Phototoxicity And Chronic Toxicity Of Cyadox

Cyadox, a new quinoxaline antimicrobial promotor in animal husbandry, had the traits of obvious growth promotion and good safety on food-producing animals. Residues resulting from the use of cyadox in food-producing animals were much lower than other quinoxalines, which could be acceptable. With growing worldwide awareness of drug residues and food safety, cyadox would have a good prospect to substitute other quinoxalines.A 7 8-week feeding study of rats and skin irradiating study were conducted to investigate chronic toxicity and phototoxicity of cyadox, respectively. To evaluate the phototoxicity of cyadox on skin, eighty female Balb/C mice were divided into 8 groups at random. Five groups with irradiation were fed doses of 10, 50, 200mg/kg cyadox, 50mg/kg olaquindox and 0.8% sodium carboxymethyl-cellulose, respectively, followed by ultraviolet-A (UVA) irradiation for 2h (20J/cm ). Other three groups without irradiation as controls were fed 200mg/kg cyadox, 50mg/kg olaquindox and 0.8% sodium carboxymethyl-cellulose, respectively. Each groups was given by gavage as a suspension in 0.8% sodium carboxymethyl-cellulose. Histopathology of auricles was performed on days 5 and 12. The auricular thickness was measured and erythema score and gross pathology were conducted once a day. The olaquindox group with irradiation showed severe erythema, oedema and necrosis of auricles. Cyadox groups (200, 50 and 10mg/kg) with irradiation had different erythema and oedema of auricles with dose-response relationship, which convalesced gradually after dosing and irradiation ceased. These results suggested that the phototoxicity of cyadox is mild and reversible.The 78-week feeding study was conducted in Wistar rats to evaluate the oral chronictoxicity of cyadox. Cyadox was fed at 0, 100, 400 and 2000mg/kg of the diet to groups of 30 male and 30 female rats in the study. Olaquindox was fed at 400 mg/kg of the diet to groups of 30 male and 30 female rats as control. Animals in satellite groups of 5 rats/sex/group were sacrificed under anesthesia with intraperitoneal sodium pentobarbital on weeks 26 and 52 to evaluate chronic toxicity. Ten rats/sex/group were sacrificed on weeks 78 and 82, respectively. All treatments were well tolerated without diarrhea or other side effects. Body weights were significantly below control levels during most of the study in male and female of 2000mg/kg cyadox and 400mg/kg olaquindox groups (p<0.01 ). Serum alkaline aminotransferase values of the rats in the 2000mg/kg cyadox group were significantly lower than those of the rats in the space control group (both sexes on weeks 26, 52 and 78, p<0.05). Serum potassium and sodium concentrations of female rats in 400mg/kg olaquindox group were significantly higher and lower than those of the rats in the space control group on week 78, respectively (p<0.05). Relative weights of liver and kidney of 2000mg/kg cyadox group and 400mg/kg olaquindox group were significantly higher than those of the rats in the space control group (both sexes on weeks 26, 52, 78 and 82, p<0.05). The histopathological examinations revealed that 2000mg/kg cyadox or 400mg/kg olaquindox groups induced swelling and fatty degeneration of the hepatocytes and proximal renal tubular epithelial cells in rats. Other parameters of hematology, biochemistry parameters and urinalysis in 2000mg/kg cyadox or 400mg/kg olaquindox groups had no difference with space control group. There were no cyadox-related effects in 400mg/kg and 100mg/kg cyadox groups on survival, hematology, biochemistry, urinalysis and relative organ weights. The histopathological examinations also did not reveal noticeable changes in 400mg/kg and 100mg/kg cyadox groups. These results indicated that cyadox is not toxic when fed to rats at up to 400mg/kg of the diet for 78 weeks. In this study, the no-observed-adverse-effect level of cyadox for rats was estimated to be 400mg/kg dietary level.Both trials were conducted according to Standard Operating Procedure of Toxicology Evaluation on New Veterinary Drug and guidelines for new animal drug evaluation of U.S. Food and Drug Administration. The phototoxicity and chronic toxicity of cyadox were firstly evaluated in China presently. Results showed that thephototoxicity and chronic toxicity of cyadox were mild, which were much milder than those of olaquindox. Results in these experiments were consistent with other studies. These provided some valuable toxicological information of cyadox, which demonstrated the good safety profile of cyadox in terms of chronic toxicity and phototoxicity.