Km. Abdo et al., 14-week toxicity and cell proliferation of methyleugenol administered by gavage to F344 rats and B6C3F1 mice, FOOD CHEM T, 39(4), 2001, pp. 303-316
Methyleugenol, a food flavor and fragrance agent, was rested for toxicity i
n male and female F344/N rats and B6C3F1 mice. Groups of 10 males and 10 fe
males per sex per species were administered 0, 10, 30, 100, 300 or 1000 mg
methyleugenol/kg body weight in 0.5% aqueous methylcellulose by gavage, 5 d
ays per week for 14 weeks. Additional groups of rats and mice of each sex w
ere dosed similarly and used for hematology and clinical chemistry studies.
Groups of 10 male and 10 female rats and mice received the vehicle by gava
ge on the same dosing schedule and served as vehicle controls. For serum ga
strin, gastric pH and cell proliferation studies groups of 10 female rats w
ere given 0, 37, 75 or 150 mg/kg, once daily 5 days per week for 30 or 90 d
ays or 300 or 1000 mg,kg for 30 days; male mice were given 0, 9, 18.5, 37,
75, 150 or 300 mg/kg for 30 or 90 days. For the gastrin, pH and cell prolif
eration studies, groups of 10 female rats and 10 male mice were given the v
ehicle for 30 or 90 days and served as controls. Methyleugenol administrati
on to rats induced erythrocyte microcytosis and thrombocytosis in male and
female rats. It also caused an increase in serum alanine aminotransferase a
nd sorbitol dehydrogenase activities and bile acid concentration, suggestin
g hepatocellular injury, cholestasis or altered hepatic function. Additiona
lly, methyleugenol induced hypoproteinemia and hypoalbuminemia, evidenced b
y decreased total protein and albumin concentrations in both male and femal
e rats, suggesting in inefficiency of dietary protein utilization due to me
thyleugenol-induced toxic effects on the liver and glandular stomach of rat
s and mice. The increase in gastrin acid gastric pH of rats and mice given
methyleugenol suggests that gastrin feedback was impaired and resulted in c
onditions not conducive to protein digestion, ln rats, methyleugenol caused
an increase in the incidences of hepatocyte cytologic alteration, cytomega
ly, Kupffer cell pigmentation, mixed foci of cellular alteration and bile d
uct hyperplasia of the liver and atrophy and chronic inflammation of the mu
cosa of the glandular stomach. In mice, it caused an increase in the incide
nce of cytologic alteration, necrosis, bile duct hyperplasia and subacute i
nflammation of the liver and atrophy, degeneration, necrosis, edema, mitoti
c alteration, and cystic glands of the fundic region of the glandular stoma
ch. The increased incidences of adrenal gland cortical hypertrophy and/or c
ytoplasmic alteration in the submandibular salivary glands, adrenal glands,
testis and uterus of rats were considered secondary to the chemical-relate
d effects observed in the liver and glandular stomach. Based on mortality,
body weight gain, clinical chemistry and gross and microscopic evaluation o
f tissues of rats and mice, the no-observed-effect level (NOEL) of methyleu
genol for both species was estimated at 10 mg/kg. (C) 2001 Elsevier Science
Ltd. All rights reserved.