| Single and 28-day repeated dose toxicity studies of botulinum toxin type A in mice and rats |
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Tae-Won Jeon1, Ji-Young Kim1, Sun-Hee Hyun1, Nam-Hee Kim1, Sang-Kyu Lee1, Chun-Hwa Kim1, Hee-Dong Woo2, Gi-Hyeok Yang2, Hyun-Ho Jung3, Tae-Cheon Jeong1 |
1College of Pharmacy, Yeungnam University
2Microbial Toxin Research Institute, Medy-Tox Inc.
3Division of Applied Biological Sciences, Sunmoon University |
| 마우스 및 랫드에서 botulinum toxin type A의 단회 및 28일 반복투여 독성시험 |
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전태원1, 김지영1, 현선희1, 김남희1, 이상규1, 김춘화1, 우희동2, 양기혁2, 정현호3, 정태천1 |
1영남대학교 약학대학
2(주)메디톡스 부설 미생물독소 연구소
3선문대학교 응용생물과학부 |
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| Abstract |
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Single and 28-day repeated dose toxicity studies of botulimnn toxin type A were carried out in ICR mice and Sprague-Dawley rats, respectively. In the single dose toxicity study, botulinwn toxin was injected intraperitoneally to male and female mice at a single dose of 40, 59, 89 133 and 200 ng/10 ml 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 botulinum toxin might be in the range of 40-59 ng/kg in both sexes. In the repeated dose toxicity study, the test material was administered intradermally for 28 days at doses of 0 (vehicle-treated control), 1.25, 2.5, 5.0 and $10.0ng/head/50{mu}{ell}$ saline in male and female rats. No test material-related changes were noted in survivals, clinical signs, food and water consumptions and gross finding in any group. Botulinum toxin treatment significantly 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 increases in aspartate 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-pendent manners. In the histopathological study, physical stimulation by needle caused slight inflammations of dennis. 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. |
| Key Words:
botulinum toxin type A, single dose toxicity, repeated dose toxicity, ICR mice, Sprague-Dawley rats |
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