Agency Response Letter GRAS Notice No. GRN 000497
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CFSAN/Office of Food Additive Safety
June 3, 2014
Kohei Homma, Ph.D.
Amino Up Chemical Co., Ltd.
Re: GRAS Notice No. GRN 000497
Dear Dr. Homma:
The Food and Drug Administration (FDA) is responding to the notice, dated December 3, 2013, 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 December 23, 2013, filed it on January 13, 2014, and designated it as GRAS Notice No. GRN 000497.
The subject of the notice is polyphenols from the fruit of Litchi chinensis Sonn. (lychee) and from the leaves of Camellia sinensis (L.) Kuntze (green tea), known hereafter as PLC. The notice informs FDA of the view of Amino Up Chemical Co., Ltd (Amino Up) that PLC is GRAS, through scientific procedures, for use as an ingredient in various food categories excluding meat and poultry products and infant formula, for use at levels as shown in Table 1.
Food Category: Intended food use Use levels (%) Breakfast cereals: Ready to eat cereals 0.08 Coffee and Tea: Tea 0.042 Dairy Product Analogs: Soy and imitation milk 0.01 Grain products and pastas: Granola, meal replacement and breakfast bars 0.08 Milk Products: Dairy based drinks (one shot)a 0.10 Milk Products: Flavored milk and milk drinks 0.01 Milk Products: Milk-based meal replacement beverages 0.08 Milk Products: Yogurt 0.02 Processed Fruits and Fruit Juices: Fruit flavored drinks (ready-to-drink and powders) 0.042 Processed Fruits and Fruit Juices: Fruit juices 0.042 Soups and soup mixes: Soups with legumes or potatoes as major ingredientsb 0.041 Soups and soup mixes: Tomato and vegetable soupsb 0.041 aFood codes representative of one-shot dairy based drinks were not identified. Fruit smoothie drinks and milk with acidophilus were used as surrogates for one-shot dairy-based drinks.
bExcluding meat/poultry-based soups
Our use of “polyphenols from the fruit of Litchi chinensis Sonn. (lychee) and from the leaves of Camellia sinensis (L.) Kuntze (green tea)” or “PLC” 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 non-standardized 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 (ONLDS) in the Center for Food Safety and Applied Nutrition.
As part of its notice, Amino Up includes the report of a panel of individuals (Amino Up’s GRAS panel) who evaluated the data and information that are the basis for Amino Up’s GRAS determination. Amino Up considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Amino Up’s GRAS panel evaluated estimates of dietary exposure, method of manufacture, and product specifications as well as published and unpublished safety studies in animals and humans. Based on this review, Amino Up’s GRAS panel concluded that PLC produced in a manner consistent with good manufacturing practices that meets its established food grade specifications is GRAS under the conditions of its intended use.
Amino Up describes PLC as a reddish-brown powder composed of oligomerized polyphenols derived from the extracts of L. chinensis fruit and C. sinensis leaves. The product consists mainly of monomeric flavan-3-ols (including catechin, epicatechin, epicatechin 3-gallate and epigallocatechin gallate) as well as procyanidins formed from the condensation of the monomeric units. The monomeric flavan-3-ols and procyanidins constitute 92.5 to 95.6% of the final product.
Amino Up describes the method of manufacture for PLC. The lychee fruit powdered extract is made by extraction of lychee fruit (L. chinensis) using 50% ethanol, followed by purification by column chromatography, concentration and drying. The powder contains greater than 70% polyphenols. The green tea leaf powdered extract is obtained by extraction of green tea leaves (C. sinensis) in 50% ethanol, followed by purification by column chromatography, concentration and drying. The powder contains a minimum of 98% total polyphenols. The powdered lychee fruit extract and powdered green tea leaf extract are blended in a ratio of 5:1 and then heated in the presence of citric acid. During this process the polyphenols are cleaved into oligomers and monomers. This is followed by filtration, purification, concentration, and drying, resulting in the final product.
Amino Up provides specifications for PLC. Specifications include total procyanidin content (>70%) and monomeric flavan-3-ols content (>10%). Specifications also include limits for moisture (≤5.0%), lead (≤0.2 milligrams per kilogram (mg/kg)), arsenic (≤1.0 mg/kg) and microbiological contaminants. The notifier presents the results of analyses of three non-consecutive batches of the product that show compliance with these specifications.
The notifier estimates the dietary exposure to PLC from the intended food uses. The calculated exposures for all users at the 90th percentile level are 65.9 mg/person per day (p/d) for monomeric flavan-3-ols and 288.4 mg/p/d for procyanidins. These approximate to 1 mg/kg body weight (bw)/d of monomeric flavan-3-ols and 5 mg/kg bw/d of procyanidins for a 60 kg individual.
Amino Up discusses published safety studies on PLC. These studies address the metabolic fate of PLC, product-specific toxicological studies including acute toxicity, two 90-day subchronic oral toxicity studies (gavage) in rats and a 90-day feeding study in mice. Amino Up reports that no treatment-related adverse effects were observed in rats at doses up to 800 mg/kg bw/d and up to 200 mg/kg bw/d in mice. Amino Up notes that one of the subchronic oral toxicological studies specifically addresses the concerns regarding nasal toxicity from green tea extract that was observed in a National Toxicology Program study. Amino Up states that the results of the study demonstrate that PLC does not produce nasal toxicity at doses up to 1,000 mg/kg bw/d. Amino Up reports that the results of genotoxicity assays indicate that PLC is neither mutagenic nor genotoxic. Additionally, Amino Up discusses three unpublished human studies and states that no adverse events were observed. Finally, Amino Up states that no cases of allergic reactions have been reported for PLC. Based on the totality of the scientific evidence, Amino Up concludes that PLC is GRAS under the conditions of its intended use.
Standards of Identity
In the notice, Amino Up states its intention to use PLC 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.
Potential Labeling Issues
In describing the information that Amino Up relies on to conclude that PLC is GRAS under the condition of its intended use, Amino Up raises a potential issue under the labeling provisions of the Federal Food, Drug and Cosmetic Act (FD&C Act). Under section 403(a) of the FD&C Act, a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FD&C Act lays out the statutory framework for the use of labeling claims that characterize the level of a nutrient in a food or that characterize the relationship of a nutrient to a disease or health-related condition. If products that contain PLC bear any claims on the label or in labeling, such claims are the purview of ONLDS. The Office of Food Additive Safety (OFAS) neither consulted with ONLDS on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about PLC on the label or in labeling.
The Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) amends the FD&C Act to require that the label of a food that is or contains an ingredient that bears or contains a “major food allergen” declare the presence of the allergen (section 403(w)). FALCPA defines a “major food allergen” as one of eight foods or food groups (i.e., milk, eggs, fish, Crustacean shellfish, tree nuts, peanuts, wheat, and soybeans) or a food ingredient that contains protein derived from one of those foods. PLC derived from lychee fruit may require labeling under FALCPA, because it may contain protein derived from lychee fruit. Lychee, also referred to as lychee nut, is listed in FDA’s guidance1 as a tree nut. Although issues associated with labeling food are the responsibility of ONLDS, issues associated with FALCPA exemptions are the responsibility of the Food Allergen Coordinator in OFAS.
Potential Requirement for a Color Additive Petition
In its notice, Amino Up states that the polyphenols present in PLC impart a reddish-brown color. As such, the use of PLC in food products may constitute the use of a color additive under section 201(t)(1) of the FD&C Act and FDA's implementing regulations in 21 CFR Part 70. Under section 201(t)(1) and 21 CFR 70.3(f), the term color additive means a material that is a dye, pigment, or other substance made by a process of synthesis or similar artifice, or extracted, isolated, or otherwise derived from a vegetable, animal, mineral, or other source, and that is capable (alone or through reaction with another substance) of imparting color when added or applied to a food; except that such term does not include any material which the Secretary,2 by regulation, determines is used (or intended to be used) solely for a purpose or purposes other than coloring. Under 21 CFR 70.3(g), a material that otherwise meets the definition of color additive can be exempt from that definition on the basis that it is used or intended to be used solely for a purpose or purposes other than coloring, as long as the material is used in a way that any color imparted is clearly unimportant insofar as the appearance, value, marketability, or consumer acceptability is concerned. Given the construct of section 201(t)(1) of the FD&C Act and 21 CFR 70.3(f) and (g), the use of a substance that is capable of imparting color may constitute use as a color additive in addition to use as a food additive or GRAS substance. For example, β-carotene is both approved for use as a color additive (21 CFR 73.95) and affirmed as GRAS for use as a nutrient supplement (21 CFR 184.1245); in some food products, β-carotene is used for both purposes. Importantly, if the use of PLC constitutes use as a color additive within the meaning of section 201(t)(1) of the FD&C Act and FDA's implementing regulations in 21 CFR 70.3(f) and (g), section 721(a) of the FD&C Act requires premarket review and approval of that use by FDA. Under section 402(c) of the FD&C Act, a food product that contains an unapproved color additive would be deemed adulterated.3
In its notice, Amino Up states that the addition of its PLC to the various food products occurs at sufficiently low levels that will not impart significant color to the resulting food products and is not intended to function as a color additive. Importantly, FDA’s response to GRN 000497 does not include any comment by FDA about Amino Up’s view on this issue. If, after receipt of this letter, Amino Up has any further questions about this issue, we recommend that Amino Up contact the Division of Petition Review in OFAS.
Section 301(ll) of the FD&C Act
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FD&C Act to, among other things, add section 301(ll). 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 Amino Up’s notice that PLC is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing PLC. Accordingly, this response should not be construed to be a statement that foods that contain PLC, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Amino Up to FDA, the agency has no questions at this time regarding Amino Up’s conclusion that PLC 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 PLC. As always, it is the continuing responsibility of Amino Up 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 000497, 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
(1)“Questions and Answers Regarding Food Allergens, including the Food Allergen Labeling and Consumer Protection Act of 2004 (Edition 4)” issued on April 6, 2006, and available at http://www.fda.gov.
(2)The Secretary of the Department of Health and Human Services.
(3)We note that section 721(b)(4) of the FD&C Act provides that a color additive shall be deemed to be safe and suitable for the purpose of listing under section 721(b) of the FD&C Act while there is in effect a published finding of the Secretary declaring that the substance is exempt from the definition of “food additive” because of its being generally recognized by qualified experts as safe for its intended use as provided in section 201(s) of the FD&C Act. Importantly, FDA’s response to GRN 000497 does not constitute a “finding of the Secretary” within the meaning of section 721(b)(4) of the FD&C Act.