Agency Response Letter GRAS Notice No. GRN 000384
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CFSAN/Office of Food Additive Safety
June 13, 2012
Peter Licari, Ph.D.
Executive Vice President, Technology
225 Gateway Blvd.
South San Francisco, CA 94080
Re: GRAS Notice No. GRN 000384
Dear Dr. Licari:
The Food and Drug Administration (FDA) is responding to the notice, dated April 29, 2011, that you submitted 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 May 2, 2011, filed it on June 15, 2011, and designated it as GRAS Notice No. GRN 000384.
The subject of the notice is algal oil derived from Chlorella protothecoides strain S106 (herein after referred to as Cp algal oil). The notice informs FDA of the view of Solazyme Inc. (Solazyme) that Cp algal oil is GRAS, through scientific procedures for use as a substitute for vegetable oil for cooking; and, as a substitute for vegetable oil at levels ranging from 1.8 to 26% in specified foods: baked goods and baking mixes, beverages and beverage bases, confections and frostings, fats and oils, frozen dairy desserts and mixes, gelatins, puddings, and fillings, grain products and pastas, milk products, nut and nut products, processed fruit and fruit juices, snack foods, soft candy, soups and soup mixes, and sweet sauces, toppings, and syrups. Solazyme states that Cp algal oil is not intended for addition to meat and poultry products, foods containing meat or poultry, egg products, or infant formula.
Our use of “Cp algal oil” 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 each ingredient must be declared by its 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 in the Center for Food Safety and Applied Nutrition.
As part of its notice, Solazyme includes the report of a panel of individuals (Solazyme’s GRAS panel) who evaluated the data and information that are the basis for Solazyme’s GRAS determination. Solazyme considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of Cp algal oil as a food ingredient. Solazyme’s GRAS panel discusses the identity, method of manufacture, specifications, estimated dietary intake, and published safety data for Cp algal oil. Based on this review, Solazyme’s GRAS panel concluded that Cp algal oil, produced in a manner consistent with current good manufacturing practices (cGMP) and meeting appropriate food-grade specifications as described, is considered safe for use as a food ingredient at the levels under the intended conditions of use.
Solazyme describes the manufacturing process for Cp algal oil from the dried biomass of a pure culture of C. protothecoides strain S106, as follows. A cryopreserved seed culture of genetically characterized C. protothecoides strain S106 is inoculated into a seed flask to initiate fermentation, then the process is subsequently scaled up to standard industrial seed fermentors. The pH, temperature, agitation, and aeration rates of the culture are controlled during the fermentation process. Solazyme describes the separation, concentration, and drying of the algal biomass, stating that it uses either hexane or mechanical extraction to extract Cp algal oil, which may be further refined, bleached, and deodorized. Food grade antioxidants may be added to the oil prior to packaging. Solazyme states that all raw materials used during the manufacturing process of Cp algal oil are safe and food-grade, and are used in accordance with applicable federal regulations and that the manufacturing process for Cp algal oil is in compliance with cGMP.
Solazyme states that Cp algal oil is composed mainly of oleic, linoleic, and palmitic acids and is qualitatively similar to commonly used oils such as olive, canola, and soybean. In the notice Solazyme provides a table comparing the fatty acid composition of three batches of Cp algal oil with these oils.
Solazyme states that it has established food grade specifications for Cp algal oil. To demonstrate compliance with these specifications, Solazyme provides data from analyses of three batches of Cp algal oil. The specifications are: free fatty acid (≤1%), unsaponifiable matter (≤2.0%), moisture (≤1.0%), residual hexane (<1 milligram per kilogram (mg/kg)), iodine value (between 70 and 100), peroxide value (≤5.0 milliequivalents per kilogram (meq/kg)), arsenic and mercury (each <0.2 mg/kg), and lead and cadmium (each <0.1 mg/kg).
Solazyme’s estimated dietary exposure to Cp algal oil is based on the use as a substitute for vegetable oil for cooking and in specified foods at levels ranging from 1.8 to 26%. Its mean estimated daily intake (EDI) for Cp algal oil for people aged two years and older is 20.1 grams per person per day (g/p/d) (0.35 gram per kilogram body weight per day (g/kg bw/d)). Solazyme estimates the 90th percentile all-user intake to be 39.4 g/p/d (0.73 g/kg bw/d). Solazyme states that it is unlikely that Cp algal oil will be used at the estimated EDI levels based on the many vegetable oils currently available and notes that similar oils such as sunflower seed oil and canola oil have daily per capita intakes of 0.25 and 11.7 g/p/d, respectively, compared with its estimate of 20.1 g/p/d for all-user mean intake of Cp algal oil.
Solazyme acknowledges that absorption, distribution, metabolism, and elimination of Cp algal oil have not been examined. However, Solazyme states that it expects Cp algal oil to be processed in humans by normal physiological processes because Cp algal oil’s qualitative fatty acid composition is similar to consumed vegetable oils such as canola, soybean, and olive oils, and because the lipids in Cp algal oil are part of the normal diet.
In support of the use of Cp algal oil, Solazyme reports on a 28 day Sprague-Dawley rat study that tested its high (48%) lipid algal biomass from C. protothecoides strain S106 (from which Cp algal oil is derived). Based on the results of this study, Solazyme calculates the no observed adverse effect level for Cp algal oil to be approximately 3.6 g/kg bw/d for male rats and 3.9 g/kg bw/d for female rats.
After a search of published literature, Solazyme reports that infections with Chorella
are rare and have been opportunistic, resulting from wound contamination with a single case of human infection. It notes that there are no live Chlorella
cells to infect and multiply in a consumer. Solazyme reports that pheophorbide-a, a breakdown product of chlorophyll,
was not detected in the C. protothecoides
strain S106 algal biomass from which Cp algal oil is derived. Solazyme also states that none of the algal or cyanobacterial toxins that have been identified in the published literature or noted in international food regulations have been detected in the C. protothecoides
strain S106 biomass.
Standards of Identity
In the notice, Solazyme states its intention to use Cp algal oil in foods, 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.
Section 301(ll) of the Federal Food, Drug, & Cosmetic (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 Solazyme’s notice that Cp algal oil is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing Cp algal oil. Accordingly, this response should not be construed to be a statement that foods that contain Cp algal oil, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Solazyme, as well as other information available to FDA, the agency has no questions at this time regarding Solazyme’s conclusion that Cp algal oil 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 Cp algal oil. As always, it is the continuing responsibility of Solazyme 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 000384, 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
 Pheophorbide-a caused several cases of photosensitive dermatitis between June 1976 and June 1977 in people consuming a Chlorella product known as “Kenbi Chlorella.”