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CFSAN/Office of Food Additive Safety
September 4, 2009
Craig Hadley, Ph.D.
Mead Johnson & Company
2400 West Lloyd Expressway
Evansville, IN 47721-0001
Re: GRAS Notice No. GRN 000233
Dear Dr. Hadley:
The Food and Drug Administration (FDA) is responding to the notice, dated August 22, 2007, that you submitted 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 August 23, 2007, filed it on September 5, 2007, and designated it as GRAS Notice No. GRN 000233.
The subject of the notice is a combination of galacto-oligosaccharides (GOS) and polydextrose (PDX). The notice informs FDA of the view of Mead Johnson & Company (Mead Johnson) that the combination of GOS and PDX is GRAS, through scientific procedures, for use as an ingredient in milk-based term infant formula at levels not to exceed 2 grams per liter (g/L) for GOS and 2 g/L for PDX.
Mead Johnson includes the findings of a panel of individuals (Mead Johnson’s GRAS panel) who evaluated the data and information that are the basis for Mead Johnson’s GRAS determination. Mead Johnson considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food.
Mead Johnson describes the identity and composition of GOS. 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-β-D-galactopyranosyl-(l-4)-β-D-glucose. The molecular weights of the individual oligosaccharides range between 342 (disaccharide) and 1315 (octasaccharide) Daltons (Da). The average molecular weight of the GOS fraction is approximately 522 Da. The GOS that is the subject of GRN 000233 is primarily 4'-galacto-oligosaccharides. The CAS Registry number for this specific type of oligosaccharide is 6587-31-1. Mead Johnson states that the GOS preparation is a product containing galacto-oligosaccharides, lactose, glucose, and a small amount of galactose.
Mead Johnson describes the identity and composition of PDX. PDX is an odorless, white to light cream, amorphous powder which consists of a polymer of glucose units with sorbitol end groups and citric acid attached to the polymer by mono- and diester bonds. The glucose molecules are randomly bonded, although the (β1-6) bond predominates. The molecular weight of polydextrose ranges between 250 and 18,000 Da with an average of about 1,500 Da. The average degree of polymerization (DP) is about 12; with the majority of polydextrose polymers having a DP of 30 or less; followed by polymers having a DP of 4 or less. Because of the random glucose-glucose and glucose-sorbitol bonds, polydextrose is more resistant to enzyme or acid hydrolysis than other glucose polymers such as insoluble starch. The CAS Registry number for PDX is 68424-04-4.
Mead Johnson describes the method of manufacture, and mentions specifications, for GOS. GOS is produced through the enzymatic conversion of edible lactose isolated from sweet whey (derived from cow’s milk) with a β-galactosidase.1 The β-galactosidase and sodium hydroxide are added to a liquid lactose slurry and mixed. This enzyme reaction gives rise to galacto-oligosaccharides with increasing chain lengths through 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. All processing aids and any impurities are removed from the product using activated carbon and cellulose. The remaining material is concentrated by water evaporation to produce either a powder or syrup product. Mead Johnson states that the final GOS product meets all food grade specifications.
Mead Johnson describes the method of manufacture, and mentions specifications, for PDX. PDX is prepared by a vacuum-melt condensation method, in which powdered glucose or a glucose-containing material such as hydrolyzed starch is heated under vacuum at 150 to 160 degree Celsius in the presence of a polyol such as sorbitol and low levels of a catalytic acid. The resulting product is then purified by ion exchange, membrane filtration, or carbon treatment to obtain PDX. PDX meeting both Joint FAO/WHO Expert Committee on Food Additives and Food Chemicals Codex (2003) specifications is available in powdered form or as an aqueous solution.
Mead Johnson provides an estimate of exposure for GOS and PDX. Mead Johnson estimates that the 90th percentile intake of GOS is 0.4 grams per kilogram body weight per day (g per kg bw per day). The notifier also estimates that the 90th percentile intake of PDX is 0.4 g per kg bw per day. Thus, the 90th percentile intake of GOS and PDX together is estimated to be 0.8 g per kg bw per day.
Mead Johnson discusses the safety of GOS. Mead Johnson discusses published and unpublished studies, including in vitro studies, studies in different animal models, as well as studies in human adults and infants. Mead Johnson notes that these studies show that consumption of up to 15 g per kg bw per day by experimental animals does not cause any adverse effects on microfloral populations, nutrient absorption and retention, weight gain, or food consumption. Based on these studies, Mead Johnson concludes that consumption of up to 20 g GOS per day by human adults does not cause any long-or short-term adverse effects and that consumption of up to 1.6 g GOS per kg bw per day by human infants does not cause any adverse effects on microfloral populations, nutrient absorption, blood biochemistry, or growth parameters.
Mead Johnson discusses the safety of PDX. Mead Johnson discusses published and unpublished studies, including in vitro studies, studies in different animal models, as well as studies in human adults and infants. Mead Johnson notes that only a small amount of PDX is digested by gastrointestinal enzymes and that PDX is more fully degraded by intestinal microbiota and subsequently excreted from the body. The notifier states that these studies showed no adverse effects in animals except as noted in one study where dosing neonatal rats with high concentrations of PDX (8 g per kg bw per day) by oral administration caused an increase in DNA and protein content in the pancreas suggesting pancreatic hyperplasia. However, this suggested pancreatic hyperplasia was not confirmed histopathologically, and such effects were not seen at lower doses of PDX (4 g per kg bw per day). Mead Johnson concludes that the totality of the available research indicates that the pancreatic response of the rat pups fed elevated levels of PDX is within the range of normal physiological response to resistant dietary carbohydrates, and is a phenomenon likely to occur during that specific developmental stage. Furthermore, Mead Johnson considers the pig digestive tract anatomically and functionally closer to that of the human and more physiologically relevant for studies of this type than a rodent model. With this consideration, Mead Johnson discusses a published pig study where neonatal pigs fed PDX did not show any toxicological effects including no adverse effects on the digestive tract and pancreas. Mead Johnson notes that no pancreatic hyperplasia was observed by thorough histopathological examination. Mead Johnson also notes that feeding PDX had no adverse effect on neonatal growth; no interference with nutrient absorption; and no detrimental effect on gastrointestinal microbiota.
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 the combination of GOS and PDX and in describing the information that Mead Johnson relies on to conclude that the combination of GOS and PDX is GRAS under the conditions of its intended use, Mead Johnson raises a number of issues under the labeling provisions of the FFDCA. If products that contain the combination of GOS and PDX 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 the combination of GOS and PDX 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. Mead Johnson should be aware that FDA’s response to Mead Johnson’s GRAS notice does not alleviate the responsibility of any infant formula manufacturer who intends to market an infant formula that contains the combination of GOS and PDX 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 Mead Johnson’s notice that the combination of GOS and PDX is GRAS for use as an ingredient in milk-based term infant formula, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing the combination of GOS and PDX. Accordingly, this response should not be construed to be a statement that foods that contain the combination of GOS and PDX, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Mead Johnson, as well as other information available to FDA, the agency has no questions at this time regarding Mead Johnson’s conclusion that the combination of GOS and PDX 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 the combination of GOS and PDX. As always, it is the continuing responsibility of Mead Johnson 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 000233, 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 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
1Mead Johnson states that β-galactosidase 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. This β-galactosidase is used in the production of GOS that is the subject of GRN 000236.