Agency Response Letter GRAS Notice No. GRN 000309
CFSAN/Office of Food Additive Safety
June 14, 2010
1424 W. Sam Houston Pkwy., Ste. 160
Houston, TX 77043
Re: GRAS Notice No. GRN 000309
Dear Mr. Cho:
The Food and Drug Administration (FDA) is responding to the notice, dated December 10, 2009, that PeopleAndTechnologies, LLC submitted on behalf of Glucan Corporation, Limited (Glucan) 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 15, 2009, filed it on December 17, 2009, and designated it as GRAS Notice No. GRN 000309. In a letter dated April 9, 2010, Glucan limited the intended use of the ingredient to those foods described in the following paragraph.
The subject of the notice is beta-glucan derived from Aureobasidium pullulans. The notice informs FDA of the view of Glucan that beta-glucan derived from A. pullulans is GRAS, through scientific procedures, for use as an ingredient in baked goods and baking mixes, beverages and beverage bases, cereal and cereal products, dairy product analogs, milk and milk products, plant protein products, processed fruits and fruit juices, and soft candy at concentrations ranging from 120 to 150 milligrams (mg) per serving.
21 CFR 101.4 states that all ingredients must be declared by their common or usual name and 21 CFR 102.5 outlines general principles to use when establishing common or usual names for nonstandardized foods. Our use of beta-glucan derived from A. pullulans in this letter should not be considered an endorsement or recommendation of that term as an appropriate common or usual name for the purpose of declaring the substance in the ingredient statement of foods that contain that ingredient. Issues associated with labeling and the appropriate common or usual name of a food are the responsibility of the Office of Nutrition, Labeling, and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition.
Glucan identifies beta-glucan derived from A. pullulans as a beta-1,3/1,6-glucan and describes it as a light brown/beige powder with high solubility in water. Glucan provides specifications for food-grade beta-glucan derived from A. pullulans, including heavy metal and microbial limitations. The specifications are consistent with those established by the Korean Food Code.
Glucan notes that beta-glucan derived from A. pullulans is intended for use as an ingredient in a variety of foods at ranges dependent on the intended food use. Glucan further notes that the use of beta-glucan derived from A. pullulans in dairy products and beverages, such as milk, yogurt, cheese, and fruit juices, is self-limiting due to aggregations of the compound at higher concentrations which lead to a tacky or slimy mouth feel.
Glucan provides information on the characteristics of A. pullulans, as well as the development, safety, and identity of the production strain. Glucan states that A. pullulans is a polymorphic fungus that can be found in lake water, on leaves and wood, as well as on foods such as cereal, tomatoes, and cheese. Glucan states that the production strain A. pullulans strain SM-2001 is developed by mutating the parental strain A. pullulans strain ATCC 42023 by ultraviolet (UV) treatment. Glucan states that A. pullulans strain SM-2001 produces more beta-glucan than the parental strain. The identity of A. pullulans strain SM-2001 is first confirmed by the size and color of the fungal colonies, and then by the amount of beta-1,3/1,6-glucan secreted before fermentation. Glucan states that A. pullulans strain SM-2001 is maintained in the Korean Culture Center of Microorganisms (KCCM) as KCCM 10307.
In the notice, Glucan describes the production of beta-glucan derived from A. pullulans. Glucan states that the beta-glucan is produced by the controlled fermentation, sterilization, and filtration of the production strain. Glucan states that the fermentation conditions are monitored periodically and the viscosity and temperature are automatically controlled. Glucan states that the purity of the culture during fermentation is monitored by measuring the heterotrophic plate count from a sample of the fermented media. Glucan also states that the quality of the fermented culture is checked by measuring the viscosity. Glucan states that once fermentation is complete, a sample is checked for beta-glucan content to verify that specifications have been met, and the whole batch is sterilized. Glucan also states that after sterilization, fungal cells and residues are removed by multiple filtration steps. beta-Glucan with the desired molecular weight is purified using ultrafiltration and the final product is spray-dried. Glucan notes that only physical force is used to purify and filter the product and no additional materials or chemicals are used during the filtration and purification steps. The notifier also notes that all materials used in the processing steps are in compliance with FDA regulations.
Glucan reports an all-user mean estimated daily intake (EDI) of 6.3 mg per kilogram body weight per day (mg/kg bw/d) or 291.3 mg per person per day (mg/p/d), and a 90th percentile of 14.5 mg/kg bw/d or 583.4 mg/p/d. Glucan uses the results from the United States Department of Agriculture (USDA) 1994-1996 Continuing Survey of Food Intakes by Individuals (USDA CSFII 1994-1996) survey (USDA, 2000) to calculate the EDI of beta-glucan derived from A. pullulans in foods under the intended uses listed above. The Institute of Medicine of the National Academies recommends a dietary allowance of fiber based on gender and age of approximately 38 gram [38,000 mg] per day (g/d) and 25 [25,000 mg] g/d for men and women, respectively.
Glucan discusses studies on beta-glucan derived from A. pullulans. The notifier states that the safety of beta-glucan derived from A. pullulans is supported by published acute toxicity, subchronic oral toxicity, and genotoxicity studies conducted in mice. Glucan states that the acute toxicy and subchronic oral toxicity studies show no evidence of toxicity; in addition, the genotoxicity studies show no adverse effects. The notifier also corroborates the safety of beta-glucan derived from A. pullulans with an unpublished subchronic oral toxicity study conducted in rats and an unpublished study conducted in humans. In the subchronic oral toxicity study, rats showed no systemic or gastrointestinal toxicity at the highest tested level of 2000 mg/kg bw/d (1000 mg/kg bw twice a day) of beta-glucan derived from A. pullulans. From the human study, Glucan concludes that 400 mg per day of beta-glucan derived from A. pullulans has no adverse effects. Glucan concludes that the results of these published and unpublished studies support the safety of beta-glucan derived from A. pullulans.
Standards of Identity
In the notice, Glucan states its intention to use beta-glucan derived from A. pullulans 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.
Potential Labeling Issues
Under section 403(a) of the Federal Food, Drug, and Cosmetic Act (FFDCA), a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FFDCA lays out the statutory framework for a health claim. In describing the intended use of beta-glucan derived from A. pullulans and in describing the information that Glucan relies on to conclude that beta-glucan derived from A. pullulans is GRAS under the conditions of its intended use, Glucan raises a potential labeling issue under these labeling provisions of the FFDCA. If products that contain beta-glucan derived from A. pullulans bear any claims on the label or in labeling, such claims are the purview of ONLDS. The Office of Food Additive Safety neither consulted with ONLDS on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about beta-glucan derived from A. pullulans on the label or in labeling.
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 Glucan’s notice that beta-glucan derived from A. pullulans is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing beta-glucan derived from A. pullulans. Accordingly, this response should not be construed to be a statement that foods that contain beta-glucan derived from A. pullulans, if introduced or delivered for introduction into interstate commerce, would not violate section 30 l(ll).
Based on the information provided by Glucan, as well as other information available to FDA, the agency has no questions at this time regarding Glucan’s conclusion that beta-glucan derived from A. pullulans 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 beta-glucan derived from A. pullulans. It is the responsibility of Glucan to continue 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 000309, 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