Food and Chemical Toxicology 135 (2020) 110949 Contents lists available at ScienceDirect Food and Chemical Toxicology journal homepage: www.elsevier.com/locate/foodchemtox FEMA GRAS assessment of natural flavor complexes: Cinnamomum and T Myroxylon-derived flavoring ingredients Ivonne M.C.M. Rietjensa, Samuel M. Cohenb, Gerhard Eisenbrandc, Shoji Fukushimad, Nigel J. Gooderhame, F. Peter Guengerichf, Stephen S. Hechtg, Thomas J. Rosolh, ∗ Jeanne M. Davidseni, Christie L. Harmani, Ian J. Murrayi, Sean V. Taylori, a Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE Wageningen, The Netherlands b Havlik–Wall Professor of Oncology, Dept. of Pathology and Microbiology, University of Nebraska Medical Center, 983135 Nebraska Medical Center, Omaha, NE 68198- 3135 USA c Food Chemistry & Toxicology, Kühler Grund 48/1, 69126 Heidelberg, Germany d Japan Bioassay Research Center, 2445 Hirasawa, Hadano, Kanagawa 257-0015, Japan e Dept. of Metabolism, Digestion, Reproduction, Imperial College London, Sir Alexander Fleming Building, London SW7 2AZ, United Kingdom f Dept. of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146 USA g Masonic Cancer Center and Dept. of Laboratory Medicine and Pathology, University of Minnesota, MMC 806, 420 Delaware St., S.E., Minneapolis, MN 55455 USA h Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, 1 Ohio University, Athens, OH 45701 USA i Flavor and Extract Manufacturers Association, 1101 17th Street NW, Suite 700, Washington, DC 20036, USA ARTICLE INFO ABSTRACT Keywords: In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a program for Cinnamon and cassia essential oils and extracts the re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavor ingredients. This Balsam essential oil and extract publication, third in the series, considers NFCs composed primarily of constituents with the 3-phenyl-2-propenyl Natural flavor complex or a cinnamyl functional group, using the procedure outlined in 2005 and updated in 2018 to evaluate the safety GRAS of naturally-occurring mixtures for their intended use as flavor ingredients. The procedure relies on a complete Safety evaluation chemical characterization of the NFC intended for commerce and organization of each NFC's chemical con- stituents into well-defined congeneric groups. The safety of the NFC is evaluated using the well-established and conservative threshold of toxicological concern (TTC) concept in addition to data on absorption, metabolism and toxicology of members of the congeneric groups and the NFC under evaluation. Six NFCs from the Myroxylon and Cinnamomum genera, Balsam Oil, Peru (FEMA 2117), Tolu Balsam Extract (FEMA 3069), Cassia Bark Extract (FEMA 2257), Cassia Bark Oil (FEMA 2258), Cinnamon Bark Extract (FEMA 2290) and Cinnamon Bark Oil (FEMA 2291) were evaluated and affirmed as generally recognized as safe (GRAS) under their conditions of intended use as flavor ingredients. 1. Introduction A key part of the FEMA GRAS program is the cyclical re-evaluation of GRAS flavoring ingredients. Flavoring ingredients are generally di- For over five decades, the Expert Panel of the Flavor and Extract vided into two categories: chemically defined flavoring materials and Manufacturers Association (FEMA) has been the primary, independent natural flavor complexes (NFCs). NFCs are mixtures, often derived from body evaluating the safety of flavoring ingredients for use in human botanical sources that are used for flavoring food. The FEMA Expert foods in the United States. Flavor ingredients are evaluated for “gen- Panel has completed two re-evaluations of chemically defined flavor erally recognized as safe” (GRAS) status for intended use consistent ingredients and in 2015 expanded the re-evaluation program to en- with the 1958 Food Additive Amendment to the Federal Food Drug and compass FEMA GRAS NFCs and other relevant NFCs. A scientifically- Cosmetic Act. To date, the FEMA Expert Panel has determined that over based procedure was developed to assist in this determination via a 2,700 flavoring ingredients have met the GRAS criteria for their in- step-wise analysis of the chemical composition of the NFC (Smith et al., tended uses. 2005). Recently, this procedure has been reviewed and updated (Cohen ∗ Corresponding author. Scientific Secretary to the FEMA Expert Panel, Flavor and Extract Manufacturers Association, 1101 17th Street, N.W., Suite700, Washington, D.C, 20036, USA. E-mail address: [email protected] (S.V. Taylor). https://doi.org/10.1016/j.fct.2019.110949 Received 17 May 2019; Received in revised form 2 November 2019; Accepted 5 November 2019 Available online 18 November 2019 0278-6915/ © 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). I.M.C.M. Rietjens, et al. Food and Chemical Toxicology 135 (2020) 110949 Abbreviations GRAS Generally recognized as safe HPBL Human peripheral blood lymphocytes BfR Bundesinstitut für Risikobewertung (German Federal IFEAT International Federation of Essential Oils and Aroma Institute for Risk Assessment) Trades BMDL10 Lower confidence limit of the benchmark dose resulting in IOFI International Organization of the Flavor Industry a 10% extra cancer incidence JFFMA Japan Fragrance and Flavor Materials Association CA Chromosomal aberration MOE Margin of exposure CF Correction factor MoS Margin of safety CFR Code of federal regulations NFC Natural flavoring complex CHO Chinese hamster ovary (cells) NOAEL No observed adverse effect level DTC Decision tree class NTP National Toxicology Program EFFA European Flavour Association OECD Organization for Economic Co-Operation and EFSA European Food Safety Authority Development ERS/USDA Economic Research Service/United States Department PBBK Physiologically based biokinetic (model) of Agriculture PCI Per capita intake FDA Food and Drug Administration SCE Sister chromatid exchange FEMA Flavor and Extract Manufacturers Association TDI Tolerable daily intake FID Flame ionization detector TTC Threshold of toxicological concern GC-MS Gas chromatography-mass spectrometry WHO World Health Organization et al., 2018a). Because the constituents of NFCs are typically derived their inner bark, which when dried and ground into a fine powder, can from common biochemical pathways, the constituents can be organized give food both sweet and savory notes or be distilled to capture its into a finite number of well-established chemical groupings called essential oil. While the Cinnamomum family consists of over 300 spe- congeneric groups. For each NFC, information is gathered on estimated cies, historically the global trades have focused on only a few types of intake, absorption, metabolism and toxicology for each constituent this plant. The four most prominent Cinnamomum species originate congeneric group and evaluated as part of the safety evaluation. In from Southeast Asia and China. References to cinnamon date back to addition, rigorous consideration is given to the unidentified con- ancient Egyptian and Chinese civilizations (ASTA, 2002; Parry, 1969). stituents. NFCs have been grouped by similarity of their chemical Cinnamon is mentioned in the Bible several times and it is noted that composition or taxonomy to facilitate the re-evaluation of all the NFCs. Nero burned a year's worth of Rome's cinnamon stockpile upon the This procedure has previously been applied in the safety evaluation of death of his wife (Ravindran and Babu, 2004). Prior to the discovery of Citrus-derived NFCs (Cohen et al., 2019a) and mint, buchu, dill and naval shipping routes, cinnamon was transported by land through the caraway-derived NFCs (Cohen et al., 2019b). The chemical composition Middle East into Europe making the spice an expensive luxury in the of the NFCs in the group evaluated in the present paper is dominated by West (Coppen, 1995; Schivelbusch, 1992). During the Age of Explora- the presence of 3-phenyl-2-propenyl or cinnamyl constituents. tion (1500's – 1700's), Western European powers sought control of both In 2015, the FEMA Expert Panel issued a call for data requesting de- naval cinnamon trading routes and their lands of production as a means tailed chemical analysis for five cinnamyl NFCs. Members from the of revenue (Ravindran and Babu, 2004). Over time, cinnamon and International Organization of the Flavor Industry (IOFI), including FEMA, cassia became commodity items and are widely available worldwide. the Japan Fragrance and Flavor Materials Association (JFFMA), the There are two types of cinnamon available in food markets, “True European Flavour Association (EFFA), in addition to the International Cinnamon” and “Cassia”. While both are commonly known as cin- Federation of Essential Oils and Aroma Trades (IFEAT), provided data on namon, True Cinnamon (C. verum syn. C. zeylanicum) is native to Sri Cinnamomum-derived NFCs and Myroxylon-derived balsam oil of Peru Lanka (formerly Ceylon) and lighter in color and milder in taste than which are currently used for flavoring food and beverage products. A sixth Cassia cinnamons (ASTA, 2002, 2008). Sri Lanka remains the pre- NFC, tolu balsam extract, was included on a later call for data and was dominant producer of True Cinnamon (Ratwatte, 1991) and cinnamon classified into this cluster. These NFCs are listed in Table 1. bark essential oil. Cassia cinnamon normally refers to the