Safety evaluation of certain food additives - ipcs inchem

390 ALKOXY-SUBSTITUTED ALLYLBENZENES
were reported at the highest dose level of methyl eugenol. Mean body weight gains
of male and female mice given 300 mg/kg bw per day were significantly less than
those of the vehicle controls. There was a statistically significant increase (P < 0.05)
in liver weights in male mice dosed with 30 mg/kg bw per day and in female mice
dosed with 300 mg/kg bw per day compared with those of the respective control
groups. In the liver of male mice at the 1000 mg/kg bw per day level as well as
female mice at the 300 mg/kg bw per day and higher levels, increased incidences
of cytological alteration, necrosis, bile duct hyperplasia and subacute inflammation
were observed. A significant increase in testis weights was observed in male mice
receiving 100 or 300 mg/kg bw per day. There were no significant findings at the
10 mg/kg bw per day dose level (National Toxicology Program, 2000).
(ii) Rats
The incidence of hepatocellular neoplasms for male rats administered
600 mg estragole/kg bw per day (4/10 cholangiocarcinomas and 1/10 adenomas)
or 1000 mg methyl eugenol/kg bw per day (1/10 adenomas) by gavage, 5 days per
week, for 13 weeks suggests that total body burdens approaching 40 000 mg/kg bw
(600 mg/kg bw per day × 5 days per week × 13 weeks) are sufficient to induce a
carcinogenic response in F344 male rats (National Toxicology Program, 2000,
2008).
In a 91-day feeding study of methyl eugenol, groups of 24 male and 24
female Sprague-Dawley rats were maintained on diets resulting in an average daily
intake of 18 mg/kg bw. Weekly measurements of body weight and food consumption
revealed no significant differences between test and control animals.
Haematological examinations, blood chemical determinations and urinary analysis
monitored at weeks 6 and 12 revealed normal values. At necropsy, organ weight
measurements indicated a small but significant (P < 0.05) increase in relative liver
weights for male rats only. Histopathological examination of 27 major organs and
tissues revealed no alterations that could be associated with administration of the
test material (Osborne et al., 1981).
Groups of 10 male and 10 female F344 rats were administered
microencapsulated methyl eugenol at 0 (control), 1, 5 or 50 mg/kg bw by dietary
admixture for 28 days. Clinical signs, body weight gain and food and water
consumption were monitored throughout the study. Haematology, blood chemistry
and urinalysis were evaluated for all animals at the end of the study, and urine
samples were collected weekly. Blood samples were collected at the start and at
termination of the study. At the termination of the treatment period, all animals were
sacrificed and subjected to macroscopic examination, and serum samples were
collected. No unscheduled deaths occurred during the study. No clinical signs of
toxicity were detected. No adverse effects on body weight gain, food consumption,
food efficiency or water consumption were detected. No treatment-related effects
on haematology, blood chemistry, urinalysis or organ weights were observed.
Macroscopic and histopathological examination revealed no treatment-related
effects. The NOEL was therefore concluded to be 50 mg/kg bw per day (Jones,
2004).