Agency Response Letter GRAS Notice No. GRN 000236
CFSAN/Office of Food Additive Safety
July 28, 2008
Gavin Thompson, Ph.D.
Environ International Corporation
4350 North Fairfax Drive
Arlington, VA 22203
Re: GRAS Notice No. GRN 000236
Dear Dr. Thompson:
The Food and Drug Administration (FDA) is responding to the notice, dated November 5, 2007, that you submitted on behalf of Friesland Foods Domo (Friesland) 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 this notice on November 6, 2007, filed it on November 7, 2007, and designated it as GRAS Notice No. GRN 000236.
The subject of the notice is galacto-oligosacharides (GOS). The notice informs FDA of the view of Friesland that GOS is GRAS, through scientific procedures, for use as an ingredient in term infant formula at a level of 5 grams per liter (g/l)(1) and other food categories at levels shown in Table 1.
|Food Category||Serving Size (g)||Maximum GOS per serving (g/serving)|
|Frozen dairy desserts||70||3.0|
|Fruit drinks and energy drinks||240||5.0|
|Fitness water and thirst quenchers||240||3.0|
|Fruit pie filling||85||5.0|
|Baby yogurt drink||125||3.0|
|Syrup flavorings for milk||40||5.0|
|Meal replacement drinks||250||5.0|
|Meal replacement drinks for children||250||3.0|
Friesland includes the findings of a panel of individuals (Friesland’s GRAS panel) who evaluated the data and information that are the basis for Friesland’s GRAS determination. Friesland considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food.
Friesland describes the identity and composition of its GOS ingredient. GOS is a mixture of di- to octasaccharides composed of 1 to 7 galactose units linked to a glucose molecule at the reducing end. The major saccharide in the GOS fraction of the preparation is the trisaccharide O-β-D-galactopyanosyl-(1-4)-O-ß-D-galactopyranosyl-(l-4)-β-D-glucose. The molecular weights of the individual oligosaccharides range between 342 (disaccharide) and 1315 (octasaccharide) Daltons (D). The average molecular weight of the GOS fraction is 522.28 D. The GOS that is the subject of GRN 000236 is primarily 4'-galacto-oligosaccharides. The CAS Registry number for this specific type of oligosaccharide is 6587-31-1. Friesland states that their preparation is a product containing galacto-oligosaccharides, lactose, glucose, and a small amount of galactose.
GOS is produced through the enzymatic conversion of lactose. Edible lactose, in suspension, is isolated from sweet whey (derived from cow's milk), and subjected to the action of a β-galactosidase from Bacillus circulans.(2) The enzyme β-galactosidase and sodium hydroxide are added to the liquid lactose slurry and mixed. This enzyme reaction gives rise to galacto-oligosaccharides with increasing chain lengths by a series of transglycosylation reactions. The mixture is then heated and citric acid is added in order to inactivate the enzyme and stop the reaction. Then residues and possible impurities are removed from the product by adsorption and filtration processes. The material is then concentrated by evaporation of the water to produce the final product.
The notifier provides product specifications for its GOS ingredient with minimum levels of total GOS (≥ 57 % dry matter (DM)) and galactose (≥ 0.8 % DM), and maximum levels of lactose (≤ 23 % DM) and glucose (≤ 22 % DM). Specifications also include limits on lead (≤ 0.2 mg/kg), arsenic (≤ 0.4 mg/kg), cadmium (≤ 0.06 mg/kg), and mercury (≤ 0.5 mg/kg). Based on specifications and batch analyses, a minimum GOS level can be calculated as ≥ 42 % of the total composition.
Based on data available from the National Health and Nutrition Examination Survey 2003-2004 and United States Department of Agriculture survey files, Friesland estimates the mean intake of their GOS ingredient as 8.0 grams/person/day (g/p/d) and 16.8 g/p/d at the 90th percentile for eaters only, two and greater years of age. The mean estimated intake by infants zero to 5 months of age is 5.3 g/infant/day, the mean intake by infants 6 to 11 months of age is 6.1 g/infant/day, and the mean intake by infants 12 to 23 months of age is 5.3 g/infant/day.
Friesland discusses published studies showing that human milk contains a complex mixture of oligosaccharides. The concentration of complex oligosaccharides in mature human milk is estimated to range from 5 to 8 g/l. Friesland notes that oligosaccharide concentrations as high as 25.6 g/l in human colostrum and 15.4 g/l in mature milk have been reported. Friesland states that bovine milk oligosaccharides are structurally similar to those found in human milk.
Friesland discusses published and unpublished studies conducted with their preparation and similar GOS-containing formulations. These studies include in vitro and in vivo studies, a 90-day animal study, and adult, term and preterm infant clinical trials. Based on these studies Friesland concludes that there is no evidence in the available literature of any adverse effects of GOS used at the intended levels.
Standards of Identity
In the notice, Friesland 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 label claims
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 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. In describing the intended use of GOS and in describing the information that Friesland relies on to conclude that GOS is GRAS under the conditions of its intended use, Friesland raises a potential issue under these labeling provisions of the FFDCA. 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 (CFSAN). 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.
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. Friesland should be aware that FDA’s response to Friesland’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 Friesland’s notice that GOS is GRAS for use as an ingredient in term infant formula and in certain foods, 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).
Based on the information provided by Friesland, as well as other information available to FDA, the agency has no questions at this time regarding Friesland’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 Friesland 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 000236, as well as a copy of the information in this notice that conforms to the information in the proposed GRAS exemption claim (proposed 21 CFR 170.36(c)(1)), is available for public review and copying on the homepage of OFAS (on the Internet at http://www.cfsan.fda.gov/~lrd/foodadd.html).
Laura M. Tarantino, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
(1)The notice dated November 5, 2007, intended the use in term infant formula to be at a level of 8 g/L. An amendment, dated February 8, 2008, amended the use in term infant formula to be at a level of 5 g/L.
(2)β-Galactosidase is the enzyme used in the production of GOS. Friesland states that this enzyme has a long history of use in food ingredients. The bacterial species used to make the β-galactosidase preparation is Bacillus circulans, strain ATCC 31382. Friesland states that B. circulans has no pathogenic activity, is not mutagenic, is negative for all tested toxins, has low acute toxicity, and has regulatory approvals in other countries.