Agency Response Letter GRAS Notice No. GRN 000639
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See also Generally Recognized as Safe (GRAS).
CFSAN/Office of Food Additive Safety
September 28, 2016
Dr. Gavin Thompson
2111 East Highland Avenue
Phoenix, AZ 85016
Re: GRAS Notice No. GRN 000639
Dear Dr. Thompson:
The Food and Drug Administration (FDA) is responding to the notice, dated March 10, 2016, that you submitted on behalf of Kemin Foods, L.C. 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 March 14, 2016, filed it on April 11, 2016, and designated it as GRAS Notice No. GRN 000639.
The subject of the notice is zeaxanthin. The notice informs FDA of the view of Kemin Foods, L.C. (Kemin) that zeaxanthin is GRAS, through scientific procedures, for use as an ingredient in baby and toddler foods, hard and soft candies, cereals, crackers, egg substitutes, frozen yogurt, gum, margarine-like spreads, salad dressings, soups, milk (dry, fermented, flavored, soy, and imitation), fruit juices, nectars, and other beverages (carbonated, energy, fruit-flavored, meal replacement and mixes) at levels of up to 300 micrograms zeaxanthin per serving.
As part of its notice, Kemin includes the report of a panel of individuals (Kemin’s GRAS panel) that evaluated the data and information that are the basis for Kemin’s GRAS determination. Kemin considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Kemin’s GRAS panel evaluated the identity, composition, method of production, product specifications, and estimates of dietary exposure, as well as published and unpublished studies supporting the safety of zeaxanthin. Based on this review, Kemin’s GRAS panel concluded that zeaxanthin produced in accordance with current good manufacturing practices (cGMP) that meets its established food grade specifications is GRAS under the conditions of its intended use.
Kemin describes the identity and composition of a purified, concentrated zeaxanthin extract. The extract is derived from flowers of a specialized variety of marigold (Tagetes erecta) bred to have higher levels of zeaxanthin relative to lutein and other carotenoids. The extract is composed of at least 50 percent crystalline zeaxanthin. The CAS Registry number for zeaxanthin [(3R,3′R)-β, β-carotene-3,3′-diol] is 144-68-3. Kemin formulates the zeaxanthin extract into oil suspensions (14% or 20% zeaxanthin) and beadlets (5% or 10% zeaxanthin).
Kemin describes the manufacturing of the zeaxanthin extract. Dried marigold flowers are extracted with hexane, compressed, and the solvent is evaporated to form a thick paste, or oleoresin, containing fatty acid esters and carotenoids. The oleoresin is purified by saponification and by filtration. The resulting cake is purified with ethanol, filtered, and rinsed with water. The wet cake is freeze dried, blended, and screened to form crystalline zeaxanthin, which is formulated into safflower oil suspensions containing 14% or 20% zeaxanthin or beadlet preparations containing 5% or 10% zeaxanthin.
Kemin provides specifications for the zeaxanthin extract. The specifications include zeaxanthin (not less than 50% of the cake), lutein (not less than 3% of the cake), meso-zeaxanthin (≤ 1.5%), and limits for heavy metals and residual solvents. Kemin analyzed three non-consecutive lots to demonstrate that the product conforms to the specifications. Kemin presents studies showing that the product is stable for at least twelve months under recommended storage conditions and at least six months at elevated temperatures and humidity.
Kemin estimates dietary exposure to zeaxanthin and to the related carotenoid, lutein. Kemin states that zeaxanthin and lutein are present in regular diets in foods such as green leafy vegetables, corn, egg yolks, artichoke hearts, and peppers. Based on food consumption data reported in the National Health and Nutrition Examination Survey, Kemin estimates the mean, cumulative exposure to lutein and zeaxanthin from intended uses and existing dietary sources for persons over one year of age to be 3.4 mg/person/day (0.06 mg/kg bw/day for a 60 kg individual) and 17.2 mg/person/day (0.29 mg/kg bw/day for a 60 kg individual) at the 90th percentile. Exposure from intended uses alone would be 2.0 mg/person/day (0.03 mg/kg bw/day for a 60 kg individual) and 3.8 mg/person/day (0.06 mg/kg bw/day for a 60 kg individual) at the 90th percentile.
Kemin discusses publically available information supporting the safe use of zeaxanthin. Kemin discusses the safety data provided in the previous FDA evaluations of GRAS notices on zeaxanthin, lutein, and related carotenoids (GRNs 000110, 000140, 000221, 000291, 000385, 000390, 000542, 000543, 000481, and 000550), all of which received ‘no questions’ letters from FDA. Kemin notes that the Joint FAO/WHO Expert Committee on Food Additives (JECFA) established an acceptable daily intake (ADI) of 2 mg/kg bw/day for lutein from T. erecta and for synthetic zeaxanthin, and the European Food Safety Authority (EFSA) established an ADI of 1 mg/kg bw/day.
Kemin discusses published animal and human clinical studies conducted with zeaxanthin, lutein, and related carotenoids and concludes that no adverse effects from zeaxanthin or lutein have been reported, demonstrating that zeaxanthin is well tolerated by humans and does not raise safety concerns. Kemin states that in vitro genotoxicity tests demonstrated that their zeaxanthin product was neither mutagenic nor clastogenic. Additionally, Kemin summarizes the results of an unpublished 90-day oral toxicity study conducted with Kemin’s zeaxanthin product (14% in safflower oil), in which Sprague Dawley rats were administered zeaxanthin by oral gavage once daily. No adverse effects were observed in these rats, and the NOAEL was reported to be 77 mg zeaxanthin/kg bw/day, the highest dose tested, corroborating the existing body of evidence supporting the safety of zeaxanthin.
Based on the totality of the available data and information, Kemin concludes that zeaxanthin is GRAS under the conditions of its intended use.
Standards of Identity
In the notice, Kemin states its intention to use 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
Under section 403(a) of the Federal Food, Drug, and Cosmetic Act (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. In the information that Kemin relies on to conclude that zeaxanthin is GRAS under the conditions of its intended use, Kemin discusses potential health benefits of zeaxanthin, which raise potential issues under these labeling provisions of the FD&C Act. If products that contain zeaxanthin bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition and Food Labeling (ONFL) in the Center for Food Safety and Applied Nutrition (CFSAN). The Office of Food Additive Safety neither consulted with ONFL on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about zeaxanthin on the label or in labeling.
Potential Requirement for a Color Additive Petition
In their notice, Kemin notes that zeaxanthin may impart color to food. As such, the use of 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, 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 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.
Kemin states that the intended use of zeaxanthin would not meet the definition of color additive under 21 CFR 70.3(f). Importantly, FDA’s response to GRN 000639 does not include any comment by FDA about Kemin’s view on this issue. If, after receipt of this letter, Kemin has any specific questions about this issue, we recommend that Kemin contact the Division of Petition Review, Office of Food Additive Safety, Center for Food Safety and Applied Nutrition, Food and Drug Administration, 5001 Campus Drive, College Park, MD 20740. You can reach this division by telephone at (240) 402-1200.
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 Kemin’s notice that zeaxanthin is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing zeaxanthin. Accordingly, this response should not be construed to be a statement that foods that contain zeaxanthin, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Kemin as well as other information available to FDA, the agency has no questions at this time regarding Kemin’s conclusion that 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 zeaxanthin. As always, it is Kemin’s continuing responsibility 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 000639, 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
 Excluding products regulated by the United States Department of Agriculture.
 In 2016, JECFA established an ADI for lutein esters from Tagetes erecta as “not specified.” This designation is given to substances considered to be of very low toxicity that do not represent a hazard to health based on available data and dietary exposure.
 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 a 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 000639 does not constitute a finding of the Secretary within the meaning of section 721(b)(4) of the FD&C Act.