Agency Response Letter GRAS Notice No. GRN 000243
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CFSAN/Office of Food Additive Safety
November 10, 2008
13840 Johnson St., NE
Ham Lake, MN 55304
Re: GRAS Notice No. GRN 000243
Dear Mr. Faulken:
The Food and Drug Administration (FDA) is responding to the notice, dated February 6, 2008, that you submitted in accordance with the agency's proposed regulation, proposed 21 CFR 170.36 (62 FR 18938; April 17, 1997; Substances Generally Recognized as Safe (GRAS); the GRAS proposal). FDA received the notice on February 7, 2008, filed it on February 8, 2008, and designated it as GRAS Notice No. GRN 000243.
The subject of the notice is D-ribose. The notice informs FDA of the view of Bioenergy, Inc. (Bioenergy) that D-ribose is GRAS, through scientific procedures, for use as an ingredient in foods listed in Table 1 (below) provided that D-ribose is used in conjunction with an additional carbohydrate energy source.
|aLow-calorie beverages are excluded from the intended uses in GRN 000243.
bExpressed on a weight per volume (w/v) basis for beverages and weight per weight (w/w) basis for all other foods.
|Fooda||Level of Use (percent)b|
|Non-cola carbonated beverages; meal replacements (non-milk based); ice cream and
frozen milk desserts (excluding frozen novelties); milk drinks (excluding malts, shakes)
|Reduced-calorie non-cola carbonated beverages; reduced-calorie fruit drinks and ades||0.4|
|Teas (specialty, spiced, and instant)||0.7|
|Meal replacements (milk-based); fruit nectars; vegetable juice||1.0|
|Soft candy (excluding chocolate bars)||1.67|
|Sports drinks; energy drinks; yogurt; frozen yogurt||2.2|
|Energy bars; meal replacement bars||5.0|
As part of its notice, Bioenergy includes the report of a panel of scientists (Bioenergy's GRAS panel) who evaluated the data and information that are the basis for Bioenergy's GRAS determination. Bioenergy considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Bioenergy's GRAS panel evaluated methods of production, product specifications, estimates of dietary exposure, and publicly available published and unpublished animal toxicity and human clinical studies of D-ribose. In addition, Bioenergy's GRAS panel noted the broad distribution of the production organism Bacillus subtilis in the environment and its safe use in the manufacture of food-grade enzyme preparations (carbohydrase (21 CFR 184.1148)) and protease (21 CFR 184.1150)) and in fermentation of the Japanese food, nattō. Based on their review, Bioenergy's GRAS panel concluded that D-ribose, when meeting food grade specifications and produced and used in accordance with current good manufacturing practices (cGMPs), is GRAS under the conditions of its intended use.
Bioenergy describes D-ribose (alpha-D-ribofuranose, Chemical Abstracts Service Registry No. 50-69-1) as a five-carbon monosaccharide whose chemical formula is C5H10O5. Bioenergy manufactures D-ribose by the controlled fermentation of a nonsporulating variant strain of B. subtilis ATCC 21951, originally obtained through ultraviolet light mutagenesis and designated as strain 716. B. subtilis strain 716 is nonpathogenic and nontoxigenic. Bioenergy describes its methods of manufacture for D-ribose using B. subtilis strain 716 as similar to patented production methods for D-ribose. Bioenergy states that D-ribose is manufactured in accordance with cGMPs. D-ribose is extensively purified and concentrated; purity exceeds 97 percent.
Bioenergy provides physical and chemical specifications for D-ribose. D-ribose is characterized as a white-to-yellow colored, crystalline powder with a fruity sweet odor and a slightly sweet taste. Specifications for D-ribose include limits for purity, melting point, specific rotation, ash, lead, arsenic, moisture content, and microorganisms.
Bioenergy provides an estimated daily intake (EDI) of D-ribose for all intended food uses listed in Table 1 using food consumption data from the National Center for Health Statistics' 2003- 2004 National Health and Nutrition Examination Survey. Bioenergy states that approximately 83 percent of the United States population is expected to consume D-ribose as an ingredient in the intended foods and estimates eaters-only intake of D-ribose to be 7.2 grams per person per day (g/p/d) at the 90th percentile.
Bioenergy discusses published studies of D-ribose metabolism and states that D-ribose is metabolized and catabolized via well established and accepted human biochemical pathways. Bioenergy notes that D-ribose is produced in the human body at levels similar to or higher than the estimated intake from consuming D-ribose in food from all intended uses described in GRN 000243.
Bioenergy discusses in vivo toxicity studies, published subchronic oral toxicity studies, and embryotoxicity/teratogenicity studies in rats and states that D-ribose has no significant safety issues. Bioenergy also discusses published and unpublished in vitro and in vivo genotoxicity studies and concludes D-ribose is not genotoxic to bacterial or mammalian cells.
The notice also summarizes clinical studies involving human subjects who consumed 10 g of D-ribose orally (twice daily for 14 days) in which no clinically adverse symptoms were reported. The authors concluded that ingestion of 20 g/p/d of D-ribose caused no adverse toxicological effects. In two other studies, the authors reported no adverse effects at the highest consumption level of 10 g; however, trial participants did experience a transient decrease in their blood glucose levels and a concurrent transient increase in their uric acid levels attributed to D-ribose-induced purine synthesis. As a result, Bioenergy states that foods containing D-ribose will also contain an additional carbohydrate source of energy to minimize any potential for these effects. From this publicly available information and other published studies, Bioenergy concludes that resulting levels of intake of D-ribose from proposed uses in GRN 000243 are well tolerated.
Standards of Identity
In the notice, Bioenergy states its intention to use D-ribose in several food categories, including foods for which standards of identity exist, located in Title 21 of the Code of Federal Regulations. We note that an ingredient that is lawfully added to food products may be used in a standardized food only if it is permitted by the applicable standard of identity.
Potential Labeling Issues
Under section 403(a) of the Federal Food, Drug, and Cosmetic Act (FFDCA), a food is misbranded if its labeling is false or misleading. Section 403(r) of the FFDCA lays out the statutory framework for the use of labeling claims that characterize the level of a nutrient in a food or that characterize the relationship of a nutrient to a disease or health-related condition. In describing the intended use of D-ribose and the information that Bioenergy relies on to conclude that D-ribose is GRAS under the conditions of its intended use, Bioenergy raises a potential issue under the labeling provisions of the FFDCA. If products that contain D-ribose bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition, Labeling, and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition (CFSAN). The Office of Food Additive Safety (OFAS) neither consulted with ONLDS on this labeling issue nor evaluated the information in the notice to determine whether it would support any claims made about D-ribose on the label or in labeling.
Section 301(ll) of the FFDCA
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FFDCA to, among other things, add section 301(ll). Section 301(ll) of the FFDCA prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FFDCA, a biological product licensed under section 351 of the Public Health Service Act, or a drug or a biological product for which substantial clinical investigations have been instituted and their existence made public, unless one of the exemptions in section 301(ll)(1)-(4) applies. In its review of Bioenergy's notice that D-ribose is GRAS for use in various foods, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing D-ribose. Accordingly, this response should not be construed to be a statement that foods that contain D-ribose, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Bioenergy, as well as other information available to FDA, the agency has no questions at this time regarding Bioenergy's conclusion that D-ribose is GRAS under the intended conditions of use provided that D-ribose is used in conjunction with an additional carbohydrate energy source. The agency has not, however, made its own determination regarding the GRAS status of the subject use of D-ribose. As always, it is the continuing responsibility of Bioenergy to ensure that food ingredients your firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements.
In accordance with proposed 21 CFR 170.36(f), a copy of the text of this letter responding to GRN 000243, as well as a copy of the information in this notice that conforms to the information in the proposed GRAS exemption claim (proposed 21 CFR 170.36(c)(1)), is available for public review and copying via the FDA home page at http://www.fda.gov. To view or obtain an electronic copy of the text of the letter, follow the hyperlinks from the "Food" topic to the "Food Ingredients and Packaging" section to the "Generally Recognized as Safe (GRAS)" page where the GRAS inventory is listed.
Laura M. Tarantino, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition