IJT - CIR - February 2024 - 72S

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International Journal of Toxicology 43(Supplement 1)
All rats survived to the end of the study. Mean body
weights ofall dosed groups were similar to those ofthe vehicle
control groups. No treatment-related clinical findings were
observed. Liver weights of all dosed groups of males and
females were significantly greater than those of the vehicle
control groups. Incidences of hepatocyte hypertrophy in all
dosed groups of males and in 500 and 1000 mg/kg females
were significantly greater than those in the vehicle control
groups; there was a dose-related increase in severity of this
lesion in males. " Hepatocyte fatty change " occurred in all
dosed males. The incidences of thyroid gland follicular cell
hypertrophy were significantly increased in 500 and 1000 mg/
kg males and in 1000 mg/kg females. The incidences of
pigmentation in the olfactory epithelium of the nose were
significantly increased in 500 and 1000 mg/kg males and in
females administered 125 mg/kg or greater.9
Ginkgo Biloba Meristem Cell. In a 13-wk oral study, groups
of 10 male and female Sprague-Dawley rats received 250,
500, or 1000 mg/kg Ginkgo Biloba Meristem Cell (further
dosing details were not provided).48 Observations made
during the treatment period included clinical signs of toxicity,
body weight and feed measurements, ophthalmology assessment,
and urinalysis. At study end, necropsy,
hematological/biochemical examinations of blood, organ
weight measurement, microscopic examination, and histopathological
examination were performed. No unscheduled
deaths or adverse clinical signs of toxicity were observed
during the treatment period in any dose group. No treatmentrelated
adverse changes were reported in any of the measured
parameters before or after necropsy. Based on the results of
this study, the no-observed-adverse-effect-level (NOAEL) in
rats for Ginkgo Biloba Meristem Cell was determined to
exceed 1000 mg/kg.
Chronic Toxicity Studies
Oral
Ginkgo Biloba Leaf Extract. There was no evidence of organ
damage or impairment of hepatic or renal function when a
standardized GBE (EGb 761®) was administered orally over 27
wk to rats and mice at doses ranging from 100 to 1600 mg/kg.47
No further details were provided.
The results of the NTP chronic toxicity bioassays are
summarized in the Carcinogenicity section below.
Developmental and Reproductive Toxicity
(DART) Studies
The reproductive and developmental toxicity ofa standardized
GBE (EGb 761®) was studied in mice. In one study, groups of
25 mated female CD-1 mice received 0, 100, 350, or 1225 mg/
kg/d GBE in tap water via gavage (20 mL/kg) on days 6
through 15 of gestation.50 The dams were observed daily for
clinical signs of toxicity. Feed and water consumption were
monitored during the study. Body weight was measured daily.
On day 17 of gestation, the dams were killed and the ovaries,
uteri, and the fetuses were removed. The internal organs and
the placentae of the dams were examined macroscopically.
The fetuses were examined for several parameters, including
external and internal damages (malformations), sex, viability,
and weight. The skeletal systems and soft tissues ofthe fetuses
were also examined.
No clinical signs oftoxicity were observed in the dams and
there were no unscheduled deaths. No treatment related effects
were observed in body weight gains or feed and water consumption.
There were no pathological findings observed
during necropsy. No embryotoxic effects were observed
during external and internal examinations of the fetuses nor
were any observed in skeletal or soft tissues. There were no
increased incidences of malformation, variations, or retardations.
The authors concluded the no-observed-effect-level
(NOEL) was greater than 1225 mg/kg/d for both the dams
and the fetuses in this study of a standardized GBE.50
Another study examined the dose response and pathologic
effects ofa standardized GBE (EGb 761®) in saline on cycling
female Swiss albino mice.51 The test material was orally
administered at doses of 0, 3.7, 7.4, or 14.8 mg/kg body
weight/d for 28 d from the day of estrus phase (prior to
mating), from day 1 to day 7 of gestation, or from day 10 to
day 18 of gestation. A total of 200 cycling female mice were
assigned for the experiments. There were 10 animals for each
group used to study the effect ofgraded doses ofGBE on antiimplantation
and abortifacient activities and the remaining
120 animals were used to study the reproductive cycle (40
mice, 10 per group). Blood hormones of non-pregnant mice
were measured on day 28. Kidneys, liver, brain, placenta,
spleen and ovaries were quickly removed and weighed from
all animals that were killed. Post-mortem evaluations included
preparing ovaries for histological examinations, and counting
ovarian follicles. Maternal toxicity, estrous cycle, reproductive
hormones, ovarian follicle counts, resorption index, implantation
index, fetal viability and fetuses, and placenta mean
weights were also evaluated.
No signs of clinical toxicity such as depressed activities,
respiratory distress, salivation, tremor, fasciculation, dull eyes,
diarrhea, or change in fur appearance were observed in the
dams during any of the treatments, and there were no unscheduled
deaths. Statistically significant decreases in body
weight gains were observed in the 14.8 mg/kg/d dose group
treated for 28 d when compared to the controls. In comparison
to body weight, there were no treatment-related differences in
the relative weights of the liver, kidney, brain, spleen, ovary,
and placenta, but there was a significant dose-dependent
decrease in the relative weight of the gravid uterus in the
14.8 mg/kg/d dose group treated for 28 d when compared to
controls. Ovarian follicle counts, resorption index, implantation
index, and fetal viability were significantly reduced in
14.8 mg/kg/d dose group. Treatment with 14.8 mg/kg bw/d of

IJT - CIR - February 2024

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