Agency Response Letter GRAS Notice No. GRN 000458
CFSAN/Office of Food Additive Safety
August 23, 2013
Susan Cho, Ph.D.
6309 Morning Dew Court
Clarksville, MD 21029
Re: GRAS Notice No. GRN 000458
Dear Dr. Cho:
The Food and Drug Administration (FDA) is responding to the notice, dated January 21, 2013, that you submitted on behalf of Shangdong Longlive Bio-technology Company, Ltd. (Shangdong Longlive) 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 January 24, 2013, filed it on February 8, 2013 and designated it as GRAS Notice No. GRN 000458.
The subject of the notice is xylooligosaccharides (XOS). The notice informs FDA of the view of Shangdong Longlive that XOS is GRAS, through scientific procedures, for use as a bulking agent in beers and ales at a level of 0.5 grams per serving (g/serving); and, as an ingredient in breakfast bars, cereal bars, cheese, chewing gums, custards, flavored and soy milk, gelatin desserts and salads, medical foods, milk and milk products, isotonic beverages, milk desserts, ready-to-drink milk-based meal replacements, power bars, puddings, protein bars, processed fruits, juice drinks and punch, ready-to-eat cereals, sports drinks, and yogurt at levels ranging from 0.2 to 2.4 g/serving.
As part of its notice, Shangdong Longlive includes a statement from a panel of individuals (Shangdong Longlive’s GRAS panel) that evaluated the data and information that are the basis for Shangdong Longlive’s GRAS determination. Shangdong Longlive considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Shangdong Longlive’s GRAS panel summarized data on the identity and source of XOS and reported its finding on the absence of adverse effects in published safety studies conducted on XOS. Based on this review, Shangdong Longlive’s GRAS panel concluded that XOS is GRAS under the conditions of its intended use.
Shangdong Longlive describes XOS as non-digestible oligosaccharides comprised of 2 to 6 xylose moieties linked by β-(1-4) glycosidic bonds. Shangdong Longlive manufactures XOS by enzymatic hydrolysis of xylan. Shangdong Longlive manufactures XOS by enzymatic hydrolysis of xylan. XOS is composed of ≥ 95% carbohydrates, with less than 5% consisting of digestible sugars (e.g., xylose, glucose, and arabinose).
Shangdong Longlive describes the method of manufacture for XOS. Powdered corncobs are pretreated with aqueous acetic acid to break down hemicelluloses. The preparation is then treated with an endoxylanase isolated from Streptomyces olivaceoviridis. Shangdong Longlive notes that this enzyme is suitable for use in food and is not present in the final XOS product. During this enzymatic reaction the β-1,4-xylosidic bonds in the β-(1,4)-linked D-xylosyl backbone of xylan are hydrolyzed to produce crude XOS. The resulting mixture is subjected to filtration, decolorization, and ion exchange purification processes using food-grade materials. The final XOS product is then concentrated and spray dried.
Shangdong Longlive describes product specifications for the 95% XOS as well as multiple product formulations of XOS concentrations of 20, 35, or 70% (dry weight basis) using maltodextrin as a diluent. Specifications include limits for moisture (≤ 6%), arsenic (≤ 0.3 milligrams per kilogram (mg/kg)), and lead (≤ 0.5 mg/kg). Specifications also include microbial limits, including total plate count (< 1000 colony forming units (cfu) per g), yeast and mold (< 25 cfu/g) and Escherichia coli, staphylococci, salmonellas, and shigellas (negative in 25 g).
Shangdong Longlive estimates dietary exposure to XOS based on food consumption data reported in the National Health and Nutrition Examination Survey (NHANES; 2009-2010). Shangdong Longlive chose NHANES food codes representative of each intended food use and assumed that 100% of products in each category would contain XOS at an average level of 1.3 g/serving. The mean and 90th percentile estimates for XOS from all intended uses would be 5.1 g per person per day (g/p/d) (equivalent to 85 mg/kg body weight per day (bw/d)) and 9.8 g/p/d (equivalent to 163 mg/kg bw/d), respectively.
Shangdong Longlive notes that XOS is a hydrolysis product of xylan, a common hemicellulose of cereal grains (corn bran, rice bran, wheat bran, and psyllium). Shangdong Longlive further notes that XOS is not naturally present in food at significant quantities. Xylose, a hydrolysis product of XOS, is naturally present in foods in small quantities. Shangdong Longlive concludes that the abundance of xylans in cereal grains is evidence of long term exposure to xylose-based, nondigestible carbohydrates in the human diet.
Shangdong Longlive discusses published information to support the safety of XOS as an ingredient in food. Shangdong Longlive discusses published data and information pertaining to the metabolic fate of XOS. Shangdong Longlive discusses that XOS remains largely undigested in the upper gastrointestinal tract and is fermented in the colon to gases and short chain fatty acids (SCFA), such as acetate, propionate, and butyrate. Shangdong Longlive considers that the metabolic profile of XOS is similar to substances such as inulins, fructooligosaccharides, and galactooligosaccharides. Additionally, Shangdong Longlive states that the metabolism of XOS does not raise safety concerns and no systemic toxicity is expected to follow ingestion of XOS.
Shangdong Longlive discusses a number of published and unpublished safety studies conducted using XOS, including single-dose acute toxicity studies in rats and mice and a 13-week subchronic toxicity studies in rats. Shangdong Longlive discusses a lack of adverse effects in a 13-week study in Sprague-Dawley rats in which the highest doses of XOS tested were 11,510 mg/kg bw/day for males and 14,950 mg/kg bw/day for females.
Shangdong Longlive also discusses a number of published tolerance studies in humans who consumed XOS orally. One study showed that up to 5 g per day of XOS in healthy adults was well tolerated and resulted in decreased fecal hardness. Another study in healthy volunteers demonstrated that when the daily XOS consumption was gradually increased from 3 g (week 1 and 2), to 5 g (week 3) and finally to 8, 10, or 12 g (week 4), the incidence of diarrhea in the treatment group was similar to the control group. Citing a review of published human tolerance studies, Shangdong Longlive states that the maximum level of XOS that does not cause gastrointestinal symptoms in men is 7.2 g/p/d.
Shangdong Longlive also discusses a number of published studies performed using substances similar to XOS, such as xylan and arabinoxylooligoosaccharide. In separate studies, feeding Wistar rats xylan or arabinoxylooligoosaccharide did not result in any adverse effects. Shangdong Longlive concludes that these studies corroborate the safety of XOS consumption because these substances are all non-digestible oligosaccharides. Shangdong Longlive also states that XOS is not mutagenic or carcinogenic. Based on the totality of evidence, Shangdong Longlive concludes that XOS is GRAS under the intended conditions of use.
Standards of Identity
In the notice, Shangdong Longlive states its intention to use XOS 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
In describing the fiber content of XOS and the clinical study information that Shangdong Longlive relies on to conclude that XOS is GRAS under the intended conditions of use, Shangdong Longlive raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act). Under section 403(a) of the FD&C Act, a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FD&C Act lays out the statutory framework for the use of labeling claims that characterize the level of a nutrient in a food or that characterize the relationship of a nutrient to a disease or health-related condition. If products that contain XOS bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition, Labeling and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition. 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 XOS on the label or in labeling.
In its notice, Shangdong Longlive informs FDA that one intended use of XOS is use in medical foods. Section 5(b) of the Orphan Drug Act (ODA) defines a medical food as a food that is formulated to be consumed or administered enterally under the supervision of a physician and that is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation. Section 403(q) of the FD&C Act lays out the statutory framework for nutrition labeling of food products. Section 403(r) of the FD&C Act lays out the statutory framework for health claims and nutrient content claims. Under section 403(q)(5)(A)(iv) of the FD&C Act and FDA's implementing regulations in 21 CFR 101.9(j)(8), the requirements for nutrition labeling do not apply to medical foods as defined in section 5(b) of the ODA. Under section 403(r)(5)(A) of the FD&C Act and FDA's implementing regulations in 21 CFR 101.13(q)(4)(ii) and 21 CFR 101.14(f)(2), the requirements for nutrient content claims and health claims, respectively, do not apply to medical foods as defined in section 5(b) of the ODA. For your information, FDA’s response to Shangdong Longlive’s notice that XOS is GRAS for use in medical foods does not address the question of whether any particular food product that contains XOS as an ingredient would be a medical food within the meaning of section 5(b) of the ODA and, thus, would be exempt from the requirements for nutrition labeling, nutrient content claims, and health claims.
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 Shandong Longlive’s notice that XOS is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing XOS. Accordingly, this response should not be construed to be a statement that foods that contain XOS, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Shangdong Longlive, as well as other information available to FDA, the agency has no questions at this time regarding Shangdong Longlive’s conclusion that XOS 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 XOS. As always, it is the continuing responsibility of Shangdong Longlive 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 000458, 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