Lab Anim Res.  2013 Mar;29(1):48-54. 10.5625/lar.2013.29.1.48.

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

• Yu WJ
• Lee IC
• Lee J
• Lee SM
• Kim SH
• Baek HS
• Moon C
• Kim SH
• Chung YH
• Kim JC

• KMID: 2312103
• DOI: http://doi.org/10.5625/lar.2013.29.1.48

Abstract

The present study investigated the potential subacute toxicity of 1,4-dichlorobutane by a 4-week repeated oral dose in Sprague-Dawley rats. The test article was administered once daily by gavage to male rats at dose levels of 0, 100, 300, and 1,000 mg/kg/day for 4 weeks. All rats were sacrificed at the end of the treatment period. During the test period, clinical signs, mortality, body weight, hematology, serum biochemistry, gross findings, and organ weight were examined. At 1,000 mg/kg/day, an increase in the clinical signs and weights of the liver and kidneys was observed in the male rats. Serum biochemical investigations revealed an increase in alanine aminotransferase, alkaline phosphatase, total cholesterol, total bilirubin, phospholipids, blood urea nitrogen, and gamma glutamyl transferase levels. There were no treatment-related adverse effects in the low and middle-dose groups. In the present experimental conditions, the target organs were determined to be liver and kidney. The no-observed-adverse-effect level was considered to be 300 mg/kg/day in rats.

Keyword

1,4-Dichlorobutane; subacute toxicity; target organ; no-observed-adverse-effect level

MeSH Terms

Alanine Transaminase
Alkaline Phosphatase
Animals
Bilirubin
Biochemistry
Blood Urea Nitrogen
Body Weight
Cholesterol
Hematology
Humans
Hydrocarbons, Halogenated
Kidney
Liver
Male
No-Observed-Adverse-Effect Level
Organ Size
Phospholipids
Rats
Rats, Sprague-Dawley
Transferases
Weights and Measures
Alanine Transaminase
Alkaline Phosphatase
Bilirubin
Cholesterol
Hydrocarbons, Halogenated
Phospholipids
Transferases

Reference

1. Rim KT, Kim SJ, Kim JK, Chung YH, Park SY, Yang JS. In vivo micronucleus test of methylcyclopentane and 1,4-dichlorobutane. J Korea Soc Environ Anal. 2011; 14:89–93.

2. Bartlett MS. Properties of sufficiency and statistical test. Proc R Soc London Series A. 1937; 160:268–282.

3. Kruskal WH, Wallis WA. Use of ranks in one-criterion analysis of variance. J Am Stat Assoc. 1952; 47:583–621.

4. Dunnett CW. New tables for multiple comparisons with a control. Biometrics. 1964; 20:482–491.

5. Fisher RA. Statistical Methods for Research Workers. 1970. 14th ed. London: Oliver and Boyd Limited;p. 354.

6. Kim JC, Shin DH, Ahn TH, Kang SS, Song SW, Han J, Kim CY, Ha CS, Chung MK. 26-Week oral repeated dose toxicity study of the new quinolone antibacterial DW-116 in Sprague-Dawley rats. Food Chem Toxicol. 2003; 41(5):637–645. PMID: 12659716.

7. Yu WJ, Chung MK, Chung YH, Kim HC, Kim SH, Lee IC, Kim JC. One-generation reproductive toxicity study of 2-methylbutane in Sprague-Dawley rats. Regul Toxicol Pharmacol. 2011; 60(1):136–143. PMID: 21419187.

8. Amacher DE. Serum transaminase elevations as indicators of hepatic injury following the administration of drugs. Regul Toxicol Pharmacol. 1998; 27(2):119–130. PMID: 9671567.

9. Ozer J, Ratner M, Shaw M, Bailey W, Schomaker S. The current state of serum biomarkers of hepatotoxicity. Toxicology. 2008; 245(3):194–205. PMID: 18291570.

10. Zimmerman HJ, Seeff LB. Coodley EL, editor. Enzymes in hepatic disease. Diagnostic enzymology. 1970. Philadelphia: Lea and Febiger;p. 1–38.

11. Sheehan M, Haythorn P. Predictive values of various liver function tests with respect to the diagnosis of liver disease. Clin Biochem. 1979; 12(6):262–263. PMID: 43785.

12. Leonard TB, Neptun DA, Popp JA. Serum gamma glutamyl transferase as a specific indicator of bile duct lesions in the rat liver. Am J Pathol. 1984; 116(2):262–269. PMID: 6147091.

13. Ramaiah SK. A toxicologist guide to the diagnostic interpretation of hepatic biochemical parameters. Food Chem Toxicol. 2007; 45(9):1551–1557. PMID: 17658209.

14. Kang BH, Son HY, Ha CS, Lee HS, Song SW. Reference values of hematology and serum chemistry in Ktc: Sprague–Dawley rats. Korean J Lab Anim Sci. 1995; 11:141–145.

15. Petterino C, Argentino-Storino A. Clinical chemistry and haematology historical data in control Sprague-Dawley rats from pre-clinical toxicity studies. Exp Toxicol Pathol. 2006; 57(3):213–219. PMID: 16343876.

16. 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. J Toxicol Environ Health. 1986; 18(2):161–188. PMID: 3712484.

17. Kim JC, Shin DH, Kim SH, Kim JK, Park SC, Son WC, Lee HS, Suh JE, Kim CY, Ha CS, Chung MK. Subacute toxicity evaluation of a new camptothecin anticancer agent CKD-602 administered by intravenous injection to rats. Regul Toxicol Pharmacol. 2004; 40(3):356–369. PMID: 15546689.