Agency Response Letter GRAS Notice No. GRN 000341
CFSAN/Office of Food Additive Safety
November 22, 2010
Tom C. Lines
Quercegen Pharma LLC
275 Grove Street, Suite 2-400
Newton, MA 02466
Re: GRAS Notice No. GRN 000341
Dear Mr. Lines:
The Food and Drug Administration (FDA) is responding to the notice, dated May 20, 2010, 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 May 21, 2010, filed it on May 26, 2010, and designated it as GRAS Notice No. GRN 000341.
The subject of the notice is quercetin. The notice informs FDA of the view of Quercegen Pharma LLC (Quercegen) that quercetin is GRAS, through scientific procedures, for use as an ingredient in beverages and beverage bases, grain products and pastas, processed fruits and fruit juices, and soft candies at levels up to 500 milligrams per serving (mg/serving).
As part of its notice, Quercegen includes the report of a panel of individuals (Quercegen’s GRAS panel) who evaluated the data and information that are the basis for Quercegen’s GRAS determination. Quercegen considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Quercegen’s GRAS panel evaluated estimates of dietary exposure, method of manufacture, and product specifications as well as published and unpublished toxicological safety studies. Based on this review, Quercegen’s GRAS panel concluded that quercetin produced in accordance with current good manufacturing practices (cGMPs) and meeting appropriate food grade specifications is GRAS under the conditions of its intended use.
Quercegen describes the identity, composition, and method of manufacture of quercetin (CAS No. 117-39-5). It is a greenish-yellow crystalline solid that consists of a flavanol characterized by a phenyl benzo gamma pyrone-derived structure. Quercetin is obtained from aqueous extraction of the quercetin glycoside, rutin, from one of many starting materials including sun-dried Fava d’Anta beans (immature), Uncaria leaves, onions or apples. Crude quercetin aglycone is released via acid hydrolysis, with subsequent neutralization followed by multiple purification steps to yield purified quercetin (greater than 99.5 percent pure). Quercegen states that the manufacturing of quercetin is in accordance with cGMPs and that all raw materials used are appropriate for food use.
Quercegen provides specifications for quercetin including purity (greater than 99.5%), moisture (less than 4 percent), sulfated ash (less than 0.15 percent), lead (less than one milligram per kilogram (mg/kg)), rutin and isoquercetin (less than one mg/kg), residual ethanol (less than 3000 mg/kg) and limits for microbiological plate counts.
Using 2003–2004 and 2005–2006 National Health and Nutrition Examination Surveys, Quercegen estimates that dietary intake from the intended uses of quercetin for all ages would be 205 milligrams per person per day (mg/p/d) at the mean and 461 mg/p/d at the 90th percentile. On a body weight basis, the mean and 90th percentile intake values are 4 milligrams per kilogram body weight per day (mg/kg bw/d) and 9 mg/kg bw/d, respectively. Quercegen states that these estimates are conservative as they include all age groups, including infants and children who are not expected to be consuming products containing added quercetin. Quercegen states that the intended uses of quercetin are targeted to exercising adults. As a result, Quercegen estimates that approximately 37.4 percent of the U.S. population would consume added quercetin.
Quercetin is commonly consumed by humans as it is naturally present in a wide variety of fruits and vegetables, especially apples and onions. Therefore, Quercegen also calculated the background consumption of quercetin from naturally occurring sources. Quercegen obtained background values of 5.9 mg/p/d (0.1 mg/kg bw/d) and 14.7 mg/p/d (0.25 mg/kg bw/d) at the mean and 90th percentile, respectively, for the total U.S. population, with a maximum intake value of 258 mg/p/d (4.3 mg/kg bw/d). Taking all these intake values into account, Quercegen conservatively estimates that the targeted consumer, an exercising adult, who is also a high-end consumer of fruits and vegetables, may potentially consume 1250 mg/p/d (20.8 mg/kg bw/d) of quercetin.
Quercegen discusses published and unpublished information to support the safety of quercetin including absorption, distribution, metabolism, and elimination (ADME) studies; acute, subchronic, and chronic toxicity studies; carcinogenicity, genotoxicity, and reproductive/developmental toxicity studies; pharmacokinetic studies; and finally, human clinical and epidemiological studies. Quercegen considered all of the available toxicology studies in multiple species, and concludes that there is a lack of significant adverse systemic toxicity. The overall lack of in vivo toxicity of quercetin is consistent with its known metabolic fate; specifically its extensive microbial degradation in the gastrointestinal tract of both animals and humans, followed by methylation, oxidation and conjugative metabolic processes that occur in the liver and kidneys and eventual elimination through the bile, feces, and urine.
Published human clinical studies, including a study with levels up to 1000 mg/d (16 mg/kg bw/d) for 12 weeks, showed that quercetin supplementation had no influence on several measures of oxidative stress and antioxidant capacity. In discussing the safety studies, Quercegen identifies a published two-year toxicity and carcinogenicity study in rats by the National Toxicology Program (NTP) as pivotal in establishing safety. Quercegen states that the no observed adverse effect level for the NTP study was considered to be approximately 2200 mg/kg bw/d (highest dose tested). Quercegen notes that even using conservative estimates, their 90th percentile estimated daily intake (EDI) value of 9 mg/kg bw/d for all users as well as the EDI of 20.8 mg/kg bw/d for the high end consumer in the targeted population does not exceed the ADI.
Quercegen concludes that the weight-of-the-evidence from toxicological safety studies, human clinical studies corroborating epidemiological studies, together with recent human pharmacokinetic studies, demonstrate that quercetin is safe for the intended use.
Standards of Identity
In the notice, Quercegen states its intention to use quercetin 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 discussing the intended uses of quercetin, Quercegen lists specific types of beverages and beverage bases, namely sports and energy drinks, and a specific type of soft candy, namely sports chews. These specific types of food products often contain health or nutrient content claims. Under section 403(a) of the Federal Food, Drug, and Cosmetic Act (FFDCA), a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FFDCA 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 quercetin bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition, Labeling, and Dietary Supplements (ONLDS). The Office of Food Additive Safety 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 quercetin on the label or in labeling.
Potential Requirement for a Color Additive Petition
In its notice, Quercegen describes quercetin as a greenish-yellow crystalline solid that imparts a bright yellow hue to beverage formulations at 250 mg/serving. As such, the use of quercetin in food products may constitute the use of a color additive under section 201(t)(1) of the FFDCA 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,1 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 FFDCA 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, beta-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, beta-carotene is used for both purposes. Importantly, if the use of quercetin constitutes use as a color additive within the meaning of section 201(t)(1) of the FFDCA and FDA's implementing regulations in 21 CFR 70.3(f) and (g), section 721(a) of the FFDCA requires premarket review and approval of that use by FDA. Under section 402(c) of the FFDCA, a food product that contains an unapproved color additive would be deemed adulterated.2
In an electronic message sent by FDA to Quercegen on November 3, 2010, FDA requested that Quercegen present its view on whether any of the intended uses of quercetin would be exempt from the definition of a color additive. In an amendment received on November 8, 2010, Quercegen stated that the intended use of quercetin “…does not include any use to impart color to any product to which it is added and any impartation of color by quercetin in any product to which it is added would be incidental and have no value positive or negative insofar as the appearance, value, marketability, or consumer acceptability of the product to which quercetin is added is concerned.” In its review of Quercegen’s notice that the ingredient quercetin is GRAS for the intended uses, FDA did not consider whether section 201(t)(1) of the FFDCA and FDA’s implementing regulations in 21 CFR Part 70 apply to the use of quercetin in foods. Accordingly, this response should not be construed to be a statement that the use of quercetin in foods is lawful under section 721(a). If, after receipt of this letter, Quercegen has any further questions about this issue, we recommend that Quercegen contact the Division of Petition Review in the Office of Food Additive Safety.
Section 301(ll) of the 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 Quercegen’s notice that quercetin is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing quercetin. Accordingly, this response should not be construed to be a statement that foods that contain quercetin, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Quercegen, as well as other information available to FDA, the agency has no questions at this time regarding Quercegen’s conclusion that quercetin 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 quercetin. As always, it is the continuing responsibility of Quercegen 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 000341, 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 via the FDA home page at http://www.fda.gov. To view or obtain an electronic copy of the text of the letter, follow the hyperlinks from the “Food” topic to the “Food Ingredients and Packaging” section to the “Generally Recognized as Safe (GRAS)” page where the GRAS Inventory is listed.
Mitchell A. Cheeseman, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
1The Secretary of the Department of Health and Human Services.
2We note that section 721(b)(4) of the FFDCA provides that a color additive shall be deemed to be safe and suitable for the purpose of listing under section 721(b) of the FFDCA 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 FFDCA. Importantly, FDA’s response to GRN 000341 does not constitute a “finding of the Secretary” within the meaning of section 721(b)(4) of the FFDCA.