Agency Response Letter GRAS Notice No. GRN 000652
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See also Generally Recognized as Safe (GRAS).
CFSAN/Office of Food Additive Safety
December 16, 2016
Keith Redenbaugh, Ph.D.
Arcadia Biosciences, Inc.
200 Cousteau Place
Davis, CA 95618
Re: GRAS Notice No. GRN 000652
Dear Dr. Redenbaugh:
The Food and Drug Administration (FDA, we) completed our evaluation of GRN 000652. We received the notice, dated May 26, 2016, 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) on May 31, 2016, and filed it on June 21, 2016. We received two amendments containing a revised intended use, a revised estimated dietary exposure, and additional safety discussion and information on September 21, 2016, and November 8, 2016.
FDA published the GRAS final rule on August 17, 2016 (81 FR 54960), with an effective date of October 17, 2016. As GRN 000652 was pending on the effective date of the GRAS final rule, we requested some additional information consistent with the format and requirements of the final rule. We received an amendment responding to this request on October 20, 2016.
The subject of the notice is gamma-linolenic acid (GLA)-containing safflower oil (GLASO) (contains approximately 40% of GLA). The notice informs FDA of the view of Arcadia Biosciences (Arcadia) that GLASO is GRAS, through scientific procedures, for use as an ingredient in nutritional beverages and medical foods (including meal replacement drinks, pediatric supplemental beverages, adult nutritional beverages, blood glucose management products, performance nutrition products) at levels of 0.05 to 4 grams (g) GLA per serving, for children (>2 years old) and adults; and, in tube-feeding or sole-source nutrition products at levels up to 4 g GLA per liter for adults.
Our use of the terms, “GLA-containing safflower oil” or “GLASO,” in this letter should not be considered an endorsement or recommendation of those terms as appropriate common or usual names for declaring the substance in accordance with FDA's labeling requirements. Under 21 CFR 101.4, 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 common or usual name of a food ingredient are under the purview of the Office of Nutrition and Food Labeling (ONFL) in the Center for Food Safety and Applied Nutrition. The Office of Food Safety (OFAS) did not consult with ONFL regarding the appropriate common or usual name for “GLA-containing safflower oil” or “GLASO.”
Arcadia describes GLASO as a refined, bleached, and deodorized oil that contains approximately 40% GLA (cis-6,9,12-octadecatrienoic acid, C18:3 n-6). Arcadia provides data and information to demonstrate that GLASO also contains a variety of other fatty acids, tocopherols, and sterols, just as in other edible oils and conventional foods. Arcadia states that GLA-containing safflower oil is produced from the seeds of a genetically engineered variety of safflower (Carthamus tinctorius L. cultivar Centennial) that produces significant amounts of GLA.
Arcadia describes the manufacturing of GLASO. GLA safflower seed is harvested, mixed, analyzed for GLA composition, and may then be mixed with high oleic acid safflower seed to adjust the relative concentration of GLA. The seeds are cleaned, cracked, and crushed with an expeller press to produce expeller oil and an expeller cake. Residual oil in the expeller cake is extracted with hexane, which is then removed by distillation, and the extracted oil is mixed with the expeller oil. The combined oil is subjected to degumming that includes the addition of 50% citric acid solution followed by heating and agitation. The water phase of the resulting mixture is removed. The degummed oil is neutralized with 50% sodium hydroxide, then agitated and heated until the alkaline fraction (known as soapstock) separates from the oil. The oil and soapstock mixture is heated, mixed with water, and centrifuged. The soapstock is removed and the resulting oil is bleached by mixing with acid-activated clays, heating under vacuum, and agitation. The resulting mixture is vacuum-dried to remove moisture and filtered to remove the acid-activated clays. The level of GLA is then adjusted to 40 to 45 percent with high oleic acid safflower oil. The resulting oil is deaerated under vacuum, heated, and steam-stripped to yield deodorized oil. The oil is then cooled to ambient temperature and mixed with citric acid and a mixture of antioxidants.
Arcadia provides specifications for GLASO including GLA (380-475 milligrams (mg)/g), palmitic acid (50-200 mg/g), stearic acid (10-100 mg/g), oleic acid (100-500 mg/g), and linoleic acid (100-300 mg/g). Specifications also include limits on moisture (≤ 0.2 %), lead (< 0.2 mg per kilogram (kg)), cadmium (< 0.2 mg/kg), arsenic (< 0.2 mg/kg), and mercury (< 0.2 mg/kg). Arcadia provides the results of 14 batch analyses to demonstrate that GLASO meets the specifications.
Arcadia estimates dietary exposure from the intended uses of GLASO in nutritional beverages and medical foods. Arcadia states that these foods are not widely consumed by the U.S. population and may be used as a sole source of nutrition. Arcadia estimates the dietary exposure to GLA from these uses at 0.3 to 2 g/person/day from ingested products and up to approximately 6 g/person/day from adult enterally-fed nutrition products for medical foods use.
Arcadia discusses the safety of GLASO consumption by emphasizing its substitutional use, as well as discussing the metabolism of the fatty acids, animal studies conducted with GLA-containing diets, and human studies conducted with GLA-supplementation in infants, children and adults. Arcadia states that GLASO will substitute for other GLA sources currently used in nutritional beverages and medical foods. Therefore, dietary exposure to GLA from the ingestion of GLASO will not exceed the exposure currently resulting from the intake of nutritional beverages and medical foods enriched with other GLA sources. Arcadia states that the absorption, distribution, metabolism and excretion (ADME) of fatty acids in GLASO will be the same as the ADME of these components from other dietary sources.
Arcadia states that the safety of the GLA was evaluated in four published animal toxicology studies. In a subchronic toxicity study in rats on borage oil (control) and GLASO diets, the mean intake of GLA for males was 888 mg GLA/kg bw/d for the control group and 913 mg GLA/kg bw/d for the GLASO group, and that for females was 1191 mg GLA/kg bw/d for the control group and 1161 mg GLA/kg bw/d for the GLASO group. Arcadia states that there were no toxicologically relevant differences between the two groups in terms of food consumption, body weight changes, growth, organ weights, hematology and histopathology of organs. Similar magnitudes of increases in ALT, AST, and LDH levels were noted in both the borage oil and GLASO-treated groups relative to normal levels of these enzymes in laboratory rats. Arcadia explains that this increase was due to the consumption of high fat diets, and considers it unlikely that similar effects would occur in humans.
Arcadia summarizes briefly more than 50 published human studies conducted with GLA-supplementation in infants, children, and adults. Ten of these studies evaluated clinical parameters, including blood biochemistries, electrolytes, liver enzymes, hematologies, and coagulation indices. Arcadia states that the GLA-supplementation was well-tolerated, did not cause serious adverse events, and resulted in no toxicologically relevant differences between the controls and the GLA groups in terms of the clinical parameters studied. Arcadia also discusses human studies with dihomo-gamma-linolenic acid (DGLA) because DGLA is a metabolic elongation product of GLA. Arcadia states that there were no toxicologically relevant effects of DGLA supplementation on platelet aggregation, hematology, blood pressure, coagulation (prothrombin time, activated partial thromboplastin time and antithrombin III) and urinalysis parameters.
Arcadia includes the statement of a panel of individuals (Arcadia's GRAS panel). Based on its review, Arcadia's GRAS panel concluded that GLASO is safe under the conditions of its intended use.
Based on the data and information provided, Arcadia concludes that prolonged intakes of high amounts of GLA and DGLA are well tolerated and do not result in adverse effects on measures of health status, such as hematology or clinical chemistries. Therefore, Arcadia concludes that GLASO is GRAS for its intended use.
Potential Labeling Issues
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 way. Section 403(r) of the FD&C Act lays out the statutory framework for labeling claims characterizing a nutrient level in a food or the relationship of a nutrient to a disease or health-related condition (also referred to as nutrient content claims and health claims). The notice raises a potential issue under these labeling provisions. This issue involves GLA supplementation in humans. In the notice, Arcadia cites studies that describe GLA as having certain health benefits. If products containing GLASO bear any nutrient content or health claims on the label or in labeling, such claims are subject to the applicable requirements and are under the purview of the ONFL. OFAS did not consult with ONFL on this issue or evaluate any information in terms of labeling claims. Questions related to food labeling should be directed to ONFL.
Arcadia informs us of its intent to use GLASO in medical foods. Section 5(b)(3) of the Orphan Drug Act (21 U.S.C. 360ee(b)(3)) defines a medical food as a “food formulated to be consumed or administered enterally under a physician's supervision.” This provision also specifies that a medical food is “intended for the specific dietary management of a disease or condition with distinctive nutritional requirements, based on recognized scientific principles, established by a medical evaluation.” Medical foods, including how they are labeled, are the purview of ONFL. OFAS did not consult with ONFL about whether any particular food product containing GLASO as an ingredient would be a medical food. Questions about medical foods should be addressed to ONFL.
Section 301(ll) of the FD&C Act
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 our evaluation of Arcadia’s notice concluding that GLASO is GRAS under its intended conditions of use, we did not consider whether section 301(ll) or any of its exemptions apply to foods containing GLASO. Accordingly, our response should not be construed to be a statement that foods containing GLASO, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information that Arcadia provided, as well as other information available to FDA, we have no questions at this time regarding Arcadia’s conclusion that GLASO is GRAS under its intended conditions of use. This letter is not an affirmation that GLASO is GRAS under 21 CFR 170.35. Unless noted above, our review did not address other provisions of the FD&C Act. Food ingredient manufacturers and food producers are responsible for ensuring that marketed products are safe and compliant with all applicable legal and regulatory requirements.
In accordance with 21 CFR 170.275(b)(2), the text of this letter responding to GRN 000652 is accessible to the public at www.fda.gov/grasnoticeinventory.
Dennis M. Keefe, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
 Arcadia states that GLASO does not contain hexanes or other solvents, and states that an analysis of four lots of GLASO demonstrates hexanes were undetectable at a limit of quantitation (1 mg/kg).
 Arcadia notes that the final oil is mixed with the following antioxidants: α- and γ-tocopherols, citric acid, ascorbyl palmitate, and rosemary extract.
 Corresponding to 5 to 33 mg/kg body weight/day (kg bw/d) and 100 mg/kg bw/d, respectively, for an average 60 kg adult.