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  1. GRAS Notice Inventory

Agency Response Letter GRAS Notice No. GRN 000623

Recently Published GRAS Notices and FDA Letters

See also Generally Recognized as Safe (GRAS).

 

August 1, 2016

Madhu Soni, Ph.D.
Soni & Associates, Inc.
749 46th Square
Vero Beach, FL 32968

Re: GRAS Notice No. GRN 000623

Dear Dr. Soni:

The Food and Drug Administration (FDA) is responding to the notice, dated January 7, 2016, that you submitted on behalf of New Francisco Biotechnology Corporation (NFBC) 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 20, 2016, filed it on February 12, 2016, and designated it as GRAS Notice No. GRN 000623.

The subject of the notice is fructooligosaccharides (FOS). The notice informs FDA of the view of NFBC that FOS is GRAS, through scientific procedures, for use as an ingredient in conventional foods, including substitutes for meat, poultry, and fish; nutritional bars; breakfast cereals; beverages and juices; cakes; cheese; cream; confectionery; cookies; crackers; dessert toppings and fillings; hard candy; ice cream; infant foods; jams and jellies; milks (acidophilus; flavored and unflavored; evaporated and condensed); muffins and quick bread; sauces, gravies, and condiments; snacks; sorbet and sherbet; soups; toddler (12-24 months old) foods; and yogurt at levels in the range 0.4 to 6.7%. NFBC states that FOS is not intended for use in meat and poultry products under USDA jurisdiction or for uses in infant formulas or follow-on formulas.

As part of its notice, NFBC includes the statement of a panel of individuals (NFBC’s GRAS panel) that evaluated the data and information that are the basis for NFBC’s GRAS determination. NFBC considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. NFBC’s GRAS panel evaluated information describing the identity and composition, manufacturing process and specifications, estimated dietary exposure, and published studies supporting the safety of FOS. Based on this review, NFBC’s GRAS panel concluded that FOS produced in accordance with current good manufacturing practices (cGMP) that meets its established food grade specifications is GRAS under the conditions of its intended use.

NFBC provides information on the identity and composition of FOS. NFBC describes FOS as fructan oligosaccharides consisting of linear chains of fructose linked by β (2-1) linkages with a terminal glucose residue. FOS primarily contains three fructans that have 2, 3, or 4 fructose units that are referred to as 1-kestose, nystose, and fructofuranosylnystose, respectively. NFBC intends to market FOS in both liquid (syrup) and powder forms.

NFBC provides a description of the manufacturing process for FOS. Sucrose is dissolved in water and β-fructofuranosidase[[1] is added. The enzyme hydrolyzes the sucrose to glucose and fructose and transfers the cleaved fructose to a growing fructose chain to yield 1-kestose, nystose, and fructofuranosylnystose. After the reaction is complete, citric acid is added to inactivate the enzyme. Decolorization with activated carbon, ion exchange chromatography, and the optional addition of maltodextrin are used in the production of commercial products, both liquid and powder. NFBC states that all raw materials and processing aids used in the manufacture of FOS are suitable, food-grade, and are used in accordance with cGMP.

NFBC provides specifications for different FOS preparations. Specifications include FOS in the range of ≥30% to ≥ 95% and associated limits on sugars (sucrose and monosaccharides combined) in the range of ≤5% to ≤50%. Specifications for the product containing ≥30% FOS also include a limit for maltodextrin (≤55%). Specifications for all preparations include limits on ash (≤0.1%), lead (<0.02 milligrams per kilogram (mg/kg)), total arsenic (≤0.05 mg/kg), cadmium (≤0.1 mg/kg), total mercury (≤0.01 mg/kg), and microbial contaminants. NFBC provides the results of five consecutive batch analyses for several preparations to demonstrate that FOS can be manufactured to meet the specifications.

NFBC states that FOS is intended for use in the same foods and at the same use levels as FOS described in GRN 000044, where the estimated dietary exposure was based on food consumption data from the Continuing Survey of Food Intake by Individuals (CSFII, 1994-96). Since the intended uses are substitutional, NFBC does not expect the dietary exposure to significantly change. The estimated dietary exposures to FOS presented in GRN 000044 ranged across age groups from 1.6 to 6.2 g/person/day (60 to 336 mg/kg body weight (bw)/day) at the mean and from 3.1 to 12.8 g/person/day (127 to 614 mg/kg bw/day) at the 90th percentile.

NFBC incorporates by reference the animal toxicology data and tolerance studies in humans from GRAS notices GRN 000537, GRN 000392, and GRN 000044 (FDA had no questions in response to these notices), and compares the FOS preparations that are the subject of GRN 000623 with the subjects of the referenced notices. NFBC concludes that the manufacturing processes, product specifications, and compositional analyses are similar; therefore, the safety information cited in the previous notices can be used to support the safety of the FOS preparations in GRN 000623.

NFBC includes an update of the literature for the time period through November 2015. NFBC summarizes and discusses one short-term (4-6 weeks) study, two subchronic (13 weeks and 4-month) studies, and one chronic (2 year) study that are all published, and two unpublished developmental toxicity studies cited in a published review on FOS. NFBC also states that FOS was neither mutagenic nor carcinogenic. NFBC states that tolerance studies in adults and children, along with the above-mentioned studies, support the conclusion that oral ingestion of 15-20 g of FOS/day is well tolerated in humans.

Based on the totality of the evidence provided and the incorporation by reference all of the safety information from GRN 000537, GRN 000392, and GRN 000044, NFBC concludes that FOS is GRAS under the conditions of its intended use.

Standards of Identity

In the notice, NFBC states its intention to use FOS in several food categories, including foods for which standards of identity exist, located in Title 21 of the CFR. 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 FOS and in describing the information that NFBC relies on to conclude that FOS is GRAS under the conditions of its intended use, NFBC raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act). 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 FOS 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 neither consulted with ONFL on this labeling issue nor evaluated the information in the notice to determine whether it would support any claims made about FOS on the label or in labeling.

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 NFBC’s notice that FOS is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing FOS. Accordingly, this response should not be construed to be a statement that foods that contain FOS, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).

Conclusions

Based on the information provided by NFBC, as well as other information available to FDA, the agency has no questions at this time regarding NFBC’s conclusion that FOS 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 FOS. As always, it is the continuing responsibility of NFBC 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 000623, 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.

Sincerely,

Dennis M. Keefe, Ph.D.
Director
Office of Food Additive Safety
Center for Food Safety
and Applied Nutrition

[1] NFBC states that Aspergillus oryzae, the soil bacterium used to produce the β-fructofuranosidase enzyme, is non-toxigenic and non-pathogenic.

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