Food and Nutrition Sciences, 2013, 4, 14-27
http://dx.doi.org/10.4236/fns.2013.47A003 Published Online July 2013 (http://www.scirp.org/journal/fns)
Acute and 26-Week Repeated Oral Dose Toxicity Study of
UP446, a Combination of Scutellaria Extract and Acacia
Extract in Rats
Young Chul Lee1, Eujin Hyun1, Mesfin Yimam2, Lidia Brownell2, Qi Jia2
1Unigen Inc., Cheonan, South Korea; 2Unigen Inc., Seattle, USA.
Received March 21st, 2013; revised April 22nd, 2013; accepted April 30th, 2013
Copyright © 2013 Young Chul Lee et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
UP446 has been used in both joint supplements and prescription medical food. The purpose of this study was to evalu-
ate the pharmaceutical safety of UP446 via acute and 26-week repeated oral dose toxicity study in SD rats. In acute tox-
icity study, UP446 was administered by oral gavage to Sprague-Dawley rats (5 males and 5 females) at a dose of 5000
mg/kg. In 26-week repeated oral dose toxicity study, UP446 at doses of 500, 1000 and 2000 mg/kg/day were given
orally to groups of rats (10 rats/dose/sex) for 26-week. UP446 at a dose of 5000 mg/kg produced no treatment-related
acute toxicity or mortality in any of the animals tested during 14 days of the study. In 26-week repeated dose toxicity
study, there was no significant difference in body weight between the control and all treatment groups. Blackish stool
and soft stool was observed in one male in the 1000 mg/kg group and in some males and females of 2000 mg/kg group.
However, these changes of stool were not considered to be toxic effects because neither histopathological change in
gastrointestinal tracks (GIT) nor body weight change were detected. No drug induced abnormalities were found as of
body weights, food consumption, ophthalmological examinations, urinalysis, hematology, clinical chemistry, organ
weights and gross necropsy in any animals in the dosing groups. These results suggest that the oral lethal dose of UP446
for male and female rats is in excess of 5000 mg/kg and the no observed adverse effect level (NOAEL) of the UP446
for both male and female rats is considered to be greater than 2000 mg/kg/day.
Keywords: Scutellaria baicalensis; Acacia catechu; Acute Oral Toxicity; Repeated Oral Toxicity
1. Introduction
The formulations containing multiple plant extracts have
attained wide recognition in comparison to crude plant
materials and extracts, due to reduction in dose, conven-
ience, and ease of administration. These formulations are
used by large sections of the human population particu-
larly in developed countries. Many synthetic drugs are
known to act on a single molecular target but the multi-
target responses of herbal formulations are proven to be
beneficial in chronic conditions [1-3]. The World Health
Organization (WHO) insists that the safety of herbal
medicines is a critical component in the quality control of
healthcare products. However, lack of adequate regula-
tions, the pharmacological complexity of herbal products,
and the insufficiency of information on the pharmacol-
ogy and toxicity of these compounds are sometimes be-
coming medical issues, even though the side effects are
minimal [4,5].
Thus a crucial standardization and toxicological evalu-
ation of the safety in pre-clinical model could be relevant.
Flavonoids are polyphenolic compounds that are ubiqui-
tous in nature and are categorized, according to chemical
structure, into flavonols, flavones, flavanones, isoflavones,
catechins, anthocyanidins, and chalcones. Over 4000
flavonoids have been identified, many of which present
in daily consumed human foods such as fruits, vegetables,
and beverages including tea, coffee, beer, wine, and fruit
drinks as well as traditional medicines and pharmaceuti-
cal drugs [6]. Usage of flavonoids include food flavor,
fruits and vegetables pigments, antimicrobial, antiviral,
antioxidants [7-9], as well as anticarcinogenic and an-
timutagenic [10]. Primarily two bioflavonoids, baicalin
from Scutellaria baicalensis (S. baicalensis) and catechin
from Acacia catechu (A. catechu) have been used sepa-
rately in many traditional medicines and pharmaceutical
products for a variety of uses including anti-inflamma-

Acute and 26-Week Repeated Oral Dose Toxicity Study of UP446, a Combination
of Scutellaria Extract and Acacia Extract in Rats
15
tory, antiviral, antibacterial, anticancer, and cardiovascu-
lar applications [7,11-17].
UP446 is a standardized bioflavonoid composition
with primarily baicalin from the roots of Scutellaria bai-
calensis (S. baicalensis) and (+)-catechin from the heart-
woods of Acacia catechu (A. catechu) [18]. It has been
used in both over the counter joint care dietary supple-
ments and prescription medical food [19]. The therapeu-
tic dosage of UP446 is 250 - 500 mg per day in clinical
applications [20]. Previous studies have shown that UP446
reduces production of eicosanoids through inhibition of
cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2),
and 5-lipoxygenase (5-LOX) enzymes and also decreases
expressions of inducible nitric oxide synthase (iNOS),
nuclear factor-kappaB (NF-κB), and tumor necrosis fac-
tor-alpha (TNF-α) [21]. Furthermore, UP446 showed anal-
gesic effects on multiple in vivo models [22].
The safety of UP446 was partially evaluated in 90
days repeated oral toxicity study in rats [23] but long
term assessment for toxicity in rats is required because
most patients with chronic arthritis diseases undergo long
term therapy.
The objective of the current study is to provide a com-
prehensive supplement to the safety profile reported pre-
viously for a standardized composition of S. baicalensis
and A. catechu. Herein, two toxicity studies were per-
formed to evaluate the safety of UP446. The acute oral
toxicity study was carried out at a high dose, whereas the
26-week repeated oral toxicity study was performed to
establish the no-observed-adverse-effect level (NOAEL)
of UP446.
2. Materials and Methods
2.1. Preparation of UP446
Detailed method for preparation of the two major flavon-
oids, baicalin and catechin, from the roots of S. baicalen-
sis and the heartwoods of A. catechu, respectively, were
disclosed in a US patent [24]. Briefly, S. baicalensis ex-
tract from roots was extracted with water and then re-
crystallized. The S. baicalensis extract contained baicalin
as the major bioflavonoid at content not less than 75% as
well as other minor free-B-ring flavonoids such as wo-
gonin-7-O-G-glucuronide, oroxylin A-7-OG-glucuronide,
and baicalein. Catechin extract was obtained from re-
peated crystallization of an aqueous extraction of the
heartwoods of an India medicinal plant, A. catechu. (+)-
Catechin is the major component in the A. catechu ex-
tract with a content of not less than 65% plus a minor
amount of its enantiomer, epicatechin, as well as other
minor amounts of flavans. Analyses of the extracts were
performed separately by two high-performance liquid
chromatography (HPLC) methods. The quantification re-
sults of baicalin, from the S. baicalensis extract and
catechin from the A. catechu extract were calculated by
comparison HPLC peak area with known standards. The
final UP446 composition was a mixture of S. baicalensis
and A. catechu standardized extracts at a ratio 4:1 with
baicalin content not less than 60% and catechin content
not less than 10%. Other minor flavonoids, such as wo-
gonin 7-glucuronide and baicalein, account for about 15%
of total weight. Moisture, ash, fat, and fiber constitute the
remainder weight (Figure 1).
2.2. Experimental Animals
Male and female Sprague–Dawley rats, aged 5 weeks,
were purchased from the ORIENTBIO INC. in Korea. In
the acute oral toxicity study, 10 rats of each sex were
used, whereas in the 26-week repeated oral dose toxicity
study, 50 rats of each sex including recovery groups were
used. All rats were labeled by tailmark and housed singly
in stainless wire mesh cages in a room maintained under
environmentally controlled conditions of 21˚C ± 2˚C and
a 12 h light-dark cycle in the animal facility of Biotox-
tech Co., Ltd. All rats were acclimatized at least one
week before starting the experiments, and had free ac-
cess to water and food. Test article was mixed in a solu-
tion of 0.5% carboxymethylcellulose sodium salt (CMC-
Na) in water (Choongwae Pharma Corp). The control
group received the vehicle only at the same volume as
the test animals. Clinical signs were observed in all ani-
mals during the experiments.
2.3. Acute Oral Toxicity Study
This study was performed at the Biotoxtech GLP insti-
tute following approval of the Institutional Animal Care
and Use Committee (Approval No.: 110947 and Study
No.: B11996) based on Animal Protection Act and con-
ducted in compliance with the Organization for Eco-
nomic Cooperation and Development (OECD) Guideline
425 adopted on the 3rd of October 2008 and Korea Food
and Drug Administration (KFDA) Guideline.
After acclimatization, 10 rats of each sex were ran-
domly divided into two groups of 5 males and 5 females
and were treated by gavage at doses of 0 and 5000 mg/kg
body weight. Mortality, clinical signs, body weight chan-
ges and gross findings were monitored during the 14
days after treatment.
2.4. 26-Week Repeated Oral Dose Toxicity Study
This study was performed at the Biotoxtech GLP insti-
tute following approval of the Institutional Animal Care
and Use Committee (Approval No.: 110736 and Study
No.: B11287) and conducted in compliance with the Or-
anization for Economic Cooperation and Development g

Acute and 26-Week Repeated Oral Dose Toxicity Study of UP446, a Combination
of Scutellaria Extract and Acacia Extract in Rats
16
Minutes
05 10 15 20 25 30
mAU
0
500
1000
1500
0
500
1000
1500
Baicalin
(a)
Minutes
024681012
mAU
0
200
400
600
0
200
400
600
Catechin
Epicatechin
(b)
Figure 1. HPLC chromatogram of UP446. (a) Baicalin contents in UP446; (b) Catechin contents in UP446.
(OECD) Guideline, ICH Harmonised Tripartite Guide-
line and Korea Food and Drug Administration (KFDA)
Guideline. 40 male and 40 female rats were divided into
four groups of 10 animals each; 10 additional animals of
each sex were used as recovery groups: five for the con-
trol and the other five for the high-dose group. UP446
(500, 1000, or 2000 mg/kg) or control group was orally
administered once daily using an oral Zonde needle for 6
months. Mortality, clinical signs, body weight, food con-
sumption and gross findings were monitored during ex-
perimental period. Ophthalmoscopic examinations were
conducted on both eyes of 5 animals/sex/group in the
main group and those of all animals in the recovery
group at 26 weeks and 30 weeks. At the end of the study,
all surviving animals were fasted overnight. 3 hours and
24 hours urine samples were collected from 5 animals/
sex/group in the main group and all animals in the re-
covery group prior to blood collection. Animals were
anesthetized with isoflurane and blood samples were col-
lected from the abdominal aorta and used to measure
hematological and biochemical parameters. The hemato-
logical parameters assessed included erythrocyte count
(RBC), hemoglobin (HGB), Hematocrit (HCT), Mean
corpuscular volume (MCV), Mean corpuscular hemoglo-
bin (MCH), Mean corpuscular hemoglobin concentration
(MCHC), platelets (PLT), leukocyte count (WBC), WBC
differential counting, Reticulocyte (Reti), prothrombin
time (PT) and activated partial thromboplastin time
(APTT). The clinical chemistry parameters assessed in-
cluded alanine aminotransferase (ALT), aspartate ami-
notransferase (AST), alkaline phosphatase (ALP), gam-
ma glutamyl transpeptidase (GGT), blood urea nitrogen
(BUN), creatinine (Crea), total bilirubin (T-Bili), total
protein (TP), albumin (Alb), Total cholesterol (T-Chol),
triglycerides (TG) and glucose (Glu). After blood collec-
tion, all animals were immediately sacrificed for gross
pathological examination of the internal organs. The or-
gans such as brain, pituitary, thymus, heart, lung, liver,
spleen, kidney, adrenal and sex organs were removed,
blotted free of blood and weighed immediately. Histopa-
thological examinations of animals were performed in
the control group and the highest dose group, and in the

Acute and 26-Week Repeated Oral Dose Toxicity Study of UP446, a Combination
of Scutellaria Extract and Acacia Extract in Rats
17
lower dose groups when appropriate. All organs were
fixed in 10% neutral-buffered formalin, and the tissue
sections were prepared with hematoxylin and eosin stain-
ing before microscopic examination for pathological chan-
ges.
2.5. Statistical Analysis
Statistical analysis was performed using SAS program
(version 9.2, SAS Institute Inc., USA). Body weights in
acute oral toxicity study were analyzed utilizing Folded-
F test for homogeneity of variance. And then Student t-
test was employed on homogeneous data for confirming
significance. Body weight, food consumption, urine vol-
ume, hematology, clinical chemistry and organ weight
data in 26-week repeated oral dose toxicity study were
analyzed utilizing Bartlett’s test for homogeneity of va-
riance. One-way analysis of variance (ANOVA) was em-
ployed on homogeneous data; then, if significant, Dun-
nett’s test was applied for multiple comparisons. Krus-
kal-Wallis test was employed on heterogeneous data. The
p values less than 0.05 were considered significant.
3. Results
3.1. Acute Oral Toxicity Study
To evaluate the acute oral toxicity of UP446, both sexes
of rats were orally administrated UP446 at the dose of
5000 mg/kg body weight. The UP446 at a dose of 5000
mg/kg produced no treatment related toxicity or mortality
in any of the animals during 14 days of the study. In ad-
dition, no body weight loss was detected (Table 1) and
all internal organs examined at necropsy were free from
any gross pathological changes. Therefore, the results
suggest that the lethal dose of UP446 is greater than 5000
mg/kg in male and female rats.
3.2. 26-Week Repeated Oral Dose Toxicity Study
No deaths and no treatment-related signs of toxicity were
observed throughout 26 and 30 weeks of the study in any
of the groups except one male and female in the control
group. Appearance and behavior of the animals were
similar for all groups of animals.
There was no statistically significant difference in
body weight between the control and all treatment groups
(Figure 2). Blackish stool was observed in males and
females in the 500, 1000 and 2000 mg/kg UP446 groups.
Soft stool was observed in one male in the 1000 mg/kg
group and in some males and females in the 2000 mg/kg
group (Table 2). However, these were not considered to
be toxic effects because neither histopathological change
in gastrointestinal tracks (GIT) nor body weight change
was detected. There were no associations between treat-
ment and the findings recorded in the ophtalmological
examinations conducted at the end of the treatment and
recovery periods (Tab le s 3 and 4). Urinalysis results also
showed that no test substance related changes in males
and females in the dosing groups in the main group and
in the recovery group (data not shown). Some hemato-
logical parameters of female rats treated with UP446 at
the dose of 2000 mg/kg/day showed statistically signifi-
cant differences when compared to those of the control
group. After 26-week of treatment, female rats had a
slightly decreased RBC, HGB and HCT at 2000 mg/kg.
However, these effects were not observed in recovery
group and male group (Tables 5 and 6). There were no
test substance related changes in males and females in
the dosing groups in the main group and in the 2000
mg/kg group in the recovery group.
Serum clinical chemistry data were shown in Ta bles 7
and 8. In male, a statistically significant decreased in
glucose at 2000 mg/kg when compared with that of the
control group. There were no significant differences be-
tween treatment and control groups in females.
The absolute and relative internal organ weights of
male and female rats treated with UP446 are summarized
in Tables 9 and 10. In absolute and relative organ
weights, no statistically significant changes were shown
in the treatment group when compared to control group.
However, the absolute adrenal gland weight was signifi-
Table 1. Body weight and body weight gain on da y 14 of rats in the acute oral toxicity study.
Body weight (g) Gain (g)
Group
Day 0 Day 1 Day 3 Day 7 Day 14 Day 0-14
Male
Control 162.9 ± 2.9 189.0 ± 4.3 212.6 ± 3.4 250.5 ± 6.6 314.0 ± 10.8 151.1 ± 8.7
UP446, 5 g/kg 163.1 ± 4.9 188.6 ± 4.8 211.2 ± 6.1 251.6 ± 8.7 317.4 ± 16.7 154.4 ± 13.9
Feamle
Control 130.9 ± 2.9 147.6 ± 4.7 162.0 ± 4.7 177.7 ± 6.0 207.3 ± 14.1 76.4 ± 11.0
UP446, 5 g/kg 131.1 ± 2.9 145.7 ± 1.7 163.5 ± 6.4 180.3 ± 8.9 203.0 ± 18.1 71.9 ± 17.7
V
alues are means ± SD (n = 5).

Acute and 26-Week Repeated Oral Dose Toxicity Study of UP446, a Combination
of Scutellaria Extract and Acacia Extract in Rats
18
Table 2. Clinical signs of UP446 for 26-week repeated oral
dose toxicity in male and female.
No. of
animals Clinical signs
No. of
animals
affected
Male
Control Decrease in food intake 1
Decrease of fecal volume 1
Prone position 1
Death 1
UP446, 500 mg/kg 10 Blackish stool 10
UP446, 1000 mg/kg 10 Blackish stool 10
Soft stool 1
Loss of teeth (upper teeth)1
UP446, 2000 mg/kg 15 Blackish stool 15
Soft stool 3
Female
Control 15 Prone position 1
Death 1
UP446, 500 mg/kg 10 Blackish stool 15
Wound (anterior neck) 1
Crust formation
(anterior neck) 1
UP446, 1000 mg/kg 10 Blackish stool 10
UP446, 2000 mg/kg 15 Blackish stool 15
Soft stool 4
cantly increased in female recovery group only. That or-
gan did not show any histopathological changes and just
exhibit in female recovery group only. There were no test
substance-related changes in male and females in the
dosing groups in the main group and in the 2000 mg/kg
group in the recovery group.
The gross and histopathological examination revealed
no findings related to the treatment (data not shown). The
findings were observed in a few animals or were equally
distributed among the groups, including in the control.
They were considered spontaneous changes that occur
commonly in normal rats of this strain and age, unrelated
to the administration of UP446.
4. Discussion
The present study demonstrated the comprehensive
safety profile of standardized composition of bioflavon-
oids extracted from S. baicalensis and A. catechu at a
dose as high as 5000 mg/kg in the acute toxicity study
and 2000 mg/kg in the 26-week repeated oral admini-
stration of. Previous study confirmed the safety of UP446
(a)
(b)
Figure 2. Effects of oral administration of UP446 for 26-
week repeated oral dose toxicity with 4-week recovery pe-
riod on mean body weights. (a) Body weight of male group
(G1: control; G2: UP446 500 mg/kg; G3: UP446 1000 mg/kg;
G4: 2000 mg/kg); (b) Body weight of female group (G1:
control; G2: UP446 500 mg/kg; G3: UP446 1000 mg/kg; G4:
2000 mg/kg). Data expressed as mean ± SD.
in 3 months repeated toxicity study using rats. NOAEL
was assumed to be over 1000 mg/kg/day [23]. However,
the systemic toxic effects of acute and long term treat-
ment should be evaluated since the target diseases of
UP446 are chronic arthritis that required long term treat-
ment.
In the acute toxicity study, UP446 caused neither treat-
ment related signs of toxicity nor mortality during 14
days of the study. No test substance related effects on
body weight and necropsy were observed in any animals
at 5000 mg/kg group. Therefore, the lethal dose of
UP446 is greater than 5000 mg/kg in male and female
rats.
In 26-week repeated oral dose toxicity study, no deaths
and no treatment related signs were observed in animals
of all groups except one male and female of control
group. Food consumption of UP446 treated groups were
found to be insignificant in male when compared to the
control groups but significantly increased food con-
sumption was observed in females in the 2000 mg/kg
group at week 14 when compared to the control group
(data not shown). However, these changes in food con-
sumption were not considered to be test substance related
effects since these were observed incidentally. Blackish
stool and soft stool was observed in one male in the 1000

Acute and 26-Week Repeated Oral Dose Toxicity Study of UP446, a Combination
of Scutellaria Extract and Acacia Extract in Rats
19
Table 3. Urinalysis results of UP446 for 26-week repeated oral dose toxicity with 4-week recover y period in male rats.
Parameters Grade Main group (mg/kg) Recovery group (mg/kg)
Group/dose (mg/kg) Control UP446, 500UP446, 1000UP446, 2000Control UP446, 2000
No. of animals 5 5 5 5 5 5
Volume (mL) 14.4 ± 6.7 17.0 ± 3.9 18.8 ± 8.3 12.2 ± 3.0 9.4 ± 2.4 8.3 ± 2.9
Color Pale yellow 4
Yellow 1 5 5 5 5 5
Transparency Clear 5 5 5 5 5 5
Mild turbidity
Turbidity
pH 5
6
6.5 1 2
7 2 3 2 3 2
8 2 1 3 4
9 1 1 3
Protein (mg/dL) 3 5 2 4 1
25 2 2 1 4 3
75 1 1
150 1
500
Glucose (mg/dL) Normal 5 5 5 5 5 5
50
100
300
1000
Ketone body (mg/dL) 5 5 5 5 5 5
5
15
50
100
Bilirubin (mg/dL) 5 5 5 5 5 5
1
3
4
Occult blood (Ery/μL) 5 5 5 5 4 5
10 1
25
50
150

Acute and 26-Week Repeated Oral Dose Toxicity Study of UP446, a Combination
of Scutellaria Extract and Acacia Extract in Rats
20
Continued
250
Cast‡ 0 5 5 5 5 5 5
1 - 5
6 - 10
>10
Epithelial cell‡ 0 5 5 5 5 5 5
1 - 5
6 - 10
>10
Leukocyte‡ 0 5 5 5 5 5 5
1 - 10
11 - 50
51 - 100
>100
Erythrocyte‡ 0 5 5 5 5 5 5
1 - 10
11 - 50
51 - 100
>100
Specific gravity 1.000 - 1.010
1.011 - 1.020
1.021 - 1.030 1
1.031 - 1.040 2 3 1
1.041 - 1.050 1 2 2 3
1.051 - 1.060 2 1 1 1 1
>1.060 1 4 4
‡Sediment.
mg/kg group and in some males and females in the 2000
mg/kg group. Although those symptoms were considered
to be test substance related effects, these were not toxic
effects since there were no changes on gastrointestinal
track at necropsy and histopathology, and there were no
effects on the body weights.
Blood is an important index of physiological and
pathological status in man and animal [25]. Some statis-
tically significant differences were observed from the
results of hematological parameters of female rats treated
with UP446 at the dose of 2000 mg/kg/day. However, all
differences in hematology parameters were not consid-
ered to be test substance-related effects because of the
small magnitude of the difference with in the normal
ranges, the lack of a clear dose response and the lack of
relationship without histological correlation. There are
strong evidences to suggest that both the traditional non
selective non-steroidal anti-inflammatory drugs (NSAIDs)
and the selective cyclooxygenase-2 (COX-2) inhibitors
are associated with an increased risk of thrombotic
events and adverse gastrointestinal effects [26,27]. To
confirm the impact of UP466 on blood coagulation, we
measured pro-thrombin and activated partial throm-
boplastin times after 26-week of repeated oral dose of
rats at dose rate as high as 2000 mg/kg/day, an equivalent
of 22.68 g average human daily dose. There was no

Acute and 26-Week Repeated Oral Dose Toxicity Study of UP446, a Combination
of Scutellaria Extract and Acacia Extract in Rats
21
Table 4. Urinalysis results of UP446 for 26-week repeated oral dose toxicity with 4-week recovery period in female rats.
Parameters Grade Main group (mg/kg) Recovery group (mg/kg)
Group/dose (mg/kg) Control UP446, 500 UP446, 1000UP446, 2000 Control UP446, 2000
No. of animals 5 5 5 5 5 5
Volume (mL) 8.2 ± 2.5 6.6 ± 2.76.6 ± 3.5 9.0 ± 2.8 6.9 ± 2.6 9.1 ± 4.5
Color Pale yellow 5
Yellow 5 5 5 5 5
Transparency Clear 5 5 5 5 5 4
Mild turbidity
Turbidity 1
pH 5
6 1 1
6.5 1
7 1 3 2 2
8 1 4 1 1 1
9 3 1 3 1 1 2
Protein (mg/dL) 5 2 5 5 2 1
25 3 3 2
75 2
150
500
Glucose (mg/dL) Normal 5 5 5 5 5 5
50
100
300
1000
Ketone body (mg/dL) 5 5 5 5 5 5
5
15
50
100
Bilirubin (mg/dL) 5 5 5 5 5 5
1
3
4
Occult blood (Ery/μL) 5 5 5 5 5 5
10
25
50
150
250
Cast‡ 0 5 5 5 5 5 5
1 - 5
6 - 10
>10

Acute and 26-Week Repeated Oral Dose Toxicity Study of UP446, a Combination
of Scutellaria Extract and Acacia Extract in Rats
22
Continued
Epithelial cell‡ 0 5 5 5 5 5 5
1 - 5
6 - 10
>10
Leukocyte‡ 0 5 5 5 5 5 5
1 - 10
11 - 50
51 - 100
>100
Erythrocyte‡ 0 5 5 5 5 5 5
1 - 10
11 - 50
51 - 100
>100
Specific gravity 1.000 - 1.010
1.011 - 1.020
1.021 - 1.030 1 1 1
1.031 - 1.040 4 2 2 2 1 1
1.041 - 1.050 1 1 3 2 1
1.051 - 1.060 1 1 1 2
>1.060 1 1
‡Sediment.
Table 5. Mean hematological parameters of UP446 for 26-week repeated oral dose toxicity with 4-week recovery period in
male rats.
Main group (mg/kg) Recovery group (mg/kg)
Parameters
Control UP446, 500 UP446, 1000 UP446, 2000 Control UP446, 2000
RBC (×106 cells/μL) 8.74 ± 0.26 8.55 ± 0.23 8.64 ± 0.35 8.61 ± 0.38 8.57 ± 0.16 8.69 ± 0.34
HGB (g/dL) 14.8 ± 0.6 14.6 ± 0.6 14.8 ± 0.7 14.9 ± 0.5 14.6 ± 0.5 15.2 ± 0.5
HCT (%) 45.8 ± 2.0 44.7 ± 1.7 45.4 ± 2.0 45.1 ± 1.4 44.5 ± 1.3 45.6 ± 1.6
MCV (fL) 52.4 ± 1.9 52.3 ± 2.1 52.6 ± 1.5 52.4 ± 1.5 52.0 ± 2.2 52.5 ± 1.0
MCH (pg) 17.0 ± 0.5 17.1 ± 0.7 17.2 ± 0.5 17.3 ± 0.5 17.1 ± 0.8 17.6 ± 0.3
MCHC (g/dL) 32.4 ± 0.5 32.8 ± 0.5 32.7 ± 0.6 33.0 ± 0.4 32.9 ± 0.3 33.4 ± 0.2*
PLT (×103 cells/μL) 1068 ± 93 1083 ± 87 1092 ± 156 1135 ± 98 1158 ± 138 1051 ± 92
Reti (%) 2.2 ± 0.3 2.3 ± 0.5 2.2 ± 0.8 2.0 ± 0.4 2.5 ± 0.3 2.3 ± 0.4
WBC (×103 cells/μL) 7.13 ± 0.81 6.96 ± 2.16 6.53 ± 1.47 6.58 ± 1.87 6.98 ± 2.47 6.67 ± 1.61
NEU 20.1 ± 3.7 20.7 ± 9.0 17.8 ± 4.9 24.6 ± 6.1 26.3 ± 6.1 14.9 ± 2.0**
LYM 72.5 ± 4.5 72.2 ± 9.8 76.2 ± 5.2 69.1 ± 6.2 67.0 ± 5.8 78.1 ± 1.9**
MONO 3.7 ± 1.0 3.8 ± 1.6 2.8 ± 1.2 3.0 ± 0.8 4.0 ± 0.9 4.1 ± 1.1
EOS 1.3 ± 0.4 1.3 ± 0.4 1.1 ± 0.2 1.1 ± 0.3 1.4 ± 0.6 1.6 ± 0.8
BASO 0.3 ± 0.1 0.3 ± 0.1 0.3 ± 0.1 0.3 ± 0.1 0.3 ± 0.1 0.2 ± 0.1
PT (sec) 15.9 ± 0.6 16.1 ± 0.6 15.6 ± 1.1 15.8 ± 0.7 16.3 ± 0.4 16.0 ± 1.0
APTT (sec) 16.6 ± 0.9 16.5 ± 1.2 16.4 ± 1.7 16.3 ± 1.2 17.1 ± 1.4 17.4 ± 0.9
Mean hematological parameters were calculated and data were expressed as mean ± SD (n = 10, except control group; n = 9, Recovery group; n = 5). Signifi-
cantly different from control by Student t-test for recovery *p < 0.05, **p < 0.01.

Acute and 26-Week Repeated Oral Dose Toxicity Study of UP446, a Combination
of Scutellaria Extract and Acacia Extract in Rats
23
Table 6. Mean hematological parameters of UP446 for 26-week repeated oral dose toxicity with 4-week recovery period in
female rats.
Main group (mg/kg) Recovery group (mg/kg)
Parameters
Control UP446, 500 UP446, 1000 UP446, 2000 Control UP446, 2000
RBC (×106 cells/μL) 7.78 ± 0.28 7.82 ± 0.30 7.71 ± 7.44 7.44 ± 0.22* 7.83 ± 0.50 7.74 ± 0.11
HGB (g/dL) 14.5 ± 0.5 14.1 ± 0.4 14.5 ± 0.4 13.7 ± 0.3** 14.8 ± 0.2 14.4 ± 0.5
HCT (%) 43.2 ± 1.8 42.3 ± 1.2 43.4 ± 1.4 41.2 ± 1.0** 43.0 ± 1.0 42.1 ± 1.6
MCV (fL) 55.6 ± 1.6 54.1 ± 1.2* 56.3 ± 1.3 55.4 ± 1.0 55.1 ± 3.0 54.4 ± 1.4
MCH (pg) 18.6 ± 0.3 18.1 ± 0.5* 18.8 ± 0.4 18.4 ± 0.3 19.0 ± 1.1 18.7 ± 0.5
MCHC (g/dL) 33.4 ± 0.5 33.4 ± 0.3 33.3 ± 0.4 33.3 ± 0.4 34.6 ± 0.9 34.3 ± 0.6
PLT (×103 cells/μL) 1029 ± 130 1149 ± 200 1049 ± 138 1011 ± 62 1053 ± 101 1022 ± 86
Reti (%) 2.0 ± 0.4 1.9 ± 0.2 2.1 ± 0.3 1.8 ± 0.4 2.2 ± 0.8 1.8 ± 0.4
WBC (×103 cells/μL) 3.13 ± 0.96 3.74 ± 1.13 3.32 ± 0.71 3.59 ± 1.04 4.82 ± 1.85 3.58 ± 1.01
NEU 19.5 ± 6.0 19.8 ± 6.8 20.5 ± 4.1 16.8 ± 3.7 16.1 ± 8.4 14.2 ± 3.3
LYM 73.6 ± 7.6 73.5 ± 7.1 72.4 ± 4.5 76.4 ± 5.3 76.3 ± 11.8 78.9 ± 2.8
MONO 3.6 ± 1.3 3.3 ± 1.1 3.6 ± 1.1 3.4 ± 1.7 3.7 ± 2.3 3.4 ± 0.8
EOS 1.5 ± 0.9 1.6 ± 0.5 1.5 ± 0.4 1.5 ± 0.5 1.4 ± 0.6 1.5 ± 0.5
BASO 0.3 ± 0.1 0.3 ± 0.1 0.3 ± 0.1 0.3 ± 0.1 0.2 ± 0.1 0.3 ± 0.2
PT (sec) 15.1 ± 1.0 15.3 ± 1.0 15.2 ± 0.7 15.5 ± 0.6 15.3 ± 0.7 15.2 ± 0.3
APTT (sec) 17.1 ± 0.8 16.8 ± 1.4 16.6 ± 0.5 17.0 ± 1.0 16.0 ± 1.7 16.4 ± 0.5
Mean hematological parameters were calculated and data were expressed as mean ± SD (n = 10, except control group; n = 9). Significantly different from con-
trol by Dunnett’s t-test: *p < 0.05, **p < 0.01.
Table 7. Mean clinical chemistry parameters of UP446 for 26-week repeated oral dose toxicity with 4-week recovery period in
male rats.
Main group (mg/kg) Recovery group (mg/kg)
Parameters
Control UP446, 500 UP446, 1000 UP446, 2000 Control UP446, 2000
ALT (U/L) 43.7 ± 16.5 36.6 ± 13.2 30.9 ± 5.7 35.8 ± 9.8 33.7 ± 6.9 31.5 ± 7.1
AST (U/L) 90.2 ± 24.5 88.9 ± 28.9 85.1 ± 17.5 81.7 ± 25.2 94.6 ± 26.6 110.6 ± 20.8
ALP (U/L) 190.5 ± 52.5 223.4 ± 37.4 209.7 ± 25.7 243.0 ± 43.8 225.2 ± 48.8 200.9 ± 27.0
GGT (U/L) 0.23 ± 0.14 0.40 ± 0.30 0.81 ± 0.34** 0.46 ± 0.30 1.15 ± 0.57 0.88 ± 0.39
Glu (mg/dL) 161 ± 15 154 ± 10 151 ± 10 139 ± 12** 165 ± 13 174 ± 19
BUN (mg/dL) 10.9 ± 0.8 10.4 ± 1.2 10.3 ± 1.5 9.4 ± 1.3 14.0 ± 1.5 12.1 ± 1.0*
Crea (mg/dL) 0.52 ± 0.05 0.50 ± 0.04 0.47 ± 0.06 0.48 ± 0.05 0.52 ± 0.05 0.53 ± 0.04
T-Bili (mg/dL) 0.06 ± 0.03 0.06 ± 0.02 0.05 ± 0.02 0.04 ± 0.01 0.07 ± 0.02 0.07 ± 0.02
T-Chol (mg/dL) 99 ± 22 97 ± 24 88 ± 26 95 ± 35 110 ± 17 106 ± 10
TG (mg/dL) 88 ± 45 105 ± 61 106 ± 80 86 ± 44 87 ± 21 73 ± 17
TP (g/dL) 6.1 ± 0.3 6.0 ± 0.2 6.1 ± 0.3 6.1 ± 0.3 6.4 ± 0.3 6.3 ± 0.2
Alb (g/dL) 2.3 ± 0.1 2.3 ± 0.1 2.3 ± 0.1 2.5 ± 0.1 2.4 ± 0.2 2.4 ± 0.1
A/G ratio 0.61 ± 0.03 0.63 ± 0.04 0.63 ± 0.03 0.67 ± 0.07 0.62 ± 0.05 0.62 ± 0.04
P (mg/dL) 5.53 ± 0.73 5.42 ± 0.61 5.75 ± 0.62 5.47 ± 0.73 5.98 ± 0.30 5.47 ± 0.25*
Ca (mg/dL) 10.3 ± 0.4 10.1 ± 0.4 10.2 ± 0.2 10.2 ± 0.2 10.1 ± 0.3 10.0 ± 0.3
Na (mmol/L) 142 ± 1 142 ± 1 143 ± 1 143 ± 1* 141 ± 1 141 ± 1
K (mmol/L) 4.7 ± 0.2 4.6 ± 0.3 4.6 ± 0.2 4.5 ± 0.2 5.0 ± 0.3 4.9 ± 0.1
Cl (mmol/L) 105 ± 1 105 ± 2 105 ± 1 105 ± 1 103 ± 1 104 ± 1
Mean clinical chemistry parameters were calculated and data were expressed as mean ± SD. Significantly different from control by Dunnett’s t-test for main
group and Student t-test for recovery group: *p < 0.05, **p < 0.01.

Acute and 26-Week Repeated Oral Dose Toxicity Study of UP446, a Combination
of Scutellaria Extract and Acacia Extract in Rats
24
Table 8. Mean clinical chemistry parameters of UP446 for 26-week repeated oral dose toxicity with 4 week recovery period in
female rats.
Main group (mg/kg) Recovery group (mg/kg)
Parameters
Control UP446, 500 UP446, 1000 UP446, 2000 Control UP446, 2000
ALT (U/L) 64.1 ± 41.3 48.4 ± 31.4 68.6 ± 83.2 60.2 ± 50.0 77.1 ± 62.3 29.7 ± 6.6
AST (U/L) 142.1 ± 89.9 105.4 ± 41.5 154.6 ± 154.3 166.5 ± 161.7 207.1 ± 162.0 98.9 ± 31.1
ALP (U/L) 92.6 ± 16.0 108.5 ± 35.9 93.6 ± 24.4 94.0 ± 16.1 81.1 ± 12.1 77.1 ± 22.3
GGT (U/L) 0.94 ± 0.34 0.78 ± 1.00 0.67 ± 0.45 0.94 ± 0.60 0.75 ± 0.43 0.37 ± 0.32
Glu (mg/dL) 162 ± 18 154 ± 14 156 ± 18 148 ± 13 170 ± 29 149 ± 7
BUN (mg/dL) 14.0 ± 1.6 13.3 ± 1.5 12.8 ± 2.7 12.8 ± 1.7 14.9 ± 1.3 13.5 ± 1.2
Crea (mg/dL) 0.55 ± 0.05 0.54 ± 0.08 0.54 ± 0.05 0.57 ± 0.08 0.57 ± 0.09 0.51 ± 0.04
T-Bili (mg/dL) 0.09 ± 0.02 0.07 ± 0.02 0.09 ± 0.02 0.08 ± 0.02 0.13 ± 0.03 0.11 ± 0.02
T-Chol (mg/dL) 116 ± 28 111 ± 19 113 ± 31 122 ± 25 107 ± 25 124 ± 19
TG (mg/dL) 32 ± 10 31 ± 9 35 ± 14 43 ± 16 52 ± 19 79 ± 25
TP (g/dL) 7.0 ± 0.4 7.0 ± 0.4 7.0 ± 0.4 7.0 ± 0.3 6.8 ± 0.4 7.1 ± 0.4
Alb (g/dL) 3.2 ± 0.2 3.2 ± 0.3 3.2 ± 0.3 3.4 ± 0.2 3.0 ± 0.1 3.2 ± 0.2
A/G ratio 0.84 ± 0.03 0.84 ± 0.09 0.84 ± 0.06 0.96 ± 0.09 0.79 ± 0.05 0.83 ± 0.04
P (mg/dL) 4.44 ± 0.82 4.35 ± 0.58 4.47 ± 0.64 4.37 ± 1.05 4.28 ± 0.36 3.82 ± 0.53
Ca (mg/dL) 10.5 ± 0.3 10.5 ± 0.4 10.6 ± 0.4 10.7 ± 0.3 10.1 ± 0.3 10.2 ± 0.2
Na (mmol/L) 142 ± 1 142 ± 1 143 ± 1 143 ± 1 141 ± 1 142 ± 1
K (mmol/L) 4.0 ± 0.3 4.0 ± 0.2 4.1 ± 0.3 4.1 ± 0.3 3.9 ± 0.2 4.0 ± 0.3
Cl (mmol/L) 105 ± 2 105 ± 3 105 ± 2 104 ± 1 104 ± 1 104 ± 1
Mean clinical chemistry parameters were calculated and data were expressed as mean ± SD.
treatment related or statistically significant changes in
coagulation parameters in each treatment group for both
males and females, when compared to the control group.
Adverse effects of traditional NSAIDs causing gastroin-
testinal lesions dosed with as little ibuprofen as 2 mg/kg/
day, equivalent to approximately 140 mg/day in humans
has been demonstrated in rats [23,28]. The current study
substantiate this findings in that after 26-week of re-
peated oral treatment of UP466 doses equivalent to as
high as 22.68 g/day for average human showed no gastric
mucosal or duodenal microscopic changes. These find-
ings suggest that the unique blend of baicalin and cate-
chin is well-tolerated by the gastrointestinal mucosa in
rats and may presumably be well tolerated in humans. In
this regard, UP446 is consistent with the reports of other
flavonoids, for instance garcinol, rutin and quercetin, shown
to either be gastro protective or have been used for the
treatment of gastric ulcerations [23,29].
This study also showed that no adverse change in
clinical chemistry parameters were observed in male or
female rats treated with UP446. Even at the highest daily
oral dosage of 2000 mg/kg, UP446 did not induce any
changes of liver enzymes such as ALT, AST, ALP and
caused no changes of absolute and relative liver weight
and no histopathology changes of liver tissues. The sta-
tistically significant changes in mean clinical chemistry
for glucose in males administered 2000 mg/kg/day were
not adverse or not related to expose to test substance be-
cause the differences in these parameters from those of
the control groups were relatively small in magnitude
they are not found in both sexes.
The absolute and relative organ weights in all treated
groups except increased absolute adrenal gland weight at
female recovery group were not significantly different
from those of control group. Therefore, it was considered
to be no toxicological significance since the organ did
not show test substance related changes in the main
group and these were secondary effects of body weight.
There were no macroscopic observations considered to
be treatment related in this study. No gross abnormalities

Acute and 26-Week Repeated Oral Dose Toxicity Study of UP446, a Combination
of Scutellaria Extract and Acacia Extract in Rats
25
Table 9. Absolute (g) and relative organ weights (g/100g body weight) of male rats with UP446 26-week repeated oral dose
toxicity with 4-week recovery period study.
Main group (mg/kg) Recovery group (mg/kg)
Parameters Control UP446, 500 UP446, 1000 UP446, 2000 Control UP446, 2000
Body weight, g 729.9 ± 83.1 713.5 ± 57.6 715.3 ± 83.4 665.9 ± 75.8 735.7 ± 123.9 695.0 ± 45.0
Brain,
g (g/100g BW)
2.19 ± 0.13
(0.30 ± 0.03)
2.19 ± 0.10
(0.31 ± 0.03)
2.18 ± 0.08
(0.31 ± 0.04)
2.20 ± 0.09
(0.33 ± 0.04)
2.20 ± 0.06
(0.30 ± 0.04)
2.13 ± 0.08
(0.31 ± 0.02)
Pituitary,
g (g/100g BW)
0.0148 ± 0.0022
0.0020 ± 0.0003
0.0154 ± 0.0022
(0.0022 ± 0.0004)
0.0144 ± 0.0011
(0.0020 ± 0.0002)
0.0154 ± 0.0016
(0.0024 ± 0.0004)
0.0148 ± 0.0020
(0.0020 ± 0.0003)
0.0157 ± 0.0025
(0.0022 ± 0.0004)
Thymus,
g (g/100g BW)
0.18 ± 0.05
(0.02 ± 0.01)
0.18 ± 0.03
(0.03 ± 0.01)
0.21 ± 0.08
(0.03 ± 0.01)
0.17 ± 0.04
(0.03 ± 0.01)
0.14 ± 0.04
(0.02 ± 0.01)
0.14 ± 0.06
(0.02 ± 0.01)
Heart,
g (g/100g BW)
1.77 ± 0.21
(0.24 ± 0.01)
1.77 ± 0.17
(0.25 ± 0.02)
1.75 ± 0.20
(0.24 ± 0.02)
1.65 ± 0.16
(0.25 ± 0.02)
1.87 ± 0.18
(0.26 ± 0.03)
1.78 ± 0.12
(0.26 ± 0.01)
Lung,
g (g/100g BW)
1.75 ± 0.18
(0.24 ± 0.01)
1.77 ± 0.07
(0.25 ± 0.02)
1.69 ± 0.13
(0.24 ± 0.02)
1.67 ± 0.18
(0.25 ± 0.02)
1.84 ± 0.18
(0.25 ± 0.03)
1.75 ± 0.09
(0.25 ± 0.02)
Liver,
g (g/100g BW)
18.51 ± 2.52
(2.53 ± 0.13)
17.87 ± 2.33
(2.50 ± 0.24)
17.64 ± 3.14
(2.46 ± 0.20)
16.93 ± 3.24
(2.53 ± 0.29)
18.85 ± 3.91
(2.56 ± 0.32)
17.95 ± 1.97
(2.58 ± 0.18)
Spleen,
g (g/100g BW)
1.06 ± 0.13
(0.15 ± 0.02)
1.05 ± 0.26
(0.15 ± 0.03)
0.98 ± 0.29
(0.14 ± 0.03)
0.89 ± 0.11
(0.13 ± 0.01)
0.92 ± 0.08
(0.13 ± 0.02)
0.96 ± 0.15
(0.14 ± 0.02)
Kidney,
g (g/100g BW)
3.74 ± 0.33
(0.52 ± 0.05)
3.91 ± 0.74
(0.55 ± 0.09)
3.76 ± 0.35
(0.53 ± 0.04)
3.77 ± 0.36
(0.57 ± 0.06)
4.03 ± 0.74
(0.55 ± 0.07)
3.97 ± 0.36
(0.57 ± 0.06)
Adrenal,
g (g/100g BW)
0.0664 ± 0.0094
(0.0091 ± 0.0008)
0.0610 ± 0.0085
(0.0086 ± 0.0011)
0.0625 ± 0.0182
(0.0086 ± 0.0017)
0.0571 ± 0.0112
(0.0087 ± 0.0023)
0.0669 ± 0.0088
(0.0092 ± 0.0013)
0.0601 ± 0.0137
(0.0087 ± 0.0020)
Testis,
g (g/100g BW)
3.68 ± 0.40
(0.51 ± 0.06)
3.69 ± 0.33
(0.52 ± 0.07)
3.63 ± 0.33
(0.51 ± 0.08)
3.70 ± 0.30
(0.56 ± 0.06)
3.98 ± 0.63
(0.54 ± 0.06)
3.76 ± 0.14
(0.54 ± 0.04)
Prostate,
g (g/100g BW)
0.65 ± 0.10
(0.09 ± 0.02)
0.50 ± 0.13
(0.07 ± 0.02)
0.54 ± 0.20
(0.08 ± 0.03)
0.56 ± 0.18
(0.08 ± 0.03)
0.60 ± 0.19
(0.08 ± 0.02)
0.55 ± 0.20
(0.08 ± 0.03)
Mean hematological parameters were calculated and data were expressed as mean ± SD (n = 10, except control group; n = 9, Recovery group; n = 5).
Table 10. Absolute (g) and relative organ weights (g/100g body weight) of female rats with UP446 26-week repeated oral dose
toxicity with 4-week recovery period study.
Main group (mg/kg) Recovery group (mg/kg)
Parameters Control UP446, 500 UP446, 1000 UP446, 2000 Control UP446, 2000
Body weight, g 369.8 ± 39.5 348.9 ± 48.7 358.3 ± 29.5 355.2 ± 42.4 343.8 ± 24.9 358.8 ± 39.0
Brain, g
(g/100g BW)
1.94 ± 0.08
(0.53 ± 0.05)
1.89 ± 0.14
(0.55 ± 0.07)
1.94 ± 0.08
(0.55 ± 0.05)
1.95 ± 0.10
(0.55 ± 0.06)
1.95 ± 0.09
(0.57 ± 0.03)
1.99 ± 0.07
(0.56 ± 0.04)
Pituitary, g
(g/100g BW)
0.0200 ± 0.0042
(0.0055 ± 0.0014)
0.0214 ± 0.0056
(0.0062 ± 0.0017)
0.0197 ± 0.0054
(0.0055 ± 0.0016)
0.0231 ± 0.0023
(0.0066 ± 0.0011)
0.0201 ± 0.0027
(0.0059 ± 0.0012)
0.0230 ± 0.0028
(0.0065 ± 0.0010)
Thymus, g
(g/100g BW)
0.14 ± 0.05
(0.04 ± 0.01)
0.16 ± 0.04
(0.05 ± 0.01)
0.14 ± 0.03
(0.04 ± 0.01)
0.15 ± 0.05
(0.04 ± 0.01)
0.10 ± 0.01
(0.03 ± 0.01)
0.13 ± 0.04
(0.04 ± 0.01)
Heart, g
(g/100g BW)
1.07 ± 0.07
(0.29 ± 0.03)
1.06 ± 0.12
(0.31 ± 0.03)
1.08 ± 0.08
(0.30 ± 0.02)
1.08 ± 0.09
(0.31 ± 0.02)
1.05 ± 0.09
(0.30 ± 0.03)
1.09 ± 0.12
(0.30 ± 0.04)
Lung, g
(g/100g BW)
1.24 ± 0.08
(0.34 ± 0.03)
1.26 ± 0.13
(0.36 ± 0.05)
1.23 ± 0.10
(0.34 ± 0.04)
1.24 ± 0.08
(0.35 ± 0.04)
1.28 ± 0.11
(0.37 ± 0.01)
1.30 ± 0.08
(0.36 ± 0.02)
Liver, g
(g/100g BW)
8.68 ± 0.76
(2.36 ± 0.24)
8.58 ± 1.28
(2.48 ± 0.38)
8.85 ± 0.95
(2.47 ± 0.17)
9.04 ± 1.06
(2.55 ± 0.21)
8.59 ± 0.72
(2.50 ± 0.13)
9.07 ± 1.07
(2.53 ± 0.23)
Spleen, g
(g/100g BW)
0.56 ± 0.05
(0.15 ± 0.02)
0.54 ± 0.09
(0.16 ± 0.03)
0.55 ± 0.08
(0.15 ± 0.02)
0.49 ± 0.06
(0.14 ± 0.02)
0.56 ± 0.13
(0.16 ± 0.03)
0.50 ± 0.06
(0.14 ± 0.01)
Kidney, g
(g/100g BW)
2.06 ± 0.13
(0.56 ± 0.06)
2.04 ± 0.19
(0.59 ± 0.08)
2.10 ± 0.18
(0.59 ± 0.04)
2.10 ± 0.23
(0.59 ± 0.06)
2.03 ± 0.19
(0.59 ± 0.05)
2.17 ± 0.24
(0.61 ± 0.05)
Adrenal, g
(g/100g BW)
0.0708 ± 0.0089
(0.0192 ± 0.0023)
0.0668 ± 0.0141
(0.0194 ± 0.0045)
0.0638 ± 0.0092
(0.0178 ± 0.0025)
0.0762 ± 0.0096
(0.0217 ± 0.0034)
0.0677 ± 0.0071
(0.0198 ± 0.0027)
0.0079 ± 0.0045*
(0.0219 ± 0.0028)
Ovary, g
(g/100g BW)
0.0712 ± 0.0273
(0.0194 ± 0.0077)
0.0638 ± 0.0208
(0.0181 ± 0.0043)
0.0690 ± 0.0171
(0.0194 ± 0.0053)
0.0674 ± 0.0140
(0.0191 ± 0.0040)
0.0767 ± 0.0269
(0.0221 ± 0.0069)
0.0687 ± 0.0175
(0.0189 ± 0.0032)
Uterus, g
(g/100g BW)
0.75 ± 0.24
(0.20 ± 0.07)
0.74 ± 0.21
(0.22 ± 0.08)
0.85 ± 0.16
(0.24 ± 0.04)
0.84 ± 0.42
(0.25 ± 0.15)
0.84 ± 0.27
(0.25 ± 0.08)
0.98 ± 0.61
(0.28 ± 0.17)
Mean hematological parameters were calculated and data were expressed as mean ± SD (n = 10, except control group; n = 9, Recovery group; n = 5). Signifi-
antly different from control by Student t-test: *p < 0.05. c

Acute and 26-Week Repeated Oral Dose Toxicity Study of UP446, a Combination
of Scutellaria Extract and Acacia Extract in Rats
26
attributed to the test article were noted for any of the
euthanized animals necropsied at the end of the 26-week
observation period. Incidental findings correspond to
historical control values for other experiments [30,31].
In the present study, the oral lethal dose of UP446 for
male and female rats is in excess of 5000 mg/kg and the
no observed adverse effect level (NOAEL) of the UP446
for both male and female rats is considered to be greater
than 2000 mg/kg/day. Based on our present study, further
toxicity study using beagle dogs with UP446 should be
also conducted in GLP institute.
5. Acknowledgements
This study was funded by Chungcheong Leading Indus-
try Promotion Project of the Korean Ministry of Know-
eldge Economy. The authors would like to express their
best gratitude to Dr. Edward Cannon, Dr. Doug Bradley,
Dr. Wenwen Ma, Dr. Padma Abeysinghe, Dr. Min Chu
and Unigen team for their incalculable support for the
completion of this research.
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