GRAS Notice (GRN) No. 903 https://www.fda.gov/food/generally-recognized-safe-gras/gras-notice-inventory NATUREX• part of Givaudan 'fR1@CG~nill~(jJ) 07 January 2020 JAN 1 5 2020 Dr. Paulette Gaynor FOOD OF, ,Li,; UF L ADDITIVE SAFETY Office of Food Additive Safety (HFS-200) __J Center for Food Safety and Applied Nutrition (CFSAN) Food and Drug Administration 5001 Campus Drive College Park, MD 20740 USA Dear Dr. Gaynor: Re: GRAS Notice for Qulllaia Extract Type 2 In accordance with 21 CFR §170 Subpart E consisting of§§ 170.203 through 170.285, Naturex SA (250 rue Pierre Bayle, BP 81218 - 84911, Avignon, Cedex 9, France], as the notifier, is submitting one hard copy and one electronic copy (on CD) of the GRAS Notice for quillaia extract type 2, containing all data and lnfonnation supporting the company's conclusion that quillaia extract type 2 is GRAS on the basis of scientific procedures, for use in specified conventional food and beverage products across multiple categories; these food uses of quillaia extract type 2 are therefore not subject to the premarket approval requirements of the Federal Food, Drug and Cosmetic Act. Information setting forth the basis for Naturex's GRAS conclusion, as well as a consensus opinion of an independent panel of experts, also are enclosed for review by the agency. I certify that the enclosed electronic files were scanned for viruses prior to submission and are thus certified as being virus-free using Symantec Endpoint Protection 12.1.4. Should you have any questions or concerns regarding this GRAS Notice, please do not hesitate to contact me at any point during the review process so that we may provide a response in a timely manner. Yours sincerely______ _ Coralle Chakour Regulatory Affairs Manager NaturexSA Naturex SA- 250 rue Pierre Bayle - BP 8121~ • 84911 Avignon Cedex 9 • France SA au capital de 14.371.089 €·RCS Avignon B 384 093 563 Tel: +33 {0)4 90 23 96 89 •Fax: +33 (0)4 90 23 73 40 - E-mail:[email protected] GRAS NOTICE FOR THE USE OF QUILLAIA EXTRACT TYPE 2 IN FOOD SUBMITTED TO: Office of Food Additive Safety (HFS-200) Center for Food Safety and Applied Nutrition (CFSAN) Food and Drug Administration 5001 Campus Drive College Park, MD 20740 USA SUBMITTED BY: Naturex SA 250 rue Pierre Bayle BP 81218 ‐ 84911 Avignon, Cedex 9 France DATE: 07 January 2020 GRAS Notice for the Use of Quillaia Extract Type 2 in Food TABLE OF CONTENTS PART 1. §170.225 SIGNED STATEMENTS AND CERTIFICATION ........................................................................... 4 1.1 Name and Address of Notifier .................................................................................................. 4 1.2 Common Name of Notified Substance ..................................................................................... 4 1.3 Conditions of Use ...................................................................................................................... 5 1.4 Basis for GRAS ........................................................................................................................... 6 1.5 Availability of Information ........................................................................................................ 6 1.6 Freedom of Information Act, 5 U.S.C. 552 ................................................................................ 6 PART 2. §170.230 IDENTITY, METHOD OF MANUFACTURE, SPECIFICATIONS, AND PHYSICAL OR TECHNICAL EFFECT ................................................................................................................................. 7 2.1 Identity ...................................................................................................................................... 7 2.1.1 Common or Usual Names and Synonyms .................................................................... 7 2.1.2 Chemical Abstract Service (CAS) Number .................................................................... 7 2.1.3 Other Identification Numbers ...................................................................................... 7 2.1.4 Botanical Source .......................................................................................................... 7 2.1.5 Chemical and Physical Characteristics ......................................................................... 8 2.1.6 Chemical Structure of Quillaia Saponins ...................................................................... 8 2.2 Manufacturing ........................................................................................................................ 10 2.2.1 Raw Materials, Processing Aids, and Additives ......................................................... 10 2.2.2 Manufacturing Process .............................................................................................. 10 2.3 Product Specifications and Batch Analyses ............................................................................ 12 2.3.1 Specifications ............................................................................................................. 12 2.3.2 Batch Analysis ............................................................................................................ 13 2.3.3 Additional Chemical Characterization ....................................................................... 16 2.4 Stability Data ........................................................................................................................... 17 PART 3. §170.235 DIETARY EXPOSURE ............................................................................................................. 18 3.1 Current Regulatory Status ...................................................................................................... 18 3.2 Estimated Intake of Quillaia Extract Type 2 and Saponins from Permitted and Proposed Uses ........................................................................................................................ 20 3.2.1 Methods ..................................................................................................................... 20 3.2.2 Estimated Intakes of Saponins from Permitted Uses of Quillaia Extract Type 1 and Proposed Uses of Quillaia Extract Type 2 ............................................... 21 3.2.3 Estimated Intakes of Quillaia Extract Type 2 from Proposed Uses............................ 23 3.2.4 Summary and Conclusions ......................................................................................... 24 PART 4. §170.240 SELF-LIMITING LEVELS OF USE ............................................................................................. 25 PART 5. §170.245 EXPERIENCE BASED ON COMMON USE IN FOOD BEFORE 1958 ......................................... 25 Naturex SA 07 January 2020 1 PART 6. §170.250 NARRATIVE AND SAFETY INFORMATION ............................................................................. 25 6.1 Introduction ............................................................................................................................ 25 6.2 Safety Assessments by Regulatory Bodies and Expert Panels ................................................ 26 6.2.1 Joint FAO/WHO Expert Committee on Food Additives (JECFA) ................................ 26 6.2.2 European Union ......................................................................................................... 28 6.3 Absorption, Distribution, Metabolism and Excretion ............................................................. 29 6.3.1 Gastrointestinal Metabolism of Related Saponins .................................................... 29 6.3.2 Absorption of Related Saponins ................................................................................ 31 6.4 Toxicological Studies ............................................................................................................... 32 6.4.1 Acute Toxicity............................................................................................................. 32 6.4.2 Repeat-Dose Toxicity ................................................................................................. 33 6.4.3 Mutagenicity and Genotoxicity ................................................................................. 40 6.4.4 Other Studies of Toxicity ............................................................................................ 43 6.5 Human Studies ........................................................................................................................ 44 6.6 Allergenicity ............................................................................................................................ 45 6.7 Quillaia Extracts and Bile Metabolism .................................................................................... 46 6.8 GRAS Panel Evaluation ............................................................................................................ 48 6.9 Conclusion ............................................................................................................................... 49 PART 7. §170.255 LIST OF SUPPORTING DATA AND INFORMATION ................................................................ 50 List of Appendices Appendix A Summary of Genotoxicity Study Results Appendix B GRAS Panel Statement List of Figures and Tables Figure 2.1.6-1 Chemical Structure of Quillaia Saponins ................................................................................... 9 Figure 2.2.2-1 Schematic Overview of the Manufacturing