SUBACUTE INTRAMUSCULAR TOXICITY OF THE ACETYLCHOLINESTERASE REACTIVATING AGENT HI-6 IN RATS AND DOGS

Studies herein describe the toxicity of HI-6 in Sprague-Dawley rats an d Beagle dogs following i.m. injection for 14 days. Dose levels were 0 , 50, 150, and 450 mg/kg/day for 10 rats/sex/dose and 0, 35, 70, and 1 40 mg/kg/day for 4 dogs/sex/dose. Three rats at the high dose, 2 males and 1 female, died prior to scheduled sacrifice. Reduced weight gain, decreased activity, tremors, hunched posture, and poor grooming were seen in high dose survivors. Increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities at the mid and high do ses suggested hepatotoxicity, although liver weights and histology wer e normal. Hematology parameters were unaffected except for slight, dos e-related increases of platelets in both sexes. Injection site inflamm ation was seen; however, serum creatine kinase activity was not altere d. In dogs, slight weight loss, vomiting, salivation, and diarrhea occ urred at the high dose, but no deaths were observed at any of the dose s. As with rats, dose-related increases in ALT and AST activities occu rred at the mid and high doses, and were, in this case, accompanied at the high dose by hepatomegaly and hepatocellular vacuolization. Cardi otoxicity was evidenced by increased relative heart weights and subtle ECG changes, the latter of which occurred almost exclusively at the h ighest dose. Injection site inflammation, which was accompanied by dos e-related elevations in serum CK-MM2 activity, was also observed.