Agency Response Letter GRAS Notice No. 000489
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CFSAN/Office of Food Additive Safety
May 22, 2014
Carol T. Culhane, PHEc, MBA
International Food Focus Ltd.
211 Carlton Street, East Office
Toronto, ON M5A 2K9
Re: GRAS Notice No. GRN 000489
Dear Ms. Culhane:
The Food and Drug Administration (FDA) is responding to the notice, dated September 16, 2013, that you submitted on behalf of International Dairy Ingredients Inc. (IDI) 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 November 6, 2013, filed it on November 25, 2013, and designated it as GRAS Notice No. GRN 000489. Additional clarifying information regarding the intended use and specifications was provided in an amendment dated February 7, 2014.
The subject of the notice is galacto-oligosaccharides (GOS). The notice informs FDA of the view of IDI that GOS is GRAS, through scientific procedures, for use as an ingredient in infant formula and follow-on formula at a maximum concentration of 4 grams per liter (g/L) of formula; in follow-on foods at a maximum concentration of 0.38%; and, in yogurts, yogurt drinks, frozen yogurts, ice milks, custards and puddings; dairy shake mixes, instant breakfasts, meal replacements, carbonated and non-carbonated beverages, juice-based beverages, juice coolers, sweetened and flavored waters, ready-to-drink iced teas and coffees, and sport and isotonic drinks at a maximum concentration of 2%.
IDI includes information about the identity and composition of GOS. IDI describes GOS as a spray-dried powder and states that GOS is synthesized from food grade lactose using a transgalactosidic reaction with a β-galactosidase enzyme derived from Aspergillus oryzae.1 The enzyme catalyzes the extension of lactose to form a mixture of β-linked disaccharide, trisaccharide, tetrasaccharide, and pentasaccharide chains. GOS also contains the monosaccharides glucose, galactose, and fructose, and the disaccharides lactose, maltose, and sucrose.
IDI describes the manufacturing process for GOS. The starting material is lactose (extracted from whey), which is first dissolved in water. The transgalactosylation reaction is initiated by adding the β-galactosidase enzyme preparation to the solution under controlled conditions. When the reaction results in an acceptable concentration of GOS, the mixture is heated to deactivate the enzyme. Activated carbon and a filter aid are then added, and the solution is filtered to remove impurities. The resulting solution is then evaporated to specified concentrations to form a GOS syrup product.
IDI provides product specifications for the GOS product. The specifications include the minimum levels of dry matter (DM) (≥ 73.5 %) and total GOS (≥ 26.0 % of DM). The specifications also include limits on moisture (≤ 26.5 %), protein (≤ 0.2 %), lactose (≤ 18 % of DM), glucose (≤ 22.0 % of DM), galactose (≥ 8.0 % of DM), and heavy metal specifications including lead (≤0.2 milligram per kilogram (mg/kg)), cadmium (≤ 0.06 mg/kg), arsenic (≤ 0.4 mg/kg), and mercury (≤ 0.5 mg/kg). The specifications further include limits on microbiological contaminants, including Enterobacteriaceae (< 10 colony forming units per g).
IDI discusses the estimated dietary exposure to GOS under its intended conditions of use, as well as a detailed summary of the estimated exposures reported in previous GRAS notices (i.e., GRNs 000236, 000286, and 000334). The highest previously-notified estimated exposures to GOS were reported in GRN 000334, where the mean and 90th percentile exposures to infants up to 1 year of age were 14.7 and 26.8 g/person/day, respectively, and the mean and 90th percentile exposures to persons aged 2 years and older were 12.2 and 25.3 g/person/day, respectively.
IDI provides an estimate of dietary exposure to GOS from the intended uses provided in GRN 000489. The exposure to GOS was determined using food consumption data from the What We Eat in America (WWEIA) dietary component of the National Health and Nutrition Examination Surveys (NHANES, 2007-2010). IDI states that the highest daily exposure to GOS from their intended use in infant formula and baby foods is by infants aged 6-11 months, where the mean and 90th percentile exposures are 3.6 and 5.2 g/person/day, respectively. The mean and 90th percentile exposures to GOS for infants and toddlers aged 6 to 35 months were determined to be 2.2 and 4.9 g/person/day, respectively. The mean and 90th percentile exposures to GOS from the intended use in foods and beverages for individuals aged two years and older were determined to be 7.17 and 14.40 g/person/day, respectively. Since the uses and proposed concentrations in GRN 000489 are not exactly the same as those in GRNs 000236, 000286, and 000334, these estimates, while generally substitutive for those in the previous notices, are lower because of lower use levels. These estimates are not additive to the previous estimated exposures in GRN 000334 and suggest that there would be no increase in exposure to GOS from this notifier’s intended uses.
IDI discusses the safety of GOS consumption, including the relevant absorption, distribution, metabolism, and elimination pathways for GOS. The disaccharides found in GOS are enzymatically broken down to monosaccharides including glucose, galactose, and fructose, which are absorbed by the body for use in normal physiologic functions. Longer chains in GOS are fermented by colonic bacteria to produce short chain fatty acids (mainly acetate, propionate, and butyrate) which are absorbed and utilized as energy sources. Fermentation of GOS also produces gases (i.e., hydrogen, carbon dioxide, methane), other biochemical substances (i.e., lactate, pyruvate, succinate and ethanol), as well as bacterial cell mass.
IDI incorporates by reference previously evaluated GRAS notices (i.e., GRNs 000236, 000286, and 000334) for the use of GOS, which included discussions of publicly available non-clinical studies. In GRN 000489 IDI focuses its discussion for GOS on published clinical trials. These clinical trials in which pre-term and term infants consumed infant formula containing up to 10 g of a mixture containing a 9:1 ratio of GOS:fructo-oligosaccharides revealed no adverse effects. In addition, clinical trials in which adults consumed GOS revealed no adverse effects at the highest levels tested.
Standards of Identity
In the notice, IDI states its intention to use GOS 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 intended use of GOS and in describing the information that IDI relies on to conclude that GOS is GRAS under the conditions of its intended use, IDI raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act). In describing the information that IDI relies on to conclude that GOS is GRAS, IDI discussed studies that show potential physiological effects of GOS that IDI views as beneficial. 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 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 (OFAS) 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.
The Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) amends the FD&C Act to require that the label of a food that is or contains an ingredient that bears or contains a “major food allergen” declare the presence of the allergen (section 403(w)). FALCPA defines a “major food allergen” as one of eight foods or food groups (i.e., milk, eggs, fish, Crustacean shellfish, tree nuts, peanuts, wheat, and soybeans) or a food ingredient that contains protein derived from one of those foods. GOS derived from milk may require labeling under FALCPA because it may contain proteins derived from milk. Although issues associated with labeling food are the responsibility of ONLDS, issues associated with FALCPA exemptions are the responsibility of the Food Allergen Coordinator in the OFAS.
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 IDI’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 301(ll).
Intended Use in Infant Formula
Under section 412 of the FD&C Act, 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. IDI should be aware that FDA's response to IDI’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.
Based on the information provided by IDI, as well as other information available to FDA, the agency has no questions at this time regarding IDI'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 IDI 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 000489, 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
1β-Galactosidase is the enzyme used in the production of GOS. The bacterial species used in the production of the enzyme is A. oryzae strain LAC4-UV6-1B. IDI provides information that states that the β-galactosidase enzyme preparation is GRAS for use as a food-processing ingredient.