Food

Agency Response Letter GRAS Notice No. GRN 000351

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CFSAN/Office of Food Additive Safety

February 11, 2011

C.K. Gund, Ph.D.
Phoenix Regulatory Associates, Ltd.
21525 Ridgetop Circle, Suite 240
Sterling, VA 20166

Re: GRAS Notice No. GRN 000351

Dear Dr. Gund:

The Food and Drug Administration (FDA) is responding to the notice, dated August 2, 2010, that you submitted on behalf of Nikken Sohonsha Corporation (Nikken) 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 August 2, 2010, filed it on August 19, 2010, and designated it as GRAS Notice No. GRN 000351.

The subject of the notice is Dunaliella bardawil. The notice informs FDA of the view of Nikken that D. bardawil is GRAS, through scientific procedures, for use as an ingredient in cheese, bread and rolls, mayonnaise, cookies, crackers, tofu, and soybean fermentation products at a level of 100 milligrams per kilogram (mg/kg).

Our use of “D. bardawil” in this letter 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. Title 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. 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.

As part of its notice, Nikken includes the report of a panel of individuals (Nikken’s GRAS panel) who evaluated the data and information that are the basis for Nikken’s GRAS determination. Nikken considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Nikken’s GRAS panel evaluated method of production, product specifications, estimates of dietary exposure, as well as published and unpublished safety studies. Based on this review, Nikken’s GRAS panel concluded that D. bardawil that meets its established food-grade specifications is GRAS under the conditions of its intended use.

Nikken provides information about the identity and characteristics of D. bardawil. Nikken states that D. bardawil is a unicellular, halophilic, photosynthetic green alga. Nikken states that D. bardawil cells are biflagellate oval or elliptical shaped cells that are 15 to 19 micrometers (μm) long and 10 to 14 μm in diameter. Nikken states that D. bardawil has a green color when grown in media with low salinity (1.0 moles/liter (molar, M) sodium chloride) and low light intensity (1/10 or less of sunlight) due to the high intracellular concentration of chlorophyll. Nikken also notes that, in contrast, exposure of D. bardawil to harsh environments such as high salinity (>2M) in the presence of high light intensity (110,000 Lux), certain nutrients (<0.5 millimolar), and extreme temperatures (<5 °C or >33°C), causes the synthesis of large amounts of β-carotene, producing an orange-reddish color.

Nikken describes the method of manufacture of D. bardawil. The steps include growing the alga in manmade salt water ponds supplemented with food-grade nutrients, carbon dioxide, phosphates, and nitrates. The environmental conditions, including pH, light penetration by depth, dissolved carbon, and salinity concentration are computer-controlled. The salt concentration in the growth pond is greater than or equal to 1.5 M. Once β-carotene levels reach 5-10 mg/liter (L) in the pond water, the medium is filtered to remove foreign matter and the D. bardawil is separated by centrifugation. The resulting D. bardawil algal paste is then heated to 85 °C and cooled to 10 °C, desalinated with water, and stirred. A second centrifugation step is conducted to remove the salt/water mixture and produce a paste that is then heated to 80 °C and spray-dried to yield D. bardawil as an orange-brownish powder. Nikken states that D. bardawil is packaged in vacuum sealed, opaque bags and is stable for two years when stored at varied temperatures (15-30 °C) and humidity ranges (30-70%).

Nikken provides specifications for food-grade D. bardawil. Specifications include target levels for moisture (<6%), ash (<20%), protein (<30%), fat (<30%), carbohydrate (<50%), total carotene (5-10%), and β-carotene (5-10%). Nikken also provides limits for heavy metals and microbial residues in food-grade D. bardawil. The specifications for heavy metals are: lead (<2 mg/kg), arsenic (<2 mg/kg), cadmium (<0.4 mg/kg), and iodine (<0.5 mg/kg). The microbial specifications are: mold (negative/25 gram (g)), E. coli (negative/g), and Salmonella (negative/25g).

Nikken calculates an estimated daily intake (EDI) for D. bardawil using the combined results from the United States Department of Agriculture’s Continuing Survey of Food Intakes by Individuals (1994-96) and the Diet and Health Knowledge Survey (1994-96). The EDI for D. bardawil would be approximately 0.6 mg per kg body weight (bw) per day (d) at the mean, and 1.2 mg/kg bw/d at the 90th percentile. Nikken also reports an EDI for β-carotene of approximately 0.05 mg/kg bw/d at the mean, and 0.1 mg/kg bw/d at the 90th percentile. Nikken notes that the exposure of β-carotene from D. bardawil compares favorably with the consumption of 2.2 mg/kg bw/d from all dietary sources previously reviewed by the FDA (Select Committee on GRAS Substances, 1979).

Nikken discusses published studies that demonstrate the safety of D. bardawil consumption. Nikken states that the results of a reproductive and developmental study in which rats were fed D. bardawil and observed for 4 generations showed no adverse effects and demonstrate that D. bardawil is safe for human consumption at levels of 333 mg/kg bw/d. Nikken states that the results of another reproductive and developmental study conducted using mice showed no adverse reproductive and developmental effects with D. bardawil consumption at the highest level tested (12,000 mg/kg bw/d). Nikken notes that the results of two published subacute toxicity studies showed that there were no adverse effects in mice and rats at the highest level tested (5,000 mg/kg bw/d) of D. bardawil for 14 days. Nikken states that the results of a subchronic toxicity study in which mice were fed 11 mg/kg bw/d D. bardawil for 100 days showed no deleterious effects on the mice. Nikken states that the results of mutagenicity and genotoxicity studies for D. bardawil demonstrated no adverse effects. Finally, Nikken states that the results of several clinical studies in which individuals consumed up to 20 mg/kg bw/d D. bardawil for up to 44 weeks showed no adverse events.

Nikken states that the results of unpublished acute toxicity studies in which mice and rats were administered a single dose of either 2,500 mg/kg bw, 5,000 mg/kg bw, or 10,000 mg/kg bw D. bardawil by oral gavage and observed for 14 days, showed no signs of toxicity or mortality. Nikken states that in an unpublished subacute toxicity study in which rats were administered 0 mg/kg bw/d, 500 mg/kg bw/d, or 2500 mg/kg bw/d D. bardawil by oral gavage, no toxic effects were seen after 4 weeks of observation.

Nikken discusses published studies that demonstrate the safety of β-carotene consumption. Nikken notes that the results of an acute toxicity study established an LD50 value of >20,000 mg/kg bw. Nikken discusses a subchronic toxicity study in rats that estimated a No Observed Adverse Effect Level (NOAEL) of 696 mg/kg bw/d for males and 2,879 mg/kg bw/d for females based on growth suppression. Nikken refers to several mutagenicity and genotoxicity studies that demonstrate the absence of mutagenic or clastogenic effects of β-carotene.

Standards of Identity

In the notice, Nikken states its intention to use D. bardawil in several food categories, including foods for which standards of identity exist, located in 21 CFR. 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 high density lipoprotein cholesterol-raising effects of D. bardawil in human clinical studies as part of the information that Nikken relies on to conclude that D. bardawil is GRAS under the conditions of its intended use, Nikken raises a potential issue under these labeling provisions of the Federal, Food, Drug, and Cosmetic Act (FFDCA). 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. If products that contain D. bardawil bear any claims on the label or in labeling, such claims are the purview of ONLDS. The Office of Food Additive Safety (OFAS) 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 D. bardawil on the label or in labeling.

Potential Requirement for a Color Additive Petition

In its notice, Nikken describes D. bardawil as containing β-carotene, which gives it an orange-reddish appearance. As such, the use of D. bardawil in food products may constitute the use of a color additive under section 201(t)(1) of the 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, 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 D. bardawil 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.(2)

In their notice, Nikken states that the addition of its D. bardawil to the various food products occurs at sufficiently low levels that the β-carotene will not impart significant color to the resulting food products. Furthermore, the subject ingredient is not intended to function as a color additive. Therefore, the incorporation of D. bardawil with its naturally occurring β-carotene falls outside of the definition of color additive (21 CFR 70.3(g)). In its review of Nikken’s notice that the ingredient D. bardawil is GRAS for the intended uses, FDA did not consider whether section 201(t)(1) of the FFDCA and FDA’s implementing regulations in 21 CFR Part 70 apply to the use of D. bardawil in foods. Accordingly, this response should not be construed to be a statement that the use of D. bardawil in foods is lawful under section 721(a). If, after receipt of this letter, Nikken has any further questions about this issue, we recommend that Nikken contact the Office of Food Additive Safety.

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 Nikken’s notice that D. bardawil is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing D. bardawil. Accordingly, this response should not be construed to be a statement that foods that contain D. bardawil, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).

Conclusions

Based on the information provided by Nikken, as well as other information available to FDA, the agency has no questions at this time regarding Nikken’s conclusion that D. bardawil 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 D. bardawil. As always, it is the continuing responsibility of Nikken 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 000351, 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,

Mitchell A. Cheeseman, Ph.D.
Acting Director
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition


(1)The Secretary of the Department of Health and Human Services.

(2)We note that section 721(b)(4) of the FFDCA provides that a color additive shall be deemed to be safe and suitable for the purpose of listing under section 721(b) of the FFDCA 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 FFDCA. Importantly, FDA’s response to GRN 000351 does not constitute a “finding of the Secretary” within the meaning of section 721(b)(4) of the FFDCA.

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