Agency Response Letter GRAS Notice No. GRN 000394
CFSAN/Office of Food Additive Safety
June 4, 2012
Susan Cho, Ph.D.
6309 Morning Dew Court
Clarksville, MD 21029
Re: GRAS Notice No. GRN 000394
Dear Dr. Cho:
The Food and Drug Administration (FDA) is responding to the notice, dated July 21, 2011, that you submitted on behalf of RFI, Inc. (RFI) 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 this notice on July 26, 2011, filed it on July 29, 2011, and designated it as GRAS Notice No. GRN 000394. You submitted additional information on November 30, 2011, to address dietary exposure.
The subject of the notice is the dried biomass of Arthrospira platensis, also known as Spirulina platensis (spirulina). The notice informs FDA of the view of RFI that spirulina is GRAS, through scientific procedures, for use as an ingredient in grape juice, blackberry juice, lime juice, low calorie fruit juice drinks, and low calorie vegetable juice drinks at a level of 0.3%, and in medical foods at a level of 1.25%.
As part of its notice, RFI includes a statement from a panel of individuals (RFI’s GRAS panel) who evaluated the data and information that are the basis for RFI’s GRAS determination. RFI considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. RFI’s GRAS panel evaluated the identity, method of manufacture, the potential exposure resulting from the intended food uses of spirulina, and published studies on spirulina. Based on this review, RFI’s GRAS panel concluded that spirulina that meets its established food grade specifications and used in accordance with current good manufacturing practice is GRAS under the conditions of its intended use.
RFI provides information about the identity, method of manufacture, and specifications for spirulina. A. platensis is a free-floating, photosynthetic, filamentous cyanobacterium. It occurs naturally in tropical and subtropical lakes with high pH and high concentrations of carbonate and bicarbonate. RFI describes the spirulina product as a free-flowing dark blue-green powder with a mild seaweed smell.
RFI provides methods of manufacture for spirulina. The manufacture of spirulina starts with the preparation of a seed culture in the laboratory. The spirulina seed culture is then cultivated in large ponds using food grade fertilizers, water and carbon dioxide. The harvested spirulina is subjected to quality control tests, washed with water to neutralize the pH, then spray dried to produce the final product. The quality control tests include tests for microbial contamination, heavy metals, and foreign material contamination. RFI states that spirulina is manufactured in accordance with current good manufacturing practices, and all raw materials used during the manufacture are food grade. RFI provides specifications for spirulina, including specifications for protein, carotenoids, heavy metals, moisture, and potential microbiological contaminants.
RFI calculates the estimated daily intake (EDI) of spirulina on the assumption that the product will be used at the maximum proposed levels in all grape juice, blackberry juice, lime juice, low calorie fruit juice drinks and low calorie vegetable juice drinks. RFI calculates an EDI of 2.95 grams per person per day (g/p/d) at the 90th percentile for the entire population; 3.1 g/p/d for males, and 2.6 g/p/d for females.
RFI discusses published literature to establish the relationships among A. platensis, A. maxima, and A. fusiformis. RFI states that genetic techniques demonstrate that the various strains of the form-genus Arthrospira are highly related, and are likely all representatives of a single nomen species. Therefore, RFI concludes that the safety studies conducted with A. maxima, and A. fusiformis are relevant to the safety assessment of A. platensis. RFI discusses published animal studies, using A. platensis, A. maxima, or A. fusiformis, including acute, subchronic, chronic, teratogenicity, mutagenicity, carcinogenicity and multi-generation reproduction studies. RFI reports that no adverse effects were observed in the studies. RFI also describes several published human studies in which healthy adults were given spirulina up to 8 g/p/d and reported no adverse effects. RFI also notes that FDA responded with no questions to a previous GRAS notice (GRN 000127) for the use of spirulina. RFI concludes that spirulina that meets its established specifications is GRAS for its intended uses in foods.
Standards of Identity
In the notice, RFI states its intention to use spirulina in 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 human studies in support of the safe use of spirulina, RFI notes some results with potential health benefits. 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 relationship of an ingredient to a disease or health-related condition. If products that contain spirulina bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition, Labeling, and Dietary Supplements (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 spirulina on the label or in labeling.
Potential Requirement for a Color Additive Petition
In GRN 000394, RFI describes spirulina as containing chlorophyll and carotenoids, which give it a dark blue-green color. As such, the use of spirulina 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,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 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 spirulina 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.2
In GRN 000394 RFI states that spirulina is not intended for use as a color additive and, thus, would be exempt from the definition of color additive under section 201(t)(1) of the FD&C Act and FDA's implementing regulations in 21 CFR 70.3(f) and (g). Importantly, FDA’s response to GRN 000394 does not include any comment by FDA about RFI’s view on this issue. If, after receipt of this letter, RFI has any specific questions about this issue, we recommend they contact the Division of Petition Review (HFS-265), Office of Food additive Safety, Center for Food Safety and Applied Nutrition, Food and Drug Administration, 5100 Paint Branch Parkway, College Park, MD 20740. You can reach this division by telephone at (240) 402-1200.
In its notice, RFI informs FDA that one intended use of spirulina 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 RFI’s notice that spirulina is GRAS for use in medical foods does not address the question of whether any particular food product that contains spirulina 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 RFI’s notice that spirulina 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 spirulina. Accordingly, this response should not be construed to be a statement that foods that contain spirulina, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information that you have provided, as well as other information available to FDA, the agency has no questions at this time regarding your conclusion that spirulina 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 spirulina. As always, it is your 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 000394, 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
1The Secretary of the Department of Health and Human Services.
2We 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 000394 does not constitute a “finding of the Secretary” within the meaning of section 721(b)(4) of the FD&C Act.