Agency Response Letter GRAS Notice No. GRN 000605

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March 17, 2016

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

Re: GRAS Notice No. GRN 000605

Dear Dr. Soni:

The Food and Drug Administration (FDA) is responding to the notice, dated October 22, 2015, that you submitted on behalf of Tata Chemicals Limited (Tata) 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 October 28, 2015, filed it on November 19, 2015, and designated it as GRAS Notice No. GRN 000605. An amendment was received on January 27, 2016.

The subject of the notice is fructooligosaccharides (FOS). The notice informs FDA of the view of Tata 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; jams and jellies; milks (acidophilus; flavored and unflavored; evaporated and condensed); muffins and quick bread; sauces, gravies, and condiments; soups;[1] snacks; sorbet and sherbet; toddler (12 to 24 months old) foods; and yogurt at levels ranging from 0.4 to 6.7%.[2]

As part of its notice, Tata includes the statement of a panel of individuals (Tata's GRAS panel) that evaluated the data and information that are the basis for Tata's GRAS determination. Tata considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Tata's GRAS panel reviewed the identity and composition, method of manufacture, specifications, and intended use and dietary exposure to FOS, as well as publicly available studies supporting the safety of FOS. Based on this review, Tata's GRAS panel concluded that FOS is GRAS under the intended conditions of use.

Tata provides information on the identity and composition of FOS. Tata describes FOS as a colorless to light-yellow syrup or a white powder product. FOS is a fructan oligosaccharide consisting of a sucrose molecule (glucose-fructose disaccharide, called GF1) linked to one, two, or three additional fructose units, called GF2 (1-kestose), GF3 (nystose), and GF4 (fructofuranosylnystose), respectively. The molecular weight of FOS is 700 daltons, which is an average molecular weight of the three different components.

Tata describes the manufacturing process for FOS. FOS is made by treating sucrose with the enzyme β-fructofuranosidase.[3] The enzyme cleaves sucrose into glucose and fructose subunits and transfers the cleaved fructose unit to a growing fructose chain, producing GF2, GF3, and GF4. Pachysolen tannophilus[4] is used to remove reducing sugars produced from the conversion of sucrose to FOS. The FOS solution is collected, decolorized by the addition of activated carbon, and filtered. FOS solution is then clarified by microfiltration to remove precipitates and residual particles. This clarification process is followed by evaporation and concentration at low temperatures to yield FOS syrup, which is pasteurized and packaged. To make FOS powder, the syrup is spray dried and then packaged. Tata states that there are no food allergens in the final products and that extensive post-fermentation purification steps would be expected to remove any potential metabolic impurities that may occur during fermentation. Tata also states that all processing aids used in the manufacture of FOS, including hydrochloric acid, sodium hydroxide, and activated carbon, are food-grade materials used in accordance with current good manufacturing practices.

Tata provides specifications for FOS. Specifications include the total FOS (95.0 ±2.0 %) with component limits for GF2 (> 30.0 %), GF3 (> 40.0 %), and GF4 (> 5.0 %). Other limits include sugars (5.0 ±2.0 %), moisture (≤ 25.0 %), ash (≤ 0.1 %), lead (≤ 1.0 milligrams per kilogram (mg/kg)), and arsenic (≤ 0.2 mg/kg). Specifications also include limits on microbial contaminants, including standard plate count (≤ 300 colony forming units (cfu) per gram (g)) and yeasts and molds (≤ 20 cfu/g) with negative results for Escherichia coli, Salmonella serovars, and Shigella sp.

Tata estimates the daily dietary exposure to FOS. Tata states that the intended use levels and food categories described in GRN 000605 are the same as those described in the supplement to GRN 000044[5] and that the uses of FOS that are the subject of GRN 000605 are substitutional for those described in GRN 000044. Tata also states that because of the substitutional usage, the intake of FOS in the overall diet is not expected to be affected by the intended use. The reported estimates for FOS as described in GRN 000044 were generated using the 1994 -1996 USDA Continuing Survey of Food Intakes by Individuals (CSFII) data for food consumption. Two-day average dietary intake data were used. Based on these data, Tata estimates the total dietary exposure to FOS to be 4.4 g per person per day (g/p/d) (73 mg/kg bodyweight (bw)/d for a 60 kg individual), and 9.1 g/p/d (152 mg/kg bw/d for a 60 kg individual) at the 90th percentile (20+ years).[6]

Tata references and discusses the safety data on FOS that were summarized in previous GRAS notices (GRN 000044, GRN 000392,[7] and GRN 000537)[8] and concurs with these findings. Tata also summarizes and discusses the safety evaluations of FOS by the European Food Safety Authority (EFSA) and Food Standards Australia New Zealand (FSANZ) for use in infant formula. Tata further states that their PubMed and Toxline searches did not reveal any new published studies that contradict previous GRAS determinations for the intended uses of FOS or the safety evaluations conducted by EFSA and FSANZ on FOS.

Based on the totality of data and information summarized and discussed in the notice, Tata concludes that FOS is GRAS for the intended conditions of use.

Standards of Identity

In the notice, Tata states its intention to use FOS 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 FOS and in describing the information that Tata relies on to conclude that FOS is GRAS under the conditions of its intended use, Tata 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 your 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 Tata’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 Tata, as well as other information available to FDA, the agency has no questions at this time regarding Tata’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 Tata 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 000605, 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] Tata states that the intended uses of FOS do not include products under the United States Department of Agriculture’s jurisdiction.

[2] In the amendment dated January 27, 2016 Tata states that the intended use of FOS does not include infant formulas or follow-on infant formulas as indicated in the original GRN 000605.

[3] Tata states that β-fructofuranosidase is derived from Aureobasidium pullulans, which is a nonpathogenic and nontoxigenic fungus that is safe for use in the production of FOS.

[4] Tata states that Pachysolen tannophilus is a nonpathogenic and nontoxigenic yeast that is safe for use in the production of FOS.

[5] Fructooligosaccharide (FOS) was the subject of GRN 000044, which informed FDA of the view of GTC Nutrition Company (GTC) that FOS is GRAS, through scientific procedures, for use as a bulking agent in acidophilus milk, nutritional bars, baby food, nutritional beverages, biscuits, cakes, confectionery, cookies, crackers, flavored and unflavored milks, hard candy, ice cream and frozen yogurt, jams and jellies, muffins, ready-to-eat cereals, sorbet, soup and yogurt at varying levels. FDA responded in a letter dated November 22, 2000, stating that the agency had no questions at that time regarding GTC’s GRAS determination. A supplement from GTC dated June 1, 2007 expanded GTC’s intended uses of FOS.

[6] OFAS calculated a cumulative estimated dietary exposure to FOS from the intended uses with the most recent National Health and Nutrition Examination Survey (NHANES, 2011-2012) data. The mean and 90th percentile exposures to FOS for persons aged one year and older were determined to be 5.6 g/p/d and 9.7 g/p/d, respectively.

[7] Oligofructose was the subject of GRN 000392, which informed FDA of the view of Pfizer Nutrition and BENEO-Orafti (Pfizer and BENEO) that oligofructose is GRAS, through scientific procedures, for use as an ingredient in milk-based term infant formula powder at a maximum level of 3.0 g/liter of formula as consumed. FDA responded in a letter dated May 7, 2012, stating that the agency had no questions at that time regarding Pfizer and BENEO’s GRAS determination.

[8] Short-chain (sc)-fructo-oligosaccharides was the subject of GRN 000537, which informed FDA of the view of Ingredion Incorporated (Ingredion) that sc-fructo-oligosaccharides is GRAS, through scientific procedures, for use as an ingredient in term infant formula at use levels up to 400 mg per 100 milliliters (mg/100 ml) in starter formula (as consumed) and 500 mg/100 ml in follow-on formula (as consumed). FDA responded in a letter dated February 5, 2015, stating that the agency had no questions at that time regarding Ingredion’s GRAS determination.