Agency Response Letter GRAS Notice No. GRN 000417
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CFSAN/Office of Food Additive Safety
August 10, 2012
John R. Endres, ND
AIBMR Life Sciences, Inc.
4117 South Meridian
Puyallup, Washington 98373
Re: GRAS Notice No. GRN 000417
Dear Dr. Endres
The Food and Drug Administration (FDA) is responding to the notice, dated January 23, 2012, that you submitted on behalf of E.I.D. Parry (India) Limited, Parry Nutraceuticals Division (Parry), 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 January 24, 2012, filed it on February 1, 2012, and designated it as GRAS Notice No. GRN 000417.
The subject of the notice is the dried biomass of Arthrospira platensis also known as Spirulina platensis (spirulina).1 The notice informs FDA of the view of Parry that spirulina is GRAS, through scientific procedures, for use as an ingredient in beverages and beverage bases, breakfast cereals, fresh fruits and fruit juices, frozen dairy desserts and mixes, grain products and pastas, milk products, plant protein products, processed fruits and fruit juices, processed vegetables and vegetable juices, snack foods, soft candy, and soups and soup mixes at a level of 0.5-3 grams spirulina per serving (g/serving).
As part of its notice, Parry includes a statement from a panel of individuals (Parry’s GRAS panel) who evaluated the data and information that are the basis for Parry’s GRAS determination. Parry considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Parry’s GRAS panel considered the identity and source of Parry’s spirulina product and similarities to other spirulinas that were the subject of prior GRAS notices to FDA. Parry’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evaluated estimates of dietary exposure, method of production, and product specifications as well as published and unpublished studies.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, Parry’s GRAS panel concluded that spirulina that meets its established food grade specifications is GRAS under the conditions of its intended use.
Parry provides information about the identity, method of manufacture, and specifications for spirulina. Spirulina refers to the dried biomass of A. platensis consisting of the whole, dry cells. A. platensis is a filamentous cyanobacterium (oxygenic photosynthetic bacterium) found worldwide in fresh and marine waters. Parry cites several published references describing the taxonomy and general characteristics of this organism. Parry describes the spirulina product as a blue-green to green fine, uniform powder with a mild odor and taste.
Parry provides a manufacturing process for spirulina. The process begins with cultivation of A. platensis in outdoor ponds. The ponds are monitored daily for several parameters, including optical density, pH, and microbial contaminants. For harvesting, the culture is filtered and the collected biomass is washed with water, then spray dried to produce the final product. Parry states that quality systems have been established to ensure that all of the algal products produced meet the requirements established under current good manufacturing processes, and all raw materials used during the manufacture process are food grade.
Parry provides specifications for spirulina including protein (59–69%), carbohydrates (mainly glucose) (15–25%), lipids (5–6%), moisture (2.5–6%), ash (6–9%), various carotenoids, heavy metals and potential microbiological contaminants. Parry provides the results of analyses for four lots of the product demonstrating compliance with product specifications. Microcystins (toxins made by some cyanobacteria) are not detected in routine tests on finished products.
Parry provides estimated daily intakes (EDI) of spirulina from the intended uses. Parry states that spirulina is intended for use as an ingredient in a variety of foods at levels of 0.5 to 3 g spirulina/serving. A publication from the United States Department of Agriculture Center for Nutrition Policy and Promotion (October 2000) states that males aged 51 and older consume the largest number of servings of food a day at 18.2 servings/day. Using this estimate of the number of servings/day, Parry bases its dietary intake calculations on the assumption that 10% of daily servings of food, or 1.8 servings, would contain spirulina. Parry multiplied the number of the daily servings (rounded to 2) with the maximum amount of 3 g spirulina/serving to obtain an EDI of spirulina from the intended food uses of 6 g/person/day.
In an amendment dated May 29, 2012, Parry provided a revised EDI. Parry noted that it was difficult to find commercially available food products in the U.S. that contain spirulina and that there were no reliable sources showing current per capita consumption of spirulina in the U.S. Therefore, Parry considers it a conservative and reasonable assumption that a maximum of 10% of a person’s daily servings of food over a lifetime would contain spirulina. Parry also explained that foods are expected to contain typically only 500–1500 milligrams (mg) of spirulina/serving as, for example, 1500 mg in a spirulina drink or 500 mg in a spirulina bar. These levels of spirulina in two servings of food would result in the consumption of 1 to 3 g/person/day.
Parry discusses published information to support the safety of spirulina. These studies include an acute toxicity study in Swiss mice, a subchronic toxicity study in Sprague-Dawley rats, a chronic toxicity study in JAX® mice (C57BL/6J), and a reproductive toxicity study in Wistar rats. Parry states that A. platensis is considered a non-toxigenic cyanobacteria species and is cultivated in controlled ponds rather than natural lakes. Parry determines that the No Observed Adverse Effect Level for a subchronic toxicity study in rats was 1200 mg/kilogram body weight/day (kg bw/d) (the highest dose level tested) for fresh A. platensis, or 120 mg/kg bw/d for dried A. platensis.
Parry discusses published literature to establish the relationships between S. maxima and A. platensis. Parry states that the various strains of the form-genus Arthrospira are closely related and that both are commonly consumed as a food source. In addition, Parry states that spirulina safety studies that do not specify the species of Arthrospira corroborate the safety evaluation of A. platensis. Furthermore, Parry concludes that the safety studies conducted with S. maxima are relevant to the safety assessment of A. platensis. Parry discusses published animal studies, using S. maxima, including subchronic, chronic, and multigenerational reproductive and developmental toxicology studies. Parry reports that no adverse effects were observed in the studies.
Parry states that a number of human clinical trials corroborate the safety of oral administration of spirulina in animals and that no adverse effects were noted in the human studies. Although some clinical variables measured in these studies could detect whether there were any adverse effects from spirulina consumption, these studies were not designed to assess safety.
Standards of Identity
In the notice, Parry states its intention to use spirulina 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 human studies in support of the safe use of spirulina, Parry 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 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 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) 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 Parry’s 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 their notice, Parry notes that spirulina may impart color to food. 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,2 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 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.3
Parry 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) of the FD&C Act and FDA's implementing regulations in 21 CFR 70.3(f) and (g). Importantly, FDA's response to GRN 000417 does not include any comment by FDA about Parry’s view on this issue. If, after receipt of this letter, Parry has any specific questions about this issue, we recommend that Parry contact the Division of Petition Review, 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.
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 Parry’s notice that spirulina is GRAS for the intended uses, 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 provided by Parry, as well as other information available to FDA, the agency has no questions at this time regarding Parry’s 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 the continuing responsibility of Parry 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 000417, 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
1We note that current taxonomy reflects that these species are members of the genus Arthrospira, generally referred to in food as spirulina.
2The Secretary of the Department of Health and Human Services.
3We 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 000417 does not constitute a “finding of the Secretary” within the meaning of section 721(b)(4) of the FD&C Act.