Agency Response Letter GRAS Notice No. GRN 000491
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CFSAN/Office of Food Additive Safety
June 6, 2014
Plaҫa Francesc Macià, 7
Re: GRAS Notice No. GRN 000491
Dear Ms. Vincente:
The Food and Drug Administration (FDA) has received 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 6, 2013, filed it on December 19, 2013, and designated it as GRAS Notice No. GRN 000491.
The subject of the notice is rooster combs extract (RCE). The notice informs FDA of the view of Bioiberica S.A. (Bioiberica) that RCE is GRAS, through scientific procedures, for use as an ingredient in baked goods and baking mixes, beverages and beverage bases, breakfast cereals, cheeses, dairy product analogs, grain products and pastas, milk and milk products, processed fruits and fruit juices, and medical foods at a maximum level of 80 milligrams per serving (mg/serving).
As part of its notice, Bioiberica includes the report of a panel of individuals (Bioiberica’s GRAS panel) that evaluated the data and information that are the basis for Bioiberica’s GRAS determination. Bioiberica considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Bioiberica’s GRAS panel evaluated the identity and composition, method of manufacture, specifications, and estimated dietary exposure, as well as published and unpublished data and information supporting the safety of RCE. Based on this review, Bioiberica’s GRAS panel concluded that RCE, produced in accordance with current good manufacturing practices (cGMP) and meeting established specifications, is GRAS under the conditions of its intended use.
Bioiberica provides information on the identity and composition of RCE. RCE is a white hygroscopic powder derived from rooster combs and is composed primarily of sodium hyaluronate.
Bioiberica describes the manufacturing process for RCE. Rooster combs are digested using an alcalase enzyme preparation.(1) Following the digestion process, the enzyme is inactivated by heat treatment. The product is then filtered, concentrated, cooled, and precipitated. The supernatant is removed and the precipitate is cleaned, anhydrificated, filtered, dried, and milled to produce the final RCE product.
Bioiberica provides specifications for RCE. Specifications include the content of sodium hyaluronate (60 to 80%) and limits for chondroitin sulfate (≤ 5%), dermatan sulfate (≤ 25%), chlorides (≤ 1%), nitrogen (≤ 8%), protein (≤ 25%), loss on drying (≤ 10%), lead (< 0.5 mg per kilogram (kg)), acetone (≤ 3000 mg/kg), and microbiological contaminants.
Bioiberica provides estimates of the dietary exposure to RCE based on its intended use in food, using food consumption data included in the 2005-2006 and 2007-2008 U.S. National Center for Health Statistics' (NCHS) National Health and Nutrition Examination Surveys (NHANES). Bioiberica calculates the mean and 90th percentile dietary exposures to RCE (users only) to be 256.4 mg per person per day (mg/person/d) (equivalent to 5.2 mg per kg body weight per d (mg/kg bw/d)) and 494.2 mg/person/d (11.3 mg/kg bw/d), respectively.
Bioiberica also provides an estimate of exposure to RCE from its intended use in medical foods, based on a maximum number of two servings per day. Bioiberica estimates the maximum dietary exposure from medical foods to be 160 mg/person/d, which is equivalent to 2.7 mg/kg bw/d for a 60 kg individual. The dietary exposure to RCE from medical foods would be substitutional for that from conventional foods.
Bioiberica describes studies on the safety of RCE. Bioiberica discusses published acute oral toxicity and oral 90-day toxicity studies on RCE in rats. Bioiberica notes that no adverse effects were observed at 600 mg/kg bw/d (the highest dose tested). Bioiberica also discusses unpublished 14-day and 4-week oral toxicity studies in rats that demonstrate the safety of RCE. Bioiberica describes a published study conducted in horses that supports the safety of RCE and additional published and unpublished studies conducted in humans, in which no adverse effects were observed. Additionally, Bioiberica considers that the safety of RCE is corroborated by published safety data on hyaluronic acid. Moreover, Bioiberica states that bacterial reverse mutation studies on RCE were negative.
Based on the data and information summarized above, Bioiberica concludes that RCE is GRAS for the intended uses.
Potential Labeling Issues
In describing the intended use of RCE and in describing the information that Bioiberica relies on to conclude that RCE is GRAS under the conditions of its intended use, Bioiberica raises a potential issue under the labeling provisions of the Federal Food Drug and Cosmetic (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 RCE bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition, Labeling, and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition. 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 RCE on the label or in labeling.
In its notice, Bioiberica informs FDA that one intended use of RCE is use in medical foods. Section 5(b) of the Orphan Drug Act (ODA) defines a medical food as a food that is formulated to be consumed or administered enterally under the supervision of a physician and that is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation. Section 403(q) of the FD&C Act lays out the statutory framework for nutrition labeling of food products. Section 403(r) of the FD&C Act lays out the statutory framework for health claims and nutrient content claims. Under section 403(q)(5)(A)(iv) of the FD&C Act and FDA's implementing regulations in 21 CFR 101.9(j)(8), the requirements for nutrition labeling do not apply to medical foods as defined in section 5(b) of the ODA. Under section 403(r)(5)(A) of the FD&C Act and FDA's implementing regulations in 21 CFR 101.13(q)(4)(ii) and 21 CFR 101.14(f)(2), the requirements for nutrient content claims and health claims, respectively, do not apply to medical foods as defined in section 5(b) of the ODA. For your information, FDA's response to Bioiberica’s notice that RCE is GRAS for use in medical foods does not address the question of whether any particular food product that contains RCE as an ingredient would be a medical food within the meaning of section 5(b) of the ODA and, thus, would be exempt from the requirements for nutrition labeling, nutrient content claims, and health claims.
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 Bioiberica’s notice that RCE is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing RCE. Accordingly, this response should not be construed to be a statement that foods that contain RCE, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Bioiberica, as well as other information available to FDA, the agency has no questions at this time regarding Bioiberica’s conclusion that RCE 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 RCE. As always, it is the continuing responsibility of Bioiberica 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 000491, 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) Bioiberica notes that the alcalase enzyme preparation is produced by a Bacillus licheniformis strain. Bioiberica provides information supporting the safety of the enzyme preparation.