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    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
    


    See Also:
       Toxicological Abbreviations
       CINNAMYL ANTHRANILATE (JECFA Evaluation)
       Cinnamyl Anthranilate (IARC Summary & Evaluation, Volume 16, 1978)
       Cinnamyl Anthranilate (IARC Summary & Evaluation, Volume 31, 1983)
       Cinnamyl anthranilate  (IARC Summary & Evaluation, Volume 77, 2000)