GRAS Notice (GRN) No. 931 https://www.fda.gov/food/generally-recognized-safe-gras/gras-notice-inventory Center for Regulatory Services, Inc. 5200 Wolf Run Shoals Road Woodbridge, VA 22192-5755 703 590 7337 (Fa\'. 703 580 8637) [email protected] consultants to the regulated industry March 5, 2020 Dr. Susan Carlson Director, Division of Biotechnology and GRAS Notice Review (HFS-255) Office of Food Additive Safety Center for Food Safety and Applied Nutrition Food and Drug Administration 5001 Campus Drive College Park, MD 20740 Dear Dr. Carlson: SUBJECT: Transmittal of the AlzChem Trostberg GmbH GRAS Notice for Creatine Monohydrate For use as source of Creatine Enclosed you will find the General Recognition of Safety Notice for Creatine Monohydrate as source of creatine in FDA regulated food as submitted by AlzChem Trostberg GmbH. I have provided a CD of the GRAS notice and all the cited references. Should you have any questions on this filing, please contact me, at your convenience. Sincerely,----- -------.... Kristi O. Smedley, Ph. Consultant to AlzChe Trostberg GmbH Attachments: AlzChem Trostberg GmbH GRN NARRATIVE of Notice ( Hard copy and CD-Copy) Appendices (within narrative file) (Hard Copy and CD-copy) Full Complement of References (CD-copy) cc: Barbara Niess, AlzChem CREAT NE MONOHYDRATE GRAS NOT F CAT ON Creatine monohydrate – Creapure® LIST OF CONTENTS LIST OF TABLES 1. INTRODUCTION AND CLAIM REGARDING GRAS STATUS ............ 4 A. Name and Address of Notifier ............................................................................... 4 B. Notifier’s US Representative.................................................................................. 4 C. Common or Usual Name of GRAS Substance ..................................................... 4 D. Intended Use............................................................................................................ 5 E. Statutory Basis for the Conclusion of GRAS status ............................................ 5 F. Exemption from Premarket Approval.................................................................. 5 G. Availability of Information.................................................................................... 5 H. Disclosure of Information...................................................................................... 6 I. Statement and signature.......................................................................................... 6 2. PRODUCT IDENTITY AND SPECIFICATION ........................................ 7 A. Identity..................................................................................................................... 7 B. Product Specification.............................................................................................. 8 C. Allergens.................................................................................................................. 9 D. Labeling, Storage and Stability Information ....................................................... 9 I. PURE SUBSTANCE ...................................................................................................... 9 II. STABILITY IN FOOD................................................................................................. 14 E. Manufacturing Process ........................................................................................ 15 3. CONDITIONS OF INTENDED USE IN FOOD AND DIETARY EXPOSURE.......................................................................................................... 17 A. Foods in which the Substance is to be Used ....................................................... 17 B. Creatine Monohydrate Intended Use.................................................................. 17 C. Dietary Intake Assessment................................................................................... 17 I. INTRODUCTION ........................................................................................................ 17 II. DAILY CONSUMPTION CALCULATION – MODELING CONSUMER EXPOSURE TO CREATINE...................................................................................................................... 18 III. RESULTS................................................................................................................ 19 IV. CONCLUSION......................................................................................................... 19 4. SELF-LIMITING LEVELS OF USE.......................................................... 21 5. EXPERIENCE BASED ON COMMON USE IN FOOD BEFORE 1958 22 6. CREATINE MONOHYDRATE SAFETY NARRATIVE ........................ 23 1 Creatine monohydrate – Creapure® A. Sources and function of creatine ......................................................................... 23 B. Metabolic fate of creatine..................................................................................... 24 C. Studies on the safety of creatine monohydrate .................................................. 25 I. INTENDED USE ........................................................................................................ 25 II. AVAILABILITY OF SAFETY STUDIES IN HUMANS...................................................... 26 III. EFFECT OF CREATINE MONOHYDRATE ON KIDNEY FUNCTION ................................ 26 1. Animal studies investigating creatine monohydrate intake and kidney function. 26 2. Human case studies investigating creatine intake and kidney function ............... 29 3. Intervention studies investigating creatine monohydrate and kidney function .... 32 IV. EFFECT OF CREATINE MONOHYDRATE ON LIVER FUNCTION................................... 35 1. Animal studies investigating creatine monohydrate intake and liver function .... 35 2. Human studies investigating creatine intake and liver function........................... 36 V. OTHER POTENTIAL ADVERSE EFFECTS OF CREATINE MONOHYDRATE ..................... 38 1. Dehydration, weight gain, cramps, gastrointestinal upset .................................... 38 2. Down regulation of creatine transporter and endogenous creatine formation...... 39 3. Formation of methylguanidine ............................................................................. 39 4. Formation of methylamine and formaldehyde ..................................................... 40 5. Formation of heterocyclic amines ........................................................................ 42 D. Toxicological Studies ............................................................................................ 47 E. Dietary upper safe level for creatine intake ....................................................... 49 F. Allergenicity........................................................................................................... 49 G. Quality of the Substance ...................................................................................... 50 H. Specific jurisdiction’s regulatory status of creatine monohydrate.................. 52 I. Risk assessments of creatine monohydrate by governmental scientific bodies 53 J. Conclusions on the safety of use of creatine monohydrate in food ................... 55 7. PUBLICATION BIBLIOGRAPHY ............................................................ 58 ANNEX 1: CERTIFICATES OF ANALYSIS FOR CREAPURE® CREATINE MONOHYDRATE......................................................................... 76 ANNEX 2: POTENTIAL EXPOSURES TO CREATINE FOR AMERICAN CONSUMERS ...................................................................................................... 83 2 Creatine monohydrate – Creapure® List of Tables Table 1: Properties of creatine monohydrate (CAS: 6020-87-7) ........................................ 7 Table 2: Product specification of Creapure® ...................................................................... 8 Table 3: Periodic controls for Creapure® ............................................................................ 8 Table 4: Labeling declaration, storage conditions and shelf-life for Creapure® ................. 9 Table 5: Stability test with three lots of Creapure® at 25 °C / 60 % r.h. .......................... 10 Table 6: Stability test with three lots of Creapure® at 40 °C / 75 % r.h. .......................... 11 Table 7: Stability tests for Creapure® at 25 °C / 60 % - results of microbiology testing . 12 Table 8: Stability testing of Creapure® at 40 °C / 75 r. h. – results of microbiology testing ........................................................................................................................................... 13 Table 9: Analysis of six retained samples of Creapure® stored for approx. 6 years......... 14 Table 10: List of food categories ...................................................................................... 18 Table 11: Intakes of creatine from natural sources plus the addition of 1 g (corresponds to 1.12 g creatine monohydrate) per portion to selected foods. ............................................ 19 Table 12: The body’s own creatine pool ........................................................................... 24 Table 13: Case reports linking creatine use to renal dysfunction ..................................... 29 Table 14: Summary of short- and long-term human safety trials with creatine monohydrate ..................................................................................................................... 43 Table 15: Estimated intakes of impurities from Creapure® creatine monohydrate