Agency Response Letter GRAS Notice No. GRN 000404
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CFSAN/Office of Food Additive Safety
October 31, 2012
Takashi Kuriki, Ph.D.
Chief Scientific Officer
Ezaki Glico Co., Ltd.
4-6-5, Utajima, Nishioyogogawa
Re: GRAS Notice No. GRN 000404
Dear Dr. Kuriki:
The Food and Drug Administration (FDA) is responding to the notice, dated September 20, 2011, 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 September 28, 2011, filed it on October 11, 2011, and designated it as GRAS Notice No. GRN 000404.
The subject of the notice is cyclic dextrin, highly branched (cyclic dextrin). The notice informs FDA of the view of Ezaki Glico Co., Ltd. (Ezaki) that cyclic dextrin is GRAS, through scientific procedures, for use as a carbohydrate source, flavoring agent or spray-drying aid in a variety of food products, including baked goods and baking mixes, beverages and beverage bases, breakfast cereals, tea, grain products, seasonings, milk and plant protein products, processed fruits and vegetables, fruit and vegetable juices, soft candy and powdered soups excluding meat and poultry products at a level ranging from 0.25 to 24 grams (g) per reference amount customarily consumed per eating occasion.
As part of its notice, Ezaki includes the report of a panel of individuals (Ezaki’s GRAS panel) who evaluated the data and information that are the basis for Ezaki’s GRAS determination. Ezaki considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Ezaki’s GRAS panel evaluated the method of manufacture, product specifications and estimates of dietary exposure, as well as published toxicological studies for cyclic dextrin. Based on this review, Ezaki’s GRAS panel concluded that cyclic dextrin, produced consistent with current good manufacturing practice (cGMP) and meeting its purity and established food grade specifications, is GRAS under the conditions of its intended use.
Ezaki discusses the identity of cyclic dextrin. Ezaki states that the molecules of branched cyclic dextrin are branched oligosaccharides composed of α-D-glucose monomers with at least 80 percent cyclic dextrin molecules with molecular weights ranging from 30,000 to 1,000,000. Cyclic dextrin is a partially degraded maize starch that is a white, odorless powder. Cyclic dextrin contains short linear chains that are composed of α-(1,4)-linked glucose units with branching through α-(1,6) glucosidic bonds. The cyclic a-glucan moieties of cyclic dextrin are linked to adjacent branched clusters through an α-(1,6) glucosidic bond. Ezaki notes that cyclic dextrin also contains smaller amounts of single glucose molecules and other saccharides with molecular weights outside the range of the cyclic dextrin.
Ezaki describes the method of manufacture for cyclic dextrin. The manufacturing process involves two sequential enzymatic reactions using α-amylase and 1,4-α-D-glucan branching enzyme (branching enzyme).1 In the first reaction, a cornstarch slurry is mixed with an α-amylase solution and heated to hydrolyze the α-(1,4) glucosidic bonds along the starch cluster and release clustered oligosaccharides composed of short linear α-(1,4) glucose chains. The mixture is cooled and the pH is adjusted for the second enzymatic step. The second enzymatic reaction involves the addition of the branching enzyme, a catalyst for the cyclization reaction to form branched cyclic dextrin molecules, to the oligosaccharide mixture. Sodium hydroxide is added during the reaction to control the pH, and hydrochloric acid is added at the end of the reaction to denature the branching enzyme, as well as re-adjust the pH of the mixture. The cyclic dextrin product is decolorized, filtered, evaporated, and spray-dried. Ezaki notes that the branching enzyme is inactivated by the high temperatures and acid conditions during the final steps. Ezaki also notes that cyclic dextrin is produced in accordance with cGMP, and all processing aids used in the manufacturing process are in compliance with applicable regulations in Title 21 of the Code of Federal Regulations (21 CFR).
Ezaki provides specifications for cyclic dextrin. Specifications include heavy metal and microbial residue limitations in cyclic dextrin. The specifications for heavy metals are: lead (< 1 milligram per kilogram, (mg/kg)) and arsenic (< 1 mg/kg). The microbial specifications are: yeasts and molds (≤ 50 colony forming units/g) and coliforms (negative). Ezaki states that the branched cyclic dextrin content of sample lots is stable at room temperature for up to 77 months.
Ezaki provides an estimated daily intake (EDI) for cyclic dextrin. Using the results from the National Health and Nutrition Examination Survey (2003-2004), Ezaki calculates an EDI of 425 mg/kg body weight (bw)/day (d) at the mean, and 1,011 mg/kg bw/d at the 90th percentile for all intended uses of cyclic dextrin.
Ezaki discusses published in vitro and in vivo metabolism studies on cyclic dextrin. Ezaki states that cyclic dextrin is hydrolyzed to maltose and maltotriose followed by complete digestion to produce glucose and that the metabolic fate of cyclic dextrin is similar to that of γ-cyclodextrin. Based on this, Ezaki considers toxicological studies on γ-cyclodextrin to be appropriate for assessing the safety of cyclic dextrin.
Ezaki discusses published safety data for γ-cyclodextrin including acute, subchronic, mutagenic, and chronic studies in animals, as well as studies in humans. Ezaki also discusses several published acute oral administration studies of γ- cyclodextrin, showing that this compound has low toxicity in rats and mice (i.e., LD50 values of < 8,000 and < 15,000 mg/kg bw, respectively). In addition, a published acute study showed that an oral dose (2,000 mg/kg bw), the highest dose tested, of cyclic dextrin had no toxicological adverse effects in rats.
Ezaki states that published subchronic studies using Wistar rats or Beagle dogs fed diets containing γ-cyclodextrin showed no adverse toxicological effects at the highest doses tested (i.e., 11,400 and 12,700 mg/kg bw/d for male and female rats, respectively; and 7,700 and 8,300 mg/kg bw/d for male and female dogs, respectively). Results of a published human study were also discussed by Ezaki, where male subjects consumed up to 35,000 mg of cyclic dextrin in a prototype sports drink, leading to the conclusion that cyclic dextrin was well-tolerated with no adverse effects or gastrointestinal symptoms.
Standards of Identity
In the notice, Ezaki states its intention to use cyclic dextrin in several food categories, including foods for which standards of identity exist, located in 21 CFR. 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 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 Ezaki’s notice that cyclic dextrin is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing cyclic dextrin. Accordingly, this response should not be construed to be a statement that foods that contain cyclic dextrin, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Ezaki, as well as other information available to FDA, the agency has no questions at this time regarding Ezaki’s conclusion that cyclic dextrin 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 cyclic dextrin. As always, it is the continuing responsibility of Ezaki 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 000404, 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
11,4-α-D-glucan branching enzyme is the subject of GRN 000405 and GRN 000406; these related notices were reviewed concurrently.