Agency Response Letter GRAS Notice No. GRN 000269
CFSAN/Office of Food Additive Safety
May 21, 2009
Melvin S. Drozen and John F. Foley
Keller and Heckman LLP
1001 G Street, N.W.
Suite 500 West
Washington, DC 20001
Re: GRAS Notice No. GRN 000269
Dear Mr. Drozen and Mr. Foley:
The Food and Drug Administration (FDA) is responding to the notice, dated October 10, 2008, that you submitted on behalf of Taiyo-Kagaku Co., Ltd (Taiyo-Kagaku) 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 November 25, 2008, filed it on November 25, 2008, and designated it as GRAS Notice No. GRN 000269.
The subject of the notice is polyglycerol fatty acid esters with a degree of polymerization (DP) of 11 to 40 for the polyglycerol backbone (PGFA (DP 11-40)). PGFAs with DP up to 10 are regulated as a food additive at 21 CFR 172.854. The notice informs FDA of the view of Taiyo-Kagaku that PGFA (DP 11-40) is GRAS, through scientific procedures, for use as emulsifiers at levels ranging from 0.05 - 0.5 per cent in conventional food and zinc- or iron-providing dietary supplements, and as cloud inhibitors at levels ranging from 0.05 - 0.5 per cent in vegetable oils and salad oils.
As part of its notice, Taiyo-Kagaku includes the report of a panel of individuals (Taiyo-Kagaku’s GRAS panel) who evaluated the data and information that are the basis for Taiyo-Kagaku’s GRAS determination. Taiyo-Kagaku considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Taiyo-Kagaku’s GRAS panel reviewed information pertaining to the method of manufacture, product specifications, and estimates of dietary exposure as well as published and unpublished studies. Based on this review, Taiyo-Kagaku’s GRAS panel concluded that PGFA (DP 11-40), meeting food-grade specifications and manufactured in accordance with current good manufacturing practices, is generally recognized as safe for use as emulsifiers and cloud inhibitors in the pre-mentioned categories.
Taiyo-Kagaku provides information about the identity and composition of PGFA (DP 11-40). PGFA (DP 11-40) is a mixture of highly polymerized polyglycerols (PGs), PG 11 up to PG 40 (PGs with a degree of polymerization of 11 up to 40), that have been reacted with one of the following fatty acids: stearic acid, palmitic acid, oleic acid, coconut fatty acid,1 capric acid, caprylic acid, lauric acid or myristic acid.
Taiyo-Kagaku describes the method of manufacture and provides specifications for PGFA (DP 11-40). The PGs are made using glycerol and glycidol as starting materials. All materials, except glycidol, used in the manufacturing of the PGFA (DP 11-40) are food-grade. The PG is obtained from ring-opening polymerization with glycidol. During this reaction glycidol is heated with an acid catalyst. The glycidol then reacts with a second molecule, losing water and yielding the diglycerol, which then reacts to give a triglycerol and so on up to PG 40. Taiyo-Kagaku states that the reaction process is designed to use up all the glycidol. These PGs are esterified with one of the fatty acids listed above. Taiya-Kagaku notes that the PGFA (DP 11-40) conforms to the specifications of the Food Chemicals Codex (6th edition) monograph including the description as “mixed partial esters formed by reacting polymerized glycerols with fatty acids.” Although no glycidol is expected to remain in the finished PGs used to make the PGFA (DP 11-40), Taiyo-Kagaku has analyzed the PGs for glycidol residues (detection limit 20 micrograms per kilogram) and none were detected.
Taiyo-Kagaku estimates the daily intake of PGFA (DP 11-40) from the intended uses in both conventional food and zinc- or iron-providing dietary supplements. For use in conventional foods, Taiyo-Kagaku estimates the total dietary intake of PGFA (DP 11-40) using the total PGFA production figures in the United States and a per capita basis consumption, attributing this use to 10 percent of the population to approximate the 90th percentile for an estimated intake of 14.2 milligrams per person per day (mg/p/d). For use in zinc- or iron-providing dietary supplements, Taiyo-Kagaku considers that PGFA (DP 11-40) provides maximum emulsifying effect at a level equaling that of the zinc or iron in the preparation, assumes the consumption of both zinc and iron-providing supplements, and estimates the amount of zinc and iron that could be ingested; based on these factors, Taiyo-Kagaku estimates the intake of PGFA (DP 11-40) would be to 180 mg/p/d. Thus, combining the food ingredient and zinc- or iron-providing dietary supplement uses and conservatively neglecting any substitutional reduction in exposure, Taiyo-Kagaku estimates the intake of PGFA (DP 11-40) would be 195 mg/p/d or 2.79 milligrams per kilogram body weight per day (mg/kg bw/d).
Taiyo-Kagaku discusses absorption, distribution, metabolism and excretion pertaining to PGFA (DP 11-40). Published reports show that lower polymerized PGFAs, PG 3 through PG 10, are hydrolyzed to their PGs and fatty acids, with the fatty acids being metabolized through known biochemical pathways and the PGs being largely excreted unchanged. Taiyo-Kagaku expects that the highly polymerized PGFAs, PG 11 up to PG 40, will also be hydrolyzed with their PGs either not being absorbed or being partially absorbed and excreted since the increased molecular size of the PG, coupled with the apparent resistance of PGs to enzymatic attack, will probably further decrease, if not prevent, absorption.
Taiyo-Kagaku also discusses the publicly available safety evaluations of PGFAs that have been undertaken by the FAO/WHO Joint Expert Committee on Food Additives (JECFA). Taiyo-Kagaku notes that JECFA established an acceptable daily intake of 25 mg/kg bw/d that was based on a published 90 day rat study with corroborative unpublished rat studies of 22 weeks and 2 years.
Standards of Identity
In the notice, Taiyo-Kagaku states its intention to use PGFA (DP 11-40) 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.
Section 301(ll) of the Federal Food, Drug, and Cosmetic Act (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 Taiyo-Kagaku’s notice that PGFA (DP 11-40) is GRAS for their intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing PGFA (DP 11-40). Accordingly, this response should not be construed to be a statement that foods that contain PGFA (DP 11-40), if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Taiyo-Kagaku, as well as other information available to FDA, the agency has no questions at this time regarding Taiyo-Kagaku’s conclusion that PGFA (DP 11-40) 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 PGFA (DP 11-40). As always, it is the continuing responsibility of Taiyo-Kagaku 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 000269, 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.
Laura M. Tarantino, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
1 Coconut fatty acid consists primarily of lauric, myristic, palmitic fatty acids and lower amounts of other fatty acids.