IJT - CIR - February 2024 - 71S

Burnett et al.
71S
details) received Ginkgo Biloba Meristem Cell at 250, 500,
and 1000 mg/kg, respectively, for 4 d.48 No unscheduled
deaths were observed. All animals vomited after receiving 500
and 1000 mg/kg of the test material. Only 1 animal vomited
after receiving the 250 mg/kg dose, but the effects were determined
to be too slight a symptom to confirm treatmentrelated
effects. No adverse effects were observed in body
weights or at necropsy. The maximum tolerated dose for
Ginkgo Biloba Meristem Cell was determined to be greater
than 1000 mg/kg in this dog study.
Intravenous
Ginkgo Biloba Leaf Extract. The LD50 after intravenous
administration of a standardized GBE (EGb 761®) was
1100 mg/kg for both rats and mice.9
Short-Term Studies
Oral
Ginkgo Biloba LeafExtract. The results of a combined liver
comet assay (see Genotoxicity section) using male and female
C3H-derived constitutive androstane receptor knockout
(CARKO) and wild-type mice found no abnormal clinical
signs and no treatment-related effects on body weight following
oral exposure ofup to 2000 mg/kg body weight/day of
a GBE used by the NTP for 3 d in either mouse genotype.49
Relative liver weights were significantly increased in male and
female wild-type mice at all doses of a GBE in a dosedependent
manner. The liver weights in the CARKO mice
were similar to the negative control group. The wild-type mice
in all GBE-treated groups had dose-dependent slight-tomoderate
hepatocellular hypertrophy in the centrilobular
area: this effect was only observed in a single CARKO mouse
in the highest dose group. No histopathological findings
suggesting cytotoxicity in the liver was observed in any GBEtreated
groups.
Ginkgo Biloba Meristem Cell. In a dose-range finding study
for a 13-wk oral repeated dose toxicity test (see below), groups
of male and female Sprague-Dawley rats received 500, 1000,
or 2000 mg/kg Ginkgo Biloba Meristem Cell for 4 wk
(number of rats/group and method of administration not described).48
No unscheduled deaths or clinical signs of toxicity
were observed during the treatment period. Additionally, no
treatment-related changes in body weight gains, feed intake,
hematological/biochemical measurements, or organ weights
were observed. No adverse effects were noted at necropsy in
any dose group.
Subchronic Toxicity Studies
Oral
Ginkgo Biloba Leaf Extract. The toxicity of a specific GBE
was investigated in a 3-mo mouse study performed by the
NTP.9 Groups of 10 male and 10 female B6C3F1/N mice
received 0, 125, 250, 500, 1000, or 2000 mg/kg body weight
of the GBE in corn oil via gavage, 5 d/wk for 14 wk. Control
groups received corn oil (5 mL/kg). Clinical findings and body
weights were recorded initially, then weekly, and at the end of
the study. Blood was collected at the end ofthe study from all
animals for hematology analyses. Sperm motility and vaginal
cytology evaluations were made on the mice in the 0, 500,
1000, and 2000 mg/kg dose groups. At the end of the study
period, tissues from over 40 sites were examined for every
animal, including ovaries and uteri in females and prostate
gland and testes with epididymis and seminal vesicles in
males.
One female mouse in the 1000 mg/kg group died of a
dosing accident during week 11. Mean body weights of
2000 mg/kg females were significantly less than those of the
vehicle control group. Ruffled fur was observed in two
1000 mg/kg males between weeks 7 and 8 and all 2000 mg/kg
males between weeks 5 and 9. No treatment-related differences
were observed in sperm parameters in males administered
500, 1000, or 2000 mg/kg or in the estrous cycle of
females administered 500 or 1000 mg/kg when compared to
controls. Female mice in the 2000 mg/kg group had a significantly
higher probability of extended estrous than did the
vehicle control females. Liver weights ofmales ofthe 250 mg/
kg or greater dose groups and females of all dose groups were
significantly greater than those of the vehicle control groups.
Kidney weights of males of the 2000 mg/kg group were
significantly less than those of the vehicle control group.
Incidences of hepatocytic hypertrophy were significantly increased
in males and females dosed with 250 mg/kg or greater.
Significantly increased incidences of focal hepatocytic necrosis
occurred in males of the 1000 and 2000 mg/kg dose
groups. The incidences ofhyaline droplet accumulation in the
respiratory epithelium ofthe nose were significantly increased
in males of the 500 mg/kg and females of the 1000 and
2000 mg/kg dose groups. In the olfactory epithelium of the
nose, the incidences of hyaline droplet accumulation were
significantly increased in the 125 (female only), 500, and
1000 mg/kg groups. Incidences of atrophy of the olfactory
epithelium were significantly increased in the 1000 mg/kg
groups. The incidences of pigment accumulation in macrophages
in the olfactory epithelium were significantly increased
in males in the 500 mg/kg or greater groups and in females in
the 1000 and 2000 mg/kg dose groups.9
The NTP also performed a 3-mo study of the same GBE
used above in rats.9 Groups of10 male and 10 female F344/N
rats received 0, 62.5, 125, 250, 500, or 1000 mg/kg body
weight of the GBE in corn oil via gavage, 5 d/wk for 14 wk.
Additional groups of 10 male and 10 female rats received the
same doses for a clinical pathology study, 5 d/wk for 23 d.
Control groups received corn oil (2.5 mL/kg). The same
methods that were followed in the mouse study described
above were used in the main study animals, while animals in
the clinical pathology study had blood samples collected on
days 4 and 23.

IJT - CIR - February 2024

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IJT - CIR - February 2024 - Cover3
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