BioMed Research International

BioMed Research International / 2020 / Article

Research Article | Open Access

Volume 2020 |Article ID 8609364 | 18 pages | https://doi.org/10.1155/2020/8609364

Acute and Subchronic Oral Toxicity Study of Polyherbal Formulation Containing Allium sativum L., Terminalia bellirica (Gaertn.) Roxb., Curcuma aeruginosa Roxb., and Amomum compactum Sol. ex. Maton in Rats

Academic Editor: Damião Pergentino de Sousa
Received03 Oct 2019
Revised09 Feb 2020
Accepted02 Mar 2020
Published26 Mar 2020

Abstract

The polyherbal formulation containing Allium sativum L., Terminalia bellirica (Gaertn.) Roxb., Curcuma aeruginosa Roxb., and Amomum compactum Sol ex. Maton has been used for hypertension treatment empirically. Our previous study showed its blood pressure-lowering effect on a rat model of hypertension. However, toxicity data were not available for this polyherbal formulation. This study is aimed at evaluating the acute and subchronic oral toxicity of the polyherbal formulation in rats. The acute toxicity study was conducted on 6 female Wistar rats using the fixed-dose method for the treatment group and 5 female Wistar rats for the control. The single dose of 2,000 mg/kg of the polyherbal formulation was given orally. There were no significant toxic effects and no death observed until the end of the study, and it was showed that the lethal dose 50% (LD50) of the polyherbal formulation was estimated to be more than 2,000 mg/kg. The macroscopic and microscopic examination of vital organs showed no symptoms of toxicity. At the subchronic toxicity study, the polyherbal formulation with 3 dose variations of 252 mg/kg, 1,008 mg/kg, and 4,032 mg/kg was administered for 91 days orally. The lowest dose of 252 mg/kg is equivalent to the daily recommended dose for a human. There were no significant toxic effects observed at all doses on physical sign and symptoms, weight gain, food intake, hematological parameters, biochemical parameters, and macroscopic and microscopic examination of organs. These findings showed that the short- and long-term oral administration of the polyherbal formulation is safe to use within its dose recommendation.

1. Introduction

Hypertension is a chronic disease that requires long-term medical treatment. Generally, antihypertensive works symptomatically to decrease blood pressure. The use of antihypertensive in the long term may cause various adverse side effects. Many researchers recommend a comprehensive approach in managing hypertension by diet regulation, exercise, and use of natural ingredients. Many medicinal plants grown in Indonesia have been traditionally used by communities to treat hypertension. Some plants have demonstrated antihypertensive activity on various hypertension animal models with various methods. These antihypertensive medicinal plants are Phyllanthus niruri [1], Catharanthus roseus [2], Momordica charantia [3], Aloe vera [4], Morinda citrifolia [5], Centella asiatica [6], and Allium sativum [7, 8]. Nigella sativa has been tested for hypertensive patients [9]. The antihypertensive mechanism of action of some plants has also been studied. Alstonia scholaris has been shown to have antihypertensive activity by inhibiting calcium ion channels [10].

The polyherbal formulation tablet containing Allium sativum L., Terminalia bellirica (Gaertn.) Roxb., Curcuma aeruginosa Roxb., and Amomum compactum Sol ex. Maton is indicated to treat hypertension. Nugrahaningsih et al. [11] reported that this polyherbal showed blood pressure-lowering effect on a rat model of hypertension. The ingredients of polyherbal formulation have been traditionally used by Indonesian people to treat cardiovascular disorders including hypertension. Some research results showed that the extract of each plant in this formulation has pharmacological activities that support its use in hypertension treatment.

Allium sativum or garlic was studied for cardiovascular disease. The meta-analysis study showed that garlic can lower the blood pressure of hypertensive patients but not for normal people [12]. Ried et al. [13] reported that garlic can lower blood pressure better than placebo. Garlic-derived polysulfides stimulate the production of the vascular gasotransmitter hydrogen sulfide (H2S) and enhance the regulation of endothelial nitric oxide (NO), which induce smooth muscle cell relaxation, vasodilation, and blood pressure reduction [8]. Garlic has been shown to have antihypertensive, antihyperlipidemic, antioxidant, and antiatherosclerotic effects [1416]. Terminalia bellirica is shown to have antioxidant and antihypertensive effects [17]. Curcuma aeruginosa rhizoma and Amomi fructus (Amomum compactum) or cardamom have also been proven as antioxidants [1820].

The development of traditional medicine requires both preclinical and clinical testing. One of the preclinical testing is toxicity test to ensure the safety of a formulation. Toxicity tests were performed to obtain data or information on the safety level of the compound in the animal. The oral acute toxicity test is a test performed on a compound that will be given orally. Acute toxicity tests are performed before further tests such as subchronic toxicity, teratogenic testing, mutagenesis testing, and carcinogenic testing. The oral subchronic toxicity test is a test to detect toxic effects after administration for a part of the animal’s lifespan, but not more than 10% of animal life. The principle of the oral subchronic toxicity test is the tested compound formulation in several doses given daily in several groups of test animals with one dose per group for 28 or 91 days. The animal should be observed daily to determine the toxicity. Animals that die during observation are immediately autopsied; organ and tissue are observed macropathologically and histopathologically. At the end of the observation, all living animals were autopsied and macropathologically observed in each organ. Hematology, clinical biochemistry, and histopathology examinations were also performed. The purpose of the subchronic toxicity test is to obtain information on the toxic effects of undetectable substances on acute toxicity tests, information of possible toxic effects after repeated exposure of the testing compound for a certain period of time, and information of the dose that does not cause toxic effects (No Observed Adverse Effect Level (NOAEL)) and to study the cumulative effects and reversibility effects of the compound [21]. In this study, acute toxicity and oral subchronic toxicity studies of polyherbal formulation tablets were performed on the rat.

2. Materials and Methods

2.1. Polyherbal Formulation

The polyherbal formulation tablets were obtained from PT. Marguna Tarulata APK Farma, Indonesia. Each tablet of polyherbal formulation weighed 600 mg containing 180 mg bulbs of Allium sativum L., 60 mg fruit of Terminalia bellirica (Gaertn.) Roxb., 60 mg rhizome of Curcuma aeruginosa Roxb., 35 mg fruit of Amomum compactum Sol ex. Maton, and 265 mg of other materials. Tablets were powderized and made suspension with adding water. For maintaining the stability of the preparation, the only fresh suspension was given to the rat by oral gavage. The suspension was given with a volume of 10 mL/kg.

2.2. Experimental Animals

The Wistar rats were obtained from Animal House, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia. They were maintained in the room with 12 h light/dark cycle, 70% humidity, 23-25°C temperature, and sufficient ventilation and housed in cages covered with wire net. All animals were given access to food and water ad libitum. Experiments were conducted following the internationally accepted principles for animal laboratory use and care and approved by the Medical and Health Research Ethics Committee of Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada–Sardjito General Hospital Yogyakarta.

2.3. Acute Oral Toxicity Study

The acute toxicity test was conducted according to OECD guideline 420 [22] using a fixed-dose procedure. The method provides information on the hazardous properties and allows the substance to be ranked and classified according to the Globally Harmonized System (GHS) for the classification of chemicals which cause acute toxicity. The OECD guidelines indicate that testing in one sex (usually females) is considered sufficient [22]. Six female Wistar rats 8-10 weeks old weighing were acclimatized for 7 days. The initial dose was chosen at 300 mg/kg with the consideration that there were no in vivo and in vitro toxicity data from the polyherbal formulation tablet. In the preliminary study on one rat with a dose of 300 mg/kg, we did not find any toxicity symptoms, so the dose was increased to 2,000 mg/kg. Further preliminary tests at a dose of 2,000 mg/kg also showed that there were no toxicity symptoms. Furthermore, in the main test, a dose of 2,000 mg/kg on 4 additional rats was continued. Each animal was observed and recorded for toxicity symptoms within the first 24 h, and observation was continued for 14 days. Then, the compound will be ranked and classified according to the Globally Harmonized System (GHS) for the classification of chemicals which cause acute toxicity [22].

2.4. Subchronic Oral Toxicity Study

The subchronic toxicity test was conducted according to the OECD guideline 408 for testing chemicals [23]. Eighty Wistar rats aged 8-10 weeks of both sexes were divided into 4 groups (, 10 males and 10 females), 3 treatment groups and 1 control group. The treatment groups were given polyherbal formulation 252, 1,008, and 4,032 mg/kg for each group. The control group was given water 10 mL/kg. The polyherbal formulation or water was given by oral gavage once daily at 7:00-8:00 am for 91 days. The rats were observed for physical signs and symptoms of the possibility of poisoning. The weight gain and food intake were calculated weekly. The laboratory examinations for hematological parameters and biochemical parameters were performed before treatment, after 45 days of treatment, and after 91 days of treatment. Macroscopic and histopathological examination for the vital organs was performed after 91 days of the study. Data were presented as . The mean difference of all groups was analyzed using one-way ANOVA continued by Tukey’s multiple comparison test. The baseline hematology and clinical chemistry values for Charles River Wistar rats [24] were used as reference as normal values for results of hematological and biochemical examination.

3. Results

3.1. Acute Oral Toxicity Study

The observations of physical signs and symptoms and the possibility for toxic symptoms were performed on the first 30 minutes, 1 h, and 24 h and continued every day for 14 days. There were no signs of toxicity in the preliminary study with a dose of 300 mg/kg on 1 rat, also when the dose of 2,000 mg/kg was given to another 1 rat, and in the main testing of the same dose (2,000 mg/kg) in 4 rats. Table 1 shows that the body weight of each rat before receiving polyherbal formulation, after 7 days, and after 14 days looks normal. The weight gain for week I and week II during the 14-day observations looks normal also.


Dose (mg/kg)No. of ratsBody weight (g) before and after receiving polyherbal formulationWeight gain
Before7 days after14 days afterWeek I (%)Week II (%)

Control11301351383.852.22
21301341373.082.24
31291331383.103.76
41291351404.653.70
51271321393.945.30

30011301351443.856.67

2,00011261321384.764.55
21261301363.174.62
31301341373.082.24
41281341384.692.99
51291331373.103.01

There were no abnormalities found on macroscopic examination of the heart, liver, lung, stomach, pancreas, kidney, brain, lymph, and ovary. Table 2 shows the absolute organ weight of rats in the acute toxicity study, and Table 3 shows the relative organ weight. Both the absolute organ weight and relative organ weight showed normal weight. In the microscopic examination, there was no abnormality found in the heart, liver, lung, pancreas, stomach, kidney, brain, lymph, testis, and ovary (Figure 1). Therefore, the polyherbal formulation tested showed that the lethal dose 50% (LD50) was more than 2,000 mg/kg. The Globally Harmonized System (GHS) classification criteria for acute toxicity suggested that this polyherbal formulation was classified in category 5 or unclassified () (OECD, 2001).


Dose (mg/kg)OrganAbsolute organ weight (g) of rat no.MeansSD
12345

2,000Heart0.500.540.530.520.530.520.02
Liver3.903.303.193.903.783.610.34
Lung1.011.041.031.031.051.030.01
Stomach1.391.321.421.391.281.360.06
Pancreas0.570.630.570.590.600.590.02
Kidney0.570.630.570.590.570.590.03
Brain1.441.451.461.451.441.450.01
Lymph0.320.290.290.330.300.310.02
Ovary0.340.360.370.340.330.350.02

ControlHeart0.570.570.560.590.600.580.02
Liver3.503.493.413.403.503.460.05
Lung1.191.201.171.161.171.180.02
Stomach1.271.341.271.261.251.280.04
Pancreas0.590.800.600.690.630.660.09
Kidney0.610.590.580.570.550.580.02
Brain1.291.271.251.281.301.280.02
Lymph0.370.360.350.330.340.350.02
Ovary0.350.310.330.340.360.340.02


Dose (mg/kg)OrganRelative organ weight (%) of rat no.MeansSD
12345

2,000Heart0.360.400.390.380.390.380.01
Liver2.832.432.332.832.762.630.24
Lung0.730.760.750.750.770.750.01
Stomach1.010.971.041.010.930.990.04
Pancreas0.410.460.420.430.440.430.02
Kidney0.410.460.420.430.420.430.02
Brain1.041.071.071.051.051.060.01
Lymph0.230.210.210.240.220.220.01
Ovary0.250.260.270.250.240.250.01

ControlHeart0.410.420.410.420.430.420.01
Liver2.542.552.472.432.522.500.05
Lung0.860.880.850.830.840.850.02
Stomach0.920.980.920.900.900.920.01
Pancreas0.430.580.430.490.450.480.06
Kidney0.440.430.420.410.390.410.02
Brain0.930.930.910.910.940.920.01
Lymph0.270.260.250.240.240.250.01
Ovary0.250.230.240.240.260.240.01

3.2. Subchronic Oral Toxicity Study

The results showed that there were no significant physical toxicity signs and symptoms in all rats in all groups. There were no symptoms of toxicity for each dose given, both male and female rats, and no death.

In male rat groups, the body weight of the rat group which received polyherbal formulation at a dose of 252 mg/kg looks lower () than that of the control group in the 2nd and 3rd week. However, the differences were observed since week 0 (before the experiment). After the 3rd week, the body weight generally had no significant difference in the control group (Figure 2). In female rat groups, the body weight of the rat group which received polyherbal formulation at a dose of 252 mg/kg was higher () than that of the control group at the 1st, 2nd, and 6th week. The body weight of the rat group which received polyherbal formulation at a dose of 4,032 mg/kg was higher () than that of the control group at the 1st week. However, there were generally no significant differences observed in body weight at the 3rd, 4th, 5th, 7th, 8th, 9th, 10th, 11th, 12th, and 13th week (Figure 3).

In male rat groups, the mean weight gain of rats in all groups which received polyherbal formulation at a dose of 252, 1,008, and 4,032 mg/kg at the 3rd, 5th, 6th, 7th, 9th, 10th, and 13th week did not show any difference () compared to that in the control group (Table 4). Group I rats which received polyherbal formulation at a dose of 252 mg/kg showed lower weight gain () than the control group at the 2nd week and 12th week and higher weight gain () than the control group at the 11th week. Group II rats which received 1,008 mg/kg of polyherbal formulation showed decreasing body weight at the 1st week; however, the weight gain at the 2nd week was higher () than the control group. At the 8th week, the weight gain of this group was lower () than the control group; at the 11th week, the weight gain was higher () than the control group, and at the 12th week, the weight gain was lower () than the control group. Group III rats which received polyherbal formulation at a dose of 4,032 mg/kg showed lower weight gain () than the control group at the 4th, 8th, and 12th week.


Group and dose ()Weight gain (g) weekly
12345678910111213

Male
 I (252 mg/kg)Mean12.902.4012.4014.408.9013.1010.404.804.406.206.802.402.30
SD6.3112.144.507.062.7718.3711.921.992.721.141.320.701.16
0.5910.0070.8150.3030.2860.0600.3800.0640.3050.0250.00010.00010.137
 II (1,008 mg/kg)Mean-4.3027.1013.9014.505.005.108.304.603.805.206.002.403.40
SD6.388.6611.256.292.670.885.772.632.300.421.051.171.26
0.0480.0220.9880.2910.1281.0000.8250.0400.1051.0000.00010.00010.390
 III (4,032 mg/kg)Mean17.9022.107.502.104.805.209.204.404.705.303.004.002.20
SD18.3813.4727.3512.062.150.794.341.961.161.250.941.330.79
0.2040.1950.3460.0370.0990.9810.6150.0240.4710.8160.5460.0240.091
 IV (water, control)Mean9.3015.9014.0010.407.305.107.606.505.405.203.305.303.00
SD21.576.035.567.594.920.742.071.082.120.791.061.570.82

Female
 I (252 mg/kg)Mean5.36-4.502.506.208.107.103.807.505.805.505.902.603.30
SD6.846.8212.3115.504.281.7913.203.101.321.180.990.971.49
0.00010.1730.0060.1410.0160.0820.3260.3170.8730.2060.00010.0310.069
 II (1,008 mg/kg)Mean-10.485.904.209.205.206.207.008.806.005.606.403.404.00
SD5.443.515.733.881.031.141.892.301.761.510.840.971.56
0.7050.1000.0200.0330.8520.8590.9750.0250.8730.2670.00010.3440.003
 III (4,032 mg/kg)Mean-3.812.403.706.806.405.106.005.405.305.603.303.802.90
SD15.488.345.231.811.260.993.681.901.341.511.061.870.88
0.0610.5110.0140.1080.3530.0820.7740.2720.2060.2670.6500.7510.208
 IV (water, control)Mean-12.120.2012.30-0.205.406.106.906.505.406.303.104.002.30
SD7.1810.003.1310.111.260.881.660.970.971.340.991.560.48

, the significant difference compared to the control group using the one-way ANOVA continued by Tukey’s multiple comparison test.

In female rat groups, the mean weight gain of rats in all groups which received polyherbal formulation at a dose of 252, 1,008, and 4,032 mg/kg at the 2nd, 7th, 9th, and 10th week did not show any difference () compared to that in the control group (Table 4). Group I rats which received polyherbal formulation at a dose of 252 mg/kg showed higher weight gain () than the control group at the 1st, 5th, 7th, 11th, and 13th week and lower weight gain () than the control group at the 3rd and 12th week. Group II rats which received 1,008 mg/kg of polyherbal formulation showed lower weight gain at the 3rd week; however, the weight gain at the 4th, 8th, 11th, and 13th week was higher () than the control group. Group III rats which received polyherbal formulation at a dose of 4,032 mg/kg showed lower weight gain () than the control group at the 3rd and 6th week. These findings showed that sometimes the weight gain was higher or lower or has no difference compared to the control group showing that there was no tendency to decrease or increase weight gain due to the administration of the polyherbal formulation.

The mean food intake of male rats in all groups which received polyherbal formulation at a dose of 252, 1,008, and 4,032 mg/kg at the 1st, 3rd, 11th, 12th, and 13th week did not show any difference () compared to that in the control group (Table 5). Group I rats which received polyherbal formulation at a dose of 252 mg/kg showed higher food intake () than the control group at the 2nd week and 10th week and lower food intake () than the control group at the 6th and 7th week. Group II rats which received 1,008 mg/kg of polyherbal formulation showed lower () food intake than the control group at the 5th, 7th, 8th, and 9th week; however, the food intake at the 10th week was higher () than the control group. Group III rats which received polyherbal formulation at a dose of 4,032 mg/kg showed lower food intake () than the control group at the 7th week; however, the mean food intake was higher () than the control group at the 10th and 12th week.


Group and dose ()Food intake (g) weekly
12345678910111213

Male
 I (252 mg/kg)Mean76.5085.0086.00110.00109.0095.00108.00112.00116.00120.00116.50118.00117.50
SD6.695.275.169.435.685.277.535.874.590.004.124.224.25
0.2130.00010.2670.7770.5180.00010.00010.1290.8200.00010.1330.4281.000
 II (1,008 mg/kg)Mean75.5076.0086.0087.0096.00101.00104.00107.00110.00120.00118.00120.00118.50
SD4.384.595.164.226.994.593.945.374.080.002.580.002.42
0.1000.1630.2670.00010.0010.2070.00010.0010.0050.00010.7030.0210.496
 III (4,032 mg/kg)Mean77.5075.0086.50108.00108.50106.00113.00115.50118.00119.00119.0117.00116.50
SD5.895.274.747.897.473.946.754.976.322.112.112.583.37
0.4040.3490.3730.3980.0280.2070.0331.0000.4950.0030.7031.0000.496
 IV (water, control)Mean79.5073.0088.50111.00107.00103.50118.50115.50116.50115.50118.50117.00117.50
SD3.693.504.748.767.153.372.423.694.124.382.422.582.64

Female
 I (252 mg/kg)Mean76.0086.0084.00116.00114.0095.00108.00114.00119.00118.50115.00120.50117.00
SD5.685.165.165.166.995.276.754.596.152.424.083.692.58
0.8440.00010.4450.1520.7710.0410.0030.00010.00010.5900.0440.0681.000
 II (1,008 mg/kg)Mean79.0075.0081.5084.0090.00120.50109.00114.50117.00120.00120.00117.50118.00
SD6.585.276.694.599.4339.333.162.843.500.000.004.252.58
0.3280.6560.0910.00010.00010.4720.0110.00010.0010.2850.1721.0000.404
 III (4,032 mg/kg)Mean77.0072.0085.50106.50108.00103.00116.00117.50119.50118.00117.00117.00114.50
SD5.874.225.996.697.892.584.593.543.692.584.223.502.84
0.8440.0800.8480.0520.0480.2270.6560.00010.00010.2850.4900.7560.042
 IV (water, control)Mean76.5076.0086.00112.00115.00114.00115.00106.50110.00119.00118.00117.50117.00
SD4.125.165.167.535.774.594.713.373.332.112.582.642.58

, the significant difference compared to the control group using the one-way ANOVA continued by Tukey’s multiple comparison test.

In female rat groups, the mean food intake of rats in all groups which received polyherbal formulation at a dose of 252, 1,008, and 4,032 mg/kg at the 2nd, 8th, and 10th week did not show any difference () compared to that in the control group (Table 5). Group I rats which received polyherbal formulation at a dose of 252 mg/kg showed higher food intake () than the control group at the 2nd, 8th, and 9th week and lower food intake () than the control group at the 6th, 7th, and 11th week. Group II rats which received 1,008 mg/kg of polyherbal formulation showed lower food intake () at the 4th and 5th week; however, the food intake at the 8th and 9th week was higher () than the control group. Group III rats which received polyherbal formulation at a dose of 4,032 mg/kg showed lower food intake () than the control group at the 5th and 13th week; however, the food intake was higher () at the 8th and 9th week. These findings showed that sometimes the food intake was higher or lower or has no difference compared to the control group showing that there was no tendency to decrease or increase food intake due to the administration of the polyherbal formulation. When we observed the feces along the experiments, they showed to be normal soft feces in both treatment and control groups indicating neither diarrhea nor constipation.

Hematologic examinations for the hemoglobin level, total red blood cell (RBC), hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), total white blood cell (WBC), eosinophils, basophils, band neutrophils, segmented neutrophil, lymphocytes, and monocytes in WBC differential are presented at Tables 68. The hematological parameters of male group rats before receiving polyherbal formulation or control showed that the MCH value of the group receiving polyherbal formulation at a dose of 1,008 mg/kg was higher () than that of the control group and that the total WBC of the group receiving polyherbal formulation at a dose of 252 mg/kg was lower () than that of the control group. However, both values of the MCH () and the total WBC () were normal values [24]. The other hematological parameters in other treatment group rats have normal value, and there were no significant differences with the control group. The hematological parameters of female group rats showed that the MCH value of the group receiving polyherbal formulation at a dose of 252 mg/kg was lower () than that of the control group, and the group which received 1,008 mg/kg of polyherbal formulation was higher than the control group. However, both values of MCH were normal values according to Charles River Laboratories [24] (Table 6).


UnitControlDose (mg/kg)
2521,0084,032

Male ()
 Hemoglobing/dL
 Total RBC106/cmm
 Hematocrit%
 MCVfL/red cell
 MCHpg
 MCHCg/dL
 Total WBC/cmm
 Eosinophil%
 Basophil%
 Band neutrophil%
 Segmented neutrophil%
 Lymphocytes%
 Monocytes%
 Platelet/cmm

Female ()
 Hemoglobing/dL
 Total RBC106/cmm
 Hematocrit%
 MCVfL/red cell
 MCHpg
 MCHCg/dL
 Total WBC/cmm
 Eosinophil%
 Basophil%
 Band neutrophil%
 Segmented neutrophil%
 Lymphocytes%
 Monocytes%
 Platelet/cmm

, the significant difference compared to the control group using the one-way ANOVA continued by Tukey’s multiple comparison test.

UnitControlDose (mg/kg)
252 mg/kg1,008 mg/kg4,032 mg/kg

Male ()
 Hemoglobing/dL
 Total RBC106/cmm
 Hematocrit%
 MCVfL/red cell
 MCHpg
 MCHCg/dL
 Total WBC/cmm
 Eosinophil%
 Basophil%
 Band neutrophil%
 Segmented neutrophil%
 Lymphocytes%
 Monocytes%
 Platelet/cmm

Female ()
 Hemoglobing/dL
 Total RBC106/cmm
 Hematocrit%
 MCVfL/red cell
 MCHpg
 MCHCg/dL
 Total WBC/cmm
 Eosinophil%
 Basophil%
 Band neutrophil%
 Segmented neutrophil%
 Lymphocytes%
 Monocytes%
 Platelet/cmm

, the significant difference compared to the control group using the one-way ANOVA continued by Tukey’s multiple comparison test.

UnitControlDose
252 mg/kg1,008 mg/kg4,032 mg/kg

Male ()
 Hemoglobing/dL
 Total RBC106/cmm
 Hematocrit%
 MCVfL/red cell
 MCHpg
 MCHCg/dL
 Total WBC/cmm
 Eosinophil%
 Basophil%
 Band neutrophil%