The FEMA GRAS Assessment of Cinnamyl Derivatives Used As Flavor Ingredients
Total Page：16
File Type：pdf, Size：1020Kb
FUlIlnlllllllil>l ELSEVIER Food and Chemical Toxicology 42 (2004) 157-185 TIIIialqy www.elsevier.com/locate/foodchemtox Review The FEMA GRAS assessment of cinnamyl derivatives used as flavor ingredients Timothy B. Adamsa,*,2, Samuel M. Cohenb,l, John Daulle,3, Victor J. Ferond,l, Jay 1. Goodmane,l, Lawrence J. Marnettf,l, Ian C. Munrog,4, Philip S. Portogheseh,l, Robert L. Smithi,l, William J. WaddeW,l, Bernard M. Wagnerk,l,l "Flavor and Extract Manufacturers Association, i620 i Street, N. w., Suite 925, Washington, DC 20006, USA hDepartment of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA CDepartment ofPharmacology and Toxicology, University ofKansas Medical Center, Kansas City, Kansas, USA dTNO Nutrition & Food Research institute, Toxicology, Utrechtseweg 48, The Netherlands CDepartment of Pharmacology and Toxicology, Michigan State University, B440 Life Science Building, East Lansing, Michigan, USA fDepartment ofBiochemistry, Vanderbilt University School ofMedicine, Nashville, Tennessee, USA gCanTox, inc., Mississauga, Ontario, Canada hDepartment ofMedicinal Chemistry, University of Minnesota, Minneapolis, Minnesota, USA iDivision of Biomedical Sciences Section ofMolecular Toxicology, imperial College School ofMedicine, South Kensington, London SW7 2AZ, UK iDepartment of Pharmacology and Toxicology, University ofLouisville School ofMedicine, Louisville, Kentucky, USA kNew York University, School of Medicine, New York, New York, USA IBernard M. Wagner, Associates, Millburn, New Jersey, USA Received 2 July 2003; received in revised form 21 August 2003; accepted 31 August 2003 Abstract This publication is the seventh in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manu facturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of cinnamyl derivatives as flavoring ingredients is evaluated. © 2003 Elsevier Ltd. All rights reserved. Abbreviations: ABS, chromosomal aberration; ADH, alcohol dehydrogenase; ALD, aldehyde dehydrogenase; B. subtilis, Bacillus subtilis; CHO, Chinese hamster ovary; CoA, coenzyme A; DNA, deoxyribonucleic acid; ECETOC, European Centre for Ecotoxicology and Toxicology of Che micals; E. coli, Escherichia coli; F. Female; FDA, United States Food and Drug Administration; FEMA. The Flavor and Extract Manufacturers Association; GRAS. Generally Recognized as Safe; GRASa, GRAS affirmed; GRASr, GRAS reaffirmed; IARC, International Agency for Research on Cancer; i.p., intraperitoneal: LDso, median lethal dose; M. Male; MLA, mouse lymphoma cell assay; NAS, National Academy of Science; NCI, National Cancer Institute; NOEL. No observed effect level; NR, Not reported; NTP, National Toxicology Program; PPARex, peroxisome proliferator-activated receptor ex; PE, polychromatic erythrocytes; ppm, parts per million; S. typhimur;um. Salmonella typhimurium; SCE, sister chromatid exchanges; SLR, scientific literature review. * Corresponding author. Tel.: + 1-202-293-5800; fax: + 1-202-463-8998. E-rnail address: [email protected] (T.B. Adams). I The authors are members of the FEMA Expert Panel. 2 Scientific Secretary to the FEMA Expert Panel. , Emeritus member of the FEMA Expert Panel 4 Consultant to the FEMA Expert Panel. 0278-6915/Si - see front maller 'f:! 2003 Elsevier Ltd. All rights reserved. doi: 1O.1016/j.fct.2003.08.021 158 T.B. Adarns et al. / Food and Chemical Toxicology 42 (2004) 157-185 Contents 1. Chemical identity 158 2. Exposure ································································ 158 2.1. Flavor use and natural occurrence 158 3. Hydrolysis, absorption, distribution, excretion and nletabolism 164 3.1. Hydrolysis 164 3.2. Absorption, distribution and excretion 164 3.3. Metabolism 165 3.3.1. Cinnamyl alcohol and cinnamaldehyde derivatives 165 3.3.2. Cinnamic acid 166 3.3.3. Ring and chain substituted cinnamyl derivatives ~ 167 3.3.4. Cinnamyl anthranilate 167 4. Toxicological studies 168 4.1. Acute toxicity 168 4.2. Short-term toxicity 168 4.3. Carcinogenicity studies on cinnamyl anthranilate, cinnamaldehyde, and anthranilic acid 171 4.3.1. Cinnamyl anthranilate 171 4.3.2. trans-Cinnanlaldehyde 174 4.3.3. Conclusion 174 4.4. Genotoxicity studies 175 4.4.1. In vitro 175 4.4.2. In vivo 178 4.4.3. Conclusion 180 4.5. Other relevant studies 180 5. Recognition of GRASr status 181 6. Correction 181 References 181 1. Chemical identity 485,050 kg in the USA. (Lucas et aI., 1999; NAS, 1970; 1982; 1987) (see Table 1). Approximately 93% of the This summary presents the key data relevant to the total annual volume in the USA is accounted for solely safety evaluation of cinnamyl alcohol, cinnamaldehyde, by cinnamaldehyde (No. 22). Production volumes and cinnamic acid (trans-3-phenylpropenoic acid), and 53 intake values for each substance are reported in Table 1. structurally related substances for their intended use as Cinnamyl compounds are a fundamental part of plant flavoring substances (Table 1). All members of this biochemistry. trans-Cinnamic acid is ubiquitous in the group are primary alcohols, aldehydes, or carboxylic plant kingdom and is required for lignin formation in acids, or their corresponding esters and acetals. The plants. It is derived from the action of L-phenylalanine primary oxygenated functional group is located on a ammonia lyase upon L-phenylalanine, forming ammo three-carbon saturated or unsaturated (i.e~, at the 2,3 nia and cinnamic acid (Goodwin and Mercer, 1972). position) chain with a benzene ring at the 3 position Cinnamic acid is also converted to p-hydroxy cinnamic (i.e., a 3-phenylpropyl or 3-phenyl-2-propenyl group). acid (p-coumaric acid) by plants. p-Coumaric acid is one The aromatic ring also may be substituted with alkyl, of the more important precursors of lignins as it can be alkoxy, or hydroxy substituents. converted to polyphenolic alcohols which readily poly merize to form lignin (Goodwin and Mercer, 1972). Twenty-two of the 56 flavoring substances in this group 2. Exposure have been detected as natural components of traditional foods (Maarse et aI., 1999) (See Table 1). Quantitative 2.1. Flavor use and natural occurrence natural occurrence data have been reported for 3-phenyl propyl acetate (No.3), ethyl 3-phenylpropionate (No.9), The total annual volume of the 56 cinnamyl deriva cinnamyl alcohol (No. 12), cinnamaldehyde (No. 22), tives used as flavoring ingredients is approximately cinnamic acid (No. 23), methyl cinnamate (No. 24), and T.B. Adams et al.j Food and Chemical Toxicology 42 (2004) 157-185 159 Table 1 Identity and exposure data for cinnamyl derivatives used as flavor ingredients Flavoring ingredient FEMA CAS No. Most recent Daily per capita intake Annual volume in Consumption No. and structure annual volume, ("eaters only") naturally ratioC kga occurring foods, kgb Jlg/d Jlg/kg bw/d 122-97-4 2885 ~OH 1. 3-Phenyl-l-propanol 236 31 0.5 + NA 104-64-3 0 2. 3-Phenylpropyl formate 2895 ~oJlH 6d 0.02 NA 122-72-5 0 3. 3-Phenylpropyl acetate 2890 CJ~/'-O~ 68 9 0.1 140 2 I~ 122-74-7 0 4. 3-Phenylpropyl propionate 2897 ~O~ 2 0.3 0.005 + NA 103-58-2 0 5. 3-Phenylpropyl isobutyrate 2893 ~o~ 122 16 0.3 NA 5452-07-3 6. 3-Phenylpropyl isovalerate 2899 ~)l)" 0.5d 0.1 0.001 NA I h 6281-40-9 a 7. 3-Phenylpropyl hexanoate 2896 ~o~ 3d 0.5 0.008 NA I~ 103-25-3 0 d 8. Methyl 3-phenylpropionate 2741 ~O/'0 23 4 0.07 NA 2021-28-5 0 9. Ethyl 3-phenylpropionate 2455 ~O~ 0.5 0.06 0.001 47 94 I~ 104-53-0 0 10. 3-phenylpropionaldehyde 2887 145 19 0.3 + NA ~HI~ 501-52-0 0 II. 3-Phenylpropionic acid 2889 ~OH 4 0.5 0.008 + NA (continued on next page) 160 T.B. Adams et a/.j Food and Chemical Toxicology 42 (2004) 157-185 Table 1 (continued) Flavoring ingredient FEMA CAS No. Most recent Daily per capita intake Annual volume in Consumption No. and structure annual volume, ("eaters only") naturally ratioC kga occurring foods, kgb Ilg/d Ilg/kg bw/d 104-54-1 12. Cinnamyl alcohol 2294 ~OH 14651 1930 32 171 0.012 5660-60-6 0) 13. Cinnamaldehyde ethylene 2287 0.05 0.006 0.0001 NA glycol acetal ~O 104-65-4 0 14. Cinnamy1 fonnate 2299 ~o)lH 127 17 OJ NA 103-54-8 0 15. Cinnamyl acetate 2293 ~O~ 2250 296 + NA 103-56-0 0 16. Cinnamy1 propionate 2301 ~O~ 191 25 0.4 NA 103-61-7 0 17. Cinnamyl butyrate 2296 ~o~ 17 0.04 + NA 103-59-3 0 18. Cinnamyl isobutyrate 2297 ~o~ 163 22 0.4 NA 140-27-2 19. Cinnamyl isova1erate 2302 ~)U" 64 0.1 NA 5320-75-2 0 d 20. Cinnamyl benzoate ~o~ 5 0.01 NA 7492-65-1 21. Cinnamy1 pheny1acetate 2300 ~o)~~ 10 0.02 NA 1 0 104-55-2 0 22. Cinnama1dehyde 2286 ~H 450417 59328 989 38642 0.09 621-82-9 0 23. Cinnamic acid 2288 ~OH 331 44 0.7 183 T.B. Adams et al.j Food and Chemical Toxicology 42 (2004) 157-185 161 Table 1 (continued) Flavoring ingredient FEMA CAS No. Most recent Daily per capita intake Annual volume in Consumption No. and structure annual volume, (Heaters only") naturally ratioC k~ occurring foods, kgb ~g/d ~g/kg bw/d 103-26-4 0 24. Methyl cinnamate 2698 ~o/ 6305 830 14 57 0.009 103-36-6 0 25. Ethyl cinnamate 2430 ~o~ 481 63 292 7778-83-8 0 26.