Agency Response Letter GRAS Notice No. GRN 000477
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CFSAN/Office of Food Additive Safety
March 4, 2014
Chris B. Vervoort
Danone Trading B.V.
Schiphol Boulevard 105,
Tower E, 1118 BG Schiphol Airport,
Re: GRAS Notice No. GRN 000477
Dear Mr. Vervoort:
The Food and Drug Administration (FDA) is responding to the notice, dated June 7, 2013, 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 June 10, 2013, filed it on July 22, 2013, and designated it as GRAS Notice No. GRN 000477. Additional clarifying information was provided on December 23, 2013.
The subject of the notice is long-chain inulin (LCinulin). The notice informs FDA of the view of Danone Trading B.V. (Danone) that LCinulin is GRAS, through scientific procedures, for use as an ingredient in exempt and non-exempt infant formulas for term infants at a maximum level of 0.8 grams (g) per liter (L) of formula, toddler formulas for children ages 12-35 months of age at a maximum level of 1.2 g/L of formula, and medical foods at maximum levels of up to 3.125 g per 1000 kilocalories (kcal).
As part of its notice, Danone includes the report of a panel of individuals (Danone’s GRAS panel) that evaluated the data and information that are the basis for Danone’s GRAS determination. Danone considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Danone’s GRAS panel discusses specifications for LCinulin, estimated daily exposure to LCinulin, and published studies conducted with LCinulin. Based on this review, Danone’s GRAS panel concluded that LCinulin is GRAS under the conditions of its intended use.
Danone includes information about the identity and composition of LCinulin. The notifier states that LCinulin is derived from inulin extracted from chicory roots (Cichorium intybus). Inulin is a member of a group of carbohydrates known as fructans, which are composed of fructose units joined by β(2-1) linkages, typically with a terminal glucosyl moiety. The chemical formula of inulin is C6H11O6C6H10O5)nOH and it is referred to as α-D-glucopyranoside-(1-2)-β-D-fructofuranosyl-[(2-1)-β-D-fructofuranosyl]n.(1) The number of sugar units (i.e., degree of polymerization (DP)) ranges from 2 to 60 with some longer chains possible in the inulin. LCinulin is prepared from inulin by removal of the shorter chain fractions leaving the longer chain fructans with DPs ≥10 and an average DP of ≥23. LCinulin is composed of >99.5% carbohydrate (>99% DP ≥ 5), < 0.5% water, and approximately 0.1% of fructose, glucose, and sucrose combined. Danone states that the CAS Registry Number for inulin is 9005-80-5, but indicates that LCinulin does not have a distinct CAS Registry Number.
Danone describes the method of manufacture for LCinulin. The manufacturing process begins with the extraction of inulin from chicory, where the roots are washed, sliced, and extracted in hot water. The extract contains inulin and other soluble substances (pulp) as well as non-inulin substances (minerals, proteins, some sugars, and cell wall particles). The pulp is mechanically separated from the extract and the non-inulin substances are precipitated using calcium hydroxide. The precipitate is filtered out and the filtrate is evaporated to produce inulin. Inulin is cooled to precipitate long-chain molecules with lower solubility. The filtrate containing salts, sugars and shorter chain fructooligosaccharides (FOS) is removed. The remaining precipitate is redissolved in water and then subjected to heat treatment to reduce the microbial load and then filtered. The solution may then be decolorized with activated carbon. The product is dried by evaporation to reduce the water content to less than 0.5%. The notifier states that LCinulin is manufactured according to current Good Manufacturing Practices and that all materials used in the production are food grade.
Danone provides product specifications for LCinulin, and notes that the manufacturer regularly analyzes the starting material, i.e., inulin, and LCinulin for possible contaminants. Specifications provided include: content of inulin (> 99.5% dry matter (DM)); and, limits for content of glucose, fructose, and sucrose (combined, ≤ 0.5 % DM), cadmium (< 0.01 milligram per kilogram (mg/kg)), mercury (< 0.01 mg/kg), lead (<0.02 mg/kg), arsenic (< 0.03 mg/kg), aflatoxin B1 (< 1 microgram (μg)/kg), Cronobacter sakazakii (negative/300 g), salmonellas (negative/250 g), Enterobacteriaceae (negative/1 g), and polychlorinated biphenyls , dioxin-like compounds , and pesticides below the limits of detection. In addition, Danone discusses the stability of LCinulin and provides data for LCinulin under long-term storage (up to 4 years), and varying temperature (20°C to 145°C) and pH (3.5 to 5) conditions.
Danone provides exposure calculations for the intended uses of LCinulin in infant and toddler formulas. Danone provides an estimate of the potential exposure to LCinulin from the intended uses utilizing food consumption data reported in the United States Department of Health and Human Service’s National Health and Nutrition Examination Survey (NHANES, 2003-2004). The notifier assumes that the total amount of infant formula consumed by NHANES participants is a representative estimation of the total amount of formula consumed by infants with metabolic disorders, and that the concentration of LCinulin is the same in all formulas. The respective estimated mean and 90th percentile exposures to LCinulin from the intended use in infant formula are 0.8 and 1.0 g/person/day for infants aged 0 to 5 months and 0.6 and 0.9 g/person/day for infants aged 6 to 11 months. The respective estimated mean and 90th percentile exposures to LCinulin from the intended use in toddler formula are 0.3 and 0.7 g/person/day for toddlers aged 12 to 35 months.
Danone intends to use LCinulin in nutritionally incomplete oral medical foods at a typical level of 1.25 g/1000 kcal and at levels up to 2.5 g/1000 kcal. Danone notes that medical foods may be consumed as part of a patient’s diet with specific nutrients and provide only a portion of total daily energy needs. Therefore, Danone describes an example scenario of a medical food providing a patient with 200 kcal (10% of a 2000 kcal diet) and 0.625 g LCinulin/day.
Danone intends to use LCinulin at a typical level of 1 g/1000 kcal and at a maximum use level of 2 g/1000 kcal in nutritionally complete oral medical foods (both orally ingested foods and tube feeds). Danone determined that for a person with a total energy intake in the range of 1500-2500 kcal, the exposure to LCinulin would be 1.5 to 2.5 g/day based on typical use levels.
The notifier clearly discusses the β(2-1) fructan class of substances, which include inulin, FOS, and oligofructose. The notifier examines the publically available absorption, metabolism, distribution, and elimination information pertaining to LCinulin, as well as the other β(2-1) fructans. In addition, the notifier points out that prior GRAS notices have analyzed published subchronic and chronic animal studies for β(2-1) fructans, which demonstrated no adverse effects, as well as in vitro genetic toxicity studies which showed a lack of genotoxic potential. Further, the notifier evaluated 43 published clinical studies on healthy term infants who received up to 0.8 g of LCinulin and 7.2 g galacto-oligosaccharide (GOS) for periods ranging from 2 weeks to 12 months. The notifier indicated that no adverse effects were reported. The notifier also reviewed 13 published clinical studies in which pre-term infants consumed infant formulas with GOS and LCinulin in a 9:1 ratio for up to 12 weeks. The notifier indicated that no adverse effects were reported. Finally, Danone reviewed and discussed published case reports as well information from their firm’s registry of consumer complaints regarding allergenicity and have determined that the risk of allergic reaction is very low. Based on the totality of the data and information described above, Danone concludes that LCinulin is GRAS for its intended use in food.
Potential Labeling Issues
In describing data and information on clinical studies that Danone relies on to conclude that LCinulin is GRAS under the conditions of its intended use, Danone 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 LCinulin 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 LCinulin on the label or in labeling.
In its notice, Danone informs FDA that one intended use of LCinulin is use in medical foods. Section 5(b) of the Orphan Drug Act (ODA) defines a medical food as a food that is formulated to be consumed or administered enterally under the supervision of a physician and that is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation. Section 403(q) of the FD&C Act lays out the statutory framework for nutrition labeling of food products. Section 403(r) of the FD&C Act lays out the statutory framework for health claims and nutrient content claims. Under section 403(q)(5)(A)(iv) of the FD&C Act and FDA's implementing regulations in 21 CFR 101.9(j)(8), the requirements for nutrition labeling do not apply to medical foods as defined in section 5(b) of the ODA. Under section 403(r)(5)(A) of the FD&C Act and FDA's implementing regulations in 21 CFR 101.13(q)(4)(ii) and 21 CFR 101.14(f)(2), the requirements for nutrient content claims and health claims, respectively, do not apply to medical foods as defined in section 5(b) of the ODA. For your information, FDA's response to Danone’s notice that LCinulin is GRAS for use in medical foods does not address the question of whether any particular food product that contains LCinulin as an ingredient would be a medical food within the meaning of section 5(b) of the ODA and, thus, would be exempt from the requirements for nutrition labeling, nutrient content claims, and health claims.
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. Danone should be aware that FDA’s response to Danone’s GRAS notice does not alleviate the responsibility of any infant formula manufacturer who intends to market an infant formula that contains LCinulin to make the submission required by section 412.
Section 301(ll) of the FD&C Act
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FD&C Act to, among other things, add section 301(ll). 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 Danone’s notice that LCinulin is GRAS for the intended use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing LCinulin. Accordingly, this response should not be construed to be a statement that foods that contain LCinulin, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Danone, as well as other information available to FDA, the agency has no questions at this time regarding Danone’s conclusion that LCinulin 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 LCinulin. As always, it is the continuing responsibility of Danone 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 000477, 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
(1) The notifier states that in addition to a differing number of fructose moieties, the terminal glucose moiety is not always present.