Modifications of azoxymethane-induced carcinogenesis and 90-day oral toxicities of 2-tetradecylcyclobutanone as a radiolytic product of stearic acid in F344 rats

Abstract

A 90-day oral toxicity test in rats was performed to evaluate the toxicity of 2-tetradecylcyclobutanone (2-tDCB), a unique radiolytic product of stearic acid. Six-week-old male and female F344 rats (n=15/group) were given 2-tDCB at concentrations of 0, 12, 60 and 300 ppm in a powder diet for 13 weeks. Slight dose-dependent increases in serum total protein and albumin in male rats were found, but these changes were not considered to be a toxic effect. The fasting, but not non-fasting, blood glucose levels of the male rats in the 300 ppm group and female rats in the 60 and 300 ppm groups were lower than those of the controls. Gas chromatography-mass spectrometry analysis showed dose-dependent accumulation of 2-tDCB in adipose tissue, notably in males. Next, we performed an azoxymethane (AOM)-induced two-stage carcinogenesis study. After injection of 6-week-old male F344 rats (n=30/group) once a week for 3 weeks, the animals received 2-tDCB at concentrations of 0, 10, 50 and 250 ppm in a powder diet for 25 weeks. The incidences of colon tumors for the 2-tDCB dosages were 34%, 45%, 40% and 37%, respectively, and were not statistically significant. These data suggest that 2-tDCB shows no toxic or tumor-modifying effects under the present conditions, and that the no-observed-adverse-effect level for 2-tDCB is 300 ppm in both sexes, equivalent to 15.5 mg/kg b.w./day in males and 16.5 mg/kg b.w./day in females.

Keywords: 2-tetradecylcyclobutanone; 90-day oral toxicity; colon carcinogenesis; food irradiation.

Fig. 1.

Structure of 2-tDCB and experimental design for AOM-induced carcinogenesis. A: 2-ACBs have a cyclobutanone ring and an alkyl chain. The alkyl chain length differs depending on the precursor fatty acid. B: For the two-stage carcinogenesis study, AOM was dissolved in 0.9% NaCl and administered subcutaneously in 6-, 7- and 8-week-old rats. At 9 weeks of age, administration of the powder diet containing 2-tDCB was begun.

Fig. 2.

Body weight, food intake and the histological appearances found during the 90-day oral toxicity test. Similar average body weights (A) and food intakes (B) were found in each group throughout the experimental period. None of the groups exhibited any histological differences in the liver (C, left) or pancreas (C, right).

Fig. 3.

Blood glucose and WBC counts in rats treated with 300 ppm 2-tDCB and 300 ppm stearic acid during the 28-day oral toxicity study. After the 300 ppm stearic acid treatment, fasting glucose decreased. No significant increase in WBC count was shown after administration of 300 ppm 2-tDCB. Data are shown as the mean ± SD.

Fig. 4.

AOM-induced carcinogenesis. The average values for body weight (A) and food intake (B) were similar. Figure 4C shows the gross appearance of the intestinal tumors in a case from the 250 ppm group. The average number of small intestine and cecum/colon tumors per rat (D) did not differ between the groups. Data are shown as the mean ± SD.