|
Single and 28-day repeated dose toxicity studies of botulimum toxin type. A were carried out in ICR mice and Sprague-Dawley rats, respectively. In the dose toxicity study, botulimum toxin was injected intraperitoneally to male and female mice at a single dose of 40, 59, 89, 133 and 200 ng/10ml saline/kg. All animals died from 59 ng/kg group. Some clinical signs, such as decrease in locomotor activity, dyspnea, prone position and ptosis, were observed in most of both sexes from 59 ng/kg group, but no signs were seen in all animals at 40 ng/kg group. The results showed that the median lethal dose of botulimum toxin might be in the range of 40-59 ng/kg in both sexes. In the repeated dose toxicity study, the test 10.0 ng/head/50 ㎕ saline in male and female rats. No test material-related changes were noted in survivals, clinical signs, food and water consumptions and gross findings in any group. Botulimum toxin treatment significantly decreased the body weight gain rate in male of 5.0 ng/head group/ Botulinum toxin treatment significnatly decreased the body weight gain rate in male of 5.0 ng/head group and over and in female of 10.0 ng/head group compared to vehicle-treated control. One or more relative organ weights (i.e., spleen, thymus, liver, and kidney) were increased significantly from 5.0 ng/head group compared to vehicle-treated control in both sexes. Serum biochemistry revealed increase in asparate aminotransferase (AST), alanine aminotransferase (ALT), creatine phosphokinase, total protein and albumin in male, and increases in AST and ALT and decreases in K+ and Cl- in female without dose-dependent manners. In the histopathological study, physical stimulation by needle caused slight inflammations of dermis. In addition, botulinum toxin treatment induced denervation of nerve cell and disuse of muscle, resulting in atrophy of skeletal muscle in both sexes from 2.5 ng/head group. When the antibodies to toxin were determined in all animals, a significant increase in serum antibodies was observed from 5.0 ng/head group. The results showed that the NOAEL of botulinum toxin might be 1.25 ng/head for 28-day repeated dose toxicity in rats.
|