Agency Response Letter GRAS Notice No. GRN 000600
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See also Generally Recognized as Safe (GRAS).
CFSAN/Office of Food Additive Safety
May 13, 2016
Madhu Soni, Ph.D.
Soni & Associates, Inc.
749 46th Square
Vero Beach, FL 32968
Re: GRAS Notice No. GRN 000600
Dear Dr. Soni:
The Food and Drug Administration (FDA) is responding to the notice, dated September 16, 2015, that you submitted on behalf of Seprox Biotech, S.L. (Seprox) 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 September 21, 2015, filed it on October 2, 2015, and designated it as GRAS Notice No. GRN 000600. Seprox provided additional information in an amendment on December 23, 2015. In an amendment dated April 15, 2016, Seprox limited the intended use discussed in the notice.
The subject of the notice is hydroxytyrosol. The notice informs FDA of the view of Seprox that hydroxytyrosol is GRAS, through scientific procedures, for use as an antioxidant in beverages, fats and oils, fresh and processed fruits and vegetables, fresh and processed fruit and vegetable juices, and gravies and sauces at a level of 5 milligrams (mg) per serving.
As part of its notice, Seprox includes the statement of a panel of individuals (Seprox’s GRAS panel) that evaluated the data and information that are the basis for Seprox’s GRAS determination. Seprox considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Seprox’s GRAS panel evaluated information describing the identity and composition, manufacturing process and specifications, and estimated dietary exposure to hydroxytyrosol, as well as published studies supporting the safety of hydroxytyrosol. Based on this review, Seprox’s GRAS panel concludes that hydroxytyrosol produced in accordance with good manufacturing practices is GRAS under the conditions of its intended use.
Seprox describes hydroxytyrosol (4-(2-hydroxyethyl)-benzene-1,2-diol) as a slightly yellow, viscous liquid with a characteristic pungent odor and bitter taste. The final product contains more than 99% hydroxytyrosol with four residual by-products (hydroxytyrosol acetate, homovanillic alcohol, iso-homovanillic alcohol, and 3-methoxy-4-hydroxyphenylglycol). Seprox clarifies that all of these substances, except hydroxytyrosol acetate, are present in the final product at concentrations below 0.1%.
Seprox describes the chemical synthesis of hydroxytyrosol. The initial step yields 2-(3,4-dihydroxyphenyl) acetic acid, which is esterified and then reduced to obtain hydroxytyrosol. Hydroxytyrosol is acetylated to form hydroxytyrosol acetate in order to separate it from other reaction products and inorganic salts. Hydroxytyrosol acetate is then washed with water, hydrolyzed into hydroxytyrosol, and further purified. Seprox states that the materials used to manufacture hydroxytyrosol are either food grade or are of a purity suitable for the intended use.
Seprox provides specifications for hydroxytyrosol. These include specifications for hydroxytyrosol (> 95% as calculated; > 99% chromatographically), hydroxytyrosol acetate (< 0.4%), moisture (< 4%), cadmium (< 0.01 mg/kilogram (kg)), mercury (< 0.01 mg/kg), lead (< 0.1 mg/kg), and residual solvents. Seprox provides analytical results from six nonconsecutive lots of hydroxytyrosol to demonstrate that their product meets specifications.
Seprox calculates the dietary exposure to hydroxytyrosol from the intended food use. The estimated mean and 90th percentile exposures to hydroxytyrosol are 25.5 and 51.1 mg/person/day (mg/p/d), respectively. For a 60 kg person, this is equivalent to estimated mean and 90th percentile exposures of 0.42 mg/kg body weight/day (bw/d) and 0.85 mg/kg bw/d, respectively. Seprox considers that the presence of hydroxytyrosol in olives results in background exposure. Seprox cites a study suggesting that consumption of 20 olives per day may result in a hydroxytyrosol intake of 20 to 40 mg/d.
Seprox discusses published and unpublished animal and published human studies to support the safety of hydroxytyrosol. Seprox discusses published subchronic toxicological studies in rats fed hydroxytyrosol, olive extract, or aqueous olive pulp extract containing hydroxytyrosol. No adverse toxicological effects were reported at levels up to 250 mg hydroxytyrosol/kg bw/d. Seprox summarizes published reproductive toxicity and teratogenicity studies in rats fed aqueous olive pulp extract. No adverse reproductive, maternal, or developmental effects were noted at 48 mg hydroxytyrosol/kg bw/d, the highest level tested. Seprox summarizes published human studies ranging from one day to eight weeks duration with olive mill water enriched with hydroxytyrosol, olive oil, high oleic sunflower oil, or olive phenolic concentrate containing hydroxytyrosol. The hydroxytyrosol levels in these studies ranged from 2 to 97 mg/p/d. No adverse toxicological outcomes were noted in any of these human studies. Seprox also discusses published in vitro and in vivo genotoxicity studies and concludes that hydroxytyrosol is not genotoxic.
Based on the totality of the data and information described above, Seprox concludes that hydroxytyrosol is GRAS for its intended use in food.
Standards of Identity
In the notice, Seprox states its intention to use hydroxytyrosol in several food categories, including foods for which standards of identity exist, located in Title 21 of the Code of Federal Regulations. FDA notes 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
Section 403(k) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) provides that a food shall be deemed to be misbranded if it bears or contains any chemical preservative, unless it bears labeling stating that fact. Section 403(i)(2) of the FD&C Act provides that a food shall be deemed to be misbranded unless its label bears the common or usual name of each ingredient. Section 403(a) of the FD&C Act provides that a food shall be deemed to be misbranded if its labeling is false or misleading in any particular. Seprox’s intended use of hydroxytyrosol as an antioxidant constitutes use as a preservative. Therefore, the ingredient statement on labels of food products that contain hydroxytyrosol must comply with the labeling regulations that implement sections 403(k) and 403(i)(2) of the FD&C Act. For example, 21 CFR 101.22(j) requires that the food to which a chemical preservative is added bear a label declaration stating both the common or usual name of the ingredient and a separate description of its function. Further, food that is subjected to any form of preservation, except as provided in 21 CFR 101.95(c), may not be labeled as “fresh.” If Seprox has any questions about the appropriate labeling of this food ingredient, Seprox should contact the staff in the Office of Nutrition and Food Labeling in the Center for Food Safety and Applied Nutrition.
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 its review of Seprox’s notice that hydroxytyrosol is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing hydroxytyrosol. Accordingly, this response should not be construed to be a statement that foods that contain hydroxytyrosol, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Seprox, as well as other information available to FDA, the agency has no questions at this time regarding Seprox’s conclusion that hydroxytyrosol 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 hydroxytyrosol. As always, it is the continuing responsibility of Seprox 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 000600, 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
 Seprox states that meat and poultry products are excluded from the intended food uses.
 Seprox provided unpublished data from a developmental toxicity study in an amendment received by FDA on December 23, 2015. No adverse findings were reported when rats received 168 mg hydroxytyrosol/kg bw/d.