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CFSAN/Office of Food Additive Safety
September 3, 2002
Lee B. Dexter
15704 Webberville Road
Austin, TX 78724
Re: GRAS Notice No. GRN 000100
Dear Ms. Dexter:
The Food and Drug Administration (FDA) is responding to the notice, dated January 28, 2002, that you submitted on behalf of Bioenergy, Inc. (Bioenergy) 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 March 1, 2002, filed it on March 14, 2002, and designated it as GRAS Notice No. GRN 000100.
The subject of the notice is D-ribose (alpha-D-ribofuranose). D-Ribose is a 5-carbon monosaccharide chemically related to other 5 carbon sugars, such as arabinose and xylose. D-ribose is a component of nucleic acids in all organisms. An ester form of D-ribose (i.e., ribose-5'-phosphate) is an intermediate in the pentose phosphate pathway of glucose metabolism and is used in the synthesis of nucleoside and nucleotide precursors of nucleic acids.
The notice informs FDA of the view of Bioenergy that D-ribose is GRAS, through scientific procedures, for use in food in general, including meat and poultry products, for multiple technical effects, including use as a flavor enhancer, humectant, nutrient supplement, nutritive sweetener, stabilizer and thickener, synergist, and texturizer. Based on these conditions of use and use levels specified in the notice, Bioenergy estimates that intake of D-ribose would be 25 grams/person/day (g/p/d) at the mean and 50 g/p/d at the 90th percentile.
Under section 201(s) of the Federal Food, Drug and Cosmetic Act, a substance that is added to food is a food additive that requires premarket review and approval by FDA, unless the safety of the use of the substance is generally recognized by qualified experts. In the GRAS proposal, FDA proposed to establish a procedure whereby any person may notify FDA of a determination that a particular use of a substance is GRAS. Such notice to FDA is a voluntary mechanism for communication between a person who determines that a use of a substance is not subject to the statutory premarket approval requirements and FDA, the federal agency responsible for implementing those statutory provisions.
A GRAS notice should be clearly written and supported by generally available and accepted scientific evidence. It should provide the basis for concluding that the conditions of use have been demonstrated to be safe. It also should provide the basis for concluding that there is consensus among qualified experts about this demonstration of safety. In other words, a GRAS notice should be sufficient to convince qualified experts that FDA need not review either the primary data that establish safety or the relevant scientific literature that bears on any safety issues raised by the primary data.
FDA has evaluated the data and information in GRN 000100 as well as other generally available data and information. FDA finds that the notice both provides lengthy and complicated discussions about data that have little or no relevance to safety, and dismisses safety-related findings without adequate support from the scientific literature. As a result, the notice does not support Bioenergy's conclusions and, thus, does not provide a basis for a determination that D-ribose is GRAS under the conditions of its intended use.
We describe below some of the specific inadequacies of Bioenergy's notice.
- Bioenergy provides a lengthy discussion of the role of D-ribose in replenishment of depressed levels of ATP, cardiac metabolism, coronary artery disease, exercise and human skeletal muscle. These studies appear to address purported benefits of D-ribose rather than safety and are largely irrelevant to a discussion of whether Bioenergy's intended use of D-ribose is exempt from premarket review and approval by FDA .
- Bioenergy describes unpublished results from four human tolerance studies that it sponsored to address biochemical, toxicological, and metabolic effects of D-ribose. These studies demonstrated a statistically significant decline in blood glucose concentration (i.e., 35 percent below baseline) in persons who consumed D-ribose in amounts of 10 grams per serving. Likewise, Bioenergy reports that blood levels of uric acid in non-fasting humans who consumed 20 grams of D-ribose per day over a 14 day period increased by day 7 and returned to baseline by day 14. Bioenergy dismisses each of these findings without adequate explanation or citations to the relevant scientific literature on the implications of these effects on safety.
- Most of the studies that Bioenergy relies on to conclude that D-ribose would be safe for consumption in amounts up to 50 g/p/d are not generally available. For example, Bioenergy relies on unpublished toxicity studies in animals to conclude that a No-Observed-Adverse-Effect-Level (NOAEL) for D-ribose is 5 percent in the diet.
- Bioenergy describes an unpublished oral embryotoxicity/teratogenicity study conducted in rats fed D-ribose at levels up to 10 percent of the diet. In this study, Bioenergy describes statistically significant increases in the incidences of fetuses showing two pathologic findings - i.e., "wavy ribs" and incompletely ossified interparietal. Bioenergy concludes that these pathologic findings have no toxicological significance to humans by relying on the opinion of a scientific consultant without support from the scientific literature.
- The information that Bioenergy provides to describe its intended conditions of use for D-ribose is unclear and inconsistent. For example, Bioenergy lists the use level of D-ribose in cheese products as 3 percent in one table and as 0 percent in other tables. As another example, the multiple tables that Bioenergy provides to describe its intended conditions of use for D-ribose include some columns that appear to be mislabeled.
In light of inadequacies such as these, the notice does not support Bioenergy's conclusions and, thus, does not provide a basis for a determination that D-ribose is GRAS under the conditions of its intended use.
In accordance with proposed 21 CFR 170.36(f), a copy of the text of this letter, as well as a copy of the information in the notice that conforms to the information in proposed 21 CFR 170.36(c)(1), is available for public review and copying on the homepage of the Office of Food Additive Safety (on the Internet at http://www.cfsan.fda.gov/~lrd/foodadd.html).
Alan M. Rulis, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition