Agency Response Letter
GRAS Notice No. GRN 000144

James C. Griffiths, Ph.D.
Director of Toxicology
Burdock Group
780 US Highway 1, Suite 300
Vero Beach, FL 32962

Re: GRAS Notice No. GRN 000144

Dear Dr. Griffiths:

The Food and Drug Administration (FDA) is responding to the notice, dated January 12, 2004, that you submitted on behalf of Linguagen Corp. (Linguagen) 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 3, 2004, filed it on February 6, 2004, and designated it as GRAS Notice No. GRN 000144.

The subjects of the notice are adenosine 5'-monophosphoric acid (AMP) and its monosodium and disodium salts. The notice informs FDA of the view of Linguagen that AMP and its monosodium and disodium salts are GRAS, through scientific procedures, for use as flavor enhancers in chewing gum, coffee and tea, snack foods, soups and soup mixes (including meat and poultry), sugar substitutes and salt substitutes at levels ranging from approximately 0.0002 percent to 0.0008 percent. Linguagen notes that the strong savory, umami-like flavor that is associated with increased use levels of AMP and its monosodium and disodium salts makes the use self-limiting.

Linguagen describes generally available information about AMP and its monosodium and disodium salts. AMP is an endogenous purine nucleotide found in all living organisms and is a structural component of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). AMP is composed of the purine base adenine covalently bound to a pentose sugar (ribose or deoxyribose), forming adenosine, which is esterified with phosphoric acid. AMP may be present as a free acid (i.e., phosphoric acid) or salt form (i.e., monosodium and disodium phosphate salt), depending on the buffer conditions of the final food. For clarity, in this letter FDA uses the term " AMP " to denote both the free acid form and the salt forms ofAMP.

Linguagen describes the method of manufacture for AMP. AMP is isolated from the RNA of hydrolyzed yeast (e.g., Saccharomyces cerevisiae or Candida utilis, or a strain approved for use in food). The yeast is grown in fermentation culture, pelleted, and autolysed by exposure to salt and heat. The resulting RNA-rich yeast extract is hydrolyzed with a pancreatic ribonuclease enzyme concentration that liberates the AMP. The AMP is then isolated by ion-chromatographic separation and dried. The resulting product is a white crystalline powder containing a minimum of 95 percent AMP. Linguagen provides specifications for AMP including limits on the maximum enzyme concentration that liberates the AMP. Linguagen also provides specifications for AMP including limits on the maximum levels of nucleotides (other than adenosine), amino acids, heavy metals, lead, and barium. Linguagen notes that the manufacturing process uses current Good Manufacturing Practices and that all reagents used in the manufacturing process conform to Food Chemicals Codex specifications.

Using the United States Department of Agriculture 1994-1996 Continuing Surveys of Food Intakes by Individuals, Linguagen estimates that the intake of purines⁽¹⁾ from Linguagen's proposed uses of AMP would be approximately 150 milligrams per person per day (mg/person/day) at the mean and 310 mg/person/day at the 90th percentile. Linguagen also estimates that the intake of purines from dietary sources would be approximately 560 mg/person/day at the mean and approximately 1120 mg/person/day at the 90th percentile. Therefore, Linguagen concludes that the total maximum intake of purines (i.e., from both Linguagen's proposed uses of AMP in conventional foods and from dietary sources) would be approximately 710 mg/person/day at the mean and approximately 1430 mg/person/day at the 90th percentile. Linguagen notes that consumption of AMP from its use in potassium chloride salt substitutes and in excipient formulations in prescription and over-the-counter drugs is negligible.

Linguagen discusses published information related to the absorption, distribution, metabolism, and excretion of AMP. Linguagen states that the human diet is abundant in DNA and RNA, and that nucleic acids are degraded to nucleotides, nucleosides, and free bases by the gastrointestinal microflora or metabolized by the gastrointestinal mucosa prior to absorption. Likewise, Linguagen reports that AMP is degraded to nucleosides and purine bases in the gastrointestinal tract and is rapidly metabolized by deamination to form its initial metabolite, 5'-inosine monophosphate (IMP). Linguagen reports that IMP has a half-life of 5 hours in rats and is completely eliminated by 24 hours, mainly through urine. Linguagen also reports that AMP is rapidly and completely metabolized to uric acid in humans and that metabolism of AMP is complete prior to intestinal absorption.

Linguagen discusses published and unpublished studies conducted with AMP and IMP in various animal species. Linguagen reports that acute, subchronic, and chronic oral toxicity studies conducted in rats, mice, and dogs showed no relevant compound-related toxicological effects. Linguagen also reports that no adverse effects were reported in reproductive toxicity studies and teratogenicity studies conducted in rats, mice and rabbits, and that no mutagenic effects were observed in genotoxicity studies conducted in vitro. In addition, Linguagen states that no significant adverse effects were observed in published human clinical studies. Linguagen notes, however, that prolonged excessive purine consumption may lead to chronically elevated plasma uric acid levels (i.e., hyperuricemia), which is a known risk factor for the development of gout⁽²⁾ Linguagen estimates the increase in serum uric acid levels from consumption of AMP in normal and gouty individuals and concludes that the small increase is well within the standard deviation of the normal range in the U.S. population and the normal fluctuations in serum uric acid levels in individuals.

Linguagen reports that the Joint Food and Agriculture Organization/World Health Organization's Expert Committee on Food Additives reviewed IMP at its eighteenth meeting held in June 1974 and approved it as a food additive with the assigned acceptable daily intake (ADI) not specified.⁽³⁾ Linguagen also reports that IMP was evaluated by the Flavor and Extract Manufacturer's Association and was found to be GRAS as a food ingredient. Furthermore, Linguagen reports that AMP and other purines are currently approved for use as food additives by the European Community.

As part of its notice, Linguagen includes the report of a panel of individuals (Linguagen's GRAS panel) who evaluated the data and information that are the basis for Linguagen's GRAS determination. Linguagen considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Linguagen's GRAS panel evaluated estimates of dietary exposure, method of manufacture, product specifications, and published and unpublished studies conducted with AMP and related purines. Linguagen's GRAS panel also assessed the potential for AMP ingestion to induce hyperuricemia. Based on this assessment, Linguagen concluded that the ADI for the total purine consumption is 1800 mg/person/day. Based on the EDI in the human diet at the 90th percentile (1120 mg/person/day), Linguagen calculated an ADI for purines (AMP) from the notified use to be 680 mg/person/day (1800-1120). Linguagen's GRAS panel concluded that AMP, manufactured in compliance with current good manufacturing practices, is GRAS, through scientific procedures, for use as a flavor enhancer in foods and beverages such that total daily intake of AMP does not exceed 680 mg/person/day.

Potential labeling issues

In the notice, Linguagen states that AMP qualifies as an ingredient exempted from the requirement for declaration on the food label under 21 CFR 101.4(b)(1), as it is a flavoring under 21 CFR 101.22. For your information, FDA has previously addressed the labeling of flavorings and flavor enhancers with regard to protein hydrolysates in a 1993 final rule (58 FR 2850 at 2865 and 2866). In the preamble of the final rule, FDA stated that the practice among some in industry had been to declare protein hydrolysates used for flavor-related purposes, such as flavor enhancement, as "flavorings"" or " natural flavors." FDA concluded that when protein hydrolysates are added to foods as flavorings, they also function as favor enhancers. The agency pointed out that the Federal Food, Drug, and Cosmetic Act does not exempt flavor enhancers from required label declaration, and consequently, any protein hydrolysate used in a food as a flavoring must be declared by its common or usual name. Accordingly, the agency established under 21 CFR 101.22(h)(7) a requirement for declaration of a protein hydrolysate by its common or usual name in the ingredient list when added to a food for flavoring or flavor-related functions. FDA advises Linguagen that the common or usual name for AMP is adenosine 5'-monophosphoric acid or adenosine 5'-monophosphate. If Linguagen has any questions about the appropriate labeling of this food ingredient, Linguagen should contact the staff in the Office of Nutritional Products, Labeling and Dietary Supplements, Food Labeling and Standards Staff. Linguagen can also reach this Staff by telephone at (301) 436-2371.

Use in Meat and Poultry Products

During its evaluation of GRN 000144, FDA consulted with the Labeling and Consumer Protection Staff of the Food Safety and Inspection Service (FSIS) of the United States Department of Agriculture (USDA). Under the Federal Meat Inspection Act and the Poultry Products Inspection Act, FSIS is responsible for determining the efficacy and suitability of food ingredients and additives in meat and poultry products as well as prescribing safe conditions of use. Suitability relates to the effectiveness of the ingredient in performing the intended purpose of use and the assurance that the conditions of use will not result in an adulterated product, or one that misleads consumers.

Because the use of AMP in food is self-limiting due to its strong, umami-like flavor, FSIS would not object to the use of AMP as a flavor enhancer in commercially prepared meat and poultry soups and soup mixes, provided that it does not exceed 0.0002 percent in the product formulation. If, however, Linguagen has any questions about the use of AMP in such products, Linguagen should direct such an inquiry to Dr. Robert Post, Director, Labeling and Consumer Protection Staff, Office of Policy, Program Development and Evaluation, Food Safety and Inspection Service, 1400 Independence Ave., S.W., Suite 602, Annex Building, Washington, DC 20250-3700. The telephone number for his office is (202)205-0279 and the telefax number is (202)205-3625.

Conclusions

Based on the information provided by Linguagen, as well as other information available to FDA, the agency has no questions at this time regarding Linguagen conclusion that AMP is GRAS under the intended conditions of use. The agency has not, however, made its own determination regarding the GRAS status of the subject use of AMP. As always, it is the continuing responsibility of Linguagen to ensure that food ingredients that the 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, as well as a copy of the information in your 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).

Sincerely,    /s/ Laura M. Tarantino, Ph.D. Director Office of Food Additive Safety Center for Food Safety      and Applied Nutrition

cc: Dr. Robert Post, Director
Labeling and Consumer Protection Staff
Office of Policy, Program Development and Evaluation
Food Safety and Inspection Service
1400 Independence Ave., SW, Suite 602, Annex
Washington, DC 20250-3700

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⁽¹⁾In correspondence dated May 7, 2004, Linguagen states that purines include the bases, nucleosides, nucleotides and nucleic acids of AMP, guanosine 5'-monophosphate (GMP), inosine 5'- monophosphate (IMP), and xanthosine monophosphate (XMP).

⁽²⁾A group of disorders of purine metabolism in which monosodium urate crystals precipitate in the synovial fluid of the joints resulting in inflammation and arthritis.

⁽³⁾The statement "ADI not specified" means that, on the basis of the available data (toxicological, biochemical, and other), the total daily intake of the substance, arising from its use or uses at the levels necessary to achieve the desired effect and from its acceptable background in food, does not in the opinion of the Committee, represent a hazard to health. For this reason, and for the reasons stated in individual evaluations, the establishment of an ADI in milligrams per kilogram body weight per day is not deemed necessary.