Agency Response Letter GRAS Notice No. GRN 000337
CFSAN/Office of Food Additive Safety
June 17, 2011
Robert S. McQuate, Ph.D
GRAS Associates, LLC
20482 Jacklight Lane
Bend, OR 97702-3074
Re: GRAS Notice No. GRN 000337
Dear Dr. McQuate:
The Food and Drug Administration (FDA) is responding to the notice, dated April 29, 2010, that you submitted on behalf of NOW Foods 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 May 4, 2010, filed it on May 7, 2010, and designated it as GRN No. 000337.
The subject of the notice is enzyme-modified steviol glycosides preparation (EMSGP). EMSGP is obtained by enzyme treatment of steviol glycosides (SGs) purified from the leaves of Stevia rebaudiana (Bertoni) Bertoni. The notice informs FDA of the view of NOW Foods that EMSGP is GRAS, through scientific procedures, for use as a general-purpose sweetener in foods, excluding meat and poultry products, at levels determined by good manufacturing practices. NOW Foods notes that purified SGs have recently been the subject of several GRAS notices and that FDA responded to these GRAS notices informing the notifiers that, at the time of its response, the agency had no questions regarding their conclusions that the purified SGs that are the subjects of their respective notices are GRAS for their intended use as a sweetener in food.
Our use of “EMSGP,” “enzyme-modified steviol glycosides preparation,” “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, Labeling, and Dietary Supplements in the Center for Food Safety and Applied Nutrition.
As part of its notice, NOW Foods includes the report of a panel of individuals (NOW Foods’ GRAS panel) who evaluated the data and information that are the basis for NOW Foods’ GRAS determination. NOW Foods considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. NOW Foods’ GRAS panel evaluated the identity, method of manufacture, product specifications, and the potential exposure resulting from the intended uses of EMSGP as well as published and unpublished studies related to the safety evaluation of EMSGP. Based on this review, NOW Foods’ GRAS panel concluded that EMSGP, produced consistent with good manufacturing practice and meeting appropriate purity and food grade specifications, is GRAS under the conditions of its intended use.
NOW Foods provides information about the identity and composition of EMSGP. NOW Foods describes EMSGP as a white to slightly off-white powder composed of >95% SGs, a group of structurally-related sweet-tasting compounds that are natural constituents of the stevia leaf, and their 1,4-α-D-glucosylated forms. The α-D-glucosylated SGs constituents (also referred to as “glucosylsteviosides” by the notifier) are generated by treatment of SGs extract preparations with an α-glycosyltransferase enzyme in the presence of maltodextrin. The α-D-glucosylated SGs have glucose side chains that have been extended, generally with 1 to 3 additional glucose moieties, as compared to the naturally occurring SGs. These additional glucose residues are attached by sterio- and regio-specific 1,4-α-D-glycosidic bonds, whereas the glucose in naturally occurring SGs is attached by β-glycosidic bonds.
NOW Foods provides information about the manufacturing process and specifications for EMSGP. The starting material for the manufacturing process is high-purity (≥95%) SGs obtained from the leaves of S. rebaudiana (Bertoni) Bertoni. NOW Foods states that the SGs starting material meets the specifications for SGs established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) at its 69th meeting in June 2008. In the first step of the manufacturing process, the starting material is treated under controlled conditions with a food-grade α-glycosyltransferase enzyme in the presence of maltodextrin as a glucose source. At this step, a glycosylation reaction takes place adding glucose moieties to the SGs, resulting in the formation of 1,4-α-D-glucosylated SGs constituents in the preparation. The preparation is then subjected to filtration, ion-exchange resin, and activated carbon steps and spray-dried to yield the final EMSGP product. NOW Foods provides specifications for its EMSGP that include the content of total SGs and α-D-glucosylated SGs (>95% by weight (w/w)) and limits for lead (≤1 milligram per kilogram (mg/kg)), arsenic (≤1 mg/kg), dextrose equivalent (≤15%), residual ethanol (<500 mg/kg), and microbial contaminants (within specified limits).
NOW Foods estimates the intake of EMSGP resulting from its intended use in foods. NOW Foods reports that it utilized the method of estimation reported in GRN 000301. In GRN 000301, the notifier used dietary exposure data for sweetener use from a published study conducted by Renwick that predicted dietary exposures for the intense sweetener rebaudioside A (Ref. 1). In this study, published data on intake of intense sweeteners were collected from a large number of countries and were converted to sucrose equivalents using estimates of sweetness relative to sucrose. Using this approach, NOW Foods determined the relative sweetness for EMSGP to be 100 times that of sucrose and states that based on this sweetness intensity factor, the maximum estimated use of EMSGP would yield an estimated daily intake (expressed as steviol equivalents1) of 1.9 mg/kg body weight per day (mg/kg bw/day). NOW Foods states that the use of EMSGP in food is self-limiting due to organoleptic factors and consumer taste considerations.
NOW Foods discusses the safety of EMSGP. In its discussion, NOW Foods describes an unpublished study on the metabolism of EMSGP using reconstituted gastric fluid and fecal culture digestion experiments and a published fecal culture digestion study of other EMSGP-related enzymatically modified SGs preparations. Based on these studies, NOW Foods concludes the final metabolic fate of EMSGP is the same as that of naturally occurring SGs, whose metabolism has been well studied. NOW Foods states that given this expected metabolic fate, the data and information to to support the safety evaluation of SGs is also applicable to the safety evaluation of EMSGP. As such, NOW Foods discusses published and unpublished studies pertaining to the safety evaluation of SGs, including studies on rebaudioside A, stevioside, steviol, and crude stevia extracts. Among the published studies considered were acute toxicity studies in rats, mice, and hamsters, subchronic toxicity studies in rats, chronic toxicity/carcinogenicity studies in rats, and reproductive/developmental toxicity studies in rats and hamsters. NOW Foods also considers published clinical studies and published and unpublished absorption, distribution, metabolism and excretion studies in animals and humans. Additional studies that NOW Foods discusses include published in vitro and in vivo mutagenicity/genotoxicity studies. Based on its consideration of all these studies and the studies on EMSGP and similar enzymatically modified steviol glycosides preparations, NOW foods concludes that EMSGP is safe for its intended use in foods.
NOW Foods notes that JECFA, the Food Standards Australia New Zealand (FSANZ) and the European Food Safety Authority (EFSA) have recently made decisions on the safety of SGs for use in food as sweeteners. NOW Foods further notes that JECFA established an acceptable daily intake (ADI) for SGs of 0 - 4 mg/kg bw/d (expressed as steviol) and FSANZ and EFSA established an ADI for SGs of 4 mg/kg bw/d (expressed as steviol).2
Standards of Identity
In the notice, NOW Foods states its intention to use EMSGP 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 (FFDCA)
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FFDCA to, among other things, add section 301(ll). Section 301(ll) of the FFDCA prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FFDCA, 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 NOW Foods’ notice that EMSGP is GRAS for the intended use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing EMSGP. Accordingly, this response should not be construed to be a statement that foods that contain EMSGP, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by NOW Foods, as well as other information available to FDA, the agency has no questions at this time regarding NOW Foods’ conclusion that EMSGP 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 EMSGP. As always, it is the continuing responsibility of NOW Foods to ensure that food ingredients 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 000337, 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.
Mitchell A. Cheeseman, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
1. 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.
2. European Food Safety Authority. 2011. Revised exposure assessment for steviol glycosides for the proposed uses as a food additive. EFSA Journal: 9(1):1972.
1For comparative purposes, the content of steviol glycosides in stevia extracts is often expressed as steviol or steviol equivalents. Each steviol glycoside has a steviol equivalency factor that is calculated based on the ratio of molecular weight between steviol and a particular steviol glycoside. NOW Foods calculates the steviol equivalence of enzyme-modified steviol glycosides using a steviol equivalence factor of 0.194. The calculation of this factor was based on the steviol equivalence of the stevia extract used as the starting material in their manufacturing process and a dilution factor. NOW Foods states that the dilution factor is determined from the ratio of the starting stevia extract and maltodextrin. Maltodextrin is the source of glucose moieties in the manufacturing process and its residue is also present in the final product.
2FDA notes that EFSA had expressed concern that the ADI would likely be exceeded at the maximum use levels proposed by the petitioners whose submission was reviewed by EFSA. The European Commission then requested EFSA to conduct a revised exposure assessment. Following this request, EFSA carried out a revised exposure assessment for SGs in children and adults from its use as a food additive (Ref. 2). In the revised assessment, the exposure estimate calculation uses the same methodology that was used by EFSA in its prior opinion on SGs but with revised use levels and food consumption data for children and the adult population. The mean dietary exposure to SGs (as steviol equivalents) in European children (1 to 14 years of age) ranged from 0.4 to 6.4 mg/kg bw/day, and from 1.7 to 16.3 mg/kg bw/day at the 95th percentile. Due to observed overestimations of consumption levels of non-alcoholic flavored drinks (soft drinks) by children at the 95th percentile within certain datasets, EFSA concluded that a correction factor was necessary. The corrected exposure estimate at the 95th percentile ranges from 1.0 to 12.7 mg/kg bw/day for children. For adults (UK population) mean dietary exposure to SGs (as steviol equivalents) were calculated to be 1.9 to 2.3 mg/kg bw/day and from 5.6 to 6.8 mg/kg bw/day for high level consumers (97.5th percentile). EFSA concluded that the main contributors to the total anticipated exposure to SGs are non-alcoholic flavored drinks (soft drinks) for both populations. FDA further notes that studies conducted in the U.S., Canada, Australia, New Zealand, and Europe estimated the intakes of aspartame and other high intensity sweeteners using post-market surveillance data. Intake modeling methods are commonly used to estimate the consumption of a particular food or food ingredient. However, a realistic, but conservative approach is to estimate the intake of a sweetener based on the data reported in published studies. Estimates of intake for different sweeteners can be calculated based on adjustments for relative sweetness intensity. In the published study by Renwick (Ref. 1), the estimated intake of rebaudioside A, one of the primary SGs, was determined assuming a relative sweetness of 200 times that of sucrose. The consumption data were primarily from studies that used specifically designed food diaries combined with actual use levels or approved levels in different foods and beverages. These data were aggregated to provide an estimate of potential consumption of rebaudioside A.