• Toxicological Research
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• v.23 no.4
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• pp.383-389
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• 2007

Recombinant human granulocyte-macrophage colony stimulating factor (hGM-CSF) regulates proliferation and differentiation of hematopoietic progenitor cells and modulates function of the mature hematopoietic cells. In the previous study, we reported that hGM-CSF could be produced in transgenic rice cell suspension culture, termed rhGM-CSF. In the present study we examined the single and repeated dose toxicity of rice cells-derived hGM-CSF in SD rats. During single dose toxicity study for 7 days, there were no any toxic effects at any dose of from 10 to $1000{\mu}g/kg$. The lethal dose ($LD_{50}$) was not found in this range. Moreover, repeated dose toxicity study of 14-days period and at the doses of 50 and $200{\mu}g/kg$ (i. v.) of rhGM-CSF did not show any changes in food and water intake. There were also no significant changes in both body and organ weights between the control and the test groups. The hematological and blood biochemical parameters were statistically not different in all the groups. These results suggest that rhGM-CSF has no toxicity in SD rats.

• Toxicological Research
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• v.20 no.3
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• pp.281-292
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• 2004

The purpose of this study was to assess the single and 5 week oral dose toxicity of calcitriol and alendronate combination (1 : 10,000) treatment for osteoporosis or Paget's disease in male and female rats. In single dose oral toxicity study, the values of $LD_{50}$ of calcitriol and alendronate mixture were 750.075 mg/kg in male rats and 775.0775 mg/kg in female rats, respectively. Body weight and food consumption were continuously increased after adminstration of calcitriol and alendronate mixtures, and there was no significant changes in body weight and food consumption in all groups. In five-week oral toxicity study of calcitriol and alendronate mixture at a dose of 0.2 $\mu\textrm{g}$ + 2 mg, 1 $\mu\textrm{g}$ + 10 mg, 5 $\mu\textrm{g}$ + 50 mg and 25 $\mu\textrm{g}$ + 250 mg, respectively, there was no mortality, abnormal behavior and appearance in all groups throughout the administration period (5 weeks) and recovery period (2 weeks). Dose-dependent changes in parameters of urinalysis and hematological analysis were not observed in male and female rats treated with calcitriol and alendronate mixtures. All the values of the parameters appeared to be in the normal range. These data indicate that both calcitriol and alendronate are drugs having low toxicity in rats. NOAEL of calcitriol and alendronate mixtures were 50.005 mg/kg in 5-week oral toxicity.

• Toxicological Research
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• v.26 no.1
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• pp.53-59
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• 2010

This study was conducted to obtain acute information of the oral dose toxicity of DHU001, a polyherbal formula in male and female mice. In order to calculated 50% lethal dose ($LD_{50}$) and approximate lethal dose (LD), test material was once orally administered to male and female ICR mice at dose levels of 2000, 1000, 500, 250 and 0 (vehicle control) ml/kg (body weight). The mortality and changes on body weight, clinical signs, gross observation, organ weight and histopathology of principle organs were monitored 14 days after treatment with DHU001. We could not find any mortalities, DHU001 treatment-related clinical signs, changes on the body and organ weights, gross and histopathological findings. The results obtained in this study suggest that $LD_{50}$ and approximate LD in mice after single oral dose of DHU001 were considered over 2000 mg/kg in both female and male mice.

• Journal of Haehwa Medicine
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• v.22 no.1
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• pp.171-184
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• 2013

Single-and repeated-dose toxicities of Compound K (CK) were evaluated according to Toxicity Test Guidelines of Korea Food and Drug Administration using Sprague-Dawley rats. For single-dose toxicity study, CK was dissolved in drinking water, orally administered and examined for 14 days. As results, CK up to a dose of 5,000 mg/kg, the limited dose, neither induced death, clinical signs and necropsy findings, nor affected body weight gain and organ weights, in which 10% lethal dose could not be estimated. Based on the results of single-dose toxicity test, CK was administered at doses of 500, 1,000 or 2,000 mg/kg for 28 days for the evaluation of repeated-dose toxicity. All doses including the limited dose (2,000 mg/kg) of CK did not cause any abnormalities of rats, including mortality, clinical signs, body weight gain, feed/water consumption, necropsy findings, organ weights, hematology, blood biochemistry. Rather, high doses (1,000 - 2,000 mg/kg) of CK reduced the serum levels of alanine transaminase (ALT), aspartate transaminase (AST), creatinine phosphokinase (CPK), lactate dehydrogenase (LDH) and triglycerides, in addition to an increase in glucose, indicative of protective effects on hepatic and muscular injuries. Thus, both maximum tolerable dose (MTD) and no observed adverse effect level (NOAEL) were not determined. The results indicate that long-term intake of high-dose CK might not induce general adverse effects.

• The Journal of Internal Korean Medicine
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• v.34 no.4
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• pp.349-361
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• 2013

Objectives : This study aimed to evaluate the single oral dose toxicity and four weeks repeated dose determination of Gamisasangja-tang (GST) in male and female Sprague-Dawley rats. Methods : In the single oral toxicity study, rats were orally administered a single dose of 0 and 5,000 mg/kg GST. There were 5 rats in each group. After single administration, mortality, clinical signs, body weight changes and gross pathological finding were observed for 14 days. In the 4-weeks repeated oral dose determination study, rats were orally administered a single dose of 0, 1,250, 2,500 or 5,000 mg/kg GST. There were 5 rats in each group. Mortality, clinical signs, body weight changes, food consumption and gross pathological finding were observed for 28 days. Organ weight, clinical chemistry and hematology were tested after 28 days. Results : There was no mortality in either of the two studies. There were also no significant differences in clinical sign, body weight, organ weights, hematological or serum chemical parameters between the GST and control groups. Conclusions : The results obtained in this study suggest that the 50% lethal dose of GST is over 5,000 mg/kg, so this finding would be expected to provide scientific evidence for the safety of GST.

• Toxicological Research
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• v.13 no.3
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• pp.237-245
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• 1997

As the development of a pharmaceutical product is a dynamic process which involves continuousfeed-back between non-clinical and clinical studies, the integration of pharmacokinetics into toxicity testing became increasingly important in recent years. Toxicokinetic measurements in the toxicity studies is considered to be an important scientific approach in the interpretation of the toxicology findings and the promotion of rational study design development. Primarily this research project was conducted to determine the systemic exposure achieved in acute toxicity test and its relationship to dose level and the time course of the toxicity study. Acute hepatotoxicity study and its relevant toxicokinetic study in mice were performed using acetarninophen (AA) as a model compound. The correlation between acute hepatotoxicity indices and toxicokinetic parameters following intraperitoneally administration of various dosages of AA in mice was evaluated and discussed minutely in the text. Based on these studies, single-dose toxicity testing of AA including kinetic studies was evaluated in ICR mice for 7 days and interpreted in the text. Our results from the integration of toxicokinetic monitoring into single-dose toxicity study enable to elucidate the relation of the exposure achieved in toxicity study to toxicological findings and assist in the selection of appropriate dose levels for use in repeated-dose toxicity or later studies.

• Biomolecules & Therapeutics
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• v.6 no.2
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• pp.182-190
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• 1998

DA-3585 is a recombinant human erythropoietin produced by Dong-A pharmaceutical Co. Ltd. using recombinant DNA technique. Recently, recombinant human erythropoietin (rHu-EPO) has been used to treat various types of anemia. In this study, we examined acute and subacute toxicity of DA-3585 in rats. DA-3585 was intravenously administered to rats at dose levels of 0, 6,250, 12,500 and 25,000 lU/kg for single dose toxicity study and at dose levels of 0,100,500 and 2,500IU/kg daily for 4 week-repeated dose toxicity study. In the single dose toxicity study, there were no death, clinical signs and changes in body weight gain related to the treatment. Necropsy revealed no evidence of toxicity related to DA-3585, In the repeated dose toxicity study, all the rats survived throughout the study. There were no treatment-related changes in clinical signs, food and water intake, and body weight. Hematological examination showed increases in the number of erythrocytes, hemoglobin concentration, hematocrit value and mean corpuscular volume, and decrease in the number of platelet in 500 and 2,500 lU/kg dosed groups. Extramedullary hematopoiesis in the spleen and erythroid hyperplasia in the bone marrow were noted as treatment-related histological changes. Toxicologically significant changes were not observed in blood biochemistry, urinalysis, organ weights and in any other examinations. The treatment-related changes observed in this study were hematological or histological changes associated with pharmacological effects of DA-3585. On the basis of the results of this study, LD5n value of DA-3585 was above 25,000 lU/kg and the no-observed-adverse-effect-level was estimated to be 100 lU/kg.

• Biomolecules & Therapeutics
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• v.16 no.1
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• pp.40-45
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• 2008

The objective of this study was to investigate the single dose and 2-week repeated dose toxicity of Aceporol 330 in ICR mice following single intravenous administration and to compare its toxicity with a commercially available solubilizer of paclitaxel, Cremophor EL. In single dose toxicity test, $LD_{50}$ of Aceporol 330 in mice was estimated to be greater than maximum applicable dose, 4 ml/kg. However, $LD_{50}$ of Cremophor EL in male mice was determined to be 4 ml/kg. Maximum tolerated dose (MTD) of males and females in Aceporol 330-treated group and MTD of females in Cremophor EL-treated group were 3 ml/kg. MTD of males in Cremophor EL-treated group was less than 3 ml/kg. Characteristic toxic symptoms, and hematological and blood chemical changes were not observed after single dose and repeated dose of Aceporol 330 or Cremophor EL. No histopathological abnormalities were found in organs of all animal groups. Based on the linear pharmacokinetic property of paclitaxel and the higher $LD_{50}$ in mice, Aceporol 330 has a potential for use as a safer solubilizer for paclitaxel than Cremophor EL.

• Toxicological Research
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• v.31 no.1
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• pp.77-88
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• 2015

Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases, including skin cancer. The oral toxicity of a hexane extract of Lithospermum erythrorhizon root (LEH) was investigated in Beagle dogs by using single escalating doses, two-week dose range-finding, and 4-week oral repeat dosing. In the single dose-escalating oral toxicity study, no animal died, showed adverse clinical signs, or changes in body weight gain at LEH doses of up to 2,000 mg/kg. In a 2 week dose range-finding study, no treatment-related adverse effects were detected by urinalysis, hematology, blood biochemistry, organ weights, or gross and histopathological examinations at doses of up to 500 mg LEH/kg/day. In the 4 week repeat-dose toxicity study, a weight loss or decreased weight gain was observed at 300 mg/kg/day. Although levels of serum triglyceride and total bilirubin were increased in a dose dependent manner, there were no related morphological changes. Based on these findings, the sub-acute no observable adverse effect level for 4-week oral administration of LEH in Beagles was 100 mg/kg/day.

• Environmental Mutagens and Carcinogens
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• v.22 no.2
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• pp.97-105
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• 2002

Nowadays a huge variety of products that aim to assist to quit smoking or reduce addictive symptoms are developed and manufactured with safety evaluation, but the safety of the most recent products of interest which do not contain tobacco and nicotine, and shape cigarettes is not evaluated and guaranteed relatively. This study was carried out to evaluate the single and repeated dose inhalation toxicity and genotoxicity of H menthol (Nicotine free-tobacco free) herbal cigarettes provided by Cigastop Ltd. in ICR mice. In this study, doses which we determined to expose to mice were 40 cigarettes for 6 hours a day to mice in single dose and 20 (high dose), 10 (middle dose) and 5 cigarettes (low dose) a day for 28 days in repeated dose inhalation toxicity, in vivo chromosome aberration test and micronucleus test. The particulate substances from H menthol herbal cigarettes also were gathered and used in the Salmonella typhimurium/microsome assay (Salmonella test; Ames test). We could find neither significant changes between control and treatment groups nor dose-response effects of test material at all except serum Ca level of female middle dose treatment group in repeated dose inhalation toxicity test. In conclusion, H menthol herbal cigarettes, when applied clinically intended dose we used, might not show any toxic and/or mutagenic effect.