Agency Response Letter GRAS Notice No. GRN 000627
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See also Generally Recognized as Safe (GRAS).
CFSAN/Office of Food Additive Safety
October 11, 2016
James T. Heimbach, Ph.D., F.A.C.N.
923 Water Street
P.O. Box 66
Port Royal, VA 22535
Re: GRAS Notice No. GRN 000627
Dear Dr. Heimbach:
The Food and Drug Administration (FDA) is responding to the notice, dated January 29, 2016, that you submitted on behalf of Guilin GFS Monk Fruit Corporation (Guilin) 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 February 5, 2016, filed it on March 1, 2016, and designated it as GRAS Notice No. GRN 000627.
The subject of the notice is Siraitia grosvenorii Swingle (Luo Han Guo) fruit juice concentrate (SGFJC). The notice informs FDA of the view of Guilin that SGFJC is GRAS, through scientific procedures, for use as a sweetener and flavoring ingredient in conventional foods and in infant and toddler foods (excluding infant formula), at levels determined by current good manufacturing practices (cGMP). SGFJC is not intended for use in foods that are under the jurisdiction of the United States Department of Agriculture.
Our use of “Siraitia grosvenorii Swingle (Luo Han Guo) fruit juice concentrate” or “SGFJC” 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, Guilin includes a summary of conclusions of a panel of individuals (Guilin’s GRAS panel) that evaluated the data and information that are the basis for Guilin’s GRAS determination. Guilin considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Guilin’s GRAS panel evaluated information describing the identity and composition, manufacturing process and specifications, and estimated dietary exposure, as well as published and unpublished studies supporting the safety of SGFJC. Based on this review, Guilin’s GRAS panel concluded that SGFJC produced in accordance with cGMP that meets its established food grade specifications is GRAS under the conditions of its intended use.
Guilin provides information about the identity and composition of SGFJC. SGFJC is described as a liquid concentrate with a Brix level of approximately 65⁰ that is extracted from the fruit of S. grosvenorii Swingle, commonly known as Luo Han Guo or monk fruit. SGFJC contains a mixture of compounds; the constituents that impart the characteristic sweet taste are cucurbitane glycosides known as mogrosides (II-VI). Guilin states that SGFJC contains 3.5% mogroside V (CAS Reg. No. 88901-36-4) and 1.5% other mogrosides. The composition of SGFJC, other than mogrosides, are sugars (e.g., sucrose, fructose, and glucose (56%)), water (35%), protein (0.1%), lipids (<0.1%), fiber (<0.1%), and 3.7% other components including primarily melanoidins and flavonoids.
Guilin describes the manufacturing process for SGFJC. Guilin states that S. grosvenorii Swingle fruits are crushed or shredded and then extracted with water. The extract is clarified by ultrafiltration to remove proteins and pectin and then subjected to cationic and anionic exchange resins resulting in a liquid concentrate that contains mostly mogrosides and sugars. Guilin states that the resins used in the manufacture of SGFJC are food-grade and comply with 21 CFR 173.25.
Guilin provides specifications for the SGFJC that includes the content of mogroside V (3.5%), Brix level (65 to 700), and limits on lead (≤ 0.5 milligram per kilogram (mg/kg)), arsenic (≤ 0.4 mg/kg), and microbial contaminants. Guilin provides results from three batch analyses to demonstrate that SGFJC meets specifications.
Guilin states that SGFJC is intended for use as a sweetener and flavoring ingredient in conventional foods like juices and juice concentrates, at a level determined by cGMP. However, Guilin states that the maximum use level in food is about 1% and usual use levels are in the range of 0.25% to 0.50%. Guilin also notes that the use levels in food are self-limiting due to the organoleptic properties.
Guilin provides estimates of dietary exposure to SGFJC from the intended use in conventional foods and based on the estimated dietary exposure to S. grosvenorii fruit extract (SGFE) that is the subject of GRN 000301. In GRN 000301, the mean and 90th percentile dietary exposure to SGFE was estimated to be 2.6 mg/kg body weight (bw)/day and 6.8 mg/kg bw/day, respectively. In GRN 000627, Guilin discusses compositional differences between SGFJC and SGFE, and notes that the mogrosides and other components (primarily melanoidins and flavonoids) that constitute 100% of the composition of the SGFE powder represent 8.9% of SGFJC, which also contains sugars (56%) and water (35%) not present in SGFE. Based on this relative difference in composition, Guilin calculates that the use level of SGFJC needed to provide the same level of mogrosides in food as SGFE is 11.24 times higher. Guilin estimates the mean and 90th percentile dietary exposure to SGFJC to be 11.24 times the SGFE levels, or 29.3 and 76.4 mg/kg bw/day, respectively. Guilin notes that this represents a conservative exposure estimate as SGFJC will be primarily used as a substitute for other fruit juices and juice concentrates used as sweeteners or flavor in foods and beverages.
Guilin discusses the intended use of SGFJC in infant and toddler foods (excluding infant formula), and notes that SGFJC is intended for use in fruit-containing baby foods and infant cereals. Guilin provides consumption data for these foods that are obtained from the 2008 Nestlé Feeding Infants and Toddlers Study. Based on these data and estimates of median bodyweight, Guilin calculates that the highest 90th percentile estimate of dietary exposure to SGFJC from its intended use in baby foods to be 47.8 mg/kg bw/day among 9 to 11.9-months old and an estimated median body weight of 8.9 kg and from use in infant cereals to be 47.9 mg/kg bw/day among 15-17.9-months old and an estimated median body weight of 10.7 kg. Based on a level of 5% mogrosides in SGFJC, Guilin concludes that the highest estimated 90th percentile intake of mogrosides from either baby food or infant cereal is 2.4 mg/kg bw/day.
Guilin discusses the safety of SGFJC containing 5% mogrosides (3.5% mogroside V and 1.5% other mogrosides) by incorporating all the safety data presented in GRN 000301, which describes SGFE that contains more than 30% mogroside V. Guilin also relies on unpublished studies presented in GRN 000359, and information in GRNs 000522 and 000556 (which describe SGFEs with mogroside V content from 12.5% to 90%) to corroborate the safety of SGFJC. Additionally, Guilin includes an update of the literature through November 2015 and discusses a recently published rat study on the metabolism and distribution of mogroside V. This study evaluated the metabolism of mogroside V in a human intestinal bacteria incubation system (in vitro), a rat hepatic 9000 g supernatant (S9) incubation system (in vitro), and a repeat dose study in which Sprague Dawley rats were gavaged 50 mg mogroside V/kg bw/day for 4 days (in vivo). Guilin notes that the results of the gavage study show that most of the orally administered mogroside V is rapidly excreted in the urine, whereas its metabolites are excreted almost entirely in feces. Moreover, Guilin notes the decision by Health Canada’s Food Directorate to authorize the use of SGFE (at a maximum use level of 0.8% mogroside V content) as a tabletop sweetener. Based on its consideration of all the available data and information, Guilin concludes that SGFJC is GRAS under the conditions of its intended use.
Standards of Identity
In the notice, Guilin states its intention to use SGFJC 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 (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 Guilin’s notice that SGFJC is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing SGFJC. Accordingly, this response should not be construed to be a statement that foods that contain SGFJC, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Guilin, as well as other information available to FDA, the agency has no questions at this time regarding Guilin’s conclusion that SGFJC 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 SGFJC. As always, it is the continuing responsibility of Guilin 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 000627, 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
 In GRN 000301, the notifier estimated the dietary exposure to SGFE resulting from its intended use as a sweetener and flavor enhancer in foods, excluding meat and poultry products, at levels determined by cGMP, as well as use as a table top sweetener. Dietary exposure was calculated using data for sweetener use from a published study (Renwick, 2008) that predicted dietary exposures for the intense sweetener, rebaudioside A. In this study, Renwick provided estimates of both mean and upper percentile estimates of intake of intense sweeteners based on their relative sweetness to sucrose. The notifier stated that SGFE has a relative sweetness that is 100 times that of sucrose.
 The composition of SGFE powder (the subject of GRN 000301) is mogroside V (39%), other mogrosides (16%), other components (primarily melanoidins and flavonoids; 43.7%) and protein (1.1%); Guilin states that these substances make up only 8.9% SGFJC. Guilin states that to provide the same amount of mogrosides as is provided by SGFE powder requires 11.24 mg SGFJC to replace 1 mg of SGFE powder (100 divided by 8.9%).