A 28-day repeated dose toxicity study of co-solvent Dimethylacetamide/Cremophor EL(DMA/CrEL) in Beagle dogs

Objective: To evaluate the potential toxicity of the dimethylacetamide /cremophor EL（ DMA/CrEL） solvent in Beagle dogs following repeated dose gastric tube feeding,and provide evidences for the selection of appropriate solvent in preclinical safety evaluation studies. Methods: Beagle dogs were randomly divided into three groups,including saline control group,solvent low dose group( DMA 18. 7 mg·kg-1,CrEL 10. 5 mg·kg-1),and high dose group( DMA 187. 3 mg·kg-1,CrEL 105. 0 mg·kg-1). Each group contained 10 dogs with female and male in half. All the animals were administered intragastrically with test articles every day continuously for 28 days followed by a 16-day recovery phase. Then a series of toxicologic parameters including clinical signs,body weight,food consumption,electrocardiogram,urinalysis,hematology,serum biochemistry and histopathologic analysis et al were determined during the quarantine period,at the end of dosing,and during the recovery period,respectively. Results: DMA / CrEL solvent of low dose had good safety. However,it caused significant toxicity at high dose,including abnormal feces,vomiting,decrease of food consumption,weight loss,increase of BIL in urine,increase of RBC,HGB,HCT,PT and APTT in peripheral blood,increase of ALT,AST,ALP,TP,TBIL,γ-GT and decrease of CHO in serum,increase of liver weight and decrease of thymus weight,and abnormal histopathologic changes in liver,gallbladder,kidney and thymus et al. The above toxicities were reversible.Conclusion: The use of large doses of DMA / CrEL co-solvent as the vehicle of test articles should be avoided in preclinical safety evaluation studies. Special attention should be paid to DMA toxicity,and selection of appropriate solvent dose.