Agency Response Letter GRAS Notice No. GRN 000446
CFSAN/Office of Food Additive Safety
April 15, 2013
James T. Heimbach, Ph.D.
P.O. Box 66
Port Royal, VA 22535
Re: GRAS Notice No. GRN 000446
Dear Dr. Heimbach:
The Food and Drug Administration (FDA) is responding to the notice, dated September 28, 2012, that you submitted on behalf of Groupe Grap’Sud 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 October 3, 2012, filed it on October 16, 2012, and designated it as GRAS Notice No. GRN 000446.
The subject of the notice is red grape pomace extract (RGPE). The notice informs FDA of the view of Groupe Grap’Sud that RGPE is GRAS, through scientific procedures, for use as an antioxidant in fruit juices (except those for which a standard of identity exists), fruit flavored beverages, fruit flavored beverage mixes and carbonated fruit flavored beverages at a concentration of up to 210 milligrams/kilogram (mg/kg) (alone or in combination with other safe and appropriate antioxidant substances).
Our use of “red grape pomace extract” or “RGPE” 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, Labeling, and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition.
As part of its notice, Groupe Grap’Sud includes the report of a panel of individuals (Groupe Grap’Sud’s GRAS panel) that evaluated the data and information that are the basis for Groupe Grap’Sud’s GRAS determination. Groupe Grap’Sud considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Groupe Grap’Sud’s GRAS panel evaluated estimates of dietary exposure, methods of production, and product specifications as well as published and unpublished studies. Based on this review, Groupe Grap’Sud’s GRAS panel concluded that RGPE that meets its established food grade specifications is GRAS under the conditions of its intended use.
Groupe Grap’Sud describes RGPE as a fine, purple powder. RGPE is composed predominantly of polyphenolic compounds, including proanthocyanidins, monomeric flavanols, anthocyanins, and non-flavonoid polyphenols.
Groupe Grap’Sud describes the method of manufacture for RGPE. RGPE is made from the pomace of red grapes (Vitis vinifera L.). After harvesting, sorting, cleaning, and removal of stems, the red grapes are pressed to extract the juice. The remaining material, referred to as grape pomace, includes pulp, skin, and seeds. The pomace is extracted with water. The extract is slightly fermented by the presence of naturally occurring Saccharomyces strains, and then centrifuged and filtered to remove suspended particulate matter. The clarified extract is passed through an adsorbent resin column (styrene-divinylbenzene copolymer compliant with 21 CFR §173.65). Polyphenols are adsorbed by the resin and are recovered with an aqueous solution of food-grade ethanol. The eluate is vacuum dried to remove the ethanol, then pasteurized. The resulting concentrate is spray-dried and the final product is then packaged.
Groupe Grap’Sud provides product specifications for RGPE. Specifications include assays for total polyphenols as catechin equivalents (>92%) and total polyphenols as gallic acid equivalents (>55 %), procyanidins (>15%), anthocyanins (>2%), and resveratrol (>100 mg/kg). Specifications include limits for moisture (<6%), residual ethanol (<100 mg/kg), lead (<2 mg/kg), arsenic (<3 mg/kg), mercury (<1 mg/kg), cadmium (<1 mg/kg), and microbial and pesticide contaminants.
Groupe Grap’Sud states that analysis of multiple production lots of RGPE demonstrate compliance with the specifications above. Groupe Grap’Sud discusses studies conducted to evaluate the stability of RGPE under various storage conditions, including in aqueous solution at various pH and storage temperatures. There was no evidence of significant degradation of RGPE under the conditions tested. Studies on the stability of RGPE in aqueous solution demonstrated a loss of procyanidin polymers, but not of anthocyanins, monomers, or dimers. RGPE solutions were more stable at acidic pH. Groupe Grap’Sud therefore concludes that RGPE is stable under normal storage conditions for the intended conditions of use.
Groupe Grap’Sud states that the estimated dietary exposure of RGPE will be identical to that of the notified substances in GRN 000125. Estimates of the daily consumption of the intended food categories were obtained from the U.S. Department of Agriculture's (USDA) 1994-96 Continuing Surveys of Food Intakes by Individuals and the 1998 Supplemental Children's Survey. On a body weight basis, the estimated 90th percentile exposure ranged from 2 mg/kg body weight (bw)/day for adults to 10 mg/kg bw/day for infants and toddlers. Groupe Grap’Sud considers that RGPE would be used substitutionally for the subjects of GRN 000125 in existing food products.
The notifier discusses the similarity of RGPE to other grape pomace extracts. An appraisal of relevant metabolic and pharmacokinetic information was made by the notifier. The notifier discusses studies with similar but not identical grape pomace extracts to the subject of GRN 000446. The notifier reviews four published subchronic studies in rats and states that no adverse effects were seen at the highest doses tested of 1410-1780 mg/kg body weight (bw)/day in males and 1501-2150 mg/kg bw/day in females. The notifier discusses a published two-generation reproductive and developmental study in rats showing no adverse effects at an exposure of 4000 mg/kg bw/day. Furthermore, the notifier evaluates two published chronic studies in mice, one for 6 months at an exposure of 500 mg/kg bw/day and a second study for one year at an exposure of 100 mg/kg bw/day, with no adverse effects in either study. Finally, the notifier describes eight published clinical studies in which individuals received up to 100 mg/kg bw/day for up to 12 weeks and had no adverse reports. Based on the available scientific evidence the notifier concludes that RGPE is GRAS for the intended uses.
Potential Labeling Issues
Section 403(k) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) provides that a food shall be deemed to be misbranded if it bears or contains any chemical preservative, unless it bears labeling stating that fact. Section 403(i)(2) of the FD&C Act provides that a food shall be deemed to be misbranded unless its label bears the common or usual name of each ingredient. Section 403(a) of the FD&C Act provides that a food shall be deemed to be misbranded if its labeling is false or misleading in any particular. Groupe Grap’Sud’s use of RPGE constitutes use as a preservative. Therefore, the ingredient statement on labels of food products that contain RPGE must comply with the labeling regulations that implement sections 403(k) and 403(i)(2) of the FD&C Act. For example, 21 CFR 101.22(j) requires that the food to which a chemical preservative is added bear a label declaration stating both the common or usual name of the ingredient and a separate description of its function. If Groupe Grap’Sud has any questions about the appropriate labeling of this food ingredient, Groupe Grap’Sud should contact the staff in ONLDS.
In describing the intended use of RGPE and in describing the information that Groupe Grap’Sud relies on to conclude that RGPE is GRAS under the conditions of its intended use, Groupe Grap’Sud raises a potential issue under the labeling provisions of the FD&C Act. Group Grap’Sud describes RGPE as an antioxidant and describes clinical studies showing physiological effects that Groupe Grap’Sud views as beneficial. 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 RGPE 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 RGPE on the label or in labeling.
Potential Requirement for a Color Additive Petition
In its notice, Groupe Grap’Sud states that RGPE contains polyphenols, which give RGPE a deep purple color. As such, the use of RGPE 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,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 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 RGPE 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.2
In their notice, Groupe Grap’Sud states that the addition of its RGPE 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. Therefore, the incorporation of RGPE with its naturally occurring polyphenols falls outside of the definition of color additive (21 CFR 70.3(g)). Importantly, FDA’s response to GRN 00446 does not include any comment by FDA about Groupe Grap’Sud’s view on this issue. If, after receipt of this letter, Groupe Grap’Sud has any further questions about this issue, we recommend that Groupe Grap’Sud 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 Groupe Grap’Sud’s notice that RGPE is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing RGPE. Accordingly, this response should not be construed to be a statement that foods that contain RGPE, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Groupe Grap’Sud, as well as other information available to FDA, the agency has no questions at this time regarding Groupe Grap’Sud’s conclusion that RGPE is GRAS under the intended of use. The agency has not, however, made its own determination regarding the GRAS status of the subject use of RGPE. As always, it is the continuing responsibility of Groupe Grap’Sud 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 000446, 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
1The Secretary of the Department of Health and Human Services.
2We 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 000446 does not constitute a “finding of the Secretary” within the meaning of section 721(b)(4) of the FD&C Act.