11.5	6.43
Urine, 120 hour	0.94 µCi	5.6	3.31
Urine, 144 hour	0.63 µCi	7.5	2.22
Urine, 168 hour	0.52 µCi	4.6	1.83
Total Urine	13.38 µCi		46.92
Feces, 6 hour	0.00 µCi	0.5	0.02
Feces, 24 hour	1.07 µCi	32.4	3.76
Feces, 48 hour	4.96 µCi	83.9	17.37
Feces, 72 hour	2.09 µCi	36.5	7.30
Feces, 96 hour	1.80 µCi	19.0	6.32
Feces, 120 hour	1.29 µCi	13.3	4.51
Feces, 144 hour	0.79 µCi	9.4	2.77
Feces, 168 hour	0.50 µCi	7.5	1.75
Total Feces	12.50 µCi		43.80
Organ and Tissues			3.11
Cage Wash			0.68
Total			94.51

 

Table 4A

Recovery of radioactivity from Group 3* male rats (average of 2 animals) dosed with the 14C-phenyl-labeled test substance

 

Sample	Radioactivity	ppm (µg/g)	% of Dose
Urine, 6 hour	0.41 µCi	10.2	1.24
Urine, 24 hour	4.54 µCi	28.3	13.81
Urine, 48 hour	3.20 µCi	18.6	9.75
Urine, 72 hour	1.82 µCi	10.9	5.57
Urine, 96 hour	1.07 µCi	5.4	3.26
Urine, 120 hour	0.57 µCi	3.4	1.72
Urine, 144 hour	0.34 µCi	2.3	1.03
Urine, 168 hour	0.18 µCi	1.2	0.54
Total Urine	12.13 µCi		36.92
Feces, 6 hour	0.02 µCi	0.4	0.07
Feces, 24 hour	3.22 µCi	60.4	9.82
Feces, 48 hour	6.92 µCi	66.6	21.08
Feces, 72 hour	3.57 µCi	42.0	10.86
Feces, 96 hour	1.76 µCi	19.8	5.37
Feces, 120 hour	0.90 µCi	10.3	2.72
Feces, 144 hour	0.38µCi	4.8	1.17
Feces, 168 hour	0.24 µCi	2.9	0.74
Total Feces	17.01 µCi		52.83
Organ and Tissues			1.18
Cage Wash			0.36
Total			91.29

 

Table 4B

Recovery of radioactivity from Group 3* female rats (average of 2 animals) dosed with the 14C-phenyl-labeled test substance

 

Sample	Radioactivity	ppm (µg/g)	% of Dose
Urine, 6 hour	0.25 µCi	17.1	0.76
Urine, 24 hour	3.80 µCi	40.4	11.56
Urine, 48 hour	4.04 µCi	36.1	12.30
Urine, 72 hour	2.46 µCi	17.5	7.47
Urine, 96 hour	1.37 µCi	12.9	4.12
Urine, 120 hour	0.77 µCi	12.9	2.33
Urine, 144 hour	0.65 µCi	9.8	1.97
Urine, 168 hour	0.51 µCi	4.8	1.54
Total Urine	13.85 µCi		42.05
Feces, 6 hour	0.00 µCi	0.1	0.00
Feces, 24 hour	2.83 µCi	55.4	8.63
Feces, 48 hour	4.76 µCi	95.2	14.48
Feces, 72 hour	3.80 µCi	49.3	11.56
Feces, 96 hour	1.97 µCi	25.0	5.97
Feces, 120 hour	0.95 µCi	19.8	2.88
Feces, 144 hour	0.58 µCi	13.6	1.76
Feces, 168 hour	0.48 µCi	6.6	1.49
Total Feces	15.37 µCi		46.77
Organ and Tissues			2.28
Cage Wash			0.86
Total			90.96

 

 

Table 5A

Recovery of radioactivity from Group 4* male rats (average of 2 animals) dosed with the 14C-phenyl-labeled test substance

 

Sample	Radioactivity	ppm (µg/g)	% of Dose
Urine, 6 hour	0.10 µCi	2150	0.27
Urine, 24 hour	2.01 µCi	1630	5.46
Urine, 48 hour	10.11 µCi	5010	26.98
Urine, 72 hour	5.42 µCi	3560	14.68
Urine, 96 hour	0.45 µCi	540	1.23
Urine, 120 hour	0.14 µCi	160	0.37
Urine, 144 hour	0.10 µCi	130	0.27
Urine, 168 hour	0.07 µCi	90	0.17
Total Urine	18.40 µCi		49.43
Feces, 6 hour	No sample available	-----	-----
Feces, 24 hour	1.31 µCi	3600	3.66
Feces, 48 hour	7.26 µCi	14,500	19.87
Feces, 72 hour	8.34 µCi	9800	23.11
Feces, 96 hour	1.10 µCi	1200	3.06
Feces, 120 hour	0.31 µCi	420	0.88
Feces, 144 hour	0.22 µCi	1030	0.59
Feces, 168 hour	0.10 µCi	120	0.27
Total Feces	18.64 µCi		51.44
Organ and Tissues			0.34
Cage Wash			0.27
Total			101.48

 

 

Table 5B

Recovery of radioactivity from Group 4* female rats (average of 2 animals) dosed with the 14C-phenyl-labeled test substance

 

Sample	Radioactivity	ppm (µg/g)	% of Dose
Urine, 6 hour	0.14 µCi	1010	0.47
Urine, 24 hour	1.27 µCi	2500	4.08
Urine, 48 hour	5.20 µCi	4280	16.82
Urine, 72 hour	6.00 µCi	2380	18.50
Urine, 96 hour	2.08 µCi	930	5.59
Urine, 120 hour	0.20 µCi	210	0.60
Urine, 144 hour	0.10 µCi	90	0.31
Urine, 168 hour	0.04 µCi	40	0.13
Total Urine	15.03 µCi		46.50
Feces, 6 hour	No sample available	-----	-----
Feces, 24 hour	0.58 µCi	3060	2.07
Feces, 48 hour	1.79 µCi	14,300	7.47
Feces, 72 hour	7.22 µCi	11,300	22.90
Feces, 96 hour	6.73 µCi	8300	17.74
Feces, 120 hour	0.69 µCi	1040	1.93
Feces, 144 hour	0.25 µCi	340	0.69
Feces, 168 hour	0.10 µCi	140	0.30
Total Feces	µCi		53.10
Organ and Tissues			0.31
Cage Wash			0.19
Total			100.10

 

* The actual doses of the test substance administered to the rats were:

 

Group 1: male 3.45 mg, 29.0 μCi and female 3.45 mg, 29.0 μCi

Group 2: male 3.43 mg, 28.5 μCi and female 3.43 mg, 28.5 μCi

Group 2A: male 4.06 mg, 33.7 μCi and female 4.06 mg, 33.7 μCi

Group 3: male 3.90 mg, 32.8 μCi and female 3.90 mg, 32.8 μCi

Group 4: male 4.35 mg 14C (36.5 μCi) + 650 mg unlabeled and female 3.92 mg 14C (32.9 μCi) + 590 mg unlabeled

 

Table 6

Biological half-lives for rats dosed with the radiolabeled test substance

 

Sample	Half-life (hours)
Low dose phenyl-labeled, Male*	55
Low dose phenyl-labeled, Female*	48
Low dose pyrimidinyl-labeled, Male**	45
Low dose pyrimidinyl-labeled, Female **	55
Low dose pyrimidinyl-labeled, Male*	48
Low dose pyrimidinyl-labeled, Female*	55
Low dose phenyl-labeled, Male***	42
Low dose phenyl-labeled, Female***	48
High dose phenyl-labeled, Male*	58
High dose phenyl-labeled, Female*	45

 

*    Rats sacrificed at 168 hours post-dosing

**  Rats sacrificed at 104.5 hours post-dosing

*** Rats preconditioned for 21 days on a diet containing 100 ppm of the test substance and   

      sacrificed at 168 hours post-dosing

Applicant's summary and conclusion

Conclusions:

The radiolabeled test substance was extensively metabolized by male and female rats after three different dosing routines with the phenyl-radiolabeled moiety and one dosing routine with the pyrimidine-radiolabeled moiety. Excretion of radioactivity in the urine and feces was rapid, with biological half-lives of approximately 50 hours under all dosing conditions.

Executive summary:

The studies were initiated to examine the tissue distribution, metabolism and excretion of the test substance administered by gavage to rats. Two radioactive forms of the test substance were included, one containing the radiolabel on the phenyl moiety of the test substance and the other containing the radiolabel on the pyrimidine moiety of the test substance.

The radiolabeled test substance was extensively metabolized by male and female rats after three different dosing routines with the phenyl-radiolabeled moiety and one dosing routine with the pyrimidine-radiolabeled moiety. Excretion of radioactivity in the urine and feces was rapid, with biological half-lives of approximately 50 hours under all dosing conditions (see Table 6). Typically 98% or more of the recovered radioactivity was excreted by 168 hours post-dosing (see Tables 1A, 1B, 2A, 2B, 3A, 3B, 4A, 4B, 5A, and 5B). Two metabolites, HPY-DPX-F6025 and ODM-DPX-F6025, comprised more than half of the 2-3% radioactivity retained in organs and tissues of low-dose animals maintained for 168 hours post-dosing. In those animals, tissue radioactivity levels did not exceed 1 ppm equivalent test substance (except for the liver, where the level was 1.5 ppm). Tissue radioactivity levels were proportionally higher in the high dose group compared to the two low dose groups, reflecting the difference in dose levels (3000 mg/kg vs. 16 mg/kg). All metabolites detected in the organs and tissues were also detected in the excreta. Evaluation of radioactivity in the excreta indicated extensive metabolism of the test substance and that less than 20% of the dose remained as intact material. The principal metabolites were hydroxylated analogs of the test substance, which included the 5-hydroxy pyrimidine analog (HPY), the demethylated analog (ODM), an analog with the chlorine replaced with a hydroxyl group (HOPY), a demethylated analog of HOPY (DI-HOPY), and a de-esterified analog of HOPY (FA-HOPY-DPX-F6025). No difference in recoveries or excreta patterns was observed which could be attributed to either dose conditions or sex of the animal. Similarly, no apparent difference in the metabolite distribution due to the sex of the animals was noted. Slight differences in metabolite ratios were observed, however, for high versus low dose rats.