GRAS Notice (GRN) No. 889 https://www.fda.gov/food/generally-recognized-safe-gras/gras-notice-inventory Longevity Labs o IT'S NATURAL ID" BE HEAiJHY. September 23rd, 2019 Office of Food Additive Safety (HFS-200) Center for Food Safety and Applied Nutrition Food and Drug Administration Att.: Ms. Szablna Stice 5001 campus Drive College Park, MD, 20740-3835 Subject: GRAS Notification for spermidlne rich wheat germ extract (SpermldineUfe•) Dear Ms. Stice! In accordance with 21 CFR 170 subpart E, (81 FR 54960; August 17, 2016), TlL The Longevity Labs GmbH, Austria, through The Executive Consulting INC., USA as its organizer hereby provides notice of a claim that the food ingredientuspermidine rich wheat germ extract• as a nutrient described in the enclosed notification document 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. We would kindly ask you to only have the redacted version of the notification document published. Some slight redactions have been made due to European privacy laws, as it's unlawful to disclose personal information (including names and other personal data). Other redactions apply to some numbers of production batches which were analyzed; knowing these numbers can reveal the applied processes to competitors. However, neither the redaction of the names nor the redaction of the batch numbers affect the overall statement and conclusion of the analyses reports and/or the notification document in any kind. For additional questions or required additional information, please feel free to contact us or our contact In US, Ms. Barbara Boedenauer by phone at +1 (404)388-9870 or by E-mail at [email protected]. Sincerely, TU 1be Longevity labs GmbH I ICratliystrasse 2 I 8020 Graz I Austria I offlcetpthelongevitylabs.com I www.thelongevltyl;ibs.com Sitz der Gesellschilft: Gm I Flrmenbuchnummer: FN 457279 w I Finnenbudlgeric:ht: H;indelsgeric:ht Gr;iz I UID-Nr. ATU71339848 BilnMrblndung: Riliffelsen-Landesb;ink Stelermart AG ( IBAN: AT57 3800 0000 0021 8347 IBIC: RZSTAT2G GENERALLY RECOGNIZED AS SAFE (GRAS) ASSESSMENT OF A SPERMIDINE RICH WHEAT GERM EXTRACT Submitted by: TLL The Longevity Labs GmbH 8010 Graz AUSTRIA Submitted to: U.S. Food and Drug Administration Center for Food Safety and Applied Nutrition Office of Food Additive Safety HFS-200 5100 Paint Branch Parkway College Park, MD 20740-3835 USA Contact for Inquiries in USA Baerbel Boedenauer The Executive Consulting, Inc. 410 Peachtree Pkwy 400. Suite 4245 Cumming, GA 30041 23rd of September, 2019 TLL Page I of 46 Wheat germ extract - GRAS GENERALLY RECOGNIZED AS SAFE (GRAS) ASSESSMENT OF SPERMIDINE RICH WHEAT GERM EXTRACT TABLE OF CONTENTS 1. Part 1-SIGNED STATEMENTS AND CERTIFICATION .. ........................................ ..................... 4 1.1. Basis of Conclusion .. .... ..... .. ... ... .. .. .... .... .................... .. ........................... ...................... .......... ... 4 1.2. Name and Address of Notifier ........................................... ....... .... .. ... .... ................................... 4 1.3. Name of Notified Substance ........................ .. ............................ ............................................... 4 1.4. Intended Conditions of Use ............................................................ .. ..................... .. ................. 4 1.5. Statutory Basis for GRAS Determination .. ... .................................................................. ........... 4 1.6. Exclusion from Premarket Approval .... .... ............................. ................................. ................... 4 1.7. Availability of Data & Information ............................. ............................................................... 4 1.8. Data Exemption from Disclosure .... .. .............. ...... .. .. ................... ............................. ... .. ... ........ 5 1.9. Certification ........................ ................. .. ...... ..................... ...................... ............ ...................... 5 1.10. Name, Position/Title of Responsible Person who Signs the Dossier and Signature ................ .S 1.11. FSIS/USDA - Use in Meat and/or Poultry .......................................... ... .............................. ...... 5 2. Part 2 - IDENTITY, SPECIFICATION, MANUFACTURING AND TECHNICAL EFFECTS ..... ............ 6 2.1. Identity ....... .............................................. ......................... ....................... .. ....................... ........ 6 2.1.1. Description ........................................................... ..................... ...................... ........................ .. 6 2.1.2. Taxonomy of Botanical Source ... ... ............... ............................................................................ 6 2.1.3. Origin of wheat germ ........................ .......................... ......................... ..................................... 7 2.2. Specifications .................................. ....... ................... ....... ......................................................... 8 2.3. Spermidine as a substance ........................................................... ................... ... .................... 14 2.4. Manufacturing Process .. ................. .. .......... .......................................................... ................. 14 2.4. Technical Effects ............................... ................................................... ..... ............................. 16 3. Part 3 - DIETARY EXPOSURE ....................................................... .......... .. ....................... .. ...... 17 3.1. Background, Intended Use Levels and Food Categories ........................................................ 17 3.1.1. Estimated Daily Intake from the Intended Uses .. .................... .............................................. 17 4. Part 4-SELF LIMITING LEVELS OF USE ....................... .................................................. ........ 19 5. Part 5 - EXPERIENCE BASED ON COMMON USE IN FOODS BEFORE 1958 .. .............. ............ 19 6. Part 6- NARRATIVE ................................. .... ............................. ... ......................... ................ 21 6.1. Traditional and Current Uses of Wheat ........................................................................... ...... 21 6.1.1. Current Uses of Wheat Germ and Wheat Germ Products .............. .. .................................... 22 6.1.1.1. Common Knowledge of Safe Use of Wheat ........................................ ......... ..................... 23 6.1 .1.2. Nutritional Value of wheat ............. .............. ... .. .................... .. .... .... ............. ..................... 23 6.1.1.3. Nutritional Value of wheat germ .. .. ......................................... .......................................... 24 TLL Page 2 of 46 Wheat germ extract- GRAS 6.2. Safety Related Studies ................... .. ........................ ............................... .................... ........... 26 6.2.1. Human Studies of wheat germ extracts and products ................................ ................... ... .... 26 6.2.2. Animal Studies of wheat germ extracts and products ..................................... ... ... ................ 29 6.2.3. Safety of high levels of spermidine from animal studies ............. ... ............. .......................... 33 6.2.4. NOAH from toxicological studies in animals ........ ....................................................... .......... 34 6.2.5. Safety issues on polyamine catabolism .. .. .. ........................................................................... 36 6.2.5.1. Toxicity of DAO products .... .. ... ..... ................................ ..................................................... 36 6.2.5.2. Toxicity of Acrolein ................. .. .. .................................................. ........................ .. .. ........ 36 6.2.6. Benzoxazinones ........................................... .............. .. .................... ........ ...................... .. ....... 37 6.2.7. Polyamines and cancer ........................................................ .................................................. 37 6.2.8. Safety of wheat germ lectins ............................ ........................ ............... ... .... ....................... 38 6.3. Expert Panel Review, Summary and Discussion .. .... ... .................. .. ....... .. ............. ..... .. .. ........ 39 6.4. Expert Panel Conclusion ...................... ..... ..................... ... ... .... ...................................... ........ 41 7. Part 7 - SUPPORTING DATA AND INFORMATION ............ .. .. .. ..................... ..................... ..... 42 8. APPENDICES .. ........................... .... ................... ................................................ ....................... 46 Appendix I: Spermidinelife® Specifications (TLL) ........................................ ............................ .............. 46 Appendix II: Wheat Germ Specifications (HOCHDORF) ...................... .................... .............................. 46 Appendix Ill: EFSA approval of spermidine-rich wheat germ extract .................... ..... .......................... 46 Appendix IV: Analytical