Agency Response Letter GRAS Notice No. GRN 000662

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CFSAN/Office of Food Additive Safety

September 29, 2016

Sidd Purkayastha, Ph.D.
PureCircle, Ltd.
915 Harger Road, Suite 250
Oak Brook, Illinois 60523

Re: GRAS Notice No. GRN 000662

Dear Dr. Purkayastha:

The Food and Drug Administration (FDA) is responding to the notice, dated August 5, 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 the notice on August 9, 2016, filed it on August 22, 2016, and designated it as GRAS Notice No. GRN 000662.

The subject of the notice is enzyme-modified steviol glycosides (EMSG). The notice informs FDA of the view of PureCircle, Ltd. (PureCircle) that EMSG is GRAS, through scientific procedures, for use as a general purpose sweetener in foods, other than infant formula and meat and poultry products, in accordance with good manufacturing practices (GMP), as well as use as a table top sweetener.

The EMSG that is the subject of GRN 000662 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, 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 EMSG, as well as published and unpublished studies supporting the safety of EMSG. Based on this review, PureCircle’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.

PureCircle provides information about the identity and composition of EMSG. PureCircle describes EMSG as an off-white to white powder that contains > 95% total SGs, which includes glucosylated SGs and unreacted SGs. The glucosylated SGs are generated by the treatment of a SGs extract preparation, which contains a minimum of 95% SGs, with a food-grade cyclomaltodextrin glucanotransferase with a source of glucose. Glucosylated SGs may have 1 to 20 additional glucose moieties, but generally have 1 to 3 additional glucose moieties, as compared to the naturally occurring SGs.

PureCircle provides information about the method of manufacture of EMSG. Stevia (Stevia rebaudiana (Bertoni) Bertoni) leaves are extracted in water and the extract solution is then filtered. The filtrate is treated with a flocculant (e.g., calcium hydroxide) and filtered. The filtrate is then subjected to ion-exchange resins followed by an adsorption resin that retains SGs. The adsorption resin is washed with water and the SGs are eluted with aqueous ethanol. The eluate is treated with activated carbon, filtered, and the ethanol then removed by evaporation. The resulting aqueous solution is deionized again using ion-exchange resins, and concentrated by filtration, and then spray dried. The spray dried product may then be subjected to recrystallization in aqueous ethanol to obtain the desired concentration of SGs. The crystalline product is then separated by centrifugation and dried. Tapioca starch is dissolved in water and treated with a cyclomaltodextrin glucanotransferase (CGTase) and/or α-amylase. The SGs product is added with additional CGTase, and the reaction mixture is incubated. When the reaction is complete, the enzymes are inactivated by heat. The reaction mixture is treated with activated carbon and filtered. The filtrate is subjected to an adsorption resin, which is then washed with water and the SGs eluted with aqueous ethanol. Ethanol is removed by evaporation and the resulting aqueous solution subjected to ion-exchange resins. The solution is then concentrated by filtration, spray dried, and sifted to yield the final EMSG product.

PureCircle provides specifications for EMSG that include the content of total SGs (> 95%), as well as limits for total ash (< 1%), loss on drying (≤ 6%), lead (≤ 1 milligrams (mg) per kilogram (kg)), arsenic (≤ 1 mg/kg), methanol (≤ 0.02%), ethanol (≤ 0.3%), and microbial contaminants (within specified limits). PureCircle provides results from five batch analyses conducted with EMSG that demonstrate compliance with these specifications.

PureCircle provides an estimate of dietary exposure to EMSG resulting from its intended use in foods. PureCircle used the methodology reported in GRN 000301, where the notifier used dietary exposure data for sweeteners and associated body weights 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. PureCircle determined the relative sweetness of EMSG to be 167 times that of sucrose and based on this sweetness intensity factor, estimates the maximum dietary exposure in adults (expressed as steviol equivalents) to be 1.33 mg/kg body weight per day (bw/d) and in children to be 1.47 mg/kg bw/d. PureCircle states that the use of EMSG in food is self-limiting due to organoleptic factors and consumer taste considerations.

PureCircle discusses published and unpublished studies pertaining to the metabolic fate and safety of EMSG. Based on these studies, PureCircle concludes that the final metabolic fate of EMSG is the same as naturally occurring SGs. PureCircle discusses acute, subchronic, and chronic studies in relation to their safety determination for EMSG. PureCircle 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 uses, 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 established an acceptable daily intake for SGs of 0-4 mg/kg bw/d (expressed as steviol). Based on all the available scientific information, PureCircle concludes that EMSG is GRAS for its intended use in foods.

Standards of Identity

In the notice, PureCircle 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 PureCircle’s notice that EMSG is GRAS for the intended uses, 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, as well as other information available to FDA, the agency has no questions at this time regarding PureCircle’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 EMSG 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 000662, 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] See GRN 000375.