Oral toxicity of a tocotrienol preparation in rats.
Tocotrienols are added as antioxidants to food. As there have been no reports of toxicological evaluation, a 13-week oral toxicity study was performed in Fischer 344 rats of both sexes at dose levels of 0 (group 1), 0.19 (group 2), 0.75 (group 3) and 3% (group 4) of a preparation in powdered diet. Suppression of body weight gain was observed in group 4 males. On hematological examination, significant decrease in mean corpuscular volume (MCV) was observed in all treated males. Platelets were significantly reduced in group 3 and 4 males. Hemoglobin concentration, MCV, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration were significantly decreased in group 3 and 4 females and hematocrit in group 4 females. On serum biochemical examination, increase in the albumin/globulin ratio (A/G) and alkaline phosphatase in all treated males, elevated alanine transaminase in group 4 of both sexes and increases in asparagine transaminase and gamma-glutamyl transaminase in group 4 females were observed. With regard to relative organ weights, liver weights in group 4 of both sexes and adrenal weights in all treated males demonstrated an increase, and ovary and uterus weights in group 4 females were reduced. Histopathologically, slight hepatocellular hypertrophy in group 3 and 4 males, and reduction of cytoplasmic vacuolation in the adrenal cortical region in group 4 males were observed. Because of pathological changes in male liver and hematological changes in females, the no-observed-adverse-effect level (NOAEL) was concluded to be 0.19% in the diet (120 mg/kg body weight/day for male rats and 130 mg/kg body weight/day for female rats). As a decrease in MCV, an increase in the A/G, elevation of alkaline phosphatase and increase in adrenal weight were observed in all treated males, a no-observed-effect level (NOEL) could not be determined in this examination.
Nakamura
H
H
Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, 158-8501, Tokyo, Japan.
Furukawa
F
F
Nishikawa
A
A
Miyauchi
M
M
Son
H Y
HY
Imazawa
T
T
Hirose
M
M
D000284:Administration, Oral; D000311:Adrenal Glands / Q000187:drug effects* / Q000473:pathology; D000818:Animals; D001772:Blood Cell Count; D002839:Chromans / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005503:Food Additives / Q000008:administration & dosage / Q000633:toxicity*; D005835:Genitalia / Q000187:drug effects / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D051381:Rats; D011916:Rats, Inbred F344; D012737:Sex Factors; D024508:Tocotrienols; D014810:Vitamin E / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity*
D002839:Chromans; D005503:Food Additives; D024508:Tocotrienols; D014810:Vitamin E; C082097:tocotrienol, delta; C013649:plastochromanol 8; C082089:tocotrienol, beta; C082032:tocotrienol, alpha