Agency Response Letter GRAS Notice No. GRN 000359
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CFSAN/Office of Food Additive Safety
April 11, 2011
David H. Bechtel, Ph.D., DABT
Cantox Health Sciences International
1011 U.S. Highway 22, Suite 200
Bridgewater, NJ 08807-2950
Re: GRAS Notice No. GRN 000359
Dear Dr. Bechtel:
The Food and Drug Administration (FDA) is responding to the notice, dated November 3, 2010, that you submitted on behalf of Guilin Layn Natural Ingredients Corp. (Layn) 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 November 4, 2010, filed it on November 10, 2010, and designated it as GRAS Notice No. GRN 000359.
The subject of the notice is Siraitia grosvenorii Swingle (Luo Han Guo) fruit extracts (SGFE) (containing 25, 45, or 55 percent mogroside V). The notice informs FDA of the view of Layn that SGFE is GRAS, through scientific procedures, for use as a sweetener and flavor enhancer in foods, excluding meat and poultry products, at levels determined by current good manufacturing practices.
Our use of Siraitia grosvenorii Swingle (Luo Han Guo) fruit extracts or “SGFE” in this letter should not be considered an endorsement or recommendation of any of these terms 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 of the Code of Federal Regulations (CFR) part 101.4 states that all ingredients must be declared by their 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, Layn includes the report of a panel of individuals (Layn’s GRAS panel) who evaluated the data and information that are the basis for Layn’s GRAS determination. Layn considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Layn’s GRAS panel evaluated published and unpublished information on SGFE, including method of manufacture, specifications, batch analyses, estimated dietary exposure, and safety studies. Based on this review, Layn’s GRAS panel concluded that SGFE containing up to 55 percent (%) mogroside V and meeting its established food-grade specifications is GRAS under the conditions of its intended use.
Layn provides information about the identity and composition of SGFE. SGFE is obtained from the fruit of S. grosvenorii Swingle, commonly known as Luo Han Guo. Layn describes the three SGFE preparations as white, water soluble powders containing 25%, 45%, or 55% mogroside V. Mogroside V (CAS Reg. No. 88901-36-4), a cucurbitane glycoside that occurs naturally in Luo Han Guo, is the primary component of SGFE and is responsible for imparting the characteristic sweet taste to SGFE.
Layn provides information about the manufacturing process for SGFE. Fresh S. grosvenorii Swingle fruit is washed and then crushed followed by aqueous extraction. Additional processes include heating, centrifugation and ultrafiltration to produce a clear concentrated liquid. This liquid is treated with activated carbon and adsorption/separation polymer resins to extract the glycosides and to remove undesired flavor undertones and pigments before spray-drying and packaging. Layn also states that SGFE containing 25% mogroside V is the least refined form, and that the two preparations containing 45% and 55% mogroside V respectively, are achieved through further processing of SGFE containing 25% mogroside V. Layn states that the three SGFE preparations are manufactured using current good manufacturing practices and all materials used in the manufacturing process are of food-grade quality.
Layn provides specifications for the SGFE preparations that include a minimum content of mogroside V for each type (25%, 45%, or 55%), limits on moisture (less than 5.0%), arsenic (less than 0.5 milligram per kilogram (mg/kg)), cadmium (less than 0.05 mg/kg), lead (less than 0.5 mg/kg), and mercury (less than 0.1 mg/kg). Layn also provides specifications for pesticide residues and microbial contaminants. In addition, Layn provides results from batch analyses of the three preparations that demonstrate conformity with the specifications. Layn notes that cucurbitacins, a group of toxic plant secondary metabolites based on the same molecular skeleton as mogrosides, are not found in Luo Han Guo fruit, and therefore, not present in the SGFE preparations.
Layn estimates the intake of SGFE resulting from its intended use in food. Layn used dietary exposure data for sweetener use from a published study by Renwick (2008).(1) This study performed an intake assessment of an intense sweetener (i.e., rebaudioside A) showing the overall projected intakes by mean and upper percentile consumers in different subpopulations.(2) The projected exposures in this study are based on sweetener substitution and assume a relative sweetness compared to that of sucrose. Layn states that based on sensory analysis testing, the three SGFE preparations with mogroside V content of 25%, 45%, or 55% have respective sweetness intensities of 160, 210, and 250 times that of sucrose. Using these relative sweetness intensities and the methodology described in the study by Renwick, Layn calculates mean and upper percentile estimated daily intakes (EDI) for SGFE and mogroside V for each of the three SGFE preparations and for different subpopulations.
For adult, non-diabetic, consumers of foods containing SGFE, Layn calculates the mean EDIs for SGFE 25%, 45%, and 55% as 1.6, 1.2, and 1.0 mg/kg body weight per day (bw/d), respectively. Based on the specifications for SGFE 25%, 45%, and 55%, the mean mogroside V EDIs by adult, non-diabetic, consumers are 0.40, 0.55, and 0.56 mg/kg bw/d, respectively. The upper percentile EDIs for SGFE 25%, 45%, and 55% by adult, non-diabetic, consumers of foods containing SGFE are 4.2, 3.2, and 2.7 mg/kg bw/d, respectively. These values correlate to upper percentile EDIs for mogroside V of 1.06, 1.45, and 1.49 mg/kg bw/d for SGFE 25%, 45%, 55%, respectively.
On a body weight basis, the highest consuming subpopulation is diabetic children. For this group, Layn calculates the mean EDIs for SGFE 25%, 45%, and 55% as 4.2, 3.2, and 2.7 mg/kg bw/d, respectively. These values correlate to mean EDIs for mogroside V of 1.05, 1.44, and 1.49 mg/kg bw/d for SGFE 25%, 45%, 55%, respectively. Upper percentile EDIs for SGFE 25%, 45%, and 55% by diabetic children who consume foods containing SGFE are 5.7, 4.3, and 3.6 mg/kg bw/d, respectively. These values correlate to upper percentile EDIs for mogroside V of 1.42, 1.95, and 1.99 mg/kg bw/d for SGFE 25%, 45%, 55%, respectively.
Layn discusses the safety of SGFE. Layn relies in part on safety data presented in GRN 000301 for a Luo Han Guo fruit extract that contains over 30% mogroside V. Additionally, Layn discusses published and unpublished studies, including short term and subchronic studies in rats and bacterial reverse mutation studies, pertaining to the safety of SGFE that contains approximately 55% mogroside V. In the subchronic studies, rats were dosed at 3124 mg/kg bw/d and 3752 mg/kg bw/d in males and females respectively (highest dose tested) with no adverse effects. Based on its consideration of all the studies, Layn concludes that SGFE is GRAS for its intended use in foods.
Standards of Identity
In the notice, Layn states its intention to use SGFE in several food categories, including foods for which standards of identity exist, located in Title 21 of the CFR. 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 Layn’s notice that SGFE is GRAS under the intended conditions of use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing SGFE. Accordingly, this response should not be construed to be a statement that foods that contain SGFE, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Layn, as well as other information available to FDA, the agency has no questions at this time regarding Layn’s conclusion that SGFE 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 SGFE. As always, it is the continuing responsibility of Layn 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 000359, 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 AG, 2008. The use of a sweetener substitution method to predict dietary exposures for the intense sweetener rebaudioside A. Food Chem Toxicol 46:S61-S69.
(2)Renwick incorporates data from different studies which define higher volume food consumers using different populations percentiles (e.g., 90th, 95th and 97.5th percentile of intake). Therefore for the purpose of the study and for this discussion, these are collectively referred to as “upper percentile” consumers.