GRAS Notification for Chlorine Dioxide and Withdrawal of FAP 2266; Resonant Biosciences, Inc.; Our File No
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I® ORIGINAL 1001 G Street, N.W. Suite 500 West Washington, D.C. 20001 tel. 202.434.4100 fax 202.434.4646 Writer's Direct Access Martha E. Marrapese (202) 434-4 123 November 11. 2010 [email protected] Via Federal Express CONTAINS CONFIDENTIAL BUSINESS INFORMATION Food and Drug Administration Division of Animal Feeds (HFV-224) Office of Surveillance and Compliance Center for Veterinary Medicine 7519 Standish Place Rockville, Maryland 20855 Re: GRAS Notification for Chlorine Dioxide and Withdrawal of FAP 2266; Resonant Biosciences, Inc.; Our File No. RE14070 Dear Sir or Madam: The purpose of this letter is to request to participate in the pilot program for a Generally Recognized as safe (GRAS) determination for the safe use of chlorine dioxide generated by the notifier's PureMash* system in the production of food grade and non-food grade ethanol and distillers grains for animal feed use (food producing livestock). 75 Fed. Reg. 31800 (June 4, 2010). In connection with this GRAS notification, Resonant Biosciences, Inc. (RBS or Notifier) is formally withdrawing Food Additive Petition (FAP) 2266. The Notifier previously met with your office to discuss residual testing and a submission plan for this product. The potential eligibility for clearance under the Federal Food, Drug, and Cosmetic Act (FFDCA) as GRAS was raised at that time. We trust that our prior discussions fully satisfy the guidance in the Federal Register that "FDA strongly encourages potential participants in the animal food pilot program to contact the Division of Animal Feeds" prior to submitting notices. 75 Fed. Reg. at 31802. We look forward to confirmation that this submission has been accepted and is complete. Should any questions arise, please contact us, preferably by telephone or e-mail, so that we can promptly respond. Martha E. Marrapese Enclosures Washington, D.C. Brussels San Francisco Shanghai www.khlaw.com Generally Recognized As Safe (GRAS) Notification for Chlorine Dioxide Prepared for: U.S. Food and Drug Administration Center for Veterinary Medicine Division of Animal Feeds (HFV-224) 7519 Standish Place Rockville, MD 20855 Notifier: Resonant Biosciences, Inc. 11757 W. Ken Caryl Ave., F-308 Littleton, CO 80127 GRAS NOTIFICATION RESONANT BIOSCIENCES, INC. ' Pagej TABLE OF CONTENTS I. Introduction 1 II. Administrative Information 2 A. Claim Regarding GRAS Status 2 B. Name and Address of the Notifier 3 C. Common or Usual Name of the Subject Substance 3 D. Intended Conditions of Use and Technical Effect 3 E. Basis for GRAS Determination 5 F. Availability of Information 5 III. Detailed Information about the Identity of the Notified Substance 6 A. Names and Other Identities 6 B. Specification and Product Analysis 6 C. Analysis of Lots 6 D. Physical Description 7 E. Method of Manufacture and Calculated Residual Levels 7 1. Chlorate (C103 ) 9 2. Chlorite 9 3. Sulfate, Sodium Salts 9 F. Self-Limiting Levels of Use 11 IV. Detailed Summary of the Basis for Notifier's GRAS Determination 11 A. Analysis of Measured Residuals 13 B. Toxicological Evaluation of Chlorate 14 1. Absorption, Distribution, and Metabolism 14 2. Acute toxicity studies 15 3. Repeated Dose Toxicology 15 4. Developmental Toxicity Studies 19 5. Long-term feeding studies 20 6. Toxicology Summary for Chlorate 22 C. Dietary Exposure Assessment for Target Animals for Chlorate and Chlorite 24 D. Safety of Chlorite in Humans and Target Animals 26 E. Safety of Chlorate in Target Animals 27 F. Human Dietary Intake for Chlorate 29 G. Safety of Chlorate and Humans 35 H. Antibiotic Resistance and Chlorine Dioxide 37 V. Conclusion 38 GRAS NOT1F1CA T10N RESONANT BIOSCIENCES, INC. Page Appendices Appendix 1 Agent Authorization Appendix 2 PureMash® Chlorine Dioxide Efficacy Data Appendix 3 Mass Spectrum for Chlorine Dioxide Appendix 4 MashGuard One® Product label, Material Safety Data Sheet, and Related Product Materials Appendix 5 Analytical Report of Chlorite and Chlorate in Generated Chlorine Dioxide Appendix 6 PureMash® System Operational Manual Appendix 7 FDA GRAS Determinations for Chlorine Dioxide Appendix Appendix 8 Report and Procedure for Determination of Chlorate, Chloride, and Chlorite in Distillers Grain by Ion Chromatography Appendix 9 Supporting Materials for Toxicology Assessment Appendix 10 Supporting Legal Analysis Figures Figure 1 Ethanol Production Process Tables Table 1 Chlorite and Chlorate Residual Levels in 4,000 ppm Chlorine Dioxide in Water Effluent Table 2 Physical properties Table 3 Calculated Residuals in DG Table 4 Levels of Chlorate, Chlorite, and Chloride in DG Table 5 Feeding Data for Food-Producing Livestock Table 6 EDIs for Target animals Table 7 NTP Results Summary/Male Rats Table 8 NTP Results Summary/Female Rats Table 9 Subchronic and Chronic Toxicology Studies on Sodium Chlorate Table 10 Direct Feed Chlorate Residue Data Table 11 Consumption Values for Chlorate Table 12 EDI Summary for Chlorite and Chlorate GRASN0T1F1CA T10N RESONANT BIOSCIENCES, INC. Page 1 I. Introduction On behalf of Resonant Biosciences, Inc. (RBS or the Notifier), Keller and Heckman LLP submits the enclosed dossier of information in support of this notificationthat chlorine dioxide produced by the Puremash® system is Generally Recognized as Safe (GRAS) for use as a processing aid in the production of non-food grade and food grade ethanol. Chlprine dioxide is typically added in the first 16 to 24 hours of a fermentation run at a rate of 10-40 ppm per batch, with a maximum application rate of 55 ppm per batch that may be applied on an intermittent basis to treat highly fouled fermentation water. One of the ethanol fermentation by-products, distillers' grain (DG), will be fed to food producing animals in accordance with good manufacturing or feeding practice. Animal feed is classified as "food" under section 201(f)(3) of the Act. Therefore, residuals in DG associated with the Notifier's GRAS substance require evaluation under the Federal Food, Drug, and Cosmetic Act (FFD&C Act), which broadly prohibits the "adulteration" of food, the statutory term for rendering food unsafe or unfit for consumption. In addition, because one of the constituents in DG due to the use of chlorine dioxide, sodium chlorate, was the subject of a National Toxicology Program ("NTP"), two-year chronic toxicology study (NTP TR517, December 2005), the safety of chlorate residuals is evaluated using FDA's procedures for addressing the situation in which the use of a substance in a food additive is known to contain minute, but detectable, levels of a presumed carcinogenic impurity. The GRAS substance, chlorine dioxide, is not carcinogenic. These procedures permit the finding that there is no safety risk associated with the chlorate constituent when chlorine dioxide generated by the PureMash® system is intentionally added to the ethanol fermentation process at the levels prescribed. The determination of GRAS is on the basis of scientific procedures, in accordance with 21 CFR § 170.30(b) and conforms to the guidance issued by the FDA under proposed 21 CFR § 570.36, 62 Fed. Reg. 18938 (Apr. 17, 1997) and the FDA's Notice of Pilot Program; Substances Generally Recognized as Safe Added to Food for Animals, 75 Fed. Reg. 31806 (June 4, 2010). This notification provides supporting information in the following areas: GRAS NOTIFICA TION RESONANT BIOSCIENCES, INC. [ , Page 2 • Identity of the substance; • A description of the method of manufacture; • An estimation of daily intake for all migrants; • Safety data and safety evaluation; and • GRAS determination, as a proposed conclusion determined by scientific procedures for use as a processing aid in the production of non-food grade and food grade ethanol. It is the Notifier's expectation that FDA will concur that the information presented fully supports the determination that the Notifier's chlorine dioxide is GRAS for use as a processing aid in the production of non-food grade and food grade ethanol. Finally, for purposes of this notification, the GRAS determination evaluates the downstream use of DG as a component of animal feed for food-producing target animals only. This notification does not attempt to assess use in conjunction with DG as a component of food administered to companion/non-food producing animals. It is the Notifier's intention to address the safety for use in food administered to animals such as cats, dogs, and horses independently, once sufficient processing data are generated to proceed with the analysis. II. Administrative Information A. Claim Regarding GRAS Status Chlorine dioxide is GRAS based on scientific procedures for use as a processing aid in the production of non-food grade and food grade ethanol. DG from the ethanol production process will be used in animal feed use for food producing animals in accordance with good manufacturing or feeding practice. Chlorine dioxide is typically added in the first 16 to 24 hours of a fermentation run at a rate of 10-40 ppm per batch, with a maximum application rate of 55 ppm per batch that may be applied on an intermittent basis to treat highly fouled fermentation water. The chlorine dioxide is generated by treatment of an aqueous solution of sodium chlorate with hydrogen peroxide in the presence of sulfuric acid and the generator effluent contains at least 90 percent by weight of chlorine dioxide with respect to all chlorine species. GRASNOT1F1CA TION RESONANT BIOSCIENCES, INC. Page 3 The use of Chlorine Dioxide from the Puremash® System in this manner has been determined to be exempt from the premarket approval requirements of the Federal Food, Drug and CSsmeJie^Act (21 U.S.C. § 301 el. «?0.)(the Act). // /It/fO apese, Esq., Agent Date B. Name and Address of the Notifier Notifier Acknowledgement of Receipt of Notification and Inquiries to be Directed to: Mr. Allen Ziegler Keller and Heckman LLP President 1001 G Street N.W. Resonant Biosciences, LLC Suite 500 West 11757 W.