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)