CINNAMYL ANTHRANILATE
Explanation
This compound has not previously been reviewed by the Joint
FAO/WHO Expert Committee on Food Additives.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
No data available.
TOXICOLOGICAL STUDIES
Special studies on carcinogenicity
Mouse
Groups of 15 male and 15 female six- to eight-week-old A/He mice
were given i.p. injections of 0.1 ml cinnamyl anthranilate (priority
unknown) in tricaprylin (purity unknown) thrice weekly for eight weeks
(total dose, 12 g/kg bw or 2.40 g/kg bw). The experiment was
terminated at 24 weeks after the start of treatment, when all
survivors were killed. The combined numbers of male and female mice
that developed lung tumours were: 21/30 and 17/30 (2.41 and 1.31 lung
tumours per mouse) in the two groups, respectively. In a vehicle-
control group, there were 11/45 lung tumour-bearing females (0.59 lung
tumours per mouse) (Stoner et al., 1973).
In a second series of experiments (Stoner et al., 1973), using
the same total dose of 12 g/kg bw or 2.4 g/kg bw of cinnamyl
anthranilate (purity unknown) in tricaprylin (redistilled), the
combined number of male and female mice that developed lung tumours
were: 21/30 and 13/30 (1.18 and 0.51 lung tumours per mouse),
respectively. In the vehicle-control group, there were 38/160 lung
tumour-bearing animals (0.22 lung tumour per mouse).
Groups of 50 male and 50 female B6C3F1 hybrid mice, six weeks of
age, were fed cinnamyl anthranilate (food grade, minimum purity: 96%)
for 103 weeks at two dose levels: 30 000 mg/kg diet (maximum tolerated
dose MTD), 15 000 mg/kg diet (1/2 MTD). Groups of 50 mice of each sex
served as matched controls. All animals under study received food and
water ad libitum. Dose-related reductions in mean body weight gain
occurred in all treated male and female mice. Mortality was not
affected by administration of cinnamyl anthranilate to the
experimental groups. At the end of the test period, all animals were
necropsied and various tissues were examined histologically. A
statistically significant increase in incidence of hepatocellular
carcinomas or adenomas in mice of both sexes was observed (in males:
14-48 (29%) in controls, 30/50 (60%) (p = 0.002) in the low dose
group, and 37/47 (79%) (p = 0.001) in the high group; in females:
3/50 (6%) in controls, 20/49 (41%) (p = 0.001) in the low dose group,
and 33/49 (67%) (p = 0.001) in the high dose group). A non-neoplastic
lesion reported in the liver of dosed animals was pigmentation
("hemosiderosis") of the hepatocytes and Kuffner's cells. The
incidence of this lesion was as follows: control 0/48, low dose 6/50
and high dose 15/47. No other compound-related lesions were reported
(NCI, 1980).
Rat
Groups of 50 male and 50 female F 344 (Fischer) rats, seven weeks
of age, were fed cinnamyl anthranilate (food grade, minimum purity:
96%) for 103 weeks at two dose levels: 30 000 mg/kg diet (MTD) or
15 000 mg/kg (1/2 MTD). Groups of 50 rats of each sex served as
matched controls. All animals under study received food and water
ad libitum.
A dose-related reduction in mean body weight grain occurred in
all treated male and female rats. In each sex, no significant effect
in the mortality rate was noted in any of the test groups. At the end
of the test period, all animals were necropsied and the various
tissues examined histologically.
The incidence of adenocarcinomas or adenomas of renal cortex was
4/39 (8%) in male rats treated with high dose. This incidence was not
statistically significantly higher than in the control group. This
tumour was not observed in low dose groups or control. In addition,
acinar-cell neoplasms of the pancreas occurred in the males of the
high dose group 3/45 (7%). This incidence is not statistically
significant when compared with matched controls. Non-neoplastic renal
lesions were seen at an increased incidence in dosed rats of each sex.
Mineralization of the kidney was dose-related in males (control 0/48,
low dose 17/50, high dose 30/49) and hemosiderosis of the spleen was
dose-related in females (control 8/47, low dose 28/50, high dose
41/50). Chronic inflammatory changes and healed infarcts were seen in
the kidneys of high dose females (NCI, 1980).
Special studies on mutagenicity
Cinnamyl anthranilate (2.5%) was not mutagenic in plate and
suspension tests using the Ames Salmonella mutagenesis assay in
strains TA-1535, TA-1537, and TA-1538 and the Saccharomyces
cerevesiae D4 yeast assay with and without activating systems
(Litton Bionetics Inc., 1976).
Special studies on teratogenicity
Chicken embryo
Cinnamyl anthranilate was tested in the developing chicken embryo
by administering in ethanol as the solvent, by two routes, and at two
stages of embryonic development; via the air cell and via the yolk at
pre-incubation (0 hours, dosage levels used: 10.0, 5.0, 2.5, 1.25, 0.5
and 0.0 mg/egg) and at 96 hours of incubation (dosage levels used:
0.4, 0.2, 0.1, 0.05, 0.02, and 0.0 mg/egg). Scattered abnormalities
were observed for all four test conditions, but in no instance were
the serious abnormalities higher in incidence than, or different from
those observed in the controls (Verrett, 1976).
Acute toxicity
LD50
Animal Route (mg/kg bw) Reference
Rat Oral 5 000 Opdyke, 1975
Rabbit Dermal 5 000 Opdyke, 1975
Short-term studies
Groups each of 10 mice B6C3F1 strain, six weeks of age, were fed
diets containing 0, 1000, 3000, 10 000 and 30 000 ppm (0, 0.1, 0.3, 1
and 3%) cinnamyl anthranilate for eight weeks. No deaths occurred in
any of the test groups and no depression of weight gain greater than
10% was observed except in male mice fed 30 000 ppm (3%) cinnamyl
anthranilate. No compound-related lesions were evident at necropsy
(NCI, 1980).
Rat
Groups each of 10 rats, Fischer 344 strain, six weeks of age,
were fed diets containing 0, 1000, 3000, 10 000 and 30 000 ppm
(0, 0.1, 0.3, 1 and 3%) cinnamyl anthranilate for eight weeks. No
deaths occurred in any of the test groups and no depression of weight
gain greater than 10% was observed in any of the test groups. No
compound-related lesions were evident at necropsy (NCI, 1980).
Comments
Cinnamyl anthranilate tested intraperitoneally in the A/He strain
mouse produced a significant increase in the incidence of lung tumours
in both males and females.
Cinnamyl anthranilate in the diet of mice, at the maximum
tolerated dose (MTD) and (1/2 MTD), in life-time feeding studies
resulted in a significant increase in the incidence of spontaneous
hepatocellular carcinomas or adenomas. In a similar study in rats, a
few kidney and pancreatic tumours were observed in the treated male
rats. However, the low incidence of these tumours does not allow for
conclusion as to their significance. Cinnamyl anthranilate is inactive
in mutagenicity studies with various strains of S. typhimurium, with
and without activation.
EVALUATION
Not to be used.
REFERENCES
Litton Bionetics Inc. (1975) Mutagenicity evaluation of compound FDA
73-59, cinnamyl anthranilate (Litton Bionetics Inc., 15 June
1975, FDA Contract No. 223-74-2104)
NCI (1980) Bioassay of cinnamyl anthranilate for possible
carcinogenicity, National Cancer Institute, Carcinogenesis
Technical Report Series No. 196, NTP No. 80-10
Opdyke, D. L. J. (1975) Special issue II. Fragrance raw materials
monograph. Cinnamyl anthranilate, Fd. Cosmet. Toxicol., 13,
751-752
Stoner, G. D. et al. (1973) Test for carcinogenicity of food additives
and chemotherapeutic agents by the pulmonary tumor response in
Strain A mice, Cancer Res., 33, 3069-3085
Verrett, M. J. (1975) Investigation of the toxic and teratogenic
effects of GRAS substances to the developing chicken embryo, U.S.
FDA/BF/D. Tox. memo dated 17 May 1976