• Proceedings of the Korean Society of Toxicology Conference
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• 2003.10b
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• pp.157-157
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• 2003

Recently we have demonstrated that a 12-day s.c. dose of 2-Bromopropane(2-BP) to pregnant mice during pregnancy resulted in significant developmental toxicity at dose levels of above 1250 mg/kg/day. However, the cause and effect relationship between maternal and developmental toxicities could not be elucidated in the previous study.(omitted)

• Environmental Mutagens and Carcinogens
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• v.21 no.2
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• pp.77-81
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• 2001

Kamijadowhan (KMD), an oriental herbal medicine used for anti-angiogenic effect, was extracted with 80% ethanol from mixture of source materials and lyophilized. KMD was orally administered to plugpositive pregnant rats from gestational days 12 to 20, dividing into three groups including vehicle-treated control, 0.5 g/kg or 3 g/kg KMD-treated groups. Dam weight during gestation and post-gestation, weight of pre- and post-weaning offsprings in male and female, and reproductive and developmental endpoints including incisor eruption, eye opening and testes descent were measured. No significant alterations in development of physical landmarks in offspring, maternal weight gain during gestation and post-gestation, and offspring weight were observed in KMD-treated group. The measurement of organ weight at post-gestational days 21 was not changed in dams. In 0.5 g/kg KMD-treated rats, kidney weights in male and female offsprings were significantly increased, and the body weight in male offspring was also increased. Liver and brain weights were not changed. Taken together, these data suggest that KMD may not significantly cross the placenta and produce no reproductive and developmental toxicity at maternally non-toxic dosages.

• Toxicological Research
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• v.34 no.2
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• pp.111-125
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• 2018

Solvents can be used in the manufacture of medicinal products provided their residual levels in the final product comply with the acceptable limits based on safety data. At worldwide level, these limits are set by the "Guideline Q3C (R6) on impurities: guideline for residual solvents" issued by the ICH. Diisopropyl ether (DIPE) is a widely used solvent but the possibility of using it in the pharmaceutical manufacture is uncertain because the ICH Q3C guideline includes it in the group of solvents for which "no adequate toxicological data on which to base a Permitted Daily Exposure (PDE) was found". We performed a risk assessment of DIPE based on available toxicological data, after carefully assessing their reliability using the Klimisch score approach. We found sufficiently reliable studies investigating subchronic, developmental, neurological toxicity and carcinogenicity in rats and genotoxicity in vitro. Recent studies also investigated a wide array of toxic effects of gasoline/DIPE mixtures as compared to gasoline alone, thus allowing identifying the effects of DIPE itself. These data allowed a comprehensive toxicological evaluation of DIPE. The main target organs of DIPE toxicity were liver and kidney. DIPE was not teratogen and had no genotoxic effects, either in vitro or in vivo. However, it appeared to increase the number of malignant tumors in rats. Therefore, DIPE could be considered as a non-genotoxic animal carcinogen and a PDE of 0.98 mg/day was calculated based on the lowest No Observed Effect Level (NOEL) value of $356mg/m^3$ (corresponding to 49 mg/kg/day) for maternal toxicity in developmental rat toxicity study. In a worst-case scenario, using an exceedingly high daily dose of 10 g/day, allowed DIPE concentration in pharmaceutical substances would be 98 ppm, which is in the range of concentration limits for ICH Q3C guideline class 2 solvents. This result might be considered for regulatory decisions.

• YAKHAK HOEJI
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• v.45 no.2
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• pp.190-204
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• 2001

This study was conducted to investigate for its effects on reproductive and developmental toxicity of recombinant human epidermal growth factor (rhEGF) in Sprague-Dawley rats. Male rats were administered rhEGF at doses of 1, 10, 100, and 1000$\mu$g/kg/day, respective1y, by subcutaneous injection from 63 days before and throughout to mating period until the day before sacrifice. Female rats were administered rhEGF at the same doses from 14 days before mating to day 20 of gestation or to day 21 of lactation. We examined the male and female fertility indices and maternal toxicity of F0 parental animals. Also, we examined the external, visceral, or skeletal malformation of fetuses, growth and development, behavior, and/or reproductive performance of F1 animals. At the highest dose (1,000 $\mu$g/kg), the mean body weights of F0 animals were significantly increased in males and females at 3 or 2 weeks after treatment, respective1y. No clinical signs and food intakes were observed at any time during the experimental period by rhEGF treatment. In autopsy examination, the relative and absolute liver weights significantly increased in both sexes of 1,000 $\mu$g/kg. At the highest dose (1,000 $\mu$g/kg), there was a statistically significant increase of pregnancy period and the number of dead fetuses. Moreover, significant increase of mean fetal body weight and decrease of number of live fetuses, which related to the difficult dilivery were observed in highest dose group. In Fl examination, no adverse effects on external, visceral, and skeletal malformation, physical and functional development, behavior or reproductive ability of Fl animals were observed in any group. Also, there was no significant difference between control and treated groups in copulation or fertility indices of Fl animals. These results indicate that rhEGF had no adverse effect on fertility and reproductive ability of Sprague-Dawley rats.

• Toxicological Research
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• v.24 no.4
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• pp.263-271
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• 2008

Recently we reported that 2-bromopropane (2-BP) has maternal toxicity, embryotoxicity, and teratogenicity in Sprague-Dawley rats. The aims of this study are to examine the potential effects of 2-BP administration on pregnant dams and embryo-fetal development, and to investigate the effects of metabolic activation induced by phenobarbital (PB) on developmental toxicities of 2-BP. Pregnant rats received 1000 mg/kg/day subcutaneous 2-BP injections on gestational days (GD) 6 through 10 (Group II and Group IIII) or 11 through 15 (Group IV). Pregnant rats in Group III received an intraperitoneal PB injection once daily at 80 mg/kg/day on GD 3 through 5 for induction of the liver metabolic enzyme system. Control rats received vehicle injections only on GD 6 through 15. All dams underwent caesarean sections on GD 20 and their fetuses were examined for external, visceral, and skeletal abnormalities. Significant adverse effects on pregnant dams and embryo-fetal development were observed in all the treatment groups, and the maternal and embryo-fetal effects of 2-BP observed in Group II were higher than those seen in Group IV. Conversely, maternal and embryo-fetal developmental toxicities observed in Group III were comparable to those seen in Group II. These results suggest that the potential effects of 2-BP on pregnant dams and embryo-fetal development are more likely in the first half of organogenesis (days $6{\sim}10$ of pregnancy) than in the second half and that the metabolic activation induced by PB pre-treatment did not modify the developmental toxic effects of 2-BP in rats.

• Korean Journal of Veterinary Research
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• v.44 no.4
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• pp.523-532
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• 2004

The present study was carried out to investigate the potential adverse effects of amitraz on pregnant dams after maternal exposure during the gestational days (GD) 1 through 19 in Sprague-Dawley rats. The test chemical was administered orally to pregnant rats at dose levels of 0, 3, 10, or 30 mg/kg/ day. During the test period, clinical signs, mortality, body weights, food consumption, serum biochemistry, gross findings, organ weights and reproductive findings on GD 20 were examined. In the 30 mg/kg group, an increase in the incidence of abnormal clinical signs and death, a suppression in the body weight gain, and a decrease in the food consumption were observed. A decrease in the liver weight and increases in the kidneys, adrenal glands and heart weights were also found. Serum biochemical investigations revealed increases in the aspartate aminotransferase (AST), total bilirubin, and chloride. In addition, an increase in the fetal death and decreases in the litter size and fetal body weight were seen at caesarean section. Inthe 10 mg/kg group, an increase in the incidence of abnormal clinical signs, decreases in the food consumption and liver weight, increases in the total bilirubin and chloride, and a decrease in the fetal body weight were observed. There were no adverse effects on clinical signs, mortality, body weights, food consumption, serum biochemistry, gross findings, organ weights and reproductive findings in the 3 mg/kg group. Based on the results, it was concluded that the 19-day repeated oral dose of amitraz to pregnant rats caused increases in the clinical signs, kidneys, adrenal glands and heart weights, AST, total bilirubin and chloride and decreases in the body weight gain, food consumption and liver weight at the dose levels of above 10 mg/kg/day. Under the present experimental conditions, the no-observed-adverse-effect level (NOAEL) of amitraz was considered to be 3 mg/kg/day.

• Journal of Society of Preventive Korean Medicine
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• v.17 no.2
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• pp.157-168
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• 2013

The objective of this study was to characterize the adverse effects of Ahnjon-Yichun-Tang during early pregnancy. Following successful mating, female Sprague-Dawley rats were given Ahnjon-Yichun-Tang(AYT) extract by oral administration daily with dose of 150mg (n=10), 300mg(n=10), 450mg(n=10) for 20 days of pregnancy. The rats in Control group(n=10) were orally administrated with Saline. All pregnant rats of Ahnjon-Yichun-Tang-treated and Control groups were sacrificed on day 20 of pregnancy. The pregnancy outcome was determined and the internal and reproductive organs of pregnant rat were observed. The fetuses were examined for the presence of various developmental toxic endpoints and stained with alcian blue and alizarin red S, and observed skeletal malformations. The results obtained in this study represent that there is no significant changes between Control and Ahnjon-Yichun-Tang-treated groups in body weight, organ weight, blood chemistry values, hematological values and pregnancy indexes of pregnant rat. The skeletal malformation of fetus was not observed as well. These results suggest that oral administration of Ahnjon-Yichun-Tang does not produce either maternal or developmental toxicity.

• Journal of Society of Preventive Korean Medicine
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• v.12 no.1
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• pp.89-102
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• 2008

Purpose : The experiments was undertaken to evaluate the effects of herbal medicine, Ojeoksan, in pregnant rats Methods : Female Sprague-Dawley rats were orally administered with the Ojeoksan at dose of 5mg/kg/day for 20 days. Pregnant rats were sacrificed at 20th day of gestation, and observed internal and reproductive organs. Approximately live fetuses in the 20th day of gestation were randomly selected and fixed in 95% ethanol. Results : Maternal body weight of Ojeoksan treated group has a tendency to increase compared to that of control group. There were no significant difference in internal and reproductive organs. There were no significant changes between two groups in blood chemistry and hematological values. There were no significant changes in number of corpus luteum, implantation, live fetuses and sex ratio. But Ojeoksan administered group showed higher delivery rate, early resorption rate than the control group. Also Ojeoksan administered group showed higher implantation rate, late resorption rate than the control group. Conclusion : From these results, it can be concluded that Ojeoksan showed no toxicity effects on maternal body weight and number of live fetuses. There were no significant changes in organ weight, hematological data, reproductive organs. We need more precise study to investigate the mechanism of early or late resoption by the herbal medicines such as Ojeoksan.

• Journal of Environmental Health Sciences
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• v.33 no.4
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• pp.306-316
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• 2007

This study have a object to found out the effects of oriental herb medicine, Antaeeum, to dams of rats and their offsprings. The Antaeeum was savaged to female Sprague-Dawley rats at a dose of 5 mg/kg/day for 3 weeks during gestation periods. Dams of rat were sacrificed at 20th day of gestation, and were observed major internal and reproductive organs. Approximately live fetuses in the 20th days of gestation were selected randomly and examined with stereo microscopes. Others offsprings were fixed with 95% ethanol for skeletal examinations. The fixed fetuses were stained with alcian blue and alizarin red S to observe skeletal variations or malformations. Maternal body weight of Antaeeum treated dams have a tendency of increasing compared with control dams. There were no significant difference in internal and reproductive organs of weight or findings. The spleenic organ relative weight of treated dams were decreased compared with the control significaltly (p<0.05). There were no significant changes between two groups in blood chemistry and hematological values. There were no significant changes in number of corpus luteum, implantation, live fetuses and implantation rate, delivery rate, late resorption rate and sex ratio. But in the Antaeeum treated group showed lower early resorption rate than that of the control dams. Fetal body weight and number of fetus a dam at Antaeeum treated group were higher than that of control group. The fetuses of dams treated with Antaeeum didn't induced external malformations. Vertebral and sternal variations were observed in Antaeeum group, but compared with the control, those variations were not significant. The ossification numbers of rib, cervical, thoracic, and lumber were normal. Fetuses treated with Antaeeum to the dams showed no significant difference in the number of caudal vertebra (P>0.01). From these results, it can be concluded that Antaeeum showed no toxicity effects on maternal side especially on body weight, early resorption rate, and number of live fetuses. Also there were no significant changes on maternal organ weights except spleen, hematological data, reproductive organs. Although skeletal variations were examined at vertebra and sternum, this Antaeeum could not induced significant choses in bone malformation.

• Toxicological Research
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• v.11 no.1
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• pp.91-101
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• 1995

A perinatal and postnatal study of KTC-1, a new semisyntheitic rifamycin antituberculous drug, was conducted in Sprague-Dawley rats. Dosages of KTC-1 0, 12, 27.6, and 63.5 mg/kg/day were administered to dams orally by gavage from day 17 of gestation to day 21 of lactation. All pregnant rats were allowed to deliver naturally for postnatal examination of their offspring. At 63.5 mg/kg/day, weakness, dark-red discharge around eyes, a loss in body weight, and a decrease in food and water consumption were observed in dams. An increase in the weight of adrenal gland and spleen, and a decrease in the weight of kidney and heart were also found. An increase in neonatal deaths during the lactation period, a loss in body weight, a delay in physical development, a decrease in traction ability, an increase in the number of errors and the time required for the multiple T-maze trial were found in F1 offspring. In addition, an increase in the incidence of visceral variations and retarded ossification were observed in F1 4 day old rats. An increase in the incience of skeletal anomalies was seen in F2 fetuses. There were no sings of maternal toxicity or embryotoxicity at 12 and 27.6 mg/kg/day. From the results mentioned above, it can be concluded that the no-effect dose levels(NOELs)for dams, F1 offspring, and F2 fetuses are 27.6 mg/kg/day.