Agency Response Letter GRAS Notice No. GRN 000294
CFSAN/Office of Food Additive Safety
January 06, 2010
Edward A. Steele
EAS Consulting Group, LLC
1940 Duke Street, Suite 200
Alexandria, VA 22314
Re: GRAS Notice No. GRN 000294
Dear Mr. Steele:
The Food and Drug Administration (FDA) is responding to the notice, dated July 7, 2009, that you submitted on behalf of Fuji Chemical Industry Co., Ltd. (Fuji) 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 9, 2009, filed it on July 10, 2009, and designated it as GRAS Notice No. GRN 000294.
The subject of the notice is Haematococcus pluvialis (H. pluvialis) extract containing astaxanthin esters (Haematococcus extract). The notice informs FDA of the view of Fuji that Haematococcus extract is GRAS, through scientific procedures, for use as a food ingredient in baked goods, beverages, cereals, chewing gum, coffee and tea, dairy product analogs, frozen dairy desserts and mixes, hard candy, milk products, processed fruits and fruit juices, processed vegetables and vegetable juices, and soft candy at a use level to provide 0.1 milligrams (mg) astaxanthin per serving.
21 CFR 101.4 states that all ingredients must be declared by their common or usual name. In addition, 21 CFR 102.5 outlines general principles to use when establishing common or usual names for nonstandardized foods. Our use of "Haematococcus extract" in this memorandum 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. 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 (CFSAN).
As part of its notice, Fuji includes the report of a panel of individuals (Fuji's GRAS panel) who evaluated the data and information that are the basis for Fuji's GRAS determination. Fuji considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Fuji's GRAS panel evaluated estimates of dietary exposure, method of production, and product specifications, as well as published and unpublished studies. Based on this review, Fuji's GRAS panel concluded that Haematococcus extract that meets its established food grade specifications is GRAS under the conditions of its intended use.
Fuji describes Haematococcus extract as a dark red, lipid-rich extract of the cell walls of the alga H. pluvialis containing a mixture of astaxanthin esters. The astaxanthin esters are composed of astaxanthin, also known as (3S,3'S)-3,3'-dihydroxy-beta,beta-carotene-4,4'-dione (CAS 472-61-7), esterified to common edible fatty acids. The notifier provides a typical fatty acid profile for astaxanthin esters, which shows that the most prevalent fatty acids are oleic acid, linoleic acid, palmitic acid, and linolenic acid.
Fuji describes the method of manufacture of Haematococcus extract, which starts with the growth of H. pluvialis cells in stainless steel photobioreactors under controlled conditions. The growth medium is composed of mineral salts, trace nutrients, and a food grade acid for pH control. Vitamin E is added to the biomass to stabilize astaxanthin against oxidation. The harvested cell walls are crushed in water and dried. The astaxanthin ester-containing lipid fraction of the dry biomass is extracted with either acetone or supercritical carbon dioxide (CO2). The notifier states that the manufacturing process is in accordance with current good manufacturing practices and the processing aids used are food grade as specified in the fifth edition of the Food Chemical Codex (2003).
The notifier provides the results of compositional analyses which show the primary constituents of Haematococcus extract as follows (approximate percentages): acylglycerols (80 percent), astaxanthin esters (16 percent; mainly monoesters and some diesters and free astaxanthin) and tocopherols (2 percent). The notifier also provides specifications for Haematococcus extract, including chemical specifications for free astaxanthin (≥ 10 percent as free form by high performance liquid chromatography) as well as purity specifications for heavy metals and microbiological counts. Haematococcus extract prepared by acetone extraction has an additional specification for residual acetone (≤ 5 mg per kilogram).
The notifier calculates the estimated daily intake of astaxanthin from the intended food uses of Haematococcus extract for all users, at the mean and at the 90th percentile intake levels as 0.64 mg per person per day (mg/person/day) and 1.08 mg/person/day, respectively. For comparison purposes, the notifier also calculates the estimated daily intake of astaxanthin from the consumption of food in which astaxanthin occurs naturally. The main dietary sources of astaxanthin are various salmon species and rainbow trout. As the astaxanthin levels vary between fish species and as consumption levels of the individual species are not known, the notifier calculates a range for the intake estimate, from 0.045 to 6.87 mg/person/day of astaxanthin from the consumption of fish.
In its safety assessment, Fuji discusses the safety of Haematococcus extract and of astaxanthin. Fuji states that the alga H. pluvialis is considered to be nontoxigenic and nonpathogenic. Fuji discusses the results of published absorption, distribution, metabolism, and excretion studies of astaxanthin esters in animals and in humans. Fuji states that the astaxanthin esters are metabolized into their component pieces – fatty acids and free astaxanthin. Fuji concludes that free astaxanthin is absorbed but has limited bioavailability and does not accumulate. Fuji also discusses the results of published studies of Haematococcus extract, including acute and subchronic rodent toxicity studies, an in vitro genotoxicity study, and several human studies. Fuji concludes, on the basis of the totality of the available evidence, including animal, in vitro, and human studies, that consumption of Haematococcus extract, which contains astaxanthin esters, is safe at the intended use levels in the specified food levels.
Standards of Identity
In the notice, Fuji states its intention to use Haematococcus extract 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 Requirement for a Color Additive Petition
FDA notes that the astaxanthin esters present in Haematococcus extract have the potential to impart color in food products to which Haematococcus extract has been added. As such, the use of Haematococcus extract in food products may constitute the use of a color additive under section 201(t)(1) of the Federal Food, Drug, and Cosmetic Act (FFDCA) 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 FFDCA 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 Haematococcus extract, which contains astaxanthin esters, constitutes use as a color additive within the meaning of section 201(t)(1) of the FFDCA and FDA's implementing regulations in 21 CFR 70.3(f) and (g), section 721(a) of the FFDCA requires premarket review and approval of that use by FDA. Under section 402(c) of the FFDCA, a food product that contains an unapproved color additive would be deemed adulterated.
Potential Labeling Issues
Under section 403(a) of the FFDCA, a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FFDCA 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 describing the intended use of Haematococcus extract and in describing the information that Fuji relies on to conclude that Haematococcus extract is GRAS under the conditions of its intended use, Fuji raises a potential issue under these labeling provisions of the FFDCA. If products that contain Haematococcus extract bear any claims on the label or in labeling, such claims are the purview of ONLDS. 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 Haematococcus extract or astaxanthin esters on the label or in labeling.
Section 301(ll) of the FFDCA
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FFDCA to, among other things, add section 301(ll). Section 301(ll) of the FFDCA prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FFDCA, 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 Fuji's notice that Haematococcus extract is GRAS under the intended conditions of use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing Haematococcus extract. Accordingly, this response should not be construed to be a statement that foods that contain Haematococcus extract, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Fuji, as well as other information available to FDA, the agency has no questions at this time regarding Fuji's conclusion that Haematococcus extract, which contains astaxanthin esters, 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 Haematococcus extract. As always, it is the continuing responsibility of Fuji 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 000294, 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 via the FDA home page at http://www.fda.gov. To view or obtain an electronic copy of the text of the letter, follow the hyperlinks from the "Food" topic to the "Food Ingredients and Packaging" section to the "Generally Recognized as Safe (GRAS)" page where the GRAS Inventory is listed.
Mitchell A. Cheeseman
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
1The Secretary of the Department of Health and Human Services.