2-Week repeated oral dose toxicity study of 1,4-dichlorobutane in rats

1,4-Dichlorobutane의 랫드 2주 반복경구투여독성시험

  • Kim, Jong-Kyu (Chemical Safety & Health Research Center, Occupational Safety & Health Research Institute) ;
  • Lee, In-Chul (College of Veterinary Medicine, Chonnam National University) ;
  • Kim, Sung-Hwan (College of Veterinary Medicine, Chonnam National University) ;
  • Baek, Hyung-Seon (College of Veterinary Medicine, Chonnam National University) ;
  • Bae, Jin-Sook (Preclinical Research Center, ChemOn Inc.) ;
  • Song, Si-Whan (Preclinical Research Center, ChemOn Inc.) ;
  • Kim, Jong-Choon (College of Veterinary Medicine, Chonnam National University) ;
  • Chung, Yong-Hyun (Chemical Safety & Health Research Center, Occupational Safety & Health Research Institute)
  • 김종규 (산업안전보건연구원 화학물질센터) ;
  • 이인철 (전남대학교 수의과대학) ;
  • 김성환 (전남대학교 수의과대학) ;
  • 백형선 (전남대학교 수의과대학) ;
  • 배진숙 ((주)켐온 전임상연구센터) ;
  • 송시환 ((주)켐온 전임상연구센터) ;
  • 김종춘 (전남대학교 수의과대학) ;
  • 정용현 (산업안전보건연구원 화학물질센터)
  • Published : 2013.03.31

Abstract

Objectives: The present study investigated the potential subacute toxicity of 1,4-dichlorobutane (1,4-DCB) by a 2-week repeated oral dose in male Sprague-Dawley rats. Materials and Methods: The test chemical was administered once daily by gavage to male rats at dose levels of 0, 74, 222, 667, and 2000 mg/kg/day for 2 weeks. All rats were sacrificed at the end of treatment period. During the test period, clinical signs, mortality, body weights, food and water consumption, urinalysis, hematology, serum biochemistry, gross findings, and organ weights were examined. Results: At 2000 mg/kg/day, treatment-related clinical signs, as evidenced by hypothermia, decreased locomotor activity, piloerection, lying on side, and prone position were observed. All the rats were found dead on test day 2. At 667 mg/kg/day, polyuria, suppressed body weight gain, food consumption, and spleen and thymus weights, and increased adrenal gland and liver weights were observed.Hematological and serum biochemical investigations revealed increases in the alanine aminotransferase, alkaline phosphataseand total bilirubinand decreases in the serum $Na^+$ level, white blood cell count and lymphocyte ratio. There were no treatment-related adverse effects in the 74 and 222 mg/kg/day groups. Conclusions: In the present experimental conditions, target organs were determined to be spleen, thymus,and liver. The no-observed-adverse-effect level was considered to be 222 mg/kg/day in male rats.

Keywords

References

  1. Andersen H, Larsen S, Spliid H, Christensen ND. Multivariate statistical analysis of organ weights in toxicity studies. Toxicology 1999:136:67-77. https://doi.org/10.1016/S0300-483X(99)00056-6
  2. Androgue HJ, Madias NE. Hyponatremia. New England Journal of Medicine 2000;342:1581-1589. https://doi.org/10.1056/NEJM200005253422107
  3. Bailey SA, Zidell RH, Perry RW. Relationships between organ weight and body/brain weight in rat: what is the best analytical endpoint? Toxicologic Pathology 2004;32:448-466. https://doi.org/10.1080/01926230490465874
  4. Dunnett CW. New tables for multiple comparisons with a control. Biometrics 1964; 20: 482-491. https://doi.org/10.2307/2528490
  5. Gehrs BC, Riddle MM, Williams WC, Smialowicz RJ. Alterations in the developing immune system of the F344 rat after perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin: II. Effects on the pup and the adult. Toxicology 1997;122:229-240. https://doi.org/10.1016/S0300-483X(97)00099-1
  6. Kang BH, Kim YB, Lee HS, Kim YH, Im WJ, Ha CS. Background data on hematology, blood biochemistry and organ weights for 2 weeks and 4 weeks repeated-dose toxicity studies using Sprague-Dawley (SD) rats. The Korean Journal of Laboratory Animal Science 2004;20:2:134-140
  7. Kim JC, Kang BH, Shin CC, Kim YB, Lee HS, Kim CY, Han J, Kim KS, Chung DW, Chung MK. Subchronic toxicity of plant sterol esters administered by gavage to Sprague-Dawley rats. Food and Chemical Toxicology 2002;196:77-86.
  8. Kim SH, Lim JH, Shin IS, Moon C, Park SH, Kim SH, Lee JS, Kwon EH, Kim JC. Evaluation of the toxicological properties and hepatoprotective effects of PAI-N002, a mixture of herbal extracts, in rats. Molecular and Cellular Toxicology 2010;6:239-246. https://doi.org/10.1007/s13273-010-0033-2
  9. Korea Occupational Safety and Health Agency (KOSHA). Listing of Preferential Assessment Substances for Hazard Identification Assessment; 2007.
  10. Kruskal WH, Wallis WA. Use of ranks in one-criterion analysis of variance. J Am Stat Assoc 1952;47: 583-621. https://doi.org/10.1080/01621459.1952.10483441
  11. Merck Millipore. 1,4-Dichloropropane Material Safety Data Sheet. Available at: http://www.chemdat.merck.de/ sweden/chemicals/1-4-dichlorobutane/MDA_CHEM-803227/p_ufub.s1OS_UAAAEnrtkB3YVi. Accessed January 3, 2013.
  12. Petterino C, Argentino-Storino A. Clinical chemistry and haematology historical data in control Sprague-Dawley rats from pre-clinical toxicity studies. Experimental and Toxicologic Pathology 2006; 57:213-219. https://doi.org/10.1016/j.etp.2005.10.002
  13. Poirier LA, Stoner GD, Shimkin MB. Bioassay of alkyl halides and nucleotide base analogs by pulmonary tumor response in strain A mice. Cancer Research 1975;35:1411-1415.
  14. Rim KT, Kim SJ, Kim JK, Chung YH, Park SY, Yang JS. In vivo micronucleus test of methylcyclopentane and 1,4-dichlorobutane. Journal of the Korea Society for Environmental Analysis 2011;14:2:89-93.
  15. Sigma-Aldrich. 1,4-Dichlorobutane Material Safety Data Sheet. Available at: http://www.sigmaaldrich.com/MSDS/MSDS/PleaseWaitMSDSPage.do?language=EN-generic&country=KR&brand=ALDRICH&productNumber=D59100&PageToGoToURL=http%3A%2F%2Fwww.sigmaaldrich.com%2Fcatalog%2Fproduct%2Faldrich%2FD59100%3Flang%3Dko. Accessed January 3, 2013.
  16. Ulrich-Lai YM, Figueiredo HF, Ostrander MM, Choi DC, Engeland WC, Herman JP. Chronic stress induces adrenal hyperplasia and hypertrophy in a subregionspecific manner. American Journal of Physiology-Endocrinology and Metabolism 2006;291:E965-E973. https://doi.org/10.1152/ajpendo.00070.2006
  17. Vinogradov GI. Autosensitizing effect in the per os uptake of chemical substances into the body. Vrach Delo 1979;9:100-102.
  18. Wolford ST, Schroer RA, Gohs FX, Gallo PP, Brodeck M, Falk HB, Ruhren R. Reference range data base for serum chemistry and hematology values in laboratory animals. Journal of Toxicology and Environmental Health 1986;18:161-188. https://doi.org/10.1080/15287398609530859