Agency Response Letter GRAS Notice No. GRN 000481
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CFSAN/Office of Food Additive Safety
April 11, 2014
Mark L. Itzkoff
Olsson Frank Weeda Terman Matz PC
600 New Hampshire Ave, NW
Washington, DC 20037
Re: GRAS Notice No. GRN 000481
Dear Mr. Itzkoff:
The Food and Drug Administration (FDA) is responding to the notice, dated August 5, 2013 that you submitted on behalf of Industrial Organica S.A. de C.V. (IOSA) 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 August 12, 2013, filed it on August 28, 2013, and designated it as GRAS Notice No. GRN 000481.
The subject of the notice is meso-zeaxanthin. The notice informs FDA of the view of IOSA that meso-zeaxanthin is GRAS, through scientific procedures, for use as an ingredient in a variety of food and beverage applications at levels ranging from 0.3 to 3.0 milligrams (mg) per reference amount customarily consumed (Table 1).
|Food Category: Intended food use||mg/RACCa|
|Baked goods and baking mixes: Cereal and energy bars||2.0|
|Baked goods and baking mixes: Crackers and crisp bread||2.0|
|Beverages and beverage bases: Bottled water||0.5|
|Beverages and beverage bases: Carbonated beverages||2.0|
|Beverages and beverage bases: Meal replacements||2.0|
|Beverages and beverage bases: Tea, ready-to-drink||0.6|
|Breakfast cereals: Instant & regular hot cereal||2.0|
|Breakfast cereals: Ready-to-eat cereal||2.0|
|Chewing gum: Chewing gum||1.0|
|Dairy product analogs: Imitation milks||2.0|
|Dairy product analogs: Soy milk||1.5|
|Egg products: Liquid, frozen or dried egg substitutes||2.0|
|Fats and oils: Margarine-like spreads||1.5|
|Fats and oils: Salad dressings||1.5|
|Frozen dairy desserts and mixes: Frozen yogurt||1.0|
|Gravies and sauces: Tomato-based sauces||0.3|
|Hard candy: Hard candy||1.0|
|Infantb and toddler foods: Junior, strained, and toddler type baby foods||1.0|
|Milk products: Dry milk||3.0|
|Milk products: Fermented milk beverages||0.6|
|Milk products: Flavored milk & milk drinks||3.0|
|Milk products: Milk-based meal replacement||3.0|
|Milk products: Yogurt||3.0|
|Processed fruit and fruit juices: Energy, sport and isotonic drinks||2.0|
|Processed fruit and fruit juices: Fruit-flavored drinks||2.0|
|Processed fruit and fruit juices: Fruit juice||2.0|
|Processed fruit and fruit juices: Nectars||2.0|
|Processed fruit and fruit juices: Vegetable juice||2.0|
|Soft candy: Chewy and nougat candy||1.0|
|Soft candy: Fruit snacks||1.0|
|Soups and soup mixesc: Canned soups||0.6|
|a RACC is defined as “reference amounts customarily consumed per eating occasion” (21 CFR 101.12).|
b The notifier states that infant formula is not included in their intended uses.
c The notifier excludes products under USDA jurisdiction from their intended uses.
As part of its notice, IOSA includes the report of a panel of individuals (IOSA’s GRAS panel) that evaluated the data and information that are the basis for IOSA’s GRAS determination. IOSA considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. IOSA’s GRAS panel reviewed the method of manufacture, specifications, dietary exposure, and published safety data. Based on this review, IOSA’s GRAS panel concluded that meso-zeaxanthin, produced consistent with good manufacturing practice and the specifications in this notice, is GRAS under the conditions of its intended use.
IOSA describes meso-zeaxanthin as a crystalline powder whose principal components are: ≥60% meso-zeaxanthin ((3R,3’S)-β, β-carotene-3,3’-diol, CAS Reg. No.31272-50-1), ≥15% lutein1 (β, ε-carotene-3,3’-diol, CAS Reg. No. 127-40-2), and ≤ 5% zeaxanthin ((3R,3’R)-β, β-carotene-3,3’-diol, CAS Reg. No. 144-68-3).
IOSA describes the manufacturing process for meso-zeaxanthin. The process starts with dried marigold (Tagetes erecta) flowers, which are washed with water, dried, ground, and then pelletized with steam. These pellets are extracted with hexane. The hexane is removed by evaporation under vacuum, yielding an oleoresin. The oleoresin is washed with an alkali solution, followed by dilute acid solutions to remove impurities, such as fatty acids, waxes, gums, and other plant materials. The oleoresin is then saponified using aqueous potassium hydroxide to free the xanthophylls and initiate the isomerization of lutein to zeaxanthin. The pH of the isomerized extract is adjusted and the product is washed with water and then further extracted with a solvent blend (hexane, acetone, and methanol). The solvents are removed using evaporation under vacuum and heat. The residue is filtered, dried, and then screened to collect the final meso-zeaxanthin product.
IOSA provides specifications for meso-zeaxanthin. These specifications include the chemical composition as described above and limits on lead (< 1 mg per kilogram (mg/kg)), arsenic (< 1 mg/kg), mercury (< 1 mg/kg), cadmium (< 1 mg/kg), hexane (< 25 mg/kg), methanol (< 50 mg/kg), and acetone (< 30 mg/kg). These specifications also include limits on microbiological contaminants. IOSA states that meso-zeaxanthin is routinely analyzed for common pesticide residues at a detection limit of < 0.01 mg/kg.
IOSA provides an estimate of the dietary exposure to meso-zeaxanthin based on the intended uses. IOSA notes that because meso-zeaxanthin will be used in place of other lutein/zeaxanthin products, the intended use of meso-zeaxanthin will not increase the dietary exposure to lutein/zeaxanthin. IOSA therefore relies on the estimated daily exposure for lutein and zeaxanthin as presented in GRN 000140.
IOSA uses the estimated exposure to lutein and zeaxanthin described in GRN 000140 that is based on food consumption data from the United States Department of Agriculture's (USDA) 1994–1996 Continuing Survey of Food Intakes by Individuals (CSFII 1994–1996) and the 1998 Supplemental Children's Survey (CSFII 1998) (USDA, 2000). The combined daily intake for lutein and zeaxanthin was calculated to be 9.6 mg/person/day (mg/p/d) and 17.6 mg/p/d at the mean and 90th percentile, respectively. Based on the differences in composition of meso-zeaxanthin, which contains a minimum of 60% meso-zeaxanthin, 5% zeaxanthin, and 15% lutein, IOSA calculated the 90th percentile exposure to these isomers as 10.58, 0.88, and 2.57 mg/p/d, respectively. This is equivalent to 0.2, 0.015, and 0.04 mg/kg body weight per day (mg/kg bw/d), respectively, for a 60 kg individual. This ingredient would be used in a large number of food categories that are considered staples of a balanced diet. Therefore, the use of food consumption data newer than those used by the notifier would not be expected to result in exposure estimates different from those in the notice.
IOSA discusses published data and information supporting the safety of meso-zeaxanthin, including acute and subchronic animal studies, clinical studies, and mutagenicity studies. IOSA also reported on the structural and physical similarities of lutein, zeaxanthin and meso-zeaxanthin (a stereoisomer of zeaxanthin2).
IOSA cites published acute oral toxicity tests in male and female rats and mice fed levels up to 10,000 mg meso-zeaxanthin/kilogram body weight (mg/kg bw) with no observed adverse events. Additionally, IOSA cites two published 90 day studies, both using 10 rats/sex/group. The no observed effect level was reported as 300 mg meso-zeaxanthin/kg bw/d. IOSA also cites a published double blind, randomized, placebo controlled human study. Volunteers consumed one capsule per day that contained 10.6 mg meso-zeaxanthin, 5.9 mg lutein, and 1.2 mg zeaxanthin (8 males and 14 females) or a placebo (9 males and 13 females) for 6 months. No adverse events were reported at levels up to the consumed amount. IOSA cites two published Ames assays, both conducted with and without metabolic activation, which demonstrate that meso-zeaxanthin is not mutagenic up to 5000 micrograms per plate. Based on the totality of evidence, IOSA concludes that meso-zeaxanthin is GRAS under the intended conditions of use.
Standards of Identity
In the notice, IOSA states its intention to use meso-zeaxanthin 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 intended use of meso-zeaxanthin and in describing the information that IOSA relies on to conclude that meso-zeaxanthin is GRAS under the conditions of its intended use, IOSA 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 meso-zeaxanthin 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 meso-zeaxanthin on the label or in labeling.
Potential Requirement for a Color Additive Petition
In its notice, IOSA notes that meso-zeaxanthin may impart color to food. As such, the use of meso-zeaxanthin 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,3 meso-zeaxanthin 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 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, 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 meso-zeaxanthin 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.4
In its notice, IOSA states that meso-zeaxanthin is not intended for use as a color additive and, thus, would be exempt from the definition of color additive under section 201(t) of the FD&C Act and FDA’s implementing regulations in 21 CFR 70.3(f) and (g). Importantly, FDA’s response to GRN 000481 does not include any comment by FDA about IOSA’s view on this issue. If, after receipt of this letter, IOSA has any specific questions about this issue, we recommend that IOSA contact the Division of Petition Review in the Office of Food Additive Safety.
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 IOSA’s notice that meso-zeaxanthin is GRAS for the intended use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing meso-zeaxanthin. Accordingly, this response should not be construed to be a statement that foods that contain meso-zeaxanthin, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by IOSA, as well as other information available to FDA, the agency has no questions at this time regarding IOSA’s conclusion that meso-zeaxanthin 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 meso-zeaxanthin. As always, it is the continuing responsibility of IOSA 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 000481, 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