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  1. GRAS Notice Inventory

Agency Response Letter GRAS Notice No. GRN 000588

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See also Generally Recognized as Safe (GRAS).

CFSAN/Office of Food Additive Safety

February 29, 2016

Madhu G. Soni, Ph.D.
Soni & Associates, Inc.
749 46th Square
Vero Beach, Florida 32968

Re: GRAS Notice No. GRN 000588

Dear Dr. Soni:

The Food and Drug Administration (FDA) is responding to the notice, dated June 25, 2015, that you submitted on behalf of OmniActive Health Technologies, Ltd. (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 July 8, 2015, filed it on July 24, 2015, and designated it as GRAS Notice No. GRN 000588. FDA received additional information on February 18, 2016.

The subject of the notice is zeaxanthin derived from paprika (Capsicum annuum L.) (paprika zeaxanthin).[1] The notice informs FDA of the view of OmniActive that paprika zeaxanthin is GRAS, through scientific procedures, for use as an ingredient in the following food categories at use levels of 0.3 to 3 milligrams (mg) zeaxanthin per serving:[2]

  • baked goods and baking mixes,
  • beverages and beverage bases,
  • breakfast cereals,
  • chewing gum,
  • dairy product analogs,
  • fats and oils,
  • frozen dairy desserts and mixes,
  • gravies and sauces,
  • hard candy,
  • milk products,
  • processed fruits and fruit juices, and
  • soft candy.

The intended use of paprika zeaxanthin does not include foods that are under the jurisdiction of United States Department of Agriculture (USDA) or infant formulas.

As part of its notice, OmniActive includes the report of a panel of individuals (OmniActive’s GRAS panel) that evaluated the data and information that are the basis for the firm’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 information describing the identity and composition, manufacturing process and specifications, and estimated dietary exposure, as well as published studies supporting the safety of paprika zeaxanthin. The GRAS panel concludes that paprika zeaxanthin produced in accordance with good manufacturing practices is considered to be GRAS when used as an ingredient in food.

OmniActive describes paprika zeaxanthin as a reddish-orange powder that may be formulated as a beadlet, powder, granule, or oil suspension. OmniActive states that these formulations use common edible oils (e.g. corn oil, sunflower oil, or safflower oil) or food grade carbohydrates. Zeaxanthin is also known as (3R,3′R)-β, β-carotene-3,3′-diol and has the CAS Registry number 144-68-3. The percentage of zeaxanthin with all trans-bonds ranges from 55 to 75% with an average content of 65%. OmniActive states that paprika zeaxanthin typically contains up to 2% of zeaxanthin with cis-bonds, up to 1% of lutein, 5 to 16% β-carotene, and 5 to 8% β-cryptoxanthin.

OmniActive describes the manufacturing processes for paprika zeaxanthin. Dried paprika pods are ground and extracted with acetone. The acetone is then removed to obtain an oleoresin that is subjected to saponification and cooled. The material is concentrated by filtration or centrifugation, washed with aqueous isopropyl alcohol or aqueous ethanol, and then filtered and dried under vacuum. Food grade antioxidant (1-2% tocopherols) are added and the product may then be formulated as beadlets, powder, granules, or an oil-suspension. OmniActive states that the production material is monitored for pesticide residues, contaminants, and residual solvent levels, and that all processing aids, solvents, and buffer salts used in the manufacturing process are food-grade as per the 8th Edition of Food Chemicals Codex.

OmniActive provides specifications for paprika zeaxanthin, including a minimum concentration of trans-isomer zeaxanthin (≥ 55%) and limits on cis-isomer zeaxanthin (≤ 2%), fats (15 to 25%), heavy metals, residual acetone, isopropyl alcohol and ethanol, and microbial contaminants. OmniActive provides the results of analyses conducted with three batches of paprika zeaxanthin to demonstrate that the manufacturing process results in a product that meets the firm’s specifications.

OmniActive discusses exposure to paprika zeaxanthin and cites the exposure estimate for lutein and zeaxanthin reported in GRN 000140,[3] which was based on food consumption data from the USDA’s 1994-1996 Continuing Survey of Food Intakes by Individuals and the 1998 Supplemental Children's Survey. OmniActive notes that the composition of the notified substance in GRN 000140 was reported to be primarily lutein rather than zeaxanthin, and that based on the intended use in food, the mean (users-only) exposure to lutein is 7.3 mg/person/day (0.14 mg/kg body weight (bw)/day) and the 90th percentile is 13.4 mg/person/day (0.28 mg/kg bw/day). OmniActive states that the intended use of paprika zeaxanthin is in the same food products and at proportional use levels to those described in GRN 000140 for the primarily lutein-containing ingredient (and effectively substitutional). Therefore, the mean and 90th percentile exposure to zeaxanthin (7.3 and 13.4 mg/person/day, respectively) is similar to the lutein exposure described in GRN 000140.

OmniActive reviews prior FDA evaluations of zeaxanthin and related compounds in support of the safety of the firm’s paprika zeaxanthin. OmniActive discusses the structural similarities between zeaxanthin, lutein, and meso-zeaxanthin. OmniActive states that FDA has received seven GRAS notifications on lutein and has responded with ‘no questions’ (GRN 000110 lutein ester; GRN 000140 crystalline lutein; GRN 000221 suspended lutein; GRN 000291 crystalline lutein; GRN 000385 lutein and zeaxanthin; GRN 000390 suspended lutein; GRN 000432 lutein diacetate). OmniActive also reported that FDA had ‘no questions’ for GRN 000481 meso-zeaxanthin and GRN 000550 mixture of lutein, zeaxanthin, and meso-zeaxanthin (meso-zeaxanthin preparation). OmniActive also states that paprika which is the source material for their zeaxanthin product is listed as GRAS under 21 CFR 182.10.

OmniActive cites a published article that reports on acute and subchronic studies conducted in rats given zeaxanthin and on an Ames assay. The zeaxanthin tested in each of these studies is the same as the subject of this GRN (000588). The Ames assay provided no evidence of mutagenicity up to the highest dose tested, 1000 micrograms  per plate. The acute study utilized female rats and after a single oral administration of 2000 mg/kg bw no toxic effects where observed over the 14 day observation period. The subchronic 90 day gavage rat study utilized 10 rats/sex/group and no adverse effects were observed up to 400 mg/kg bw/day, the highest dose tested.

OmniActive cites a published two-generation reproductive rat feeding study using synthetic zeaxanthin and reported no adverse effects at 150 mg/kg bw/day. OmniActive cites a published one year feeding study in female Rhesus Macaques. No ocular or renal (pertaining to urinary creatinine and protein levels) toxicity was observed at approximately 10 mg/kg bw/day zeaxanthin after one year of exposure to monkeys.

OmniActive concludes, based on the totality of evidence, that paprika zeaxanthin used as specified in this notice and manufactured in accordance to good manufacturing practice is GRAS.

Standards of Identity

In the notice, OmniActive states its intention to use paprika zeaxanthin in several food categories, including foods for which standards of identity exist, located in Title 21 of the Code of Federal Regulations. FDA notes 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 paprika zeaxanthin and in describing the information that OmniActive relies on to conclude thatpaprika zeaxanthin is GRAS under the conditions of its intended use, OmniActive raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act). In describing the information that OmniActive relies on to conclude that paprika zeaxanthin is GRAS, OmniActive discussed studies that show potential physiological effects of paprika zeaxanthin that OmniActive 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 paprika 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. The Office of Food Additive Safety (OFAS) neither consulted with ONFL on this labeling issue nor evaluated the information in OmniActive’s notice to determine whether it would support any claims made about paprika zeaxanthin on the label or in labeling.

Potential Requirement for a Color Additive Petition

In its notice, OmniActive notes that paprika zeaxanthin may impart color to food. As such, the use of paprika 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 paprika 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.

In its notice, OmniActive states that the addition of paprika zeaxanthin would fall outside the definition of color additive. OmniActive states that paprika zeaxanthin when used in the food categories described above may incidentally contribute its own color to the food. OmniActive states that its intended use is a nutritional use, and cites 21 CFR 70.3(f) "Food Ingredient" Exemption and 21 CFR 70.3(g) “Unimportant color” exemption since the intended use of paprika zeaxanthin in food is to provide a source of zeaxanthin in the diet and does not relate to any use of the ingredient as a color additive. Importantly, FDA’s response to GRN 000588 does not include any comment by FDA about OmniActive’s view of this issue. If, after receipt of a response letter, OmniActive has any specific questions about this issue, FDA recommends that OmniActive contact the Division of Petition Review in OFAS.

Section 301(ll) of the FD&C Act

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 paprika zeaxanthin is GRAS for use as an ingredient in a variety of specified foods, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing paprika zeaxanthin. Accordingly, FDA’s response should not be construed to be a statement that foods that contain paprika zeaxanthin, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).

Conclusions

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 paprika 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 paprika zeaxanthin. As always, it is the continuing responsibility of to ensure that food ingredients that the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements.[1] Paprika and paprika oleoresin are regulated as color additives (for uses that impart color), and are also listed as GRAS in the Code of Federal Regulations for use as a spice and natural extract, respectively.

In accordance with proposed 21 CFR 170.36(f), a copy of the text of this letter responding to GRN 000588, 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.

Sincerely,

Dennis M. Keefe, Ph.D.
Director
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition

[1] Paprika and paprika oleoresin are regulated as color additives (for uses that impart color), and are also listed as GRAS in the Code of Federal Regulations for use as a spice and natural extract, respectively.

[2] OmniActive states that the intended use of paprika zeaxanthin is in the same food categories and at levels proportional to those described in GRN 000110, GRN 000140, and GRN 000291 on the basis of the equivalence of lutein and zeaxanthin.

[3] GRN 000140 describes the intended use of a mixture of the carotenoids lutein and zeaxanthin (referred to as “crystalline lutein” by the notifier) in a variety of food categories at levels up to 3 mg/day.