Agency Response Letter GRAS Notice No. GRN 000619
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See also Generally Recognized as Safe (GRAS).
CFSAN/Office of Food Additive Safety
May 27, 2016
Sidd Purkayastha, Ph.D.
915 Harger Road, Suite 250
Oak Brook, IL 60523
Re: GRAS Notice No. GRN 000619
Dear Dr. Purkayastha:
The Food and Drug Administration (FDA) is responding to the notice, dated December 22, 2015, 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 December 30, 2015, filed it on February 2, 2016, and designated it as GRAS Notice No. GRN 000619.
The subject of the notice is purified steviol glycosides (SGs). The notice informs FDA of the view of PureCircle 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.
The SGs that is the subject of GRN 000619 is a highly purified component of the leaves of the stevia plant. As such, FDA notes that a GRAS notice for the use of a specific purified component of stevia, such as SGs, and FDA’s response do not necessarily apply to the uses of other stevia products.
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 nonstandardized 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, PureCircle includes the statement of a panel of individuals (PureCircle’s GRAS panel) that evaluated the data and information that are the basis for PureCircle’s GRAS determination. PureCircle considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. PureCircle’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, PureCircle’s GRAS panel concludes 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.
PureCircle provides information about the identity and composition of SGs. SGs contains ≥95% total steviol glycosides, a group of structurally-related sweet compounds that are constituents of the stevia leaf. PureCircle provides information on various steviol glycosides that are identified in the literature and notes that the molecular structures are similar. Steviol glycosides consist of a common steviol backbone linked to varying numbers and combinations of glucose, rhamnose, xylose, and/or other sugars (e.g., fructose or deoxyglucose) in varying orientations on the steviol backbone.
PureCircle provides information about the manufacturing process for SGs. SGs is obtained from the leaves of Stevia rebaudiana (Bertoni) Bertoni through extraction and multiple purification steps. The leaves are first extracted in water. The extract is filtered and treated with calcium hydroxide to precipitate impurities, which are removed by filtration. The filtrate is deionized using ion-exchange resins and then subjected to a macroporous adsorption resin that retains the steviol glycosides. The resin is washed with water and the steviol glycosides are then eluted with aqueous ethanol. The ethanol solution is treated with activated carbon and then filtered. Ethanol is removed by evaporation, and the resulting aqueous solution is deionized using ion-exchange resins. The solution is concentrated using nanofiltration and then concentrated by spray drying. PureCircle notes that some SGs preparations may then be recrystallized using aqueous ethanol. The resulting SGs crystals are separated by centrifugation and dried under vacuum.
PureCircle provides specifications for SGs that include the content of total steviol glycosides (≥95%), limits for moisture (≤6%), lead (<1 milligrams per kilogram (mg/kg)), arsenic (<1 mg/kg), cadmium (<1 mg/kg), mercury (<1 mg/kg), and limits on microbial contaminants. PureCircle states that specifications for SGs are consistent with 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 steviol glycosides not included in the nine steviol glycosides listed in the JECFA specifications. PureCircle provides the results of multiple batch analyses conducted with two SGs preparations to demonstrate that SGs meets the specifications described above.
PureCircle provides an estimate of the dietary exposure to SGs resulting from its intended use in food. PureCircle used dietary exposure data for sweetener use from a published study (Ref. 1) in which the author estimated dietary exposure assessments of an intense sweetener (i.e., rebaudioside A) in different subpopulations. PureCircle states that SGs have a sweetness that is 200 to 350 times that of sucrose. Using this relative sweetness intensity and the methodology described in Ref. 1, PureCircle calculates the mean and upper percentile dietary exposure to SGs for different subpopulations. PureCircle calculates the maximum daily exposure (expressed as steviol equivalents) to be 2.24 mg/kg body weight/day (bw/d) in adults and 3.28 mg/kg bw/d in children.
PureCircle discusses published and unpublished studies pertaining to the metabolic fate and safety of SGs. PureCircle discusses previously reviewed acute, subchronic and chronic animal studies in relation to their safety determination for SGs. To further support its view that SGs is GRAS for the intended use, PureCircle summarizes recent decisions by the Joint FAO/WHO Expert Committee on Food Additives (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. PureCircle notes that JECFA, FSANZ and EFSA established an acceptable daily intake (ADI) for SGs of 0–4 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, PureCircle concludes that SGs is GRAS for its intended use in foods.
Standards of Identity
In the notice, PureCircle 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 PureCircle’s notice that SGs is GRAS for the intended use, 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 PureCircle, as well as other information available to FDA, the agency has no questions at this time regarding PureCircle’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 PureCircle 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 000619, 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.