Food

Agency Response Letter GRAS Notice No. GRN 000656

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CFSAN/Office of Food Additive Safety

September 28, 2016

Katrina Emmel, Ph.D.
GRAS Associates, LLC
27499 Riverview Center Blvd., Suite 212
Bonita Springs, FL 34134

Re: GRAS Notice No. GRN 000656

Dear Dr. Emmel:

The Food and Drug Administration (FDA) is responding to the notice, dated May 18, 2016, that you submitted on behalf of GLG Life Tech Corporation (GLG) 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 1, 2016, filed it on July 26, 2016, and designated it as GRAS Notice No. GRN 000656.

The subject of the notice is enzyme-modified steviol glycosides (EMSG). The notice informs FDA of the view of GLG Life Tech Corporation that EMSG is GRAS, through scientific procedures, for use as a general purpose sweetener in foods, excluding infant formula and meat and poultry products, at levels determined by good manufacturing practices (GMP), as well as use as a table top sweetener.

The EMSG that is the subject of GRN 000656 is made from 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 EMSG, and FDA’s response do not necessarily apply to the uses of other stevia products.

Our use of “EMSG,” “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, GLG includes the statement of a panel of individuals (GLG’s GRAS panel) that evaluated the data and information that are the basis for GLG’s GRAS determination. GLG considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. GLG’s GRAS panel evaluated information describing the identity and composition, manufacturing process and specifications, and estimated dietary exposure to EMSG, as well as published and unpublished studies supporting the safety of EMSG. Based on this review, GLG’s GRAS panel concludes that EMSG 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.

GLG provides information about the identity and composition of EMSG. GLG describes EMSG as an off-white to white powder that contains ≥ 95% total SGs, which includes ≥ 80% α-D-glucosylated SGs and ≤ 15% unreacted SGs. The α-D-glucosylated SGs are generated by the treatment of a stevia extract preparation, which contains a minimum of 95% SGs, with a food-grade cyclomaltodextrin glucanotransferase in the presence of maltodextrin. The α-D-glucosylated SGs have extended glucose side chains, generally with 1 to 3 additional glucose moieties, as compared to the naturally occurring SGs. These additional glucose residues are attached by stereo- and regio-specific1,4-α-D-glycosidic bonds, whereas the glucose in naturally occurring SGs is attached by β-glycosidic bonds.

GLG provides information about the method of manufacture of EMSG. Stevia rebaudiana (Bertoni) Bertoni leaves are extracted in water and the extract solution is then filtered. The filtrate is subjected to ion-exchange resins and the glycoside components are subsequently trapped using an adsorption resin. The glycosides are eluted from the resin with ethanol. The eluate is deionized using ion-exchange resins, decolored with activated carbon, concentrated by evaporation, and then spray dried. The dried product is dissolved in ethanol, crystallized, filtered, and spray dried to yield a purified intermediate that contains > 95% SGs. This product is added to an aqueous solution containing maltodextrin and a cyclomaltodextrin glucanotransferase. After the enzymatic reaction is complete, the enzyme is deactivated and the solution subjected to an adsorption resin. The glycosides are eluted with ethanol, which is then subjected to ion-exchange resins, concentration, and spray drying.

GLG provides specifications for EMSG that include the content of total SGs (≥ 95%), which includes glucosylated SGs (≥ 80%) and unreacted SGs (≤ 15%), as well as limits for total ash (< 1%), loss on drying (≤ 4%), lead (≤ 1 milligrams (mg) per kilogram (kg)), arsenic (≤ 1 mg/kg), residual methanol (≤ 0.02%), residual ethanol (≤ 0.5%), and microbial contaminants (within specified limits). GLG provides results from five batch analyses conducted with EMSG that demonstrate compliance with these specifications.

GLG provides an estimate of dietary exposure to EMSG resulting from its intended use in foods. GLG used the methodology reported in GRN 000301, where the notifier used dietary exposure data for sweeteners from a published study to predict dietary exposures to rebaudioside A (Ref. 1). In this study, published data on intake of intense sweeteners were converted to sucrose equivalents using estimates of sweetness relative to sucrose. GLG determined the relative sweetness of EMSG to be 130 times that of sucrose and based on this sweetness intensity factor, estimates the maximum dietary exposure in adults (expressed as steviol equivalents) to be 1.21 mg/kg body weight per day (bw/d) and in children to be 1.33 mg/kg bw/d. GLG states that the use of EMSG in food is self-limiting due to organoleptic factors and consumer taste considerations.

GLG discusses published and unpublished data pertaining to the metabolic fate and safety of EMSG. Based on these data, GLG concludes that the final metabolic fate of EMSG is the same as naturally occurring SGs. GLG discusses acute, subchronic and chronic studies in relation to their safety determination for EMSG. GLG summarizes a previous evaluation of published and unpublished in vitro and in vivo mutagenicity/genotoxicity studies that showed no effects. [1] To further support its view that EMSG is GRAS for the intended use, GLG 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. GLG 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). Based on all the available scientific information, GLG concludes that EMSG is GRAS for its intended use in foods.

Standards of Identity

In the notice, GLG states its intention to use EMSG 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 GLG’s notice that EMSG is GRAS for the intended use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing EMSG. Accordingly, this response should not be construed to be a statement that foods that contain EMSG, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).

Conclusions

Based on the information provided by GLG, as well as other information available to FDA, the agency has no questions at this time regarding GLG’s conclusion that EMSG 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 EMSG. As always, it is the continuing responsibility of GLG 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 000656, 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

Reference

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.


[1] As reviewed in GRN 000375.

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