Agency Response Letter GRAS Notice No. GRN 000385
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CFSAN/Office of Food Additive Safety
December 16, 2011
Madhu G. Soni, Ph.D.
Soni & Associates Inc.
749 46th Square
Vero Beach, FL 32968
Re: GRAS Notice No. GRN 000385
Dear Dr. Soni:
The Food and Drug Administration (FDA) is responding to the notice, dated June 7, 2011, that you submitted on behalf of OmniActive Health Technologies Ltd., (hereafter referred to as OmniActive), 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 June 15, 2011, filed it on June 21, 2011, and designated it as GRAS Notice No. GRN 000385.
The subject of the notice is lutein preparation from marigold flowers (Tagetes erecta) (hereafter referred to as lutein preparation). The notice informs FDA of the view of OmniActive that lutein preparation is GRAS, through scientific procedures, for use as an ingredient in baked goods and baking mixes, beverages and beverage bases, breakfast cereals, chewing gum, dairy product analogs, egg products, fats and oils, frozen dairy desserts and mixes, gravies and sauces, hard candy, infant and toddler foods (other than infant formula), milk products, processed fruit and fruit juices, soft candy, soups and soup mixes, and medical foods intended as the sole item of the diet at levels ranging from 0.3 to 3.0 milligrams (mg) per reference amount customarily consumed.
Our use of "lutein preparation" 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 in the Center for Food Safety and Applied Nutrition.
As part of its notice, OmniActive includes the report of a panel of individuals (OmniActive's GRAS panel) who evaluated the data and information that are the basis for OmniActive's GRAS determination. OmniActive considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. OmniActive's GRAS panel evaluated the method of manufacture, product specifications and estimates of dietary exposure, as well as published and unpublished toxicological studies for lutein preparation. Based on this review, OmniActive's GRAS panel concluded that lutein preparation, produced consistent with current good manufacturing practices and meeting its purity and established food grade specifications, is GRAS under the conditions of its intended use.
OmniActive describes the method of manufacture for lutein preparation. Dried marigold (Tagetes erecta) flowers are subjected to solvent extraction with hexane to isolate an oleoresin. The oleoresin is then subjected to saponification with potassium hydroxide and 1-propanol. Following saponification, the contents are washed with ethyl acetate, extracted with hexane, and then filtered. The wet cake is washed with ethanol, filtered, and dried under vacuum to remove the remaining organic solvents. The resulting dried concentrate consists of lutein and zeaxanthin, which is then formulated into the final preparation using food grade materials. Tocopherols are added as antioxidants.
OmniActive provides the identity and specifications for lutein preparation. OmniActive describes the preparation as a reddish-orange crystalline powder with a characteristic odor of marigold flowers. OmniActive provides specifications for the total carotenoids in lutein preparation and percentages of lutein and zeaxanthin. OmniActive reports that lutein preparation contains greater than 67 percent lutein by weight and approximately 13.5 percent zeaxanthin by weight (for a total of greater than 80 percent total carotenoids by weight). OmniActive states that the zeaxanthin portion is a 50:50 mixture of two zeaxanthin isomers (i.e., zeaxanthin, (3R,3'R)-β, β-carotene-3,3'-diol and meso-zeaxanthin (3R,3'S)-β, β-carotene-3,3'-diol). Specifications also include limits on residual hexane (< 50 mg/kilogram(kg)), residual ethyl acetate (< 25 mg/kg), residual ethanol (< 25 mg/kg), lead (< 1 mg/kg), arsenic (< 1 mg/kg), mercury (< 1 mg/kg), cadmium (< 1 mg/kg), pesticides and related contaminants (<0.01 mg/kg) and, microbial contaminants.
OmniActive provides an estimated daily intake (EDI) for their lutein preparation based on its proposed use in the same foods as in GRN 000110 and GRN 000140. OmniActive used ratios to adjust for the lower concentration of zeaxanthin and higher concentration of lutein in this preparation. By using proportional use levels and assuming substitutional uses, OmniActive states that the mean and 90th percentile EDI for lutein from its uses will remain at 7.3 and 13.4 mg lutein/person (p)/day (d) (0.12 and 0.22 mg lutein/kg body weight (bw)/d), respectively. The mean and 90th percentile EDI for zeaxanthin will be 0.7 and 1.2 mg/p/d (0.01 and 0.02 mg/kg bw/d), respectively.
OmniActive discusses the safety of lutein ingredients that have been the subject of four GRAS notices (lutein ester-GRN 000110; crystalline lutein-GRN 000140; suspended lutein-GRN 000221; crystalline lutein-GRN 000291). OmniActive also discusses the evaluation of the safety of lutein/zeaxanthin by the Joint FAO/WHO Expert Committee on Food Additives (JECFA, 2006). OmniActive notes that FDA, at the time of its response, had "no questions" to the GRAS notices listed above on lutein and its esters under the intended conditions of use. OmniActive notes that JECFA also evaluated the safety of lutein/zeaxanthin and concluded that no adverse effects were documented in any toxicity studies in animals, including mice, rats, monkeys, or in chemical studies in humans. JECFA established a group acceptable daily intake of 0 to 2 mg/kg bw for lutein and zeaxanthin.
OmniActive discussed published and unpublished safety studies on lutein preparation from T. erecta, as well as lutein, zeaxanthin, and meso-zeaxanthin from other sources, conducted in various animals and humans with respect to absorption, distribution, metabolism, and excretion (ADME) and toxicity. OmniActive summarized relevant toxicological studies, published subsequent to GRAS notices received by FDA and JECFA's evaluation that support the safe use of lutein. OmniActive also discusses unpublished acute and subchronic oral toxicity studies in rats and in vitro genotoxicity/mutagenicity studies on its lutein preparation, as well as the meso-zeaxanthin isomer. OmniActive concludes that results of these studies show no toxic or adverse effects from the consumption of lutein preparation from T. erecta or from lutein, zeaxanthin, or meso-zeaxanthin from other sources. OmniActive also considers published clinical studies in infants and adults as well as epidemiological studies, and reports that there is strong evidence for the safe use of lutein at levels up to 20 mg/d in healthy individuals. Studies in the elderly (persons aged 60 years and older) with or without age-related macular degeneration showed that consumption of lutein at doses up to 10 mg/d for 6 months was safe and without any apparent toxicity or side effects.
OmniActive concludes that the use of lutein and zeaxanthin is safe basedon the totality of the published and unpublished studies in animals, humans, clinical trials, and in vitro studies. Furthermore, specific toxicity studies conducted with lutein preparation and meso-zeaxanthin support their safety.
Standards of Identity
In the notice, OmniActive states its intention to use lutein preparation in several food categories, including foods for which standards of identity exist, located in Title 21 of the Code of Federal Regulations (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.
Potential Requirement for a Color Additive Petition
In its notice, OmniActive states that lutein preparation may incidentally contribute its own color to the product. As such, the use of lutein preparation in food products may constitute the use of a color additive under section 201(t)(1) of the Federal Food, Drug, and Cosmetic Act (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,  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 lutein preparation 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. 
In its notice, OmniActive states that the intended use of lutein preparation would not be included in the definition of a color additive, in accordance with 21 CFR 70.3(f). In its review of OmniActive's notice that the ingredient lutein preparation is GRAS for the intended uses, FDA did not consider whether section 201(t)(1) of the FD&C Act and FDA's implementing regulations in 21 CFR Part 70 apply to the use of lutein preparation in foods. Accordingly, this response should not be construed to be a statement that the use of lutein preparation in foods is lawful under section 721(a). If, after receipt of this letter, OmniActive has any further questions about this issue, we recommend that OmniActive contact the Division of Petition Review in the Office of Food Additive Safety.
In its notice, OmniActive informs FDA that one intended use of lutein preparation 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 OmniActive's notice that lutein preparation is GRAS for use in medical foods does not address the question of whether any particular food product that contains lutein preparation 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 OmniActive's notice that lutein preparation is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing lutein preparation. Accordingly, this response should not be construed to be a statement that foods that contain lutein preparation, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by OmniActive, as well as other information available to FDA, the agency has no questions at this time regarding OmniActive's conclusion that lutein preparation 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 lutein preparation. As always, it is the continuing responsibility of OmniActive 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 000385, 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
 The Secretary of the Department of Health and Human Services.
 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 000385 does not constitute a "finding of the Secretary" within the meaning of section 721(b)(4) of the FD&C Act.