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EC number: 617-769-9 | CAS number: 858956-08-8
- 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
- Study period:
- 10 July 2007 to 07 March 2008
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 010
- Report date:
- 2010
Materials and methods
- Objective of study:
- absorption
- distribution
- excretion
- metabolism
- toxicokinetics
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 417 (Toxicokinetics)
- Version / remarks:
- adopted 4 April 1984
- Deviations:
- no
- GLP compliance:
- yes
Test material
- Reference substance name:
- 6-amino-5-chloro-2-cyclopropylpyrimidine-4-carboxylic acid
- EC Number:
- 617-769-9
- Cas Number:
- 858956-08-8
- Molecular formula:
- C8H8ClN3O2
- IUPAC Name:
- 6-amino-5-chloro-2-cyclopropylpyrimidine-4-carboxylic acid
1
- Radiolabelling:
- yes
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Crl:CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina, USA
- Age at study initiation: at least 8 weeks
- Weight at study initiation: 228 - 279 g (males), 164 - 218 g (females)
- Housing: individually in stainless steel, wire-mesh cages suspended above cage boards
- Diet: PMI® Nutrition International, LLC Certified Rodent LabDiet® 5002, ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 6 days with the exception of cannulated rats which were quarantined for at least 3 days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 26
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: To:
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- methylcellulose
- Remarks:
- 0.5%
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The target radioactive dose was 30 μCi/250 g animal. The 14C-test substance was diluted with test substance to the appropriate specific activity for the selected dose level. The test substance, 14C-test substance and dose vehicle (0.5% methylcellulose) were weighed into a vial and mixed to a clear solution or homogeneous suspension. Dose preparations were prepared and stored refrigerated until use.
- Duration and frequency of treatment / exposure:
- single oral administration
Doses / concentrationsopen allclose all
- Dose / conc.:
- 25 mg/kg bw/day
- Remarks:
- pilot material balance study and main pharmacokinetics study
- Dose / conc.:
- 500 mg/kg bw/day
- Remarks:
- main pharmacokinetics study and metabolite profile study
- No. of animals per sex per dose / concentration:
- 1 (pilot material balance study)
4 (main pharmacokinetics study ) + 1 additional rat per sex dosed at 500 mg/kg bw/day for analytical method development (metabolite profile)
3 (metabolite profile study) - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: the dose levels were based on the results of a toxicity study.
- Details on dosing and sampling:
- TOXICOKINETIC / PHARMACOKINETIC STUDY (absorption, distribution, excretion)
- Tissues and body fluids sampled: 14C exhaled volatiles and 14CO2, urine, faeces, blood, cage wash, residual feed (pilot material balance study), plasma and red blood cells (RBC) (main pharmacokinetics study)
- Time and frequency of sampling: 14C exhaled volatiles and 14CO2 for 48 h at 24 h intervals (e.g. 0-24 and 24-48 h), urine and feces were collected at 24 h intervals for a total of 168 h, cage wash was collected throughout the study, blood samples (plasma and RBC) were collected pre-dose and at 5, 15 and 30 minutes, 1, 2, 4, 8, 12, 24, and 30 h post dose
- From how many animals: 1 rat per sex and dose (pilot material balance study), 4 animals per sex and dose (main pharmacokinetics study)
- Other: The following tissues were collected for analyses at the end of the study: blood (plasma and RBC were analyzed separately for 14C content), fat liver, kidney, muscle, heart, lung, testes, ovaries, uterus, bone and bone marrow (analyzed separately for 14C content), brain, spleen, adrenals, pituitary, gastro-intestinal tract and contents (analyzed separately for 14C content), pancreas, skin sample, thyroid, thymus, bladder (urine in the bladder at the time of sacrifice was aspirated and placed in the terminal urine sample vial) and remaining carcass (pilot material balance study). Liquid scintillation counting was used for quantitation of radioactive residues.
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: plasma (control and 500 mg/kg bw/day dose groups at 0.5 h timepoint), urine and feces ( 25 mg/kg bw/day dose group at 0-24 h intervals)
- Time and frequency of sampling: plasma was collected 0.5 h after test substance administration (metabolite profile study), urine and feces was collected at 24 h intervals for a total of 168 h (pilot material balance study)
- From how many animals: 3 samples per sex and dose (metabolite profile study), 1 sample per sex and dose (pilot material balance study)
- Method types for identification: quantification of radioactivity in plasma, urine, and feces was performed by HPLC with in-line radioactivity (LC/ARC). Observed radiochemical chromatographic peaks were identified by performing peak fractionation and LC/MS. Each of the prepared samples was also analyzed by LSC to verify adequate extraction recoveries
Clinical Observations and Mortality
Cage-site examinations to detect moribund or dead rats and abnormal behavior and/or appearance among rats were conducted at least once daily throughout the study.
(For further details on study design please refer to table 1 in the "Any other information and methods incl. tables" section.) - Statistics:
- Group data are represented as a mean ± SD.
Results and discussion
- Preliminary studies:
- The test substance was rapidly eliminated after single oral gavage administration. No 14C residues were detected in exhaled breath. These results suggest that the position of the radiolabeled carbon was stable to metabolic biotransformation. Excretion occurred via the urine and feces in approximately equal proportions and was substantially complete within the first 24 h after dosing. Tissue 14C residues, with the exception of 0.039% in the male rat carcass, were below the limit of detection by 168 h after dosing. (For details on Toxikokinetic parameters please refer to table 4 and 5 in the "Any other information on results incl. tables" section.)
Main ADME resultsopen allclose all
- Type:
- absorption
- Results:
- The results indicated rapid absorption of the test substance.
- Type:
- distribution
- Results:
- Test substance is predominantely found in plasma. Tissue 14C residues, with the exception of male rat carcass ( 0.039%), were below the limit of detection by 168 h after dosing.
- Type:
- metabolism
- Results:
- No biotransformation was evident under the condition of single dose administration at 25 or 500 mg/kg bw in plasma urine and feces.
- Type:
- excretion
- Results:
- Radioactivity was not detected in respired breath (exhaled volatiles or CO2). Excretion occurred in both the urine and feces and was substantially complete in the first 24 h after dosing.
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- The results indicated rapid absorption with peak concentrations in plasma at 0.4 to 1 h after dosing. The mean Tmax values in red blood cells were 0.3 to 1 h. The peak concentrations in red blood cells were 0.33 to 0.48 fractionally lower than those observed in plasma indicating very limited potential for binding within red blood cells. The red blood cell concentration data were insufficient for calculation of pharmacokinetic parameters. The mean peak concentrations in plasma (3.8-5.0 μg equiv/g at the low dose and 57.3-61.6 μg equiv/g at the high dose, respectively) were approximately proportional to the 20-fold increase in dose from 25 to 500 mg/kg bw. Near direct proportionality was observed for the AUCINF values suggesting linear first-order kinetic processes for uptake and elimination. (For details on Toxikokinetic parameters please refer to table 4 and 5 in the "Any other information on results incl. tables" section.)
- Details on distribution in tissues:
- The peak concentrations in red blood cells were 0.33 to 0.48 fractionally lower than those observed in plasma indicating very limited potential for binding within red blood cells. The test substance is distributed within plasma. By 168 h after dosing, 14C residues were not detected in any of the various tissues collected to evaluate tissue distribution. One exception was the male rat carcass which contained 0.039% of the dose. Radioactivity detected in cage wash and residual feed was 1.4% and 0.4% of the administered dose for the male and female rat, respectively. The overall material balance was 69.9% for the single male rat and 107.9% for the single female rat. (Please refer to table 2 in the "Any other information on results incl. tables" section.)
- Details on excretion:
- Radioactivity was not detected in respired breath as either exhaled volatiles or CO2, and thus collection was stopped at 48 h. Excretion occurred in both the urine and feces and was substantially complete in the first 24 h after dosing. By 168 h after dosing, the individual male and female rat urine contained 36.3% and 55.8%, respectively; and the percentages were approximately equal to the 32.1% and 51.7% excreted in the feces. Radioactivity detected in cage wash and residual feed was 1.4% and 0.4% of the administered dose for the male and female rat, respectively. The overall material balance was 69.9% for the single male rat and 107.9% for the single female rat. In plasma, the terminal elimination half-lives were 5.6 to 5.7 h for male and female rats with no difference between the low (25 mg/kg bw) or high (500 mg/kg bw) dose levels. Plasma 14C residues were quantifiable for up to 30 h after dosing. (Please refer to table 2, 3, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15 and 16 in the "Any other information on results incl. tables" section.)
Toxicokinetic parametersopen allclose all
- Key result
- Toxicokinetic parameters:
- half-life 1st: Plasma: 5.6 h in males and 5.7 h in females (25 and 500 mg/kg bw)
- Remarks:
- The half-lives were unchanged with the 20-fold increase in dose.
- Key result
- Toxicokinetic parameters:
- Cmax: Plasma: 3.8 and 5.0 μg equiv/g in male and female rats, respectively (25 mg/kg bw dose) 57.3 and 61.6 μg equiv/g for male and female rats, respectively (500 mg/kg bw dose)
- Key result
- Toxicokinetic parameters:
- Cmax: Red blood cells: 1.3 and 2.0 μg equiv/g in males and females, respectively (25 mg/kg bw/day) 27.2 and 28.7 in males and females, respectively (500 mg/kg bw/day)
- Key result
- Toxicokinetic parameters:
- Cmax: RBC/Cmax plasma ratios: 0.33 and 0.4 in males and females, respectively (25 mg/kg bw/day) 0.48 and 0.47 in males and females, respectively (500 mg/kg bw/day)
- Remarks:
- (very limited potential for uptake and binding in the red blood cell)
- Key result
- Toxicokinetic parameters:
- AUC: Plasma: 7.0 and 9.0 hr*μg/g in males and females, respectively (25 mg/kg bw dose) 150.8 and 168.4 hr*μg/g in males and females, respectively (500 mg/kg bw dose)
- Key result
- Toxicokinetic parameters:
- Tmax: Plasma: 0.5 h and 0.4 h in males and females, respectively (25 mg/kg bw dose) 6.0 h and 1.0 h in males and females, respectively (500 mg/kg bw dose)
- Toxicokinetic parameters:
- Tmax: Red blood cells: 0.5 h and 0.3 h in males and females, respectively (25 mg/kg bw dose) 6.0 h and 1.0 h in males and females, respectively (500 mg/kg bw dose)
Metabolite characterisation studies
- Metabolites identified:
- no
- Details on metabolites:
- No metabolite was evident under the condition of single dose administration of 25 or 500 mg/kg bw in plasma at 0.5 h timepoint and urine or feces 0-24 h time interval (pilot study). Only test substance, as parent chemical was confirmed in all 3 matrices by radiochemical and mass spectral analysis. Biotransformation of the test substance was absent in rats under conditions of single oral gavage at the 25 and 500 mg/kg bw doses. One expected metabolite, 5-chloro-2-cyclopropyl-pyrimidin-4-ylamine, was not observed. This metabolite has been quantified in rat plasma at Day 56 of a 90-day toxicity study by dietary administration at concentrations corresponding to 100 to 945 mg/kg bw/day for male rats and 129 to 1268 mg/kg bw/day in female rats. Although not identified under conditions of the current study, the metabolite 5-chloro-2-cyclopropyl-pyrimidin-4-ylamine appears to be formed by de-carboxylation of the test substance upon repeated daily uptake of the test substance. Under the conditions of this study, no metabolism of the test substance was observed.
Any other information on results incl. tables
Table 2: Material balance for rats administered a single oral dose of14C-test substance (25 mg/kg bw)
|
|
Percent of dose |
|
Sample |
Hour |
Male |
Female |
|
|
101M |
102F |
urine |
168 h |
36.304 |
55.761 |
feces |
168 h |
32.145 |
51.688 |
exhaled a |
48 h |
<LOD |
<LOD |
cage wash |
168 h |
1.209 |
0.358 |
residual feed |
168 h |
0.197 |
0.076 |
tissues |
168 h |
<LOD |
<LOD |
carcass |
168 h |
0.039 |
<LOD |
|
Total |
69.9 |
107.9 |
a Includes data from 3 traps (CO2, volatiles, and water).
LOD limit of detection
LOQ limit of quantitation
Table 3: Percent recovery in excreta of rats administered a single oral dose of14C-test substance (25 mg/kg bw)
Percent of dose |
|
|
|
Cumulative percent of dose a |
|
Male Female |
|
Male |
Female |
Male |
Female |
Sample |
Hour |
101M |
102F |
101M |
102F |
urine |
Pre-dose |
<LOD |
<LOD |
0 |
0 |
urine |
24 h |
35.8876 |
53.7113 |
35.888 |
53.711 |
urine |
48 h |
0.2835 |
1.5093 |
36.171 |
55.221 |
urine |
72 h |
0.0893 |
0.5271 |
36.260 |
55.748 |
urine |
96 h |
0.0184 |
0.0086 |
36.279 |
55.756 |
urine |
120 h |
0.0048 |
0.0025 |
36.284 |
55.759 |
urine |
144 h |
0.0164 |
0.0016 |
36.300 |
55.760 |
urine |
168 h |
0.0041 |
0.0008 |
36.304 |
55.761 |
feces |
Pre-dose |
<LOD |
<LOD |
0 |
0 |
feces |
24 h |
31.1368 |
47.9955 |
31.137 |
47.996 |
feces |
48 h |
0.84 |
3.6031 |
31.977 |
51.599 |
feces |
72 h |
0.1249 |
0.0804 |
32.102 |
51.679 |
feces |
96 h |
0.014 |
0.0068 |
32.116 |
51.686 |
feces |
120 h |
0.0062 |
0.0023 |
32.122 |
51.688 |
feces |
144 h |
0.0176 |
<LOQ |
32.140 |
51.688 |
feces |
168 h |
0.0054 |
<LOD |
32.145 |
51.688 |
a Pre-dose time point assigned zero hour and concentration for graphical representation
LOD limit of detection
LOQ limit of quantitation
Table 4: Concentration (μg equiv/g) in plasma and red blood cells following a 25 or 500 mg/kg bw single oral dose of14C-test substance
|
25 mg/kg bw |
500 mg/kg bw |
||||||
Hour |
Male |
Female |
Male |
Female |
||||
Plasma |
Mean |
SD |
Mean |
SD |
Mean |
SD |
Mean |
SD |
Pre-dose |
NAa |
NA |
NA |
NA |
NA |
NA |
NA |
NA |
5 m |
1.13 |
0.32 |
2.58 |
0.60 |
3.98 |
1.22 |
6.69 |
3.58 |
15 m |
3.09 |
0.85 |
4.86 |
1.13 |
28.37 |
5.41 |
35.57 |
14.08 |
30 m |
3.01 |
0.20 |
4.35 |
1.25 |
54.40 |
18.45 |
54.28 |
20.60 |
1 h |
2.74 |
1.52 |
2.91 |
0.61 |
51.17 |
8.27 |
52.92 |
14.50 |
2 h |
1.14 |
0.50 |
1.57 |
0.82 |
29.68 |
4.30 |
42.77 |
7.73 |
4 h |
0.13 |
0.05 |
0.13 |
0.02 |
4.66 |
1.20 |
3.69 |
1.66 |
8 h |
0.07 |
0.02 |
0.11 |
0.07 |
2.35 |
0.32 |
1.84 |
0.75 |
12 h |
0.05 |
0.04 |
0.05 |
0.04 |
1.36 |
0.56 |
1.45 |
0.34 |
24 h |
NA |
NA |
NA |
NA |
0.46 |
NA |
0.43 |
NA |
30 h |
0.005 |
0.002 |
0.01 |
0.002 |
0.16 |
0.02 |
0.13 |
0.04 |
Red blood cells |
||||||||
Pre-dose |
NA |
NA |
NA |
NA |
NA |
NA |
NA |
NA |
5 m |
0.38 |
0.10 |
0.88 |
0.17 |
1.90 |
NA |
2.60 |
1.10 |
15 m |
1.07 |
0.21 |
1.99 |
0.66 |
11.46 |
2.05 |
14.69 |
5.96 |
30 m |
0.99 |
0.09 |
1.76 |
0.60 |
25.68 |
8.47 |
23.47 |
9.69 |
1 h |
0.95 |
0.49 |
1.14 |
0.26 |
23.96 |
4.74 |
24.23 |
7.07 |
2 h |
0.43 |
0.19 |
0.60 |
0.30 |
13.97 |
2.57 |
19.72 |
4.03 |
4 h |
0.07 |
NA |
NA |
NA |
1.78 |
0.52 |
2.06 |
NA |
8 h |
0.03 |
NA |
0.06 |
NA |
1.07 |
NA |
0.97 |
NA |
12 h |
0.04 |
NA |
0.04 |
NA |
0.73 |
NA |
NA |
NA |
24 h |
NA |
NA |
NA |
NA |
NA |
NA |
NA |
NA |
30 h |
0.004 |
NA |
NA |
NA |
NA |
NA |
NA |
NA |
a Pre-dose samples and others with mean values designated NA had individual animal concentrations that were <LOD
NA not applicable
Table 5: Pharmacokinetic parameters in plasma and red blood cells following a 25 or 500 mg/kg bw single oral dose of14C-test substance
Parameter |
25 mg/kg bw |
500 mg/kg bw |
||||||
Plasma |
Male |
Female |
Male |
Female |
||||
|
Mean |
SD |
Mean |
SD |
Mean |
SD |
Mean |
SD |
Elimination half-life (h) |
5.6 |
0.5 |
5.7 |
0.4 |
5.6 |
0.3 |
5.7 |
0.7 |
Area-under-the-curve (AUCINF, hr*µg/g) |
7.0 |
1.4 |
9.0 |
1.9 |
150.8 |
28.7 |
168.4 |
26.2 |
AUCINF/dose (hr*kg*µg/g/mg) |
0.3 |
0.1 |
0.4 |
0.1 |
0.3 |
0.1 |
0.3 |
0.1 |
Peak concentration (Cmax, µg eq/g) |
3.8 |
0.9 |
5.0 |
1.2 |
57.3 |
14.2 |
61.6 |
13.0 |
Half peak concentration (Cmax/2, µg) a |
1.9 |
|
2.5 |
|
28.7 |
|
30.8 |
|
Time of Cmax (Tmax, h) |
0.5 |
0.4 |
0.4 |
0.1 |
0.6 |
0.3 |
1.0 |
0.7 |
Time of Cmax/2 (Tmax/2, hr a |
1.4 |
|
1.2 |
|
2.0 |
|
2.3 |
|
Red blood cells (RBC) b |
||||||||
Peak concentration (µg eq/g) |
1.3 |
0.3 |
2.0 |
0.7 |
27.2 |
6.2 |
28.7 |
4.7 |
Time of Cmax (Tmax, h) |
0.5 |
0.4 |
0.3 |
|
0.1 |
0.6 |
0.3 |
1.0 |
Ratio (Cmax RBC)/(Cmax plasma) a |
0.33 |
|
0.40 |
|
0.48 |
|
0.47 |
|
a Calculated from Mean value, SD not given.
b Only Cmax and Tmax are presented. Time course data were insufficient to calculate other kinetic parameters.
AUCINF area under the concentration vs. time curve, extrapolated to infinity
AUCINF/D AUCINF, normalized to dose
Table 6: Concentration (μg equiv/g) in plasma of rats administered 0 or 500 mg/kg bw single oral dose of
14C-test substance
Dose |
|
|
Plasma concentration (µg equiv/g) |
Plasma concentration (µM)a |
||
(mg/kg bw) |
Sex |
Hour |
Mean |
SD |
Mean |
SD |
0 b |
Male |
0.5 |
<LOD |
NA |
<LOD |
NA |
|
Female |
0.5 |
<LOD |
NA |
<LOD |
NA |
500 c |
Male |
0.5 |
53.4 |
17.6 |
250 |
82 |
|
Female |
0.5 |
63.3 |
21.7 |
296 |
102 |
a Calculated using MW = 213.62 g/mol
b Control sample (n =1 per sex)
c Treated samples used for metabolite profiling (n = 3 per sex)
Table 7: Summary of retention times for reference standards and components in plasma from rats administered14C-test substance
|
|
Reference Standard HPLC/14Ca |
Sample Summary HPLC/14C |
||
[M+H] |
Peak Retention Time |
Fraction Collection Window |
Minimum Retention Time |
Maximum Retention Time |
|
|
(dalton) |
(minutes) (minutes) |
(minutes) |
(minutes) b |
(minutes) b |
Test substance |
214 |
5.02 |
4.51-5.25 |
5.02 |
5.02 |
Metabolite (INLXT69) |
170 |
N/Ac |
5.26-6.00 |
NId |
NI |
a 14C retention time for radiolabeled 14C-test substance reference standard spiked into the sample matrix.
b Retention time of base peak if tailing occurred and resulted in multiple integrations.
c Not applicable since the metabolite is not 14C radiolabeled.
d Not identified in the matrix.
Table 8:Summary of components identified in plasma of rats administered14C-test substance (A-male, B-female)
Component |
M+H (Da) a |
Peak Fraction Collection Window (min) |
Dose Group b |
Mass Spectral Criteria Figure
|
Test substance |
214 |
4.51-5.25 |
A,B |
Spectral and retention time match with reference standard. |
a Most abundant ion in molecular ion cluster
b The structural identification was confirmed for the respective dose group: A – 601M-603M, 1F-603F.
Table 9: Summary of test substance parent concentrations in plasma
Time (minutes) |
Subject |
oncentration in plasma (µM) Test substance - Parent |
30 |
601M |
254 |
|
602M |
108 |
|
603M |
296 |
|
Mean |
219 |
|
SD |
99 |
30 |
601F |
231 |
|
602F |
358 |
|
603F |
165 |
|
Mean |
251 |
|
SD |
98 |
Table 10: Summary of retention times for reference standards and components in urine from rats administered14C-test substance
|
|
Reference Standard HPLC/14C a |
Sample Summary HPLC/14C |
||
[M+H] |
Peak Retention Time |
Fraction Collection Window |
Minimum Retention Time |
Maximum Retention Time |
|
|
(dalton)n) |
(minutes) |
(minutes) |
(minutes) b |
(minutes) b |
Test substance |
214 |
5.02 |
4.51-5.25 |
5.02 |
5.02 |
Metabolite |
170 |
N/Ac |
5.26-6.00 |
NId |
NI |
a 14C retention time for radiolabeled14C-test substance reference standard spiked into the sample matrix.
b Retention time of base peak if tailing occurred and resulted in multiple integrations.
c Not applicable since the metabolite is not14C radiolabeled.
d Not identified in the matrix.
Table 11: Summary of components identified in urine of rats administered14C-test substance (A-male, B-female)
|
[M+H] (dalton) a |
Peak fraction collection window (minutes) |
Dose roup b |
Mass spectral criteria |
Test substance |
214 |
4.51-5.25 |
A, B |
Spectral and retention time match with reference standard. |
a Most abundant ion in molecular ion cluster
b The structural identification was confirmed in the 24-hour dose group: A – 101M, B – 102F.
Table 12: Summary of components identified in urine of rats administered with 14C-test substance as percent of administered dose
Identified component |
14C Retention time (min) |
Component as percent of dose 500 mg/kg bw |
||
|
Minimum |
Maximum |
Male |
Female |
Test substance |
5.02 |
5.02 |
35.9 |
53.7 |
Identified |
|
|
35.9 |
53.7 |
Not identified |
|
|
0 a |
0 |
Total |
|
|
35.9 |
53.7 |
a Zero indicates not identified (detected)
Table 13: Summary of retention times for reference standards and components in feces from rats administered14C-test substance
|
|
Reference Standard HPLC/14C a |
Sample Summary HPLC/14C |
||
|
[M+H] |
Peak Retention Time |
Fraction Collection Window |
Minimum Retention Time |
Maximum Retention Time |
|
(dalton) aa |
(minutes) |
(minutes) |
(minutes) b |
(minutes) b |
Test substance |
214 |
5.17 |
4.51-5.25 |
5.18 |
5.33 |
Metabolite |
170 |
N/A c |
5.26-6.00 |
NI d |
NI |
a 14C retention time for radiolabeled14C-test substance reference standard spiked into the sample matrix.
b Retention time of base peak if tailing occurred and resulted in multiple integrations.
c Not applicable since the metabolite is not14C radiolabeled.
d Not identified in the matrix.
Table 14: Summary of components identified in feces of rats administered14C-test substance (A-male, B-female)
|
[M+H] (dalton) a |
Peak fraction collection window (minutes) |
Dose group b |
Mass spectral criteria |
Test substance |
214 |
4.51-5.25 |
A, B |
Spectral and retention time match with reference standard. |
a Most abundant ion in molecular ion cluster
b The structural identification was confirmed in the 24-h sample dose group: A – 101M, B - 102F.
Table 15: Summary of components identified in feces of rats administered with14C-test substance as percent of administered dose
|
14C Retention time (min) |
Component as percent of dose 500 mg/kg bw |
||
|
Minimum |
Maximum |
Male |
Female |
Test substance |
5.18 |
5.33 |
31.1 |
48.0 |
Identified |
|
|
31.1 |
48.0 |
Not identified |
|
|
0 a |
0 |
Total |
|
|
31.1 |
48.0 |
a Zero indicates not identified (detected)
Table 16: Summary of components quantified in urine and feces of rats administered 14C-test substance
Dose mg/kg bw |
Proposed or identified component |
Parent or component as percent of dose
|
|||||
25 |
|
Urine |
Feces |
Urine + Feces |
|||
|
Male |
Female |
Male |
Female |
Male |
Female |
|
Test substance |
35.9 |
53.7 |
31.1 |
48.0 |
67.0 |
101.7 |
|
Identified |
35.9 |
53.7 |
31.1 |
48.0 |
67.0 |
101.7 |
|
Not identified |
0.0 |
0.0 |
0.0 |
0.0 |
0.0 |
0.0 |
|
Total |
35.9 |
53.7 |
31.1 |
48.0 |
67.0 |
101.7 |
Applicant's summary and conclusion
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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