GRAS Notice (GRN) No. 902 https://www.fda.gov/food/generally-recognized-safe-gras/gras-notice-inventory Al AIBMR Life Sciences, Inc. December 17, 2019 Susan Carlson, PhD Division Director Division of Biotechnology and GRAS Notice Review Office of Food Additive Safety (HFS-200) Center for Food Safety and Applied Nutrition Food and Drug Administration Department of Health and Human Services 5001 Campus Drive College Park, MD 207 40 Dear Dr. Carlson: In accordance with regulation 21 CFR Part 170 Subpart E (Generally Recognized as Safe (GRAS) Notice), on behalf ofHealthTech BioActives, S.L.U. (the notifier), the undersigned, Kayla Preece, submits, for FDA review, the enclosed notice that neohesperidin dihydrochalcone is GRAS for use in foods. Should you have any questions or concerns regarding this notice, please contact me at 253-286-2888 or [email protected]. Sincerely, Kayla Preece (agent of the notifier) Scientific and Regulatory Consultant AIBMR Life Sciences, Inc. ("AIBMR") JAN 8 2020 OFFICE OF , FOOD ADDITIVE SAF~fY Neohesperidin dihydrochalcone GRAS 2 #902 Notice to US Food and Drug Administration of the Conclusion that the Intended Use of Neohesperidin dihydrochalcone is Generally Recognized as Safe Submitted by the Notifier: HealthTech BioActives, S.L.U. Ctra. Beniel a Zeneta, 143-145 El Raiguero-La Villa 30130 Beniel (Murcia) Spain Prepared by the Agent of the Notifier: AIBMR Life Sciences, Inc. 2800 E. Madison, Suite 202 Seattle WA 98112 � December 17, 2019 ��(C �'¥7�(Q) JAN 8 2020 OFFICE OF FOOD ADDITIVE SAFETY ~• ,.1BMR Life Sciences, Inc. Table of Contents Part 1: Signed Statements and Certification ............................................................ 6 1.1 Submission of GRAS Notice .......................................................................... 6 1.2 Name and Address of the Notifier and Agent of the Notifier ........................ 6 1.3 Name of the Substance ................................................................................... 6 1.4 Intended Conditions of Use ............................................................................ 6 1.5 Statutory Basis for GRAS Conclusion ........................................................... 7 1.6 Not Subject to Premarket Approval ............................................................... 7 1. 7 Data and Information Availability Statement ................................................ 7 1.8 Exemption from Disclosure under the Freedom of Information Act ............. 7 1.9 Certification of Completion ........................................................................... 8 Part 2: Identity, Manufacture, Specifications, and Physical or Technical Effect .... 9 2.1 Identification .................................................................................................. 9 2.1.1 Sweetness ............................................................................................... 10 2.2 Manufacturing .............................................................................................. 10 2.2.1 Manufacturing Overview ....................................................................... 10 2.2.2 Good Manufacturing Practice ................................................................ 12 2.2.3 Raw Materials ........................................................................................ 12 2.3 Specifications ............................................................................................... 12 2.3 .1 Batch Analysis ....................................................................................... 14 2.3.2 Impurities ............................................................................................... 15 2.3.3 Residual Solvent Analysis ..................................................................... 18 2.3.4 Residual Contaminant Analysis ............................................................. 18 2.3 .5 Residual Pesticide Analysis ................................................................... 18 2.3.6 Heavy Metal Analysis ........................................................................... 18 2.3.7 Shelf-Life Stability ................................................................................ 19 2.4 Physical or Technical Effect ........................................................................ 21 Part 3: Dietary Exposure ........................................................................................ 22 3 .1 Intended Use ................................................................................................. 22 3 .2 Exposure Estimates ...................................................................................... 23 Part 4: Self-limiting Levels of Use ........................................................................ 27 Part 5: Experience Based on Common Use in Food Prior to 1958 ........................ 28 Part 6: Narrative ..................................................................................................... 29 6.1 Absorption, distribution, metabolism, and excretion (ADME) .................... 29 6.2 Toxicology Studies ....................................................................................... 31 6.2.1 Bacterial Reverse Mutation Test ........................................................... 31 6.2.2 Jn vitro Mammalian Chromosomal Aberration Test ............................. 31 6.2.3 In vivo Mammalian Micronucleus Test ................................................. 31 6.2.4 Genotoxicity Summary .......................................................................... 32 6.2.5 Ninety-day Repeated-Dose Oral Toxicity Study ................................... 33 Neohesperidin dihydrochalcone GRAS 3 .A:.~ AIBMR Life Sciences, Inc. 6.2.6 Summary of Sub-chronic Trials ............................................................ 36 6.2.7 Chronic studies ...................................................................................... 37 6.2.8 Carcinogenicity Study ........................................................................... 37 6.2.9 Reproductive and Developmental Toxicity Studies .............................. 39 6.2.10 Summary of Chronic, Carcinogenicity, Reproductive and Developmental Toxicity Studies .................................................................... 40 6.3 Additional Scientific Studies ........................................................................ 42 6.3.1 Human Studies ....................................................................................... 42 6.4 Authoritative Safety Opinions ...................................................................... 42 6.4.1 Select Committee on GRAS Substances ............................................... 42 6.4.2 European Food Safety Authority ........................................................... 42 6.4.3 World Health Organization ................................................................... 42 6.4.4 United States .......................................................................................... 42 6.5 Allergenicity ................................................................................................. 43 6.6 Past Sales and Reported Adverse Events ..................................................... 43 6.7 Basis for the GRAS Conclusion ................................................................... 43 6. 7 .1 Data and Information that Establish Safety ........................................... 44 6. 7 .2 Data and Information that is Corroborative of Safety ........................... 45 6. 7.3 General Recognition .............................................................................. 45 6.8 Data and Information that are Inconsistent with the GRAS Conclusion ..... 45 6.9 Information that is Exempt from Disclosure under FOIA ........................... 46 Part 7: Supporting Data and Information ............................................................... 4 7 7 .1 Data and Information that are not Generally Available ............................... 4 7 7 .2 References that are Generally Available ...................................................... 4 7 Neohesperidin dihydrochalcone GRAS 4 ~I. ,.IBMR Life Sciences, Inc. Figures and Tables Figure 1. Neohesperidin dihydrochalcone1 ................................................. ..................... 9 Figure 2: Neohesperidin13 •••• : .•••.....•••••••••••••••••...•••••••....•••••••••• •••••••••.•• • •••..•..••••••..•••••.•••• 11 Figure 3. Manufacturing Flowchart ................................................................................. 12 Table 1. NHDC Specifications ........................................................................................ 13 Table 2. NHDC Batch Analyses ..................................................................................... 14 Table 3: Impurities Detected in 67 Independent Batches of NHDC ............................... 17 Table 4. NHDC Heavy Metal Analysis ............................................................................ 19 Table 5. Real-Time Stability Study ................................................................................. 20 Table 6. Accelerated Stability Study (Irradiation Time= 12 hours) ................................ 21 Table 7. Intended use of NHDC ..................................................................................... 22 Table 8. Total (aggregate) absolute exposure to NHDC by proposed use food consumers using NHANES 2015-16 data ....................................................... 24