GRAS Notice (GRN) No. 896 https://www.fda.gov/food/generally-recognized-safe-gras/gras-notice-inventory NOV 1 8 2019 OFFICE OF FOOD ADDITI\/t: SAFETY GENERALLY RECOGNIZED AS SAFE (GRAS) NOTIFICATION FOR ALPHA-GALACTO­ OLIGOSACCHARIDES (ALPHAGOS®) IN CONVENTIONAL FOODS AND BEVERAGES AND NON-EXEMPT INFANT FORMULAS Prepared for: Olygose Pare Technologique des Rives de l'Oise BP 50149, F-60201 Compiegne Cedex France Prepared by: Spherix Consulting Group, Inc. 11821 Parklawn Drive, Suite 310 Rockville, MD 20852 USA November 13, 2019 GRAS Notification for the Use of alpha-GOS November 13, 2019 Prepared for Olygose TABLE OF CONTENTS I. SIGNED STATEMENT OF THE CONCLUSION OF GENERALLY RECOGNIZED AS SAFE (GRAS) AND CERTIFICATION OF CONFORMITY TO 21 CFR §170.205-170.260 .... 1 A. SUBMISSION OF GRAS NOTICE .................................................................................1 B. NAME AND ADDRESS OF THE SPONSOR ................................................................1 C. COMMON OR USUAL NAME .......................................................................................1 D. TRADE SECRET OR CONFIDENTIAL INFORMATION ............................................1 E. INTENDED USE ..............................................................................................................1 F. BASIS FOR GRAS DETERMINATION .........................................................................1 G. PREMARKET APPROVAL ............................................................................................3 H. AVAILABILITY OF INFORMATION ...........................................................................3 I. FREEDOM OF INFORMATION ACT ............................................................................3 J. INFORMATION INCLUDED IN THE GRAS NOTIFICATION...................................3 II. IDENTITY, METHOD OF MANUFACTURE, SPECIFICATIONS, AND PHYSICAL OR TECHNICAL EFFECT OF THE NOTIFIED SUBSTANCE ........................................................ 4 A. COMMON OR USUAL NAME .......................................................................................4 B. TRADE NAME .................................................................................................................4 C. DESCRIPTION OF ALPHAGOS® .................................................................................4 1. Identity .......................................................................................................................... 4 2. Biochemical Characterization ....................................................................................... 5 D. PRODUCTION PROCESS ...............................................................................................6 1. Production of AlphaGOS® .......................................................................................... 6 2. Processing Facilities ..................................................................................................... 8 3. Raw Materials, Processing Aids, and Food Contact Substances .................................. 8 E. FINISHED PRODUCT SPECIFICATIONS AND OTHER QUALITY ATTRIBUTES 9 1. Product Specifications .................................................................................................. 9 2. Other Quality Attributes ............................................................................................. 12 F. STABILITY OF ALPHAGOS® .....................................................................................18 1. Stability of AlphaGOS® Powder and Syrup .............................................................. 18 III. DIETARY EXPOSURE ........................................................................................................ 21 A. INTENDED EFFECT .....................................................................................................21 B. HISTORY OF USE .........................................................................................................21 C. INTENDED USE ............................................................................................................22 -ii- SPHERIX CONSULTING GROUP, INC. GRAS Notification for the Use of alpha-GOS November 13, 2019 Prepared for Olygose D. ESTIMATED DAILY INTAKE .....................................................................................23 1. Food Consumption Survey Data................................................................................. 23 2. Food Usage ................................................................................................................. 25 IV. SELF-LIMITING LEVELS OF USE .................................................................................... 26 V. COMMON USE IN FOOD BEFORE 1958 ........................................................................... 27 VI. NARRATIVE ON THE CONCLUSION OF GRAS STATUS ............................................ 28 A. ABSORPTION, DISTRIBUTION, METABOLISM AND EXCRETION ....................29 B. GENOTOXICITY STUDIES .........................................................................................29 1. Bacterial Reverse Mutation (Ames) Test ................................................................... 30 2. In Vitro Chromosomal Aberration Test in Cultured Human Lymphocytes ............... 31 C. TOXICOLOGY STUDIES .............................................................................................36 1. Summary ..................................................................................................................... 36 2. Subchronic Toxicity of AlphaGOS® in Rats ............................................................. 36 3. Developmental Toxicity of AlphaGOS® in Piglets ................................................... 45 4. Corroborative Animal Studies with alpha-GOS ......................................................... 57 D. CLINICAL STUDIES .....................................................................................................60 1. AlphaGOS® ............................................................................................................... 60 2. Alpha-Linked Galacto-Oligosaccharides ................................................................... 75 E. ALLERGENICITY .........................................................................................................77 1. Summary ..................................................................................................................... 77 2. Residual Allergenicity of AlphaGOS® Compared to Dun Pea Protein ..................... 78 F. REGULATORY APPROVALS ACROSS THE WORLD ............................................81 VII. SUPPORTING DATA AND INFORMATION................................................................... 82 A. REFERENCES ................................................................................................................82 B. EXPERT PANEL STATEMENT ...................................................................................90 -iii- SPHERIX CONSULTING GROUP, INC. GRAS Notification for the Use of alpha-GOS November 13, 2019 Prepared for Olygose LIST OF TABLES Table 1. Alpha-Galacto-Oligosaccharide Content of AlphaGOS® ............................................... 5 Table 2. AlphaGOS® Processing Aids’ Regulatory Compliance ................................................. 9 Table 3. Specifications and Batch Analysis for AlphaGOS® Powder ........................................ 10 Table 4. Specifications and Batch Analysis for AlphaGOS® Syrup ........................................... 11 Table 5. Specific Oligosaccharide Content in AlphaGOS® Powder .......................................... 12 Table 6. Specific Oligosaccharide Content in AlphaGOS® Syrup ............................................. 12 Table 7. Wheat and Soy Proteins in AlphaGOS® ....................................................................... 13 Table 8. Mycotoxin Screen in AlphaGOS® Powder ................................................................... 14 Table 9. Dioxins and PCBs Screen in AlphaGOS® Powder ....................................................... 15 Table 10. Pesticides Not Detected in Two Batches of AlphaGOS® Powder .............................. 16 Table 11. Phenoxy Carboxylic Acids Screen in AlphaGOS® Powder, Shown as Totals After Hydrolysis ..................................................................................................................................... 17 Table 12. Perchlorate Screen in AlphaGOS® Powder ................................................................ 18 Table 13. Stability of AlphaGOS® Syrup ................................................................................... 19 Table 14. Stability of AlphaGOS® Powder ................................................................................ 20 Table 15. Foods Proposed To Contain AlphaGOS® ................................................................... 22 Table 16. Estimated “All-user” Daily Intake (EDI) of AlphaGOS® in Targeted Foods by Population Group (2013-2014 NHANES Data) ........................................................................... 25 Table 17. Results of Bacterial Reverse Mutation (Ames) Test When Exposed to AlphaGOS®, Direct Plate Incorporation Method ............................................................................................... 32 Table 18. Results of AlphaGOS® in the In Vitro Chromosome Aberration Test (Main Test) ... 35 Table 19. Mean Body Weight Change (g) in Rats Fed AlphaGOS®