Agency Response Letter GRAS Notice No. GRN 000626
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See also Generally Recognized as Safe (GRAS).
CFSAN/Office of Food Additive Safety
May 27, 2016
Alex Eapen, Ph.D.
15407 McGinty Road West
Wayzata, MN 55391
Re: GRAS Notice No. GRN 000626
Dear Dr. Eapen:
The Food and Drug Administration (FDA), is responding to the notice, dated February 1, 2016, 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 this notice on February 3, 2016, filed it on March 1, 2016, and designated it as GRAS Notice No. GRN 000626.
The subject of the notice is purified steviol glycosides from Saccharomyces cerevisiae (SGs). The notice informs FDA of the view of Cargill, Incorporated (Cargill) that SGs is GRAS, through scientific procedures , for use as a general-purpose sweetener in foods, excluding infant formula and products under USDA’s jurisdiction, at levels determined by good manufacturing practices (GMP), as well as use as a table top sweetener.
Our use of “steviol glycosides,” or “SGs” in this letter should not be considered an endorsement or recommendation of that term as an appropriate common or usual name for the purpose of declaring the substance in the ingredient statement of foods that contain that ingredient. Title 21 CFR 101.4 states that each ingredient must be declared by its common or usual name. In addition, 21 CFR 102.5 outlines general principles to use when establishing common or usual names for non-standardized foods. Issues associated with labeling and the appropriate common or usual name of a food are the responsibility of the Office of Nutrition and Food Labeling in the Center for Food Safety and Applied Nutrition.
As part of its notice, Cargill includes the statement of a panel of individuals (Cargill’s GRAS panel) that evaluated the data and information that are the basis for Cargill’s GRAS determination. Cargill considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Cargill’s GRAS panel evaluated information describing the identity and composition, manufacturing process and specifications, and estimated dietary exposure to SGs, as well as published and unpublished studies supporting the safety of SGs. Based on this review, Cargill’s GRAS panel concluded that SGs produced in accordance with GMP and meeting appropriate purity and food grade specifications, is GRAS, by scientific procedures, under the conditions of its intended use.
Cargill provides information about the identity and composition of SGs. SGs contains ≥95% total steviol glycosides, a group of structurally-related sweet compounds. Cargill states that SGs contains rebaudiosides A, B, C, D, E, F, M, stevioside, steviolbioside, rubusoside, and dulcoside A, and that the distribution of steviol glycosides present in the final product may vary.
Cargill provides information about the manufacturing process for SGs. SGs is obtained from S. cerevisiae that is engineered to produce steviol glycosides. Cargill provides information on the parent S. cerevisiae strain, methodology used to construct the production strain, and a summary of the enzymes and their functions that are expressed by the production strain. Cargill concludes that the production strain is neither toxigenic nor pathogenic and does not contain or produce any known pathogenic proteins, toxins, allergens, or pyrogens. An inoculum of the S. cerevisiae production strain is mixed with fermentation medium and aerobically fermented for 90 to 140 hours. The fermentation broth is heated to stop fermentation and heat-kill the yeast; the pH is optionally lowered to 4.2 with citric acid and the biomass is then centrifuged or micro-filtered to remove yeast biomass. Potassium sorbate and sodium benzoate may be added to the filtrate and the pH may be adjusted to minimize further microbial contamination. The filtrate is subjected to an adsorption resin that retains steviol glycosides, which are subsequently eluted with ethanol. The ethanol is removed by evaporation, and the eluate is then subjected to ion-exchange resins, optional pH adjustment, and treatment with activated carbon to remove impurities and decolorize. The eluate is concentrated by evaporation, optionally dried, and then recrystallized using either aqueous ethanol or methanol. The resulting crystals are rinsed with ethanol and then dried to obtain the final SGs product.
Cargill provides specifications for SGs that include the minimum content of total steviol glycosides (≥95%), limits for moisture (≤10%), ash (≤1%), lead (≤1 milligram per kilogram (mg/kg)), arsenic (≤0.2 mg/kg), ethanol (≤0.5%), methanol (≤0.02%), and limits on microbial contaminants. Cargill states that SGs meets the specifications for steviol glycosides established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) at its 73rd meeting in June 2010, however, the total steviol glycosides in SGs may include rebaudiosides E and M in addition to the nine steviol glycosides listed in the JECFA specifications. Cargill provides the results of four batch analyses to demonstrate that SGs meets specifications.
Cargill provides estimates of dietary exposure to SGs resulting from its intended use in food. Cargill used dietary exposure data for sweetener use from a published study (Ref. 1) in which the author estimated dietary exposure to rebaudioside A in different subpopulations. Cargill states that SGs have a sweetness that is 200 times that of sucrose. Using this relative sweetness intensity and the methodology described in Ref. 1, Cargill calculates the mean and upper percentile dietary exposure to SGs for different subpopulations. Cargill calculates the maximum daily exposure (expressed as steviol equivalents) to be 1.37 mg/kg body weight per day (bw/d) in adults and 1.52 mg/kg bw/d in children.
Cargill summarizes published studies pertaining to the metabolic fate of SGs. Cargill points to previously reviewed acute, subchronic, and chronic toxicity studies; reproductive and developmental toxicology studies; as well as in vitro and in vivo mutagenicity/genotoxicity studies in relation to their safety determination for SGs. To further support its view that SGs is GRAS for the intended use, Cargill summarizes recent decisions by JECFA, the Food Standards Australia New Zealand (FSANZ), Health Canada, the European Food Safety Authority (EFSA), and other governmental bodies on the safety of SGs for use in food as a sweetener. Cargill notes that JECFA, FSANZ, EFSA and Health Canada have established an acceptable daily intake (ADI) for SGs of 4 mg/kg bw/d (expressed as steviol). This ADI was based on a no observed adverse effect level of 970 mg/kg bw/d (383 mg/kg bw/d, as steviol) from a two-year rat study, and the application of a one hundred-fold safety factor for intra- and inter-species differences. Based on all the available scientific information, Cargill concludes that SGs is GRAS for its intended use in foods.
Standards of Identity
In the notice, Cargill states its intention to use SGs 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.
Section 301(ll) of the Federal Food, Drug, and Cosmetic Act (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 Cargill’s notice that SGs is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing SGs. Accordingly, this response should not be construed to be a statement that foods that contain SGs, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Cargill, as well as other information available to FDA, the agency has no questions at this time regarding Cargill’s conclusion that SGs is GRAS under the intended conditions of uses. The agency has not, however, made its own determination regarding the GRAS status of the subject uses of SGs. As always, it is the continuing responsibility of Cargill 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 000626, 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
- Renwick, A.G. 2008. The use of a sweetener substitution method to predict dietary exposures for the intense sweetener rebaudioside A. Food and Chemical Toxicology 46:S61–S69.