The Toxicity Of Tilmicosin Hosphate

Tilmicosin, a semisynthetic macrolides antibiotics for livestock and poultry, was developed by the Elanco company in the1980’s, It can inhibit all the gram positive bacteria and parts of gram negative bacteria. It is used to treat the infectious diseases of goats, cows, pigs, chickens and other animals. However, there were some restrictions and limitations for using of tilmicosin in the veterinary clinics because of its soluble. To adapt to the market demand and clinical application, tilmicosin phosphate was developed through the improvement of tilmicosin. Although the improved tilmicosin phosphate is water-soluble, the physical and chemical properties of the improved tilmicosin phosphate was changed. Therefore, the toxicology of tilmicosin phosphate was investigated to understant the toxicological properties.To understand the acute toxic effects of tilmicosin phosphate, the acute toxic effects of tilmicosin phosphate by the single dose was tested on mice. The results showed that the maximum tolerated dose of tilmicosin phosphate by oral administration in mice is201.5mg/kg (counted with tilmicosin phosphate), and the maximum tolerated dose of tilmicosin by oral administration in mice is488mg/kg. The LD50of tilmicosin phosphate is814.7mg/kg, while the LD50of control drug tilmicosin is1953mg/kg.To understand the subchronic toxic effects of tilmicosin phosphate, subchronic toxicity tests were detected after oral administered continuously for30days by the dosage of162.94mg/kg,81.47mg/kg,54.31mg/kg. The results showed that non-toxic effects occurred in SD rats within81.478mg/kg～54.31mg/kg dosage of tilmicosin phosphate, except for light clinic symptoms such as consciousness, reluctant activities after30days of high dosage of tilmicosin phosphate (162.94mg/kg). Hematologic and blood biochemical parameters, pathological lesions were did not observed in any group of the tested animals.To objectively evaluate the clinical security of tilmicosin phosphate, Ames test, Bone marrow micronucleus test and Mouse sperm morphology test were used to investigate the mutagenic effect on mice in this study. Within dosage of0.5～5000μg/plate, with or without metabolic activation system (S9), the average number of revertant colonies per dish is less than twice that of the solvent (sterile distilled water) in4test strains of the salmonella typhimurium histidine auxotrophic (TA97, TA98, TA100, TA102). No dose-response relationship was observed. The negative effect of Ames test suggest that the mutagenic effect in Salmonella typhimurium was not induced by tilmicosin phosphate. The bone marrow micronucleus test was detected by the dosage of407.35mg/kg,203.68mg/kg,101.84mg/kg tilmicosin phosphate. The results showed that tilmicosin phosphate was no mutagenic effect on mice. In sperm abnormality test, tilmicosin phosphate was also no mutagenic effect on mice after administrated by dosage of407.35mg/kg,203.68mg/kg,101.84mg/kg.The traditional teratogenicity tests were tested with dosage of tilmicosin phosphate on the81.478mg/kg,20.372mg/kg and5.093mg/kg. The results showed that within81.478～5.093mg/kg dosage range, the behavior of the tested pregnant rats was no significant difference, with normal ovarian weight, number of corpus luteum, implantation number, uterine weight and number of live births in each dose groups compared with the control group. The test substance cause still birth and impact The growth and development of the fetal rat was did not effected by tilmicosin phosphate; No teratogenic effects of fetal mice were caused according to the appearance of fetal malformations, visceral malformations, skeletal deformities. The results indicate that tilmicosin phosphate within dosage range of81.478mg/kg～5.093mg/kg did not affect the reproductive function of pregnant Wistar rats, and no teratogenic effects on fetal mice.The results of the cumulative toxicity test showed that the cumulative dose of the tilmicosin phosphate were0,10,4,2,1of LD50respectively by daily administrating tilmicosin phosphate at dosage of407.35mg/kg,162.94mg/kg,81.47mg/kg,40.74mg/kg for20days. Given once a LD50dose of tilmicosin phosphate, tilmicosin phosphate did not induce the toxic accumulation in mice, however the tolerance against tilmicosin phosphate was induced in mice after20days of oral administration.