GRAS Notice (GRN) No. 726 https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/default.htm DSM DSM Nutritional Products Regulatory Affairs 45 Waterview Boulevard Parsippany, NJ 07054 United States of America August 15, 2017 Office of Food Additive Safety (HFS-200), Center for Food Safety and Applied Nutrition, Food and Drug Administration, 5001 Campus Drive, College Park, MD 20740. Subject: GRAS Notification - elaVida ™ To whom it may concern: DSM Nutritional Products LLC is submitting for FDA review a GRAS notification. The enclosed document provides notice of a claim that the food ingredient elaVida TM, which is a polyphenol-rich preparation derived from olive fruits, described in the enclosed notification, is exempt from the premarket approval requirement of the Federal Food, Drug, and Cosmetic Act because it has been determined to be generally recognized as safe (GRAS) based on scientific procedures. If you have any questions or require additional information, please do not hesitate to contact the undersigned at your convenience. Sincerely yours, (b) (6) Georges Bergen (Primary Contact) Senior Manager, Regulatory Affairs DSM Nutritional Products LLC Human Nutrition & Health Ph (973) 257-8366 e-mail: [email protected] {R1~~~~~~[Q) AUG ·1 7 2017 OFFI' '=OF fOOD ~.DOI .i-f SAFETY HEALTH • NUTRITION • MATERIALS Summary of Information Supporting the Generally Recognized As Safe (GRAS) Status of elaVida™ (A Polyphenol Preparation From Olive Fruits) for Use as an Ingredient in Selected Foods - Final ­ Prepared for: DSM Nutritional Products, LLC 45 Waterview Boulevard Parsippany, New Jersey 07054 August 15, 2017 Summary of Information Supporting the Generally Recognized As Safe (GRAS) Status of elaVida™ (A Polyphenol Preparation From Olive Fruits) for Use as an Ingredient in Selected Foods Table of Contents Page 1.0 STATEMENTS AND CERTIFICATION .............................................................................7 1.1 Compliance with 21 C.F.R. § 170.30..............................................................................7 1.2 Name and Address of Notifier ........................................................................................7 1.3 Name and Address of Manufacturer ...............................................................................7 1.4 Name and Address of Exclusive Distributor ...................................................................7 1.5 Name of the Notified Substance .....................................................................................8 1.6 Intended Conditions of Use and Technical Effects of the Notified Substance ................8 1.7 Basis for GRAS Determination .......................................................................................8 1.8 Exemption from Premarket Approval ..............................................................................9 1.9 Availability of Information for FDA Review .....................................................................9 1.10 Copying .......................................................................................................................... 9 1.11 Accessibility to Raw Data ...............................................................................................9 1.12 Exemption From Disclosure ...........................................................................................9 1.13 Certification................................................................................................................... 10 2.0 Identity, Method of Manufacture, Specifications, and Physical or Technical Effect 11 2.1 Identity: elaVida™ (A Polyphenol Preparation From Olive Fruits) ................................11 2.2 Manufacturing and Specifications .................................................................................12 2.2.1 Manufacturing ........................................................................................................... 12 2.2.2 Specifications and Analyses .....................................................................................16 2.3 Compositional analysis of elaVida™ ............................................................................18 2.3.1 Methods .................................................................................................................... 18 2.3.2 Analytical results ....................................................................................................... 18 2.3.3 Other phenols ........................................................................................................... 20 2.4 Stability ......................................................................................................................... 23 2 2.5 Acrylamide .................................................................................................................... 23 2.6 Polyaromatic Hydrocarbons .........................................................................................24 2.7 Physical or Technical Effect .........................................................................................25 3.0 Intended Food Uses and Projected Dietary Exposure................................................26 3.1 Proposed food uses......................................................................................................26 3.2 Available data and methods .........................................................................................28 3.2.1 Consumption data .....................................................................................................28 3.2.2 Existing dietary sources ............................................................................................29 Table 3-2: Average hydroxytyrosol concentration of olives and olive oila ............................30 3.2.3 Dietary supplement uses ..........................................................................................30 3.2.4 Analysis.....................................................................................................................32 3.3 Results.......................................................................................................................... 33 3.2.1 Existing Dietary Exposure.........................................................................................33 3.3.2 Proposed uses ..........................................................................................................33 3.3.3 Cumulative estimated intake of hydroxytyrosol .........................................................35 4.0 SELF LIMITING LEVELS OF USE ..................................................................................38 5.0 EXPERIENCE BASED ON COMMON USE IN FOOD BEFORE 1958 ...........................39 5.1 Scientific Procedures ....................................................................................................39 5.2 Natural occurrence and benefit ....................................................................................39 6.0 NARRATIVE SAFETY .....................................................................................................41 6.1 Forms of olive extract or hydroxytyrosol tested for safety ............................................41 6.2 Absorption, Distribution, Metabolism and Excretion (ADME) of polyphenols focused on hydroxytyrosol ......................................................................................................................... 42 6.2.1 Summary of published ADME data of hydroxytyrosol in mammals ..........................42 6.2.2 Potential drug interactions ........................................................................................45 6.2.3 Plasma data from safety studies ...............................................................................45 6.3 Toxicology studies with olive extracts and hydroxytyrosol ...........................................46 6.3.1 Acute toxicity studies ................................................................................................46 6.3.2 Repeat Dose Toxicity................................................................................................48 6.3.3 Pivotal Subchronic Toxicity Studies ..........................................................................52 6.3.4 Genotoxicity / Mutagenicity ...................................................................................67 6.3.5 Carcinogenicity ......................................................................................................... 78 6.3.6 Reproduction Toxicity ...............................................................................................79 3 6.4 Human Safety Data ......................................................................................................83 6.4.1 Human data .............................................................................................................. 83 6.4.2 Olive oil and polyphenol content ...............................................................................84 6.4.3 Olive extracts ............................................................................................................ 84 6.4.4 Pure hydroxytyrosol ..................................................................................................86 6.5 Safety Summary and Acceptable Daily Intake (ADI) ....................................................86 7.0 LIST OF SUPPORTING DATA AND INFORMATION .....................................................88 APPENDIX