Acute, subchronic and chronic toxicity studies of a synthetic antioxidant, 2,2'-isobutylidenebis(4,6-dimethylphenol) in rats.
General toxicity studies on 2,2'-isobutylidenebis(4,6-dimethylphenol)(IBBMP) were conducted using male and female Wistar rats. In the acute test, the oral LD50 values were 119 mg/kg BW in males and 103 mg/kg BW in females. Hypersensitivity, loss of righting reflex and abdominal position were observed. In the subchronic test, rats were fed a diet containing IBBMP at levels of 0, 20, 100 or 500 ppm for 13 weeks with interim sacrifice at 4 weeks (equal to 0, 1.1, 5.5 or 27.9 mg/kg BW/day in males and 0, 1.1, 5.9 or 29.6 mg/kg BW/day in females). In both sexes, there were no changes in general condition, body weight gains and food intakes in all groups. No deaths were observed in all groups. Significant increase in AST was observed in 500 ppm males at Week 4. However, the change was not observed at Week 13. Slight but significant decreases in creatinine were also observed in 100 ppm females at Week 13 and 500 ppm males and females at Weeks 4 and 13. Total cholesterol (T-CHO) was significantly elevated in females of the 500 ppm group at Weeks 4 and 13. Absolute and relative liver weights were increased in 500 ppm of both sexes at Week 4. In females, the increases were also observed at Week 13. However, no remarkable histopathological findings were observed in all treated groups. In the chronic test, rats were fed a diet containing IBBMP at levels of 0, 100, 500 and 1500 ppm for 18 months with interim sacrifices at 6 and 12 months (equal to 0, 3.8, 19.4 or 59.4 mg/kg BW/day in males and 0, 4.3, 20.9 or 67.5 mg/kg BW/day in females). No remarkable changes in general appearance were observed in any rats. Body weight gains, food intakes and survival rates in all treated animals were comparable to those of the control. No remarkable changes in the hematological parameters were observed. T-CHO was significantly elevated in females of the 1500 ppm groups throughout the experiment. Significant increases or tendencies for increase in relative liver weights were observed in the 500 and 1500 ppm animals of both sexes. Increased incidences of swelling in liver cells were observed in 1500 ppm males at 6 months and 1500 ppm females at 12 and 18 months. At 18 months, dose-dependent increases in thickness of basement membrane of renal tubules and Bowman's capsule and cell infiltration to the interstitium of the kidney were observed in males. Significant increases of hyaline cast and basophilic change were also observed in 1500 ppm males. In females, increased incidences of hyaline cast were observed at 500 ppm and higher at 18 months. No other toxicity was apparent. No neoplastic lesions that could be attributed to IBBMP were observed in any organs of either sex. From the result of the chronic toxicity test, the no-observed-adverse-effect level (NOAEL) for IBBMP was concluded to be 100 ppm in the diet (4.26 mg/kg BW/day) in female rats on the basis of induction of hyaline cast in renal tubules at 500 ppm, whereas, in males, only a lowest-observed-adverse-effect level (LOAEL) was given as 100 ppm (3.84 mg/kg BW/day) on the basis of induction of thickening of basement membrane in renal tubules at 100 ppm.
Takagi
Atsuya
A
Division of Cellular & Molecular Toxicology, National Institute of Health Sciences, Tokyo, Japan. takagi@nihs.go.jp
Sekita
Kiyoshi
K
Saitoh
Minoru
M
Kanno
Jun
J
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D004032:Diet; D005260:Female; D006403:Hematologic Tests; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012737:Sex Factors; D013997:Time Factors; D023382:Toxicity Tests, Acute; D036401:Toxicity Tests, Chronic; D014992:Xylenes / Q000008:administration & dosage / Q000633:toxicity*
D000975:Antioxidants; D014992:Xylenes; C089778:2,2'-isobutylidene-bis(4,6-dimethylphenol)