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EC number: 603-837-5
CAS number: 134605-64-4
Table 1: Average percent of radioactivity in bile at
each sampling interval for male and female rats
Data extracted from report HWI 6117 -331
SD: Standard Deviation
Total recovered includes bile, urine and feces, cage
wash, cage wipe and carcass
Table 2: Average percent of radioactivity in urine and
feces at each sampling interval for male and female rats
Total excreted in urine and feces
Table 3: Quantitative 2D-TLC metabolite distributions
for the 0 - 4 hour pooled bile composites from male and female rats
(expressed as percent of assigned 14C and as percent of dose)
POD: Percent of dose
Zones U9 - U14 are primarily conjugates of the known
* Assumes 0 - 4 hrs is representative of total bile
% of dose basis = % of assigned zone x total POD in bile
The study was performed in accordance with EPA OPP 85-1.
Four male and four female rats which had been duodenally cannulated were
treated orally with a single dose of phenyl-14C-test substance. The test
substance had a specific activity of 41.6 μCi/mg and was dissolved in
PEG/EtOH/water (5/3/2). The actual average dose rate was 0.5 mg test
substance per kg body weight. Bile, urine and feces were collected from
all animals at specified time intervals until the rats were sacrificed
at 48 hours after dose.
After 48 hours, the average recovery in bile and excreta
was 100.15% for males and 100.43% for females. Elimination was rapid
with the majority of the dose being excreted within 24 hours. The
average percent of dose eliminated by various routes was as follows
(male/female): Bile: 78.70 / 74.30; Urine: 1.55 / 7.23; Feces: 19.90 /
18.90; Total: 100.15 / 100.43. The average total amount of absorbed dose
(urinary plus biliary elimination) was comparable for males (80.25%) and
females (81.53%). There was a slight gender related difference in the
primary excretion pattern as seen above.
Pooled composites of bile from the first four-hour
collection interval from each rat were prepared to simplify comparisons
between male and female bile. The composites of male and female bile
samples were profiled and quantified by 2D-TLC. Qualitatively, the
profiles were similar for both genders.
No parent compound was observed in the bile. The
chromatographic profile of the bile was consistent with the metabolite
profile of the excreta from a previous metabolism study in rats (The
metabolism of phenyl-14C-test substance in rats, Characterization and
identification of metabolites. Emrani J). The major biliary metabolites
were shown to have the same 2D-TLC behavior as available standards. Bile
samples were co-chromatographed with selected standards and also with
high dose male feces extract to verify the applicability of the TLC
assignments. The pooled bile profiles were calculated on a percent of
dose basis to compare biliary metabolites in males and females. The
excess percent of dose in male bile was largely due to the CGA-293731
metabolite. The metabolites CGA-293730 and CGA-368221 were present in
slightly higher abundance in the female bile than in male bile.
The major metabolite of test substance observed in bile
was CGA-293731(60.9% - 73.3% dose ) . Minor metabolites included
HO-CGA-293731 (1.5% - 3.0%) and CGA-368221(2.2% - 4.5%). Several minor
(polar) components present at low levels (≤2% dose) in the male and
female bile samples were characterized as glucuronide conjugates of the
This study showed that more than 80% of the total dose
was absorbed in both male and female rats at the low (nominal 0.5 mg/kg)
dose level. Characterization showed that the major metabolites in the
bile were the same as the metabolites identified in the excreta from the
aforementioned rat study (Emrani J). Minor components in the bile were
characterized as conjugates of the known major metabolites.
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