Agency Response Letter GRAS Notice No. GRN 000334
CFSAN/Office of Food Additive Safety
October 27, 2010
Claire L. Kruger, Ph.D.
Spherix Consulting, Inc.
6430 Rockledge Drive, Ste. 503
Bethesda, MD 20817
Re: GRAS Notice No. GRN 000334
Dear Dr. Kruger:
The Food and Drug Administration (FDA) is responding to the notice, dated April 20, 2010, that you submitted on behalf of Yakult Pharmaceutical Industry Co., Ltd. (Yakult) 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 April 23, 2010, filed it on May 3, 2010, and designated it as GRAS Notice No. GRN 000334.
The subject of the notice is galacto-oligosacharides (GOS). The notice informs FDA of the view of Yakult that GOS is GRAS, through scientific procedures, for use as an ingredient in term infant formula at a concentration of 7.2 grams1 per liter (g/L) and other food categories as shown in Table 1.
|Food Category||Approximate serving size (g)||Maximum g GOS per serving|
|Milk, milk substitute such as soy milk||250||5.0|
|Milk based meal replacement||250||5.0|
|White sauces, milk gravies and cheese sauces||80||1|
|Milk desserts, frozen like ice creams||75||1.5|
|Pudding and custards including baby foods||108||1.5|
|Egg soups; soups with legumes as major ingredient; soups with grain products as major ingredient; potato soups; deep-yellow vegetable soups; tomato soups; other vegetable soups||245||1.5|
|Cakes, heavy weight||125||1.25|
|Cakes, medium weight||80||0.8|
|Cakes, light weight||55||0.55|
|Coffee cakes, crumb cakes, doughnuts, Danish, sweet rolls, sweet quick type breads, muffins, toaster pastries||55||0.55|
|Crackers that are usually used as snacks||30||0.3|
|French toast, pancakes||110||1.1|
|Pies, cobblers, fruit crisps, turnovers, other pastries||125||1.25|
|Grain-based bars with or without filling or coating, e.g., breakfast bars, granola bars, rice cereal bars||40||0.4|
|Ready-to-eat cereals (dry) for baby food||15||0.6|
|Ready-to-serve cereals for baby food||110||0.6|
|Fruit juices (including citrus fruit juices) and nectars||250||4|
|Fruit juices, vegetable juices and juice mixtures baby food||125||2|
|Jellies, jams, preserves||20||5.0|
|Fruit drinks such as fruit juice drinks, fruit flavored drinks, sports drinks, etc||250||5.0|
|Non fruit beverages, including energy drinks||250||11|
|Beverage concentrated (powder)||250||5.0|
As part of its notice, Yakult includes the report of a panel of individuals (Yakult’s GRAS panel) who evaluated the data and information that are the basis for Yakult’s GRAS determination. Yakult considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food and term infant formula. Yakult’s GRAS panel evaluated composition, method of manufacture, product specifications, exposure, current use in other countries, consumption estimates, published and unpublished literature, and its intended use. Based on this review, Yakult’s GRAS panel concluded that GOS is GRAS under the intended conditions of use.
Yakult includes information about the identity and composition of GOS. GOS is a mixture of di- to hexasaccharides composed of 1 to 5 galactose units linked to a glucose molecule at the reducing end. The major saccharide in the GOS fraction is the trisaccharide O-β-D-galactopyranosyl-(1-4)-O-β-D-galactopyranosyl-(l-4)-β-D-glucose. The molecular weights of the individual oligosaccharides range between 342 (disaccharide) and 991 (hexasaccharide) Daltons. The GOS that is the subject of GRN 000334 is primarily 4'-galacto-oligosaccharides.
GOS is prepared from food-grade lactose. The lactose is subjected to the action of two β-galactosidases from Sporobolomyces singularis and Kluyveromyces lactis.2 Yakult notes that β-galactosidases possess hydrolytic activity, which breaks the galactose-β-4-glucose bond, and transgalactosylic activity, which converts lactose into galacto-oligosaccharides. β-Galactosidase derived from S. singularis possesses transgalactosylation activity; this enzyme is used primarily to catalyze the production of galacto-oligosaccharides with increasing chain length by a series of transglycosylation reactions. Yakult states that the enzyme derived from K. lactis is used primarily to degrade unreacted lactose. GOS is manufactured in syrup and powder forms; both forms contain GOS, residual lactose, glucose, and galactose.
Yakult provides product specifications for the GOS ingredient. Specifications include minimum levels of GOS (55 percent dry weight (DW)), and maximum limits on lead (less than 1 milligram/kilogram (mg/kg)), arsenic (less than 1 mg/kg), and moisture (powdered product only; less than 3 percent).
Yakult estimates the daily intake of GOS based on intended use levels in adult foods and infant formula and consumption data available from the 2003–2004 National Health and Nutrition Examination Survey. Yakult estimates the mean intake in infants up to 1 year of age as 14.7 grams per person per day (g/p/d) and the 90th percentile as 26.8 g/p/d. Yakult estimates the mean intake for the total population as 12.2 g/p/d and the 90th percentile as 25.3 g/p/d.
Yakult discusses absorption, distribution, metabolism (including in vitro) and excretion studies of GOS. Published information has shown that GOS is indigestible by gastric juice and α-amylase but it is fermented when it reaches the colon. In the colon, GOS is metabolized by colonic microflora to fermentation products (short-chain fatty acids, carbon dioxide, methane and hydrogen gases). The notifier states that the safety of GOS is supported by published subchronic and genotoxicity studies conducted in animals. Yakult also discusses published clinical studies in adults and infants including pre-term and term infants to further support its view that GOS is GRAS for the intended uses in infant formula.
Potential Labeling Issues
In describing the colonic microflora in the clinical studies that Yakult relies on to conclude that GOS is GRAS under the conditions of its intended use, Yakult raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FFDCA). In addition, in describing the intended use of GOS, Yakult list energy drinks, sport drinks, and term infant formula; these food categories often contain health or nutrient content claims. Under section 403(a) of the 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 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 GOS 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 GOS on the label or in labeling.
Intended Use in Infant Formula
Under section 412 of the FFDCA, a manufacturer of a new infant formula must make a submission to FDA, providing required assurances about the formula, at least 90 days before the formula is marketed. Yakult should be aware that FDA’s response to Yakult’s GRAS notice does not alleviate the responsibility of any infant formula manufacturer who intends to market an infant formula that contains GOS to make the submission required by section 412.
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 Yakult’s notice that GOS is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing GOS. Accordingly, this response should not be construed to be a statement that foods that contain GOS, if introduced or delivered for introduction into interstate commerce, would not violate section 30l(ll).
Based on the information provided by Yakult, as well as other information available to FDA, the agency has no questions at this time regarding Yakult’s conclusion that GOS 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 GOS. As always, it is the continuing responsibility of Yakult 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 000334, 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
1The notice dated April 20, 2010, intended the use in term infant formula to be at a concentration of 8 g/L. An amendment, dated August 17, 2010, amended the use in term infant formula to be at a concentration of 7.2 g/L.
2β-Galactosidase is the enzyme used in the production of GOS. Yakult notes that this enzyme has a long history of use in food ingredients. The bacterial species used in the production are S. singularis YIT 10047 and K. lactis. Yakult states that both microorganisms are non-toxigenic and non-pathogenic, noting that K. lactis is approved for the production of lactase enzyme preparations under regulation 21 CFR 184.1388.