Agency Response Letter GRAS Notice No. GRN 000414
CFSAN/Office of Food Additive Safety
November 20, 2012
Edward A. Steele
EAS Consulting Company, LLC
1940 Duke Street, Suite 200
Alexandria, VA 22314
Re: GRAS Notice No. GRN 000414
Dear Mr. Steele:
The Food and Drug Administration (FDA) is responding to the notice, dated December 21, 2011, that you submitted on behalf of The Procter and Gamble Company (P&G) 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 December 30, 2011, filed it on January 12, 2012, and designated it as GRAS Notice No. GRN 000414.
The subject of the notice is L-lysine monohydrochloride (lysine HCl). The notice informs FDA of the view of P&G that lysine HCl is safe, through scientific procedures, for reducing the formation of acrylamide in fabricated snack products at use levels up to 1.5% (1.2% as lysine).
As part of its notice, P&G includes the report of a panel of individuals (P&G’s GRAS panel) who evaluated the data and information that are the basis for P&G’s GRAS determination. P&G considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. P&G’s GRAS panel evaluated estimates of dietary exposure, method of production, and product specifications as well as published and unpublished studies. Based on this review, P&G’s GRAS panel concluded that lysine HCl that meets its established food grade specifications is GRAS under the conditions of its intended use.
P&G provides information about the chemical identity and specifications for lysine HCl. Lysine HCl is a hydrochloride salt of the essential amino acid lysine. Lysine HCl is identified by CAS registry number 657-27-2 and the empirical formula is NH2(CH2)4(NH2)CHCOOH-HCl. Specifications for lysine HCl include purity (> 99.5%) and limits on iron (≤ 0.003%), lead (≤ 0.5 milligrams per kilogram (mg/kg)), sulfate (≤ 0.03%), arsenic (≤ 1 mg/kg), ammonium (≤ 200 mg/kg), heavy metals (≤ 10 mg/kg), and microbial contamination.
P&G describes the method of manufacture for lysine HCl. Lysine HCl is produced by fermentation using raw sugar and molasses. Sterilized raw sugar and molasses are added along with seed culture to a fermentation tank. The fermentation microorganism is a nonpathogenic, nontoxigenic species and strain (Corynebacterium glutamicum) commonly used in food processing. After fermentation, the broth is passed through an ion exchange resin. The filtrate is evaporated and hydrochloric acid is added to form lysine monohydrochloride. The crystallized product is centrifuged, dissolved in water, and decolorized. The decolorized product is purified by crystallization, centrifugation, and drying to obtain the final product. The notifier states that all equipment and materials used in the production process have a safe history of use in food processing. Lysine HCl is manufactured in accordance with current good manufacturing practices.
P&G states that lysine HCl is intended for use in the manufacture of fabricated snack foods at use levels up to 1.5%. Lysine HCl will be added to snack food products, prior to frying, to reduce acrylamide formation in the finished product. The notifier provides an estimate of lysine intake from the diet normally, and provides an estimated daily intake (EDI) of lysine from the intended use in food. P&G notes that the majority of the added lysine monohydrochloride remains unreacted in the finished food.
P&G provides an EDI for lysine from the intended use in fabricated snack foods using a 14-day survey by Market Research Corporation of America (MRCA) (1991-92), and a published study that provides an estimated intake of snack foods using MRCA data. Based on these consumption estimates, the intended use of lysine HCl at 1.5% (1.2% lysine) in snack foods will result in 587 milligrams per day (mg/d) on a per eating occasion basis, and 180 mg/d on a 14 day average consumption basis for the highest user group (13-to-17 year old males). Using a background EDI of 3400 mg/d from dietary lysine in protein and the EDI from the intended use (587 and 180 mg lysine/d) from the calculations above, the notifier states that the total daily lysine consumption would be 3987 mg/d and 3580 mg/d, respectively.
P&G notes that lysine is an essential amino acid in humans and discusses its well-known absorption and metabolism. P&G describes a published 13-week toxicity study conducted in male and female rats. No treatment-related toxicological or behavioral effects of lysine HCl were observed at 3670 mg per kilogram of body weight/d (mg/kg bw/d), the highest dose tested (5% of the diet).
The notifier also discusses a number of published reproductive and teratological studies of additional lysine in the diet. A published study demonstrated that the consumption of excess lysine through the diet at levels up to approximately 2000 mg/kg bw/d, from day zero through day twenty of pregnancy in rats, did not adversely affect pregnancy course and outcomes. The notifier states that the available evidence supports the conclusion that the intended use of lysine HCl is unlikely to cause any reproductive or teratogenic effects.
P&G also summarizes a number of published human studies conducted in infants, children, and adults. The consumption of supplemental lysine at levels up to 3000 mg/d for up to six months in these studies did not result in any adverse effects, and lysine supplementation was well-tolerated. The levels of lysine used in these studies were more than seven fold higher than those estimated to result from the intended uses of lysine HCl in fabricated snacks. Further, a review article on the safety of lysine added to an omnivorous diet concluded that oral supplementation of 1000 to 3000 mg/d lysine (equivalent to 1250 to 3750 mg/d lysine HCl) divided among meals is safe for long-term use. P&G concludes that the totality of available evidence supports the conclusion that lysine HCl is generally recognized as safe for its intended use in snack food.
Section 301(ll) of the Federal Food, Drug, and Cosmetic Act (FD&C Act)
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FD&C Act to, among other things, add section 301(ll). Section 301(ll) of the FD&C Act prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FD&C Act, 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 P&G’s notice that lysine HCl is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing lysine HCl. Accordingly, this response should not be construed to be a statement that foods that contain lysine HCl, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by P&G, as well as other information available to FDA, the agency has no questions at this time regarding the notifier’s conclusion that lysine HCl 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 lysine HCl. As always, it is the continuing responsibility of P&G 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 000414, 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 at www.fda.gov/grasnoticeinventory.
Dennis M. Keefe, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition