Agency Response Letter GRAS Notice No. GRN 000620
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See also Generally Recognized as Safe (GRAS).
CFSAN/Office of Food Additive Safety
July 21, 2016
12 Vreeland Road
Florham Park, NJ 07932
Re: GRAS Notice No. GRN 000620
Dear Ms. Callen:
The Food and Drug Administration (FDA) is responding to the notice, dated December 22, 2015, that you submitted on behalf of Nestlé Nutrition (Nestlé) in accordance with the agency’s proposed regulation, proposed 21 Code of Federal Regulations (CFR) 170.36 (62 FR 18938; April 17, 1997; Substances Generally Recognized as Safe (GRAS); the GRAS proposal). FDA received the notice on January 4, 2016, filed it on February 8, 2016, and designated it as GRAS Notice No. GRN 000620. FDA received an amendment to the notice on May 9, 2016.
The subject of the notice is galactooligosaccharides (GOS). The notice informs FDA of Nestlé’s view that GOS is GRAS, through scientific procedures, for use as an ingredient in non-exempt infant formulas for term infants and in follow-on formulas at a level providing up to 7.8 grams of GOS per liter (g/L) of reconstituted or ready-to-drink formula.
As part of its notice, Nestlé includes the statement of a panel of individuals (Nestlé’s GRAS panel) that evaluated the data and information that are the basis for Nestlé’s GRAS determination. Nestlé considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Nestlé’s GRAS panel evaluated information describing the identity and composition, manufacturing process and specifications, and estimated dietary exposure, as well as published studies supporting the safety of GOS. Based on this review, Nestlé’s GRAS panel concluded that GOS produced in accordance with current good manufacturing practices (cGMP) and that meets its established food grade specifications is GRAS under the conditions of its intended use.
Nestlé provides information on the identity and composition of GOS. Nestlé describes GOS as a powder that is ≥46% GOS on a dry weight basis, with the remainder primarily consisting of lactose, glucose, and galactose. Nestlé states that GOS is a mixture of β-linked polymers that include di- to octasaccharides composed of one to seven galactose units linked to a glucose molecule at the reducing end. Nestlé states that GOS contains 0.2 to 0.3% 3’-sialyllactose and 6’-sialyllactose, which originate from the starting material. In addition, Nestlé states that residual milk proteins present in GOS (typically <2%) are expected to be small proteins and peptide fragments of whey protein.
Nestlé provides a description of the manufacturing process for GOS. GOS is synthesized using concentrated demineralized sweet whey permeate as a source of lactose. Treatment with a β-galactosidase preparation purified from a non-pathogenic and non-toxigenic strain of Aspergillus oryzae catalyzes the transgalactosylation reaction that hydrolyzes lactose and leads to the formation of GOS. The resulting GOS has a degree of polymerization that typically ranges from 2 to 5. The enzyme is inactivated by heat treatment and the solution is filtered to reduce the mineral content and residual lactose, glucose, and galactose. The product is heat-treated, further concentrated by evaporation, and finally spray-dried to produce GOS powder.
Nestlé provides specifications for GOS that include the minimum levels of GOS (≥46% on a dry matter basis (DM)) and sialyllactose (≥0.2% DM), typical lactose levels (20 to 40% DM), limits on glucose (≤10% DM), galactose (≤5% DM), moisture (≤5.5% DM), and protein (≤4.47% DM), as well as limits and ranges for various minerals. Additionally, limits on lead (≤0.02 milligrams per kilogram (mg/kg)), arsenic (≤0.02 mg/kg), cadmium (≤0.02 mg/kg), mercury (≤0.02 mg/kg), and microbial contaminants are provided. Nestlé provides the results of seven non-consecutive batch analyses to demonstrate that GOS meets specifications. Nestlé states that the results of an ongoing stability study show that GOS is stable for at least one year when stored at 25⁰C.
Nestlé discusses the dietary exposure to GOS based on the intended use and formula consumption data from the 2003-2004 National Health and Nutrition Examination Surveys (NHANES) (CDC, 2006; USDA, 2009). Nestlé estimates the mean and 90th percentile exposures to be 6.4 and 9.2 g/person/day for infants aged 0 to 6 months, 5.6 and 8.6 g/person/day for infants aged 7 to 11 months, and 3.0 and 7.1 g/person/day for toddlers aged 1 to 2 years, respectively.
Nestlé discusses the metabolism and safety of GOS. Nestlé states that its ingredient is chemically and structurally similar to GOS that was the subject of GRN 000236. Nestlé states that GOS is neither digested nor absorbed until it reaches the large intestine, where it is hydrolyzed to glucose and galactose and is subsequently metabolized to short chain fatty acids, CO2, and H2 gas by the intestinal microbiota. Nestlé describes three published subchronic oral repeat-dose studies using non-Nestlé GOS in rats; none of these studies reported toxicologically relevant adverse effects even at the highest doses tested. Nestlé also discusses unpublished studies using either GOS described in GRN 000236 or Nestlé’s GOS described in this notice as supportive evidence of safety. A developmental and reproductive toxicity study of non-Nestlé GOS in rats that did not show any toxicologically relevant adverse effects at the highest dose tested was also discussed in the notice. Nestlé states that GOS is not genotoxic based on published studies using non-Nestlé GOS and supported by unpublished studies using Nestlé GOS.
Nestlé discusses several human tolerance studies on Nestlé GOS and other GOS preparations. Because Nestlé intends to increase the use level of GOS in infant formulas from 7.2 to 7.8 g/L, resulting in an approximately 8.3% increase in dietary intake in infants, Nestlé discusses in the notice and in an amendment dated May 9, 2016 studies that relate to the safety of this higher use level. Nestlé cites and discusses two published and two unpublished studies in infants using Nestlé GOS at levels up to 8 and 10 g/L, as well as two published studies in infants using other GOS preparations at up to 8 and 20 g/L. Nestlé states that these studies all suggest that GOS up to the highest levels tested is well tolerated, as none of these studies reported significant, toxicologically-relevant adverse effects. Nestlé also states that despite a prior use level of 7.2 g/L GOS plus 0.8 g/L fructooligsaccharides (FOS), it is reasonable to expect no adverse physiological consequences in substituting 0.8 g/L FOS with 0.8 g/L GOS, since both contain simple monosaccharides (glucose, galactose, fructose) and are similarly metabolized. Nestlé states that the use of GOS in infant formulas is the subject of prior GRAS notices that received “No questions” letters from FDA, as well as evaluations by international regulatory bodies, such as Food Standards Australia New Zealand (FSANZ). Nestlé also cites FSANZ evaluations showing that GOS singularly used at levels up to 8 g/L in infant and follow-on formulas is unlikely to pose a risk to infants.
Based on the totality of the available data and information, Nestlé concludes that GOS is GRAS under the conditions of its intended use.
Potential Labeling Issues
In describing the intended use of GOS and in describing the information that Nestlé relies on to conclude that GOS is GRAS under the conditions of its intended use, Nestlé raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act). This issue consists of discussions in the notice on GOS studies that show physiological effects that Nestlé 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 and Food Labeling (ONFL) in the Center for Food Safety and Applied Nutrition. The Office of Food Additive Safety (OFAS) neither consulted with ONFL 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 FD&C Act requires 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)). The FD&C Act 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 the FD&C Act, because it may contain proteins derived from milk. Questions about the submission of petitions or notifications for exemptions from food allergen labeling requirements should be directed to the Division of Biotechnology and GRAS Notice Review in OFAS. However, questions about food labeling in general should be directed to ONFL.
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. Nestlé should be aware that FDA’s response to Nestlé’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 FD&C Act
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 Nestlé’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).
Based on the information provided by Nestlé, as well as other information available to FDA, the agency has no questions at this time regarding Nestlé’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 Nestlé 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 GRN000620, 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
 Nestlé states that the β-galactosidase preparation is GRAS for use in the manufacture of food ingredients.
 Nestlé states that sialyllactose is typically found at levels of 0.2 to 0.3% DM.
 Nestlé states that GOS is intended for use in Nestlé’s infant formulas and is added prior to thermal processing; therefore, Nestlé states that microbial specifications for Cronobacter sakazakii for GOS itself are not necessary.
 Prior GRAS notices involving infant formula use specified that GOS be used in conjunction with FOS at a 9:1 (GOS:FOS) ratio at up to 8 g/L of GOS plus FOS. This GOS:FOS ratio translates to a maximum use level of GOS at 7.2 g/L (and 0.8 g/L FOS).
 Nestlé references the following GRAS notices: GRNs 000233, 000236, 000285, 000286, 000334, 000484, 000489, 000495, and 000518.