Agency Response Letter GRAS Notice No. GRN 000339
CFSAN/Office of Food Additive Safety
November 6, 2010
Robert G. Bursey, Ph.D.
Ajinomoto Corporate Services, LLC
1120 Connecticut Ave, N.W., Suite 1010
Washington, DC 20036
Re: GRAS Notice No. GRN 000339
Dear Dr. Bursey:
The Food and Drug Administration (FDA) is responding to the notice, dated May 7, 2010, 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 May 7, 2010, filed it on May 13, 2010, and designated it as GRAS Notice No. GRN 000339.
The subject of the notice is polyglutamic acid (PGA). The notice informs FDA of the view of Ajinomoto Corporate Services, LLC (Ajinomoto) that PGA is GRAS, through scientific procedures, for use as a “debittering” agent in salt substitute products for table top, food preparation or for food production applications, containing potassium chloride at concentrations ranging from 0.15 to 0.4 percent (%) by weight of the salt substitute product.
As part of its notice, Ajinomoto includes the report of a panel of individuals (Ajinomoto’s GRAS panel) who evaluated the data and information that are the basis for Ajinomoto’s GRAS determination. Ajinomoto considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Ajinomoto’s GRAS panel evaluated published and unpublished information on PGA, including method of manufacture, specifications, batch analyses, intended use levels, estimated dietary exposure, metabolism and safety studies, including potential allergenicity. Based on this review, Ajinomoto’s GRAS panel concluded that PGA, meeting appropriate food-grade specifications and manufactured according to current good manufacturing practice (cGMP), is GRAS for the intended condition of use.
Ajinomoto provides information about the chemical identity, and method of manufacture for food-grade PGA. Synonyms for PGA include poly-gamma-glutamic acid and polyglutamate. Ajinomoto describes PGA as an odorless, white or yellowish fine powder. PGA is a polymer of gamma-linked D- and L-glutamic acid with a molecular weight distribution of 28,500-32,000 grams per mole, and has the empirical formula of [C5H7NO3]n. Ajinomoto states that PGA is produced by liquid fermentation using a strain of Bacillus subtilis that they refer to as Bacillus AJ12757. Ajinomoto considers Bacillus AJ12757 to be comparable to strains used in the production of natto (soybeans fermented with B. subtilis) and strains used in the production of various food enzymes that are usually classified as B. subtilis or B. amyloliquefaciens. Ajinomoto discusses a study of the potential virulence of the Bacillus AJ12757 strain and concludes that the strain is non-pathogenic and non-toxigenic, and is a safe source for use in the production of PGA. Ajinomoto states that the production organism is adapted to the production fermentation broth and conditions for 15-30 hours then cultivated in the production media for 72-130 hours. The fermentation broth includes hydrolyzed soy protein. Following fermentation, the broth is acid hydrolyzed and decolorized before being filtered, concentrated and sterilized multiple times. The resulting preparation is then spray dried to yield the final PGA product. Ajinomoto states that all the raw materials used during the fermentation and purification processes are food-grade and widely used in food processing.
Ajinomoto provides a table of specifications for PGA that includes assay (≥75%), lead (≤1 milligram per kilogram (mg/kg)), arsenic (≤4 mg/kg), and microbiological limits (≤10,000 colony forming units/gram). Ajinomoto also provides results from five lot analyses that demonstrate compliance with the specifications. Ajinomoto notes that the results of stability testing indicate that PGA is stable for up to 12 months at temperatures ranging from 5 to 44 degrees Celsius.
Ajinomoto provides an estimated daily intake (EDI) of PGA based on the assumption that all added salt is replaced with a salt substitute product containing potassium chloride and sodium chloride in a 1:1 ratio (by weight). Ajinomoto summarizes the estimated daily intake of total (table top or optional and non-optional) salt (low sodium and regular) for NHANES 2003-2004 participants to be 7.06 grams per person per day (g/p/d) and 11.6 g/p/d for the user-only mean and 90th percentile, respectively.1 Based on these dietary intakes of salt and assuming a 0.4% use level of PGA in the salt substitute product, Ajinomoto estimates the dietary intake of PGA as 28.2 mg/p/d at the mean and 46.4 mg/p/d at the 90th percentile. For a 60 kg person the mean dietary intake of PGA would be 0.48 mg/kg body weight (bw)/d and 0.92 mg/kg bw/d at the 90th percentile.
In the notice, Ajinomoto discusses published and unpublished studies using PGA, and the history of consumption of natto.2 Ajinomoto discusses a published 90-day subchronic toxicity study in rats and concludes that there were no statistically significant dose-related adverse effects at the highest dose tested (2616 mg/kg bw/d in males and 2728 mg/kg bw/d in females). In addition, Ajinomoto discusses published genotoxicity studies including bacterial reverse mutation assay, mouse micronucleus assay, as well as chromosome aberration tests and concludes that there was no evidence of mutagenicity. Ajinomoto also discusses an unpublished acute oral toxicity study in rats. Ajinomoto also discusses the history of safe consumption of PGA as a component of natto in support of their safety determination. Ajinomoto discusses the issue of allergenicity of PGA, and concludes that there is no residual soy protein or fragments of soy protein that are carried over from the fermentation broth to the PGA ingredient. Ajinomoto concludes that PGA, manufactured consistent with cGMP and meeting the appropriate food-grade specifications is GRAS for the intended use.
The Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) amends the Federal Food, Drug, and Cosmetic Act (FFDCA) to require that the label of a food that is or contains an ingredient that bears or contains a “major food allergen” declare the presence of the allergen (section 403(w)). FALCPA defines a “major food allergen” as one of eight foods or food groups (i.e., milk, eggs, fish, crustacean shellfish, tree nuts, peanuts, wheat, and soybeans) or a food ingredient that contains protein derived from one of those foods. Issues associated with labeling food are the responsibility of the Office of Nutrition, Labeling, and Dietary Supplements.
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 Ajinomoto’s notice that PGA is GRAS for the intended use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing PGA. Accordingly, this response should not be construed to be a statement that foods that contain PGA, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Ajinomoto, as well as other information available to FDA, the agency has no questions at this time regarding Ajinomoto’s conclusion that PGA is GRAS for the intended uses. The agency has not, however, made its own determination regarding the GRAS status of the subject use of PGA. As always, it is the continuing responsibility of Ajinomoto 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 responding to GRN 000339, as well as a copy of the information in this notice that conforms to the information in the 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.
Mitchell A. Cheeseman, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
1FDA notes that the estimate provided by Ajinomoto should not be mistaken for an estimate for the dietary intake of sodium in the United States (approximately 3400 mg/d at the mean from 2003-2006 NHANES data).
2Ajinomoto notes that natto contains about 300 mg PGA per 100 grams of natto.