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(GRN) 960, Hypromellose Acetate Succinate

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(GRN) 960, Hypromellose Acetate Succinate GRAS Notice (GRN) No. 960 https://www.fda.gov/food/generally-recognized-safe-gras/gras-notice-inventory ff~ AIBMR Life Sciences Inc. June 18, 2020 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 20740 Dear Dr. Carlson: In accordance with regulation 21 CFR Part 170 Subpart E (Generally Recognized as Safe (GRAS) Notice), on behalf of Shin-Etsu Chemical Co. , Ltd. (the notifier), the undersigned, Timothy Murbach, submits, for FDA review, the enclosed notice that Shin-Etsu AQOAT®, Hypromellose Acetate Succinate (HPMCAS) 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, Timothy Murbach, ND, DABT (agent of the notifier) Senior Scientific & Regulatory Consultant AIBMR Life Sciences, Inc. ("AIBMR") Shin-Etsu AQOA1'1ll, hypromellose acetate succinate (HPMCAS), GRAS Notice 2 Notice to US Food and Drug Administration of the Conclusion that the Intended Use of Shin-Etsu AQOAT® Hypromellose Acetate Succinate (HPMCAS) is Generally Recognized as Safe Submitted by the Notifier: Shin-Etsu Chemical Co., Ltd. Prepared by the Agent of the Notifier: AIBMR Life Sciences, Inc 1425 Broadway, Suite 458 Seattle, WA 98122 June 18, 2020 ,lAIBMR 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 ............................................................................ 7 1.5 Statutory Basis for GRAS Conclusion .................... ........................................ ? 1.6 Not Subject to Premarket approval ................................................................. 7 1.7 Data and Information Availability Statement. ................................................ 8 1.8 Exemption from Disclosure under the Freedom of Information Act.. ... ......... 8 1.9 Certification of Completion .......... ... ... ............................. ..... .. ........................ 8 Part 2: Identity, Manufacture, Specifications, and Physical or Technical Effect.. ... 9 2.1 Identification ................................................................................................... 9 2.2 Manufacturing ................................... ..... ....................................................... I 0 2.2 .1 Manufactu1ing Overview .. ............... ...................................................... 10 2.2.2 Good Manufacturing Practice ................................................................ 11 2.2.3 Raw Materials ............................. .. .................... .. .... ...................... .. ....... 11 2.3 Specifications .. ............. ................. .... .. ... .... .... ........... .. .... .. .. ...................... .... 11 2.3 .1 Batch Analysis ........................................................................................ 12 2.3.2 Residual Solvent Analysis ............... .................................................... ... 13 2.3.3 Heavy Metal Analysis ................................................ ............................ 13 2.3 .4 Shelf- Life Stability ................................................................................ 13 2.4 Physical or Technical Effect ... .. ................................................ .................... 14 2.4.1 Technical Element .................................................................................. 14 Part 3: Dietary Exposure ......................................................................................... 15 3.1 Intended Use ......................................................................................... .. ...... 15 3 .2 Estimated Daily Intake (ED !)-Exposure ............................ .. ...................... 15 Part 4: Self-limiting Levels of Use ................ .................... .. ...... .. ........................... 19 Part 5: Experience Based on Common Use in Food Prior to 1958 ........................ 20 Part 6: Nan·ative ................................... ... ............................. ................................... 21 6.1 Absorption, distribution, metabolism, and excretion (ADME) .................... 21 6.1.1 Toxicokinetics of Hypromellose Acetate Succinate (HPMCAS) ...... .. .. 21 6.1.2 Toxicokinetics of Related Substances .................................................... 22 6.2 Toxicology Studies Conducted on HPMCAS ...................................... ... .... .. 23 6.2.1 Acute Toxicity ............................................. ... ................... ............ .. ... .... 23 6.2.2 Subchronic Repeated Dose Oral Toxicity (8-week) ..... ......................... 24 6.2.3 Chronic Repeated Dose Oral Toxicity (26-week) ..... ............ ................. 26 6.2.4 Fertility Study in Rats ................... ... ................ ...................................... 28 6.2.5 Embryo-fetal Developmental Toxicity Study with Extended Evaluation in Rats .............................................................................................................. 30 Shin-Etsu AQOA T1i', hypromellose acetate succinate (HPMCAS), GRAS Notice 3 .,..l, AIBMR Life Sciences, Inc. 6.2.6 Embryo-fetal Developmental Toxicity Study in Rabbits ....................... 32 6.2.7 Peri- and Postnatal Developmental Toxicity Study with Extended Evaluation in Rats ..... ... .. ............................ ............................................. ... ..... 34 6.2.8 Emb1yo-fetal Developmental Toxicity Study in Rats and Rabbits ........ 38 6.3 Toxicological Studies on HPMC ................ .. ....................... .. .. .. .. ............... .40 6.4 Additional Scientific Studies ....... ........ ........................................................ .40 6.4.1 Studies on HPMCAS in Laborato1y Animals ....................................... .40 6.4.2 Hu1nan Studies ... ... ... .................................................. ................... ......... 44 6.5 Authoritative Safety Opinions ..................................................................... .44 6.5.1 European Food Safety Authority ... .. ...................................................... .44 6.5.2 World Health Organization ................. ... .. ....... ..................... ...... .. ... ...... .44 6.6 Allergenicity .. ... ... ................ .. .. ..... .. ... ... .. ........ .. .............. ......... ..................... 45 6.7 Histo1y of Consumption ....................... ... ................................. ..... ............... .45 6.8 Adverse Events .. ..... .. ............ ......... .. .............. .... .. .. ...... .. .............. .... ............ .46 6.9 Cunent Regulatory Status ..... .......... ....... ..... .. ...... .............................. ... ........ .46 6.10 Basis for the GRAS Conclusion ................................................................ .46 6.10. 1 Data and Information that Establish Safety ......... ............ ... ...... .. ......... .47 6.10.2 Data and Information that are Conoborative of Safety ... .. ...... .... ....... .48 6. 10.3 General Recognition ... ..... ....... .. ... ..... ...... .. ........................ ........ ... ........ .49 6. 10.4 Data and Infonnation that are Inconsistent with the GRAS Conclusion ................. .... ..................... ............... ...... ... ........ ............ ................................... 49 6.10.5 Information that is Exempt from Disclosure under FOIA .................. .49 Part 7: Supporting Data and Information ..... .. .................................. ....... ...... ... ..... 50 7.1 Data and Information that are not Generally Available ............................ .. .. 50 7.2 References that are Generally Available ....................... .................... ........... 50 Shin-Etsu AQOA T®, hypromellose acetate succinate (HPMCAS), GRAS Notice 4 ,lAIBMR Life Sciences, Inc. Figures and Tables Table 1. Intended use of Shin-Etsu AQOAT® HPMCAS ............... ....... .................... .. ... .. .. 7 Figure 1. Chemical Structure of Various Grades of Shin-Etsu AQOAT® HPMCAS .... .... .. 9 Figure 2. Manufacturing Flowchart .. .. ... .... .. ...... ................... ...................... ........ ............. 1 O Table 2. Shin-Etsu AQOAT® HPMCAS, Specifications ......... .. .......... .... .. .. .... .................. 11 Table 3. Shin-Etsu AQOAT® HPMCAS Batch Analyses .......... ...... ........ ...... .. ................ 12 Table 4. Stability Data Shin-Etsu AQOAT® HPMCAS (AS-MF) ... ................ .. .......... .. ..... 14 Table 5. Intended use of Shin-Etsu AQOAT® HPMCAS ................................ .. ... ............ 15 Table 6. Total (aggregate) absolute exposure to Shin-Etsu AQOAT® HPMCAS by proposed use consumers using NHANES 2011 - 12 data ...... .... ...... .. .. .... ......... 17 Table 7. Total (aggregate) exposure to Shin-Etsu AQOAT® HPMCAS by proposed use consumers relative to body weight using NHANES 2011 - 12 data .. .. ... .. .........
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