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EC number: 618-690-2 | CAS number: 90982-32-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
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
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 983
- Report date:
- 1983
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 985
- 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
- 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
Constituent 1
- 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 / concentrationsopen allclose all
- Dose / conc.:
- 16 mg/kg bw (total dose)
- Remarks:
- Phenyl-labeled moiety without preconditioning
- Dose / conc.:
- 16 mg/kg bw (total dose)
- Remarks:
- Pyrimidine-labeled moiety without preconditioning
- 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
- 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 resultsopen allclose all
- 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.
- 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.
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