Toxicology Of Diaveridine In Wistar Rats

Diaveridine is a class of compounds with anti-bacterial synergism of drugs. Though diaveridine was used in animals for long time, there is also less toxicological data presented, such as lack of toxicology and pharmacology of the specific information. In order to evaluate the safety of diaveridine, systematic toxicological tests should be conducted. In the present study, acute toxicity, subchronic toxicity, reproduction test and feeding teratogenicity test were carried out, therefore the results of diaveridine were used to calculate acceptable daily intake (ADI) and safe concentration (SC) to provide toxicological safety evaluation.1 Acute toxicity testHealthy 16 SPF adult Wstar rats/sex were selected for determine the LD50 value of diaveridine in Wistar rats with up-and-down (UDP) method. Diaveridine was suspended in 0.25% sodium carboxymethyl cellulose (CMC), and all rats were orally administrated by gavage in a single dose at one time. After administration, all rats were fed with blank diet and observed for 2 weeks. The LD50 value of diaveridine was 2330 mg/kg b.w. in female rats and 3100mg/kg b.w. in male rats, which 95% PL confidence interval is 1798 to 4540 and 2311 to 4080. The result showed that diaveridine was a low toxic substance.290-day feeding testHealthy 170 SPF Wistar rats were randomly divided into 5 groups and were fed with the diets containing diaveridine (0,23,230,1150 and 2000 mg/kg) to investigate its potential subchronic toxicity for 13 w.5 rats/sex/group were sacrificed under anesthesia on days 45, and 10 rats/sex/group were sacrificed under anesthesia on days 90. There were 20 male and 20 female rats in the control group and 2000 mg/kg diaveridine diet group. There were 15 males and 15 females in 23,230 and 1150 mg/kg diet group. The groups were continuously fed for 13 weeks. All animals were weighed and measured of food consumption once a week, and the food efficiency was calculated. After 90 days, the left Wistar rats in control group and 2000 mg/kg were fed blank diet 14 days in the recover period. The results showed that there were no effects at 23 and 230 mg/kg diet groups on clinical observations, weight gain, food consumption, food efficiency, hematology indices, blood biochemical indicators, relative organ weights and histopathological examinations. During the experiment, body weights were significantly decreased in the 1150 and 2000 mg/kg group diet. From the third week, the average body weights of rats in 230 mg/kg dose group were significantly lower than control group (p<0.01). Body weights of 1150 mg/kg and 2000 mg/kg dose groups were significantly decreased from the beginning when compared with controls (p<0.01). The kidneys, liver, testis (with epididymis) and brain were significantly larger than the control group in female rats at 2000 mg/kg dose group. Liver, kidney and brain were significantly larger than the control group in male rats at 2000 mg/kg dose group. At days 90, significantly increase of ALP, Na+ and k+ levels were observed in 1150 and 2000 mg/kg diet group. However, only k+ values have pathological significance. Histopathologic examinations revealed that central venous portion of inflammatory infiltration of lymphocytes, some of the kidney cortex and medulla were abnormal lesions, blisters adrenal cortical lesions. Histopathologic examinations showed that the target organs of sub-chronic toxicity was kidneys in Wistar rats. The NOAEL of diaveridine for rats was 23 mg/kg dietary dose level.3 Two generation reproduction testHealthy 215 SPF Wistar rats (F0) were randomly divided into 5 groups (18 males and 25 females) to investigate the potential reproductive toxicity of diaveridine. In the first generation, rats were fed with diets containing diaveridine (0,23,230,1150 and 2000 mg/kg) through a 13-weeks prebreed period and to mate. After weaning, males and females of F1 generation weanlings were selected randomly for the reproduction test of F2 generation. Experiment observations included parent and fetuses mean body weight, food efficiency, average fetal mean body weight and histopathological examinations of reproductive organs. The reproductive index was calculated. The results showed that in the F0 and F1 generation of diaveridine 1150,2000 mg/kg diet groups, mean body weights, food efficiency, weight gain of pregnant rats, the litter and the average number of live fetus, fetus body weight on 0th,4th,7th,14th and 21th days were significantly decreased compared with the control group (p<0.01). In each dose group, no significant changes were found in male genital pathology tests and some of the highest dose group of female uterine wall contraction reduced the uterine cavity and uterine tumors were observed. The NOAEL of diaveridine for reproduction test was 23 mg/kg dietary dose level.4 Feeding teratogenicity testCombined with the 2nd generation of reproduction test to investigate the teratogenic toxicity of diaveridine in Wistar rats, every groups rats were fed randomly with the diets containing diaveridine (0,23,230,1150 and 2000 mg/kg) for 13 weeks. The pregnant rats were subjected to caesarean section on 20th gestational days for examination. Through external, skeletal, and visceral examinations in fetus determine teratogenic toxicity of diaveridine. The result showed that relative to control group, mean body weights and food efficiency in the prebreed period significantly decreased at 1150 and 2000 mg/kg diaveridine groups. At 1150 and 2000 mg/kg diaveridine groups, relative to control group, litter weights, body weights and body length and tail length of fetus decreased on 0th,4th, 7th,14th and 21th. The number of early fetal death significantly increased in this test. No obvious external, skeletal and visceral effect in all groups. The NOAEL of diaveridine for teratogenic test was 23 mg/kg dietary dose level.5 Calculating ADI and SCThe test of feeding teratogenic test and two generation reproduction results about diaveridine NOAEL was 2.3 mg/kg b.w., ADI was 0.0023 mg/kg b.w. according to the method of FDA. In muscle, liver, kidney and fat the safe concentration (SC) were 0.46, 1.38,2.76,2.76 mg/kg.All tests were basically designed and conducted according to the U.S. Food and Drug Administration (FDA) enacted toxicological evaluation of food safety principles, Organization for Economic Cooperation and Development (OECD) guidelines of toxicology, veterinary medicine up the International Coordination Bureau (VICH) of the new beast drug safety evaluation requirements for standardized and improved. Acute toxicity, subchronic toxicity, reproductive toxicity and teratogenicity of a systematic toxicological about diaveridine were eveluted in this study. Through this research can provide the scientific basis for clinical use of diaveridine.