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EC number: 936-023-6 | CAS number: 950782-86-2
- 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:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 008
- Report date:
- 2008
Materials and methods
- Objective of study:
- absorption
- distribution
- excretion
- metabolism
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 417 (Toxicokinetics)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics)
- Deviations:
- no
- GLP compliance:
- yes
Test material
- Reference substance name:
- N-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]-6-[(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine
- EC Number:
- 619-749-5
- Cas Number:
- 730979-19-8
- Molecular formula:
- C16H20FN5
- IUPAC Name:
- N-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]-6-[(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine
- Reference substance name:
- N-[(1R,2S)-2,6-Dimethyl-2,3-dihydro-1H-inden-1-yl]-6- [(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine
- IUPAC Name:
- N-[(1R,2S)-2,6-Dimethyl-2,3-dihydro-1H-inden-1-yl]-6- [(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine
Constituent 1
Constituent 2
- Radiolabelling:
- yes
- Remarks:
- 14C
Test animals
- Species:
- rat
- Strain:
- other: Wistar Hanover
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Wilmington, MA
- Age at study initiation: approx. 10 weeks
- Weight at study initiation: approx. 200-300 g
- Fasting period before study: Immediately prior to dosing, the rats were fasted for approximately 10 hours.
- Housing: Rats in the low dose experiments (LDE) were housed in individual Nalgene rodent metabolic cages (Havard Bioscience, South Natick, MA) which allowed separation and collection of urine, feces, and respired 14CO2 and volatile metabolites. Rats in the bile cannulation experiments (BCE) were housed in individual rodent restraint cages which allowed separation and collection of urine, feces, and bile.
- Individual metabolism cages: yes
- Diet: Rodient Diet (PMI Nutrition International, Inc., St. Louis, MO), ad libitum after dosing
- Water: ad libitum after dosing
- Acclimation period: at least 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 70±5
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: canola oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Low Dose Experiments:
Individual dosing solutions of [Indane-3-14C] AE1170437 or [Triazine-2,4-14C] AE1170437 were prepared for each rat in 10-ml pear-shaped flasks. A total of five dosing solutions per experiment were prepared.
For the I-LDE-M ([Indane-3-14C] low dose) group, an aliquot (1.01 mL, 5.00 mg) of the [Indane-3-14C] AE 1170437 stock solution was placed in a 10-mL volumetric flask and an aliquot (16.10 mg) of nonlabelled AE1170437 (Vial No. K-1480) was added. The solution was dissolved in a total of 10.00 mL of acetonitrile (ACN) and vortex mixed for 2 min. Triplicate 10-μl aliquots of the diluted solution were radioassayed. A 2.00-mL aliquot of the ACN solution was placed in each of five, 10-mL pear-shaped flasks, and the flasks were individually labelled with the compound, study number, test group, dose number, and date prepared. The solvent was removed in vacuo on a rotary-evaporator at ambient temperature, and the flasks with residue were sealed and stored in laboratory freezer (< -20 °C) until used. Immediately prior to dosing, the individual flasks holding the dry residue were removed from the freezer and allowed to warm to ambient temperature. To each flask was added 1.50 mL of canola oil; each flask was vortexed for 2 min and sonicated (Branson Ultrasonics Corp., Model 8510, Danbury, CT) for 2 min to generate a homogeneous suspension.
Each rat was dosed by oral gavage, using a separate syringe and needle, with the contents of one of the flasks. Each individual syringe was labeled with the identification number of the rat dosed. Following dosing, the amount of residual material in the flask and syringe used to dose each rat was measured. Based on the recovered radioactivity and the initial amount of material in each flask, the theoretical dose administered to each rat was determined. The residue in the dose flask and dosing syringe for each rat was analyzed by HPLC.
For the T-LDE-M ([Triazine-2,4-14C] low dose) group, an aliquot (1.50 mL, 5.00 mg) of the [Triazine-2,4-14C] AE1170437 stock solution was placed in a 10-mL volumetric flask and an aliquot (16.10 mg) of nonlabelled AE1170437 (Vial No. K-1480) was added. The subsequent steps were identical to that for the I-LDE-M group.
Bile Cannulation Experiments:
For the I-BCE-M ([Indane-3-14C] Bile Cannulation) group, an aliquot (1.01 mL, 5.00 mg) of the [Indane-3-14C] AE1170437 stock solution was placed in a 10-mL volumetric flask and an aliquot (23.14 mg) of nonlabelled AE1170437 (Vial No. K-1480) was added. The subsequent steps were identical to that for the I-LDE-M group.
For the T-BCE-M ([Triazine-2,4-14C] Bile Cannulation) group, an aliquot (1.52 mL, 5.00 mg) of the [Triazine-2,4-14C] AE1170437 stock solution was placed in a 10-mL volumetric flask and an aliquot (23.14 mg) of nonlabelled AE1170437 (Vial No. K-1480) was added. The subsequent steps were identical to that for the I-LDE-M group.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Vegetable oils are commonly used vehicles for oral dosing by gavage
- Concentration in vehicle: 2.813 mg/mL and 3.752 mg/mL in the low dose and the bile cannulation experiments, respectively.
- Amount of vehicle (if gavage): 1.5 mL/animal
- Purity: Edible, for human nutrition; received from local grocery store.
HOMOGENEITY AND STABILITY OF TEST MATERIAL:
Dosing preparations were throroughly vortexed and sonicated prior to administration to ensure a homogeneous suspension. - Duration and frequency of treatment / exposure:
- Single exposure by gavage
Doses / concentrationsopen allclose all
- Dose / conc.:
- 4.22 other: mg/animal
- Remarks:
- in the low dose experiments (corresponding to an average dose of 11.50 mg/kg bw for the I-LDE and 14.98 mg/kg bw for the T-LDE)
- Dose / conc.:
- 5.628 other: mg/animal
- Remarks:
- in the bile cannulation experiments (corresponding to an average dose of 14.00 mg/kg bw for the I-BCE and 13.35 mg/kg bw for the T-BCE)
- No. of animals per sex per dose / concentration:
- 4 and 5 males, respectively (5 males in bile cannulation experiment with [Triazine-2,4-14C] AE1170437 only)
- Control animals:
- no
- Positive control reference chemical:
- not applicable
- Details on dosing and sampling:
- PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, feces, blood, bone, brain, fat, heart, kidney, liver, lung, muscle, skin, spleen, testes, thyroid, gastrointestinal tract, remaining carcass, cage washes, bile, expired CO2 and volatile metabolites.
- Time and frequency of sampling: Urine was collected at 6, 12, 24, and 48 hours posttreatment. During the I-LDE-M and T-LDE-M experiments, urine was also collected at 72 hours posttreatment. The weight of urine at each interval was determined, and triplicate aliquots (0.010 to 0.100 mL) were radioassayed.
Feces were collected in separate containers at 24 and 48 hours posttreatment intervals until sacrifice. As with urine, during the I-LDE-M and T-LDE-M experiments feces were also collected at 72 hours posttreatment. Each feces sample was weighed and homogenized manually using a mortar and pestle. Aliquots (0.0081 to 0.0425 g) of the fecal homogenates were oxidized and radioassayed.
In the I-BCE-M and T-BCE-M experiments bile was collected 1, 2, 3, 4, 6, 8, 12, 24, 30, and 48 hours posttreatment. The weight of bile at each interval was determined, and triplicate aliquots (0.010 mL) were radioassayed.
At the conclusion of each experiment , individual rats were anesthetized with isofluorane exsanguinated through cardiac puncture using a 10-ml disposable syringe pretreated with heparin. Triplicate blood samples were pipetted into combustion pads for oxidation and radioassay. In all of the experiments, bone, brain, fat, heart, kidney, liver, lung, muscle, skin, spleen, testes, and thyroid were collected and weighed; aliquots of each tissue were oxidized and radioassayed.
The gastrointestinal tract (GIT) of each rat was collected and weighed, and the entire sample was homogenized using liquid nitrogen and an Ultra-Turrax Tissumizer. The homogenized GIT samples were placed in open plastic bags in a walk-in freezer (<-20 °C), and the liquid nitrogen was allowed to evaporate. Triplicate aliquots from each GIT were oxidized and radioassayed.
The remaining carcass was dissolved in 3 N ethanolic potassium hydroxide (KOH) solution (75 g of KOH dissolved in 425 mL of ethanol and 25 mL of H2O). Aliquots (1.0 mL) of the KOH solution were radioassayed.
In an attempt to detect and collect respired 14CO2 and all other volatile compounds in the I-LDE-M and T-LDE-M experiments, the rats were housed in metabolism cages equipped with a flow-through system which allowed for the separation and collection of respired gases. Atmospheric air was drawn through each cage at approximately 2000 mL/min using a vacuum pump. The air leaving each cage was sequentially passed through ethylene glycol (200 mL) to trap organic volatile compounds and 1 N aqueous sodium hydroxide (NaOH) solution (200 mL) to trap carbon dioxide (14CO2). Respired gas collection was discontinued 48 hours posttreatment. Respired gases were not collected during the I-BCE-M and T-BCE-M experiments.
- Other:
Following completion of each experiment, each metabolism cage was washed with methanol/water (MeOH/H2O; 1:1), and the washes from each cage were separately radioassayed. The urine and feces collection containers used in the I-LDE-M and T-LDE-M experiments were also washed with MeOH/H2O (1:1), and the combined washes from the urine and feces containers for each rat were radioassayed.
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces, bile
- Time and frequency of sampling: Quantitation and identification/characterization of radioactive components in urine, feces and bile were made from composite urine samples. Composite urine, feces and bile samples were prepared for each time interval described above.
- From how many animals: Composite samples for each time interval were prepared by combining one-half of the urine, feces and bile, respectively, collected from each rat at a given time interval.
- Method type(s) for identification (HPLC, LC/ESI-MS, NMR): Aliquots (0.010 to 0.100 mL) of the composite urine samples were radioassayed and analysed by HPLC. Individual components were isolated by HPLC, and isolated metabolites were analysed by liquid chromatography/electrospray interface - mass spectrometry (LC/ESI-MS).
Aliquots (0.0160 to 0.0526 g) of the composite feces samples were oxidised and radioassayed. A portion of each composited samples was extracted with ACN/H2O (4:1 v/v) using a tissumizer and centrifuged. Washing with fresh solvent was repeated twice, and supernatants and filtered solids, respectively, were combined. The combined supernatants were radioassayed and analysed by HPLC; the filtered solids were radioassayed. Individual components were isolated by HPLC and isolated metabolites were analysed by LC/ESI MS.
The composite bile samples were radioassyed and analysed by HPLC. Individual components were isolated by HPLC, and isolated metabolites were analysed by LC/ESI-MS and nuclear magnetic resonance (NMR) spectroscopy.
- Limits of detection and quantification:
Minimum sensitivity (µg/g; ppm) liquid samples: I-LDE-M and T-LDE-M: 0.0009; I-BCE-M and T-BCE-M: 0.0011
Minimum sensitivity (µg/g; ppm) solid samples: I-LDE-M and T-LDE-M: 0.0027; I-BCE-M: 0.0036; T-BCE-M: 0.0037 - Statistics:
- All calculations were performed using Microsoft Excel 2002 (10.6841.6839; SP-3).
Results and discussion
- Preliminary studies:
- Not performed.
Main ADME resultsopen allclose all
- Type:
- absorption
- Results:
- approximately 90.6%
- Type:
- distribution
- Results:
- in total approximately 0.2-5.0% in tissues (highest in GI-tract, liver, skin and thyroid gland)
- Type:
- excretion
- Results:
- approx. 35-49% of dose in urine and approx. 62-70% in the feces (the latter including 38-48% contribution of the bile)
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- In the low dose experiments the majority of the dose was excreted in the feces (62.2%), while 38.1% was excreted in the urine. Approximately 10% of the administered dose was excreted as unmetabolised parent compound in the feces and was therefore considered not to be absorbed. In conclusion, about 90% of the administered dose have been absorbed via the gastrointestinal tract. Total radioactive recovery in the respective experiments ranged from 101.4 to 106.7%.
Similar results were obtained from the bile cannulation experiments; summing the renal (37.0-48.8%) and biliary (37.9-48.3%) excretion with the residual amount of the dose in tissues shows a minimum bioavailability of 90.1-90.7% of the administered dose. Total radioactive recovery in the respective experiments ranged from 100.8 to 106.7%. - Details on distribution in tissues:
- Less than 1% of the administered dose remained in the carcass and tissues at sacrifice with the highest amounts in the gastrointestinal tract and the liver, followed by skin and thyroid gland. Slight differences in amount of radioactivity occurred depending on the location of the radioactive label in the test substance, especially in the bile cannulation experiments. In these experiments up to 4.9% of radioactivity was found in the tissues, in contrast to only 0.2% in the low dose experiments.
- Details on excretion:
- In the low dose experiments a total of 10 metabolites were detected in urine accounting for between <1% of the administered dose and approximately 23% of the administered dose. Five of the isolated metabolites accounted for >32% of the administered dose. A total of five metabolites were detected in composite feces extracts accounting for between 2% and approximately 40% of the administered dose. All five of the isolated metabolites accounted for approximately 58% of the administered dose. A total of approximately 90% of the administered dose was identified in the I-LDE-M experiment.
In the T-LDE-M experiment a total of six metabolites were detected in urine accounting for between <1% and approximately 22% of the administered dose. Individual metabolites were isolated from composite urine for identification. All six of the isolated metabolites accounted for >34% of the administered dose. A total of 10 metabolites were detected in feces extracts accounting for between <1% and approximately 44% of the administered dose. Individual metabolites were isolated from composite feces extract for identification. Five of the isolated metabolites, accounting for approximately 59% of the administered dose, were identified in the T-LDE-M feces extracts. A total of approximately 94% of the administered dose was identified in the T-LDE-M experiment.
In the bile cannulation experiments a total of 10 metabolites were detected in I-BCE-M urine accounting for between <1% and approximately 16% of the administered dose. Five of the isolated metabolites accounted for >29% of the administered dose. A total of nine metabolites were detected in feces extracts accounting for between <1% and approximately 12% of the administered dose. Six of the isolated metabolites accounted for approximately 18% of the administered dose. A total of sixteen metabolites were detected in bile extracts accounting for between <1% and approximately 19% of the administered dose. Five of the isolated metabolites accounted for approximately 38% of the administered dose. A total of approximately 85% of the administered dose was identified in the I-BCE-M experiment.
In the T-BCE-M experiment A total of 12 metabolites were detected in urine accounting for between <1% and approximately 25% of the administered dose. Six of the isolated metabolites accounted for >39% of the administered dose. A total of nine metabolites were detected in feces extracts accounting for between <1% and approximately 5% of the administered dose. Six of the isolated metabolites accounted for approximately 9% of the administered dose. A total of 13 metabolites were detected in bile accounting for between <1% and approximately 13% of the administered dose. Five of the isolated metabolites, accounted for >33% of the administered dose. A total of approximately 81% of the administered dose was identified in the T-BCE-M experiment.
The majority (84.1% in the low dose and 94.6% in the bile cannulation experiment) of the absorbed doses was excreted within 24 hours.
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- unmetabolised AE 1170437 parent: 1-12% feces, 4% bile;
AE 1170437-carboxylic acid: 16-25% urine, 1-44% feces, 13-19% bile;
AE 1170437-dihydroxy: 6-10% urine, < 1% feces, 2-3% bile;
AE 1170437-hydroxy GA (3-hydroxyindane GA + hydroxymethyl GA): < 1% urine, 10-13% bile;
AE 1170437-3-hydroxyindane acid: 1-2% urine, < 1-11% feces, 1% bile;
AE 117437-3-hydroxyindane acid epimer: 2-7% urine, 4% feces;
AE 1170437-3-ketoindane acid: < 1-2% urine, < 1-1% feces, 1% bile;
AE 1170437-3-ketohydroxymethyl: 1% feces;
AE 1170437-diaminotriazine: 1-2% urine; < 1% feces;
AE 1170437-hydroxyethyl acid: 3% feces
Metabolic degradation of AE 1170437 is rapid and complete, with between 0% and 10% of the administered dose being recovered as unmetabolised parent. In all experiments, 38 to 66% of the administered dose was excreted as AE 1170437 carboxylic acid, indicating that oxidation is the main route of metabolism for the parent compound. A variety of other oxidation products were also detected. Several glucuronic acid conjugates were observed, particularly in bile.
Any other information on results incl. tables
Distribution of radioactivity among tissues and excreta of rats after administration of [14C] AE 1170437:
Matrix |
Percent Dose (averages from all rats/group) |
|||
[Indane-3-14C] AE 1170437 (I-LDE-M) |
[Triazine-2,4-14C] AE 1170437(T-LDE-M) |
[Indane-3-14C] AE 1170437 (I-BCE-M) |
[Triazine-2,4-14C] AE 1170437 (T-BCE-M) |
|
Urine |
||||
0-6 h |
10.4 |
6.6 |
4.2 |
13.5 |
6-12 h |
17.5 |
17.8 |
21.3 |
19.1 |
12-24 h |
8.8 |
8.4 |
7.2 |
14.9 |
24-48 h |
1.3 |
1.6 |
4.3 |
1.3 |
48-72 h |
0.1 |
0.2 |
NC |
NC |
Total urine |
38.1 |
34.6 |
37.0 |
48.8 |
Feces |
||||
0-24 h |
47.4 |
56.9 |
16.1 |
7.4 |
24-48 h |
14.0 |
12.7 |
4.3 |
2.9 |
48-72 h |
0.8 |
0.8 |
NC |
NC |
Total feces |
62.2 |
70.4 |
20.4 |
10.3 |
Bile |
||||
0-1 h |
NC |
NC |
1.0 |
0.7 |
1-2 h |
3.7 |
1.8 |
||
2-3 h |
5.3 |
2.4 |
||
3-4 h |
4.9 |
3.5 |
||
4-6 h |
9.0 |
5.8 |
||
6-8 h |
6.5 |
4.7 |
||
8-12 h |
7.8 |
7.1 |
||
12-24 h |
7.6 |
9.9 |
||
24-30 h |
0.9 |
1.4 |
||
30-48 h |
1.6 |
0.6 |
||
Total bile |
48.3 |
37.9 |
||
Expired air |
<0.1 |
<0.1 |
NC |
NC |
Tissues |
0.2 |
0.2 |
4.9 |
3.9 |
Cage wash |
1.1 |
1.5 |
0.1 |
0.1 |
Total recovered |
101.6 |
106.7 |
110.7 |
101.0 |
NC = Not collected
Distribution of radioactivity in rat tissues/organs after administration of [14C] AE 1170437:
|
Ppm (µg of residue in AE 1170437 equivalents/g of tissue; averages of all rats/group) |
|||
Tissue/organ |
[Indane-3-14C] AE 1170437 (I-LDE-M) |
[Triazine-2,4-14C] AE 1170437(T-LDE-M) |
[Indane-3-14C] AE 1170437 (I-BCE-M) |
[Triazine-2,4-14C] AE 1170437 (T-BCE-M) |
Bone |
0.007 |
0.007 |
0.043 |
0.126 |
Brain |
0.004 |
0.004 |
0.012 |
0.102 |
Fat |
0.015 |
0.006 |
0.084 |
0.263 |
GI tract |
0.084 |
0.063 |
6.780 |
8.015 |
Heart |
0.006 |
0.006 |
0.050 |
0.398 |
Kidney |
0.014 |
0.012 |
0.177 |
0.445 |
Liver |
0.056 |
0.050 |
0.411 |
0.711 |
Lung |
0.006 |
0.006 |
0.074 |
0.357 |
Muscle |
0.004 |
0.005 |
0.053 |
0.160 |
Skin |
0.024 |
0.025 |
0.140 |
0.300 |
Spleen |
0.008 |
0.006 |
0.077 |
0.248 |
Thyroid gland |
0.012 |
0.025 |
0.066 |
0.314 |
Testes |
0.004 |
0.006 |
0.025 |
0.160 |
Whole blood |
0.008 |
0.009 |
0.061 |
0.110 |
Carcass |
0.007 |
0.010 |
0.040 |
0.053 |
CONCLUSION
The uptake and excretion of AE 1170437 was rapid. Following oral administration, greater than 84% of the administered dose was excreted within 24 hours. In general, the majority of the radioactivity was excreted in the feces with fecal:renal excretion ratios ranging from 1:1 to 2:1. No volatile residues were detected, and no mineralization was observed. Residue levels in tissues were highest in GIT and liver. Higher residue levels were found in the residual carcass of animals in the bile cannulation experiments.
Once absorbed, the metabolism of AE 1170437 was rapid, occurring mainly through oxidative pathways. A maximum of 10% of the administered dose was recovered unmetabolized in the feces, and that was likely not absorbed.
Applicant's summary and conclusion
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