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Han, Yang, Kim, Han, Lee, Jeong, Roh, Seok, Lee, Kim, and Min: Two-Week Repeated Dose Toxicity of Atractylodis Rhizoma Alba in F344 Rats
Original Article

Natural Product Sciences 2016;22(3):180-186.

Published online: 17 January 2016

DOI: https://doi.org/10.20307/nps.2016.22.3.180

Two-Week Repeated Dose Toxicity of Atractylodis Rhizoma Alba in F344 Rats

Hyoung-Yun Han1, Young-Su Yang1, Soo Nam Kim1, Su-Cheol Han1, Jong-Hwa Lee1, Ja Young Jeong2, Hang-sik Roh2, Ji Hyeon Seok2, Joo Sang Lee3, Jeong-Ah Kim4, Byung-Sun Min3, ∗

1Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea

2Toxicological Research Division, Toxicological Evaluation and Research Department, National Institute of Food and Drug Safety Evaluation, Chungcheongbuk-do 28159, Korea

3College of Pharmacy, Drug Research and Development Center, Catholic University of Daegu, Gyeongsangbuk-do 38430, Korea

4College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea

∗Author for correspondence Byung-Sun Min, College of Pharmacy, Drug Research and Development Center, Catholic University of Daegu, Gyeongsangbuk-do 38430, Korea. Tel: +82-53-850-3613; E-mail: bsmin@cu.ac.kr

Received 6 January 2016       Revised 29 February 2016       Accepted 29 February 2016

Copyright © 2016 The Korean Society of Pharmacognosy

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

This research is to estimate the toxicity of Atractylodis Rhizoma Alba (ARA) in F344 rats and to find a dose level for the 13 weeks toxicity study. A hot water extract of ARA (ARWE) was administered orally to F344 rats at dose levels of 0 (vehicle control), 500, 1000, 2000, 3500, and 5000 mg/kg/day for 2 weeks. Each group was composed to five male and five female F344 rats. According to the result, there were no ARWE-related adverse changes in mortality, body weights, food consumption, urinalysis, hematology, clinical chemistry, gross finding at necropsy, and organ weight examination. Salivation was observed in 3500 and 5000 mg/kg/day in male and female rats but it could not have found any relationship with ARWE administration. Based on our findings, ARWE may not cause toxicity in rats under the experimental conditions. Therefore, dose level of 5000 mg/kg/day as a highest treatment group in 13-week exposure study is recommended for further toxicity assessment.

Keywords: Atractylodis Rhizoma Alba, Toxicity test, F344 rats, Water extract

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Fig. 1.
Changes of body weights after treatment with 500, 1000,2000, 3500 and 5000 mg/kg/day ARWE in male rats.
nps-22-180f1.tif
Fig. 2.
Changes of body weights after treatment with 500, 1000,2000, 3500 and 5000 mg/kg/day ARWE in female rats.
nps-22-180f2.tif
Table 1.
Comparison of food intake after treatment with 500, 1000, 2000, 3500 and 5000 mg/kg/day ARWE between the treatment groups (Unit : g)
Group Dose (mg/kg/day) G1 0 G2 500 G3 1000 G4 2000 G5 3500 G6 5000
Males
Day 2 Mean 16.3 15.4 16.1 15.9 15.8 16.3
  S.D. 1.01 1.69 1.45 0.94 0.31 1.37
Day 9 Mean 17.4 16.5 16.8 16.6 15.5 15.6
  S.D. 1.08 0.37 0.75 0.08 0.11 0.34
Females
Day 2 Mean 11.3 10.2 10.6 10.8 10.4 9.7
  S.D. 0.58 1.33 0.32 1.00 1.32 1.77
Day 9 Mean 11.2 11.2 10.8 11.9 9.9 10.1
  S.D. 0.41 0.25 0.45 0.39 0.26 0.95
Table 2.
Hematological values observed after treatment with 500, 1000, 2000, 3500 and 5000 mg/kg/day ARWE
Group Dose (mg/kg/day) G1 0 G2 500 G3 1000 G4 2000 G5 3500 G6 5000
Male
WBC ×103/µ L 6.35 5.65 5.97 5.5 5.94 6.22
RBC ×106/µ L 8.97 9.26 9.14 9.04 9 8.94
HGB g/dL 15.8 16.2 16.1 15.8 15.9 15.7
HCT % 49.8 51.8 51.4 50.3 50 49.3
MCV fL 55.5 56 56.2 55.7 55.6 55.2
MCH pg 17.5 17.5 17.6 17.5 17.7 17.6
MCHC g/dL 31.6 31.3 31.3 31.4 31.8 31.8
PLT ×103/µ L 958.6 959.4 951.8 986.2 891.8 923.6
RET% % 3.56 3.85 3.85 3.76 3.74 3.67
RETA ×109/µ L 316.9 354.9 351.2 337.3 336.3 325.7
NEU% % 21.6 19.3 20.4 19.2 19.1 21.4
LYM% % 73.7 75.7 74.6 75.9 75.8 73.1
EOS% % 0.8 0.8 0.9 0.8 0.8 0.9
MON% % 2.3 2.4 2.3 2.0 2.3 2.7
BAS% % 0.7 0.7 0.7 0.9 0.8 0.7
LUC% % 0.8 1.1 1.0 1.1 1.2 1.1
NEUA ×103/µ L 1.36 1.10 1.22 1.07 1.16 1.33
LYMA ×103/µ L 4.69 4.27 4.45 4.17 4.47 4.55
EOSA ×103/µ L 0.05 0.04 0.06 0.05 0.05 0.06
MONA ×103/µ L 0.15 0.14 0.14 0.11 0.14 0.17
BASA ×103/µ L 0.05 0.04 0.05 0.05 0.04 0.05
LUCA ×103/µ L 0.05 0.06 0.05 0.06 0.08 0.07
Female
WBC ×103/µ L 6.76 6.38 5.6 6.21 6.25 5.86
RBC ×106/µ L 9.22 9.06 9.23 8.96 9.3 9.21
HGB g/dL 16.6 16.3 16.8 16.2 16.8 16.7
HCT % 52.2 50.7 52 50.8 52.4 51.9
MCV fL 56.6 56 56.3 56.7 56.3 56.4
MCH pg 18 18 18.2 18.1 18.1 18.2
MCHC g/dL 31.9 32.2 32.3 31.9 32.1 32.2
PLT ×103/µ L 891.8 933.8 881 981.6 855.6 881.2
RET% % 3.43 3.36 3.28 3.74 3.36 3.04
RETA ×109/µ L 316.7 304.8 302.0 332.4 312.6 280.1
NEU% % 10.8 13.3 11.9 12.1 13.6 13.2
LYM% % 79.4 81.3 83.5 83.2 81.8 81.8
EOS% % 0.8 0.9 0.9 0.9 1.1 1.3
MON% % 5.3 2.5 2.3 2.2 2.2 2.2
BAS% % 0.6 0.6 0.6 0.6 0.5 0.7
LUC% % 3.1 1.4 0.8 1.1 0.7 0.9
NEUA ×103/µ L 0.78 0.88 0.67 0.75 0.85 0.77
LYMA ×103/µ L 5.47 5.14 4.68 5.16 5.12 4.80
EOSA ×103/µ L 0.05 0.06 0.05 0.06 0.07 0.07
MONA ×103/µ L 0.27 0.16 0.12 0.14 0.14 0.13
BASA ×103/µ L 0.04 0.03 0.03 0.04 0.03 0.04
LUCA ×103/µ L 0.15 0.10 0.05 0.07 0.05 0.05
Table 3.
Clinical chemical values observed after treatment with 500, 1000, 2000, 3500 and 5000 mg/kg/day ARWE
Group Dose (mg/kg/day) G1 0 G2 500 G3 1000 G4 2000 G5 3500 G6 5000
Male
GLU mg/dL 127.6 138.9 137.6 139.1 119.9 134.5
BUN mg/dL 16.15 16.21 16.55 16.14 16.64 15.38
CREA mg/dL 0.58 0.56 0.57 0.58 0.57 0.52
TP g/dL 6.88 7.02 7 7.31 6.88 6.56
ALB g/dL 4.73 4.81 4.8 4.93 4.74 4.62
A/G ratio 2.21 2.17 2.18 2.13 2.22 2.4
AST IU/L 108.1 119 115.5 113.6 139.2 100.9
ALT IU/L 47.8 53.4 50.1 50.7 66.3 43.5
TBIL mg/dL 0.086 0.088 0.088 0.091 0.091 0.084
ALP IU/L 605.2 604.6 652.3 628.6 620.1 577.8
TCHO mg/dL 56.8 59.8 58.0 60.8 58.2 47.2
TG mg/dL 51.7 57.3 55.3 50.4 49.8 43.8
CK IU/L 701.8 736.2 771.8 707.2 884.2 660.0
PL mg/dL 102.2 107.0 107.4 107.6 102.8 89.0
Female
GLU mg/dL 86.5 77.3 77.2 71.9 87.8 84
BUN mg/dL 19.08 18.55 18.31 18.24 18.07 17.95
CREA mg/dL 0.53 0.53 0.52 0.55 0.54 0.53
TP g/dL 6.54 6.54 6.58 6.43 6.65 6.56
ALB g/dL 4.59 4.6 4.6 4.5 4.65 4.62
A/G ratio 2.36 2.37 2.33 2.34 2.34 2.38
AST IU/L 111.4 111.3 106 108.4 137 101.1
ALT IU/L 37.2 35.7 35.5 37.1 51.9 35.9
TBIL mg/dL 0.089 0.085 0.088 0.091 0.087 0.084
ALP IU/L 508.4 498.3 470.9 509.1 493.0 492.1
TCHO mg/dL 95.8 88.0 91.2 92.0 87.4 90.4
TG mg/dL 76.9 76.1 70.2 78.8 69.6 69.0
CK IU/L 947.6 869.0 813.2 891.0 952.8 744.0
PL mg/dL 161.6 151.0 158.6 155.6 151.0 157.4
Table 4.
Absolute organ weights after treatment with 500, 1000, 2000, 3500 and 5000 mg/kg/day ARWE (Unit : g)
Group Dose (mg/kg/day) G1 0 G2 500 G3 1000 G4 2000 G5 3500 G6 5000
Males
Brain 1.760 1.739 1.796 1.808 1.771 1.749
Pituitary gland 0.005 0.006 0.006 0.006 0.006 0.006
Liver 6.509 6.862 6.676 6.718 6.838 6.550
Spleen 0.492 0.475 0.502 0.506 0.515 0.479
Heart 0.721 0.708 0.712 0.729 0.738 0.716
Thymus 0.326 0.31 0.341 0.346 0.32 0.361
Salivary glands 0.351 0.353 0.35 0.355 0.361 0.348
Seminal vesicle 0.535 0.495 0.547 0.545 0.602 0.565
Prostate 0.123 0.106 0.129 0.103 0.100 0.106
Kidneys 1.530 1.597 1.587 1.667 1.622 1.573
Adrenal glands 0.037 0.038 0.039 0.043 0.043 0.040
Testes 2.653 2.654 2.723 2.602 2.666 2.657
Epididymides 0.483 0.465 0.511 0.488 0.486 0.517
Lung 0.942 0.869 0.934 0.967 0.99 0.906
Thyroid/Parathyroid 0.013 0.012 0.014 0.011 0.012 0.011
Females
Brain 1.640 1.604 1.650 1.669 1.633 1.638
Pituitary gland 0.007 0.007 0.007 0.008 0.007 0.007
Liver 4.252 4.357 4.351 4.553 4.424 4.394
Speen 0.328 0.346 0.327 0.365 0.326 0.340
Heart 0.527 0.528 0.497 0.525 0.525 0.499
Thymus 0.312 0.306 0.301 0.317 0.301 0.292
Salivary glands 0.263 0.254 0.267 0.282 0.271 0.273
Kidneys 1.062 1.096 1.101 1.107 1.083 1.087
Adrenal glands 0.045 0.046 0.041 0.046 0.045 0.048
Ovaries 0.741 0.750 0.687 0.753 0.716 0.750
Lung 0.010 0.008 0.009 0.011 0.009 0.009
Thyroid/Parathyroid 0.283 0.325 0.247 0.214 0.301 0.265
Uterus/Cervix 0.069 0.071 0.064 0.071 0.074 0.081
Table 5.
Relative organ weights after treatment with 500, 1000, 2000, 3500 and 5000 mg/kg/day ARWE (Unit:%)
Group Dose (mg/kg/day) G1 0 G2 500 G3 1000 G4 2000 G5 3500 G6 5000
Male
Brain 0.902 0.903 0.94 0.912 0.898 0.914
Pituitary gland 0.003 0.003 0.003 0.003 0.003 0.003
Liver 3.323 3.535 3.481 3.379 3.466 3.410
Spleen 0.252 0.246 0.262 0.255 0.260 0.250
Heart 0.369 0.366 0.371 0.367 0.373 0.373
Thymus 0.167 0.161 0.178 0.176 0.163 0.189
Salivary glands 0.180 0.182 0.182 0.178 0.183 0.182
Seminal vesicle 0.274 0.251 0.284 0.27 0.303 0.289
Prostate 0.063 0.054 0.066 0.051 0.050 0.054
Kidneys 0.782 0.824 0.828 0.839 0.820 0.819
Adrenal glands 0.019 0.020 0.020 0.021 0.022 0.021
Testes 1.359 1.367 1.419 1.304 1.350 1.383
Epididymides 0.248 0.237 0.264 0.242 0.245 0.266
Lung 0.483 0.450 0.487 0.487 0.502 0.472
Thyroid/Parathyroid 0.006 0.006 0.007 0.006 0.006 0.006
Female
Brain 1.365 1.339 1.376 1.358 1.382 1.396
Pituitary gland 0.006 0.006 0.006 0.006 0.006 0.006
Liver 3.526 3.638 3.624 3.696 3.748 3.736
Speen 0.272 0.288 0.273 0.295 0.276 0.289
Heart 0.437 0.441 0.414 0.426 0.445 0.424
Thymus 0.259 0.255 0.251 0.257 0.254 0.248
Salivary glands 0.219 0.212 0.222 0.229 0.229 0.232
Kidneys 0.882 0.914 0.917 0.900 0.916 0.925
Adrenal glands 0.037 0.038 0.035 0.037 0.038 0.041
Ovaries 0.057 0.059 0.053 0.057 0.063 0.069∗
Lung 0.617 0.626 0.572 0.612 0.605 0.637
Thyroid/Parathyroid 0.008 0.007 0.008 0.009 0.007 0.008
Uterus/Cervix 0.233 0.267 0.206 0.174 0.255 0.226

∗ Significant differences from control group (p < 0.05).

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