A 4-week Oral Toxicity Study of Water-soluble Chitosan in Sprague-Dawley Rats

수용성 키토산의 SD 랫드에 대한 4 주 반복 경구 투여 독성시험

  • Jang, Beom-su (Division of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Chungnam National University) ;
  • Lim, Jong-hwan (Division of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Chungnam National University) ;
  • Yun, Hyo-in (Division of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Chungnam National University)
  • 장범수 (충남대학교 수의과대학 수의약리독성학교실) ;
  • 임종환 (충남대학교 수의과대학 수의약리독성학교실) ;
  • 윤효인 (충남대학교 수의과대학 수의약리독성학교실)
  • Accepted : 2003.06.17
  • Published : 2003.06.30

Abstract

Chitosan is known to have antibacterial, antitumorogenic, hypolipidemic and immunopotentiating activities, hence finding diverse uses as a component in varying functional foodstuffs. However, some investigators reported it caused mineral absoiption inhibition and excess coagulation. From the chemical viewpoint, conventional chitosans are high-molecule polymers lacking water solubility, which could be related with their possible toxicity. A newly developed low- molecule water soluble chitosan is thought to have low toxicity compared to conventional chitosans. But no investigation was carried out to evaluate its toxicity. In this study, a 28-day subacute oral toxicity study of the water-soluble chitosan was performed in Sprague-Dawley rats of both sexes. Each 36 male and female rats were orally administered with 500, 1,000 and 2,000 mg/kg/day for 28 consecutive days, respectively. Clinical parameters (growth rate, feed and water consumption, daily inspection, urine analysis) during the 28 days indicated the water-soluble chitosan did not induce any abnonnal changes. There were no abnormal findings due to the administration of the test substance in gross and microscopic findings. We had not found alteration in absolute and relative organ weight between the control and treated groups, with only exception in the liver but lacking dose-dependency. The results of hematology and serum biochemistry examination revealed that no treatment related changes were between control and all dose groups. In conclusion, it was suggested that subacute toxicity of the water-soluble chitosan was low and the no-observed adverse effect level was considered to be over 2,000 mg/kg in rats.

References

  1. 식품의약품안전청 국립독성연구소. 의약품의 독성시험 기준해설, 1999, 28-34
  2. Aiba, S. Preparation of N-acetylchitooligasacchahdes by hydrolysis of chitosan with chitinase followed by N-acetylation. Carbohydr. Res. 1994, 265(2), 323-328
  3. Andrady, A. L. and Xu, P. Elastic behavior of chitosan films. J. Poly. Sci.: Part B: Poly. Phys. 1997, 35, 517-521
  4. Horowitz, S. T., Roseman, S. and Blumenthal, H. J. The preparation of glucosamine oligosaccharide. I. Separation. J. Am. Chem. Soc. 1957, 79, 5046-5049
  5. Jeon, Y. J., Kim, G. H., Park, P. J. and Kim, S. K. Calcium absorption accelerating effect of chitosan 0li-gosaccharides prepared by ultrafiltration membrane enzyme reactor. J. Korean Fish Soc. 1999, 32(3), 247- 251
  6. Jeon, Y. J. and Kim, S. K. Continuous production of chitosanoligosaccharides using a dual reactor system, Process Biochemistry, 2000, 35, 623-632
  7. Kim, H. C., Kang, B. H., Ha, C. S., Han, S. S. and Roh, J. K. A 4-week subcutaneous toxicity of recombinant hunan interferon A (LBD-007) in Sprague Dawley rats. J. Toxicol. Sci. 1993, 18, 43-56
  8. Landes, D. R. and Bough, W. A. Effect of chitin - a coagulating agent for food processing wastes in the diets of rats on growth and liver and blood composition. Bull. Environm. Contam. Toxicol. 1976, 15, 555-563
  9. Lorke, D. A new approach to practical toxicity testing. Arch. Toxicol. 1983, 54, 275-287
  10. Macleod, G. S., Fell, J. T., Collett, J. H., Sharma, H. L. and Smith, A. M. Selective drug delivery to the colon using pectin:chitosan:hydroxypropyl methylcellulose film coated tablets, Int. J. Pharm. 1999, 187, 251-257
  11. Maezaki, Y., Tsuji, K., Nakagawa, Y., Kawai, Y., Akimoto, M., Tsugita, T., Takekawa, W., Terada, A., Hara, H. and Mitsuoka, T. Hypocholesterolemic effect of chitosan in adult males. Biosci. Biotech. Biochem. 1993, 57, 1439-1444
  12. Pae, H. 0., Seo, W. G., Kim, N. Y., Oh, G. S., Kim, G. E., Kim, Y. H., Kwak, H. b., Yun, Y. G., Jun, C. D. and Chung, H. T. Induction of granulocytic differentiation in acute promyelocytic leukemia cells (HL-60) by water-soluble chitosan oligomer. Leuk. Res. 2001, 25(4), 339-346
  13. Qin, C., Du, Y., Xiao, L., Li, Z. and Gao, X. Enzymic preparation of water-soluble chitosan and their antitumor activity, Int. J. Biol. Macromol. 2002, 31(1-3), 111-117
  14. Seo, S. B., Jeong, a J., Chung, H. S., Lee, J. D., You, Y. 0., Kajiuchi, T. and Kim, H. M. Inhibitory effect of high molecular weight water-soluble chitosan on hypoxia-induced inflammatory cytokine production. Biol. Pharm. Bull. 2003, 26(5), 717-721
  15. Song, C. W., Hwang, H. S., and Han, H. S. Studies on the basic data of ktc: SD rats with age. Kor. J. Ani. Sci. 1990, 6, 33-43
  16. Tanaka, Y., Tanioka, S., Tanaka, M., Tanigawa, T., Kitamura. Y., Minami, S., Okamoto, Y., Miyashita, M. and Nanno, M. Effects of chitin and chitosan particles on BALB/c mice by oral and parenteral administration. Biomaterials. 1997, 18(8), 591-595
  17. Tokoro, A., Kobayashi, M., Tatewaki, N., Suzuki, K., Okawa, Y., Nikami, T., Suzuki, S. and Suziiki, M. Protective effect of N-acetyl chitohexaose on Ltsteria monocytogens infection in mice. Microbiol. Immunol. 1989, 33, 357-367
  18. Tokura, S., Tamura, H. and Azuma, I. Immunological aspects of chitin and chitin derivatives administered to animals. EXS. 1999, 87, 279-292
  19. Wada, M., Nishimura, Y., Watanabe, Y., Takita, T. and Innami, S. Accelerating effect of chitosan intake on urinary calcium excretion by rats. Biosci. Biotech. Biochem. 1997, 61, 1206-1208