L-Methionine
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October 24, 2011 Lisa Brines, Ph.D. National List Manager USDA/AMS/NOP, Standards Division 1400 Independence Ave. SW Room 2646-So., Ag Stop 0268 Washington, DC 20250-0268 RE: Petition for inclusion of L-Methionine on the National List at §205.605(b) as a synthetic non-agricultural substance allowed in or on processed infant formula products labeled as “organic” or “made with organic (specified ingredients)” with the annotation “for use only in infant formula based on isolated soy protein.” Dear Dr. Brines, The International Formula Council (IFC) is an association of manufacturers and marketers of formulated nutrition products (e.g., infant formulas and adult nutritionals) whose members are based predominantly in North America. IFC members support the American Academy of Pediatrics’ (AAP) position that breastfeeding is the preferred method of feeding infants. We also agree with the AAP that, for infants who do not receive breast milk, iron-fortified infant formula is the only safe and recommended alternative, IFC members are committed to providing infant formulas of the highest quality for those mothers who cannot or choose not to breastfeed, discontinue breastfeeding prior to one year or choose to supplement. This petition seeks to add L-Methionine to the National List to permit its addition as a nonagricultural ingredient in infant formula based on isolated soy protein. L-Methionine is an essential amino acid for humans of all ages. Amino acids are the building blocks of protein. An essential amino acid is one that must be provided in the foods in our diet since our bodies do not have the capability of producing enough of it for normal metabolism and growth. Supplementing isolated soy protein with L-methionine improves the biological value of the protein and makes it nutritionally similar to breast milk protein and the protein of milk-based infant formula in its ability to sustain normal growth and development of young infants. L-Methionine must be added to infant formulas based on isolated soy protein to satisfy the protein biological quality requirement in the U.S. Food and Drug Administration (FDA) regulation for infant formula [21 CFR 107.100(f)] and to support normal growth and development of full-term infants fed soy isolate infant formulas. Only the L-form of methionine is permitted in infant food by FDA regulation [21 CFR 172.230]. Thus, L- methionine is necessary for the production of the organic product identified as infant formula based on isolated soy protein. Our petition and its appendices provide answers to all of the questions in the Guidelines on Procedures for Submitting National List Petitions, and in a manner that satisfies the criteria in the OFPA. We are available to provide any additional information that is required to complete your review process and recommendation. Sincerely, Mardi K. Mountford, MPH Executive Vice President Petition for Inclusion of L-Methionine on the National List for Use in Infant Formula Based on Isolated Soy Protein Item A The petitioned substance L-Methionine will be included on § 205.605, Non-agricultural (non- organic) substances allowed in or on processed products labeled as „„organic‟‟ or „„made with organic (specified ingredients),‟‟ with the annotation “for use only in infant formula based on isolated soy protein.” Item B 1. The substance’s chemical or material common name. The name of the substance is (L)-Methionine. L-Methionine is an essential amino acid for humans of all ages. Amino acids are the building blocks of protein. An essential amino acid is one that must be provided in the foods in our diet since our bodies do not have the capability of producing enough of it for normal metabolism and growth. Synonyms for L-methionine include the following: (S)-2-Amino-4-(methylthio)butanoic acid 2-Amino-4-(methylthio)butyric acid, (S)- 2-Amino-4-methylthiobutanoic acid (S)- Butanoic acid, 2-amino-4-(methylthio)-, (S)- L(-)-Amino-gamma-methylthiobutyric acid L-alpha-Amino-gamma-methylmercaptobutyric acid L-alpha-Amino-gamma-methylthiobutyric acid L-gamma-Methylthio-alpha-aminobutyric acid It is important to stress that the form of methionine used in human infant nutrition must be the natural “L-form,” the physiologically occurring form of methionine. Use of the unnatural “D-form” in the present application is prohibited by the FAO/WHO Codex Alimentarius Commission Standard for infant formula and by FDA regulation (21 CFR 172.230: “DL-Methionine (not for infant foods)”). 2. The manufacturer’s or producer’s name, address and telephone number and other contact information of the manufacturer/producer of the substance listed in the petition. Two manufacturers currently certified as suppliers of L-methionine are Sekisui Medical Company and Evonik-Rexim Pharmaceutical Company. Sekisui Medical Company KDX Nihombashi 313 building 5F 3-13-5, Nihombashi, Chuo-ku, Tokyo, 103-0027 Tel.: +81-3-3272-0671 / Fax: +81-3-3278-8774 http://www.sekisuimedical.jp/ Petition for Inclusion of L-Methionine on the National List for Use in Infant Formula Based on Isolated Soy Protein Evonik Rexim (Nanning) Pharmaceutical Co., Ltd No.10, Wenjiang Road Wuming County 530100 Nanning, China c/o Evonik Degussa Corp. USA 379 Interpace Parkway Parsippany,NJ 07054 Tel.: 973-541-8000 / Fax: 973-541-8040 3. The current use of L-Methionine is as a nutritionally essential amino acid used to improve the biological value of infant formula based on isolated soy protein. 4. L-Methionine is currently used as an ingredient in infant formulas based on isolated soy protein. Isolated soy protein contains sufficiently less of the essential amino acid methionine than do the proteins in breast milk and milk-based infant formula to make methionine the “limiting essential amino acid” (the essential amino acid in lowest relative amount for adequate growth and development) of isolated soy protein. Supplementing isolated soy protein with L-methionine improves the biological value of the protein and makes it nutritionally equivalent to breast milk protein and the protein of milk-based infant formula in its ability to sustain normal growth and development of young infants. 5. The source of the substance and a detailed description of its manufacturing or processing procedures from the basic component(s) to the final product. The following information is excerpted and adapted from the description of L-methionine in the Hazardous Substances Data Base prepared by the National Library of Medicine and taken from an authoritative and reliable source1. The production method of choice for L-methionine is the enzymatic resolution of racemic N- acetyl-DL-methionine using acylase from Aspergillus oryzae. The production is carried out in a continuously operated fixed-bed or enzyme membrane reactor. Alternatively, L-methionine may be produced by microbial conversion (fermentation) of the corresponding 5-substituted hydantoin. Growing cells of Pseudomonas sp. strain NS671 convert DL-5-(2- methylthioethyl)hydantoin to L-methionine; a final concentration of 34 g/L and a molar yield of 93% have been obtained. 1 Eggersdorfer M et al; Ullmann's Encyclopedia of Industrial Chemistry 7th ed. (2008). New York, NY: John Wiley & Sons; Vitamins. 2 Petition for Inclusion of L-Methionine on the National List for Use in Infant Formula Based on Isolated Soy Protein The most economic way for production of DL-methionine is the chemical process based on acrolein, methyl mercaptan, hydrogen cyanide, and ammonium carbonate. β- Methylthiopropionaldehyde, formed by addition of methyl mercaptan to acrolein, is the intermediate that reacts with hydrogen cyanide to give alpha-hydroxy-gamma- methylthiobutyronitrile. Treatment with ammonium carbonate leads to 5-(β- methylthioethyl)hydantoin that is saponified by potassium carbonate giving DL-methionine in up to 95% yield, calculated on acrolein. Additional synthetic production processes for DL-methionine are mentioned in the 2001 TAP Review for DL-methionine usage in organic livestock production. See page 3, Appendix A. Supplier Evonik Rexim uses an enzymatic process for the final step in the production of L- methionine. Supplier Sekisui Medical Co. synthesizes DL-methionine via hydantoin intermediates and then isolates the L-amino acid by enzymatic resolution. 6. A summary of any available previous reviews by State or private certification programs or other organizations of the petitioned substance. The National List currently includes DL-methionine, DL-methionine hydroxyl analog, and DL- methionine hydroxyl analog calcium, as feed additives for use in organic poultry production, at §205.603(d)(1). The National Organic Standards Board Technical Advisory Panel Review for the USDA National Organic Program on methionine for livestock use dated May 21, 2001 is attached as Appendix A. NOP posted a Final Rule on synthetic Methionine in organic livestock production on March 14, 2011 that extended the allowance for methionine in organic poultry production until October 1, 2012, at the following maximum allowable limits of methionine per ton of feed: 4 pounds for layers, 5 pounds for broilers, and 6 pounds for turkeys and all other poultry. Critically, the sources of methionine allowed on the National List for livestock (poultry) include the racemic DL-form and two synthetic analogs of methionine, all three of which are NOT allowed in infant formula products. The L-form of methionine has not been petitioned or formally reviewed for use in organic handling of infant formula based on isolated soy protein. The report in the National