Food

Agency Response Letter GRAS Notice No. GRN 000648

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See also Generally Recognized as Safe (GRAS) and about the GRAS Notice Inventory

CFSAN/Office of Food Additive Safety

December 13, 2016

Mark L. Itzkoff
The Law Office of Mark Itzkoff
500 New Hampshire Avenue, NW
Suite 500
Washington, DC 20037

Re: GRAS Notice No. GRN 000648

Dear Mr. Itzkoff:

The Food and Drug Administration (FDA, we) completed our evaluation of GRN 000648. We received the notice, dated April 7, 2016, that you submitted on behalf of Apeel Sciences 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 April 11, 2016 and filed it on May 17, 2016. We received amendments containing additional information about the manufacturing process and revisions to Apeel Sciences’s safety narrative on August 1, August 19, and October 3, 2016.

FDA published the GRAS final rule on August 17, 2016 (81 FR 54960), with an effective date of October 17, 2016. As GRN 000648 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 1- and 2-monoglycerides primarily of palmitic acid (monoglycerides).[1] The notice informs FDA of the view of Apeel Sciences that monoglycerides are GRAS, through scientific procedures, for use as a surface-finishing agent and/or texturizer to protect freshness and extend shelf-life of agricultural products such as fruits (e.g., berries, grapes, citrus, bananas, mangoes, avocados) and vegetables (e.g., legumes, roots, tubers). The monoglycerides form a thin, edible physical barrier against moisture loss and oxidation when applied to the surfaces of certain fruits and vegetables.

Our use of the terms “1- and 2-monoglycerides primarily of palmitic acid” or “monoglycerides” in this letter is not our 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. We did not consult with ONFL regarding the appropriate common or usual name for “1- and 2-monoglycerides primarily of palmitic acid” or “monoglycerides.”

Apeel Sciences states that monoglycerides are composed primarily (≥ 91% by weight) of 2,3-dihydroxypropyl palmitate (CAS registry number: 542-44-9) and/or 1,3-dihydroxypropan-2-yl palmitate (CAS registry number: 23470-00-0) along with other monoglycerides of varying chain lengths. The ratio of 1- to 2-monoglyceride derivatives depends upon the specific application; it will vary by type of fruit or vegetable to be treated and the desired shelf life extension period. The notifier states that monoglycerides are a white to pale yellow powder.

Apeel Sciences describes the manufacturing process for monoglycerides, beginning with conversion (protection) of the two primary alcohol groups on the glycerol backbone to non-reactive moieties. Free fatty acids are then esterified selectively to the secondary alcohol using an acid catalyst in the presence of a solvent to generate the modified monoglycerides. Solvent is removed by distillation, and the mixture is purified by removal of unreacted starting materials and residual catalyst using a liquid-liquid separation. Any non-reactive moieties protecting the primary alcohols on the glycerol backbone are then chemically cleaved (deprotection) using a metal catalyst with hydrogen in the presence of a solvent. Subsequent filtration removes the metal catalyst and the resultant filtrate is crystalized and dried under vacuum to form the final product (1- and 2-monoglycerides). Apeel Sciences states that all processing agents and starting materials used in the manufacture of monoglycerides are food-grade chemicals used in accordance with current good manufacturing practices. Apeel Sciences provides specifications for monoglyceride (≥ 91%) and diglyceride (≤ 7%) levels as well as limits for ethyl acetate (≤ 100 milligrams per kilogram (mg/kg)), acetonitrile (≤ 5 mg/kg), toluene (≤ 5 mg/kg), hexane (≤ 25 mg/kg), and individual heavy metals (including Lead (≤ 1 mg/kg), Palladium (≤ 3 mg/kg) and Arsenic (≤ 0.2 mg/kg)), in the finished product.

Apeel Sciences intends to use the ingredient on the outside peel of fruits and vegetables; however, for the purposes of the exposure calculation, certain raw fruits and vegetables with edible peels were chosen as representative. Apeel Sciences estimates dietary exposure to monoglycerides from the intended use based on (1) the maximum amount of coating applied to apples, grapes, strawberries, baked and boiled potatoes, and string beans and (2) the average daily intakes of the representative fruits and vegetables: apples (14 grams/person/day (g/p/day)), grapes (12 g/p/day), strawberries (3 g/p/day), baked and boiled potatoes (13 g/p/day) and string beans (7 g/p/day). Apeel Sciences reports that the estimated dietary exposure to monoglycerides from the intended use is 108 mg/p/day from fruit and 110 mg/p/day from vegetable consumption, for a combined dietary exposure of 218 mg/p/day (3.6 mg/kg bodyweight/day for a 60 kg individual) at the 90th percentile for the U.S. population aged 2 years or more.

As part of the narrative in its GRAS notice, Apeel Sciences presents several lines of scientific evidence along with data to support its conclusion of the safety of monoglycerides on fruits and vegetables. Apeel Sciences references the safety data from both published and unpublished studies described in previous GRAS notices for different oils that contained a small amount of monoglycerides (GRN 000056, GRN 000115, GRN 000192, and GRN 000269). Next, Apeel Sciences discusses safety data on the oral ingestion of monoglycerides evaluated by the Cosmetic Ingredient Review (CIR) Expert Panel (CIR, 2004).[2] Apeel Sciences concurs with the CIR report, which states that monoglycerides have been approved for use as direct and indirect food additives, and that the nature of the metabolism of monoglycerides along with available information on genotoxicity and carcinogenicity raises no questions regarding the safety of monoglycerides. In addition, the absorption, digestion, and metabolism of dietary fats outlined by Apeel Sciences are well-accepted scientific principles and serve to support the safety of the consumption of monoglycerides.

Apeel Sciences states that a comprehensive search of the scientific literature for safety and toxicity information on monoglycerides and other related compounds was conducted through February 2016. Apeel Sciences discusses the findings of published feeding studies of diacylglycerol in rats, dogs or humans for periods ranging from 90 days to 2 years. They report that no toxicity or adverse effects were seen with these exposures that ranged from 163 mg/kg body weight (bw)/day to 4488 mg/kg bw/day across species. Apeel Sciences also reviewed published findings that encompassed genotoxic, reproductive and developmental effects in addition to carcinogenic effects associated with diacylglycerol exposure, and noted that no related adverse effects were found. Apeel Sciences then made the scientific argument to use diacylglycerol exposure-effect data to derive corresponding monoglyceride exposures by assuming diacylglycerol oil contains monoglycerides at the 5% level. Considering this factor, Apeel Sciences determined that no adverse effects were seen in the toxicology studies noted above at monoglyceride exposures of 8.2 mg/kg bw/day through 224 mg/kg bw/day.

Based on available scientific evidence, Apeel Sciences concludes that monoglycerides are GRAS for the intended use.

Section 301(ll) of the Federal Food, Drug, and Cosmetic Act (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 Apeel Sciences’s notice concluding that monoglycerides are GRAS under its intended conditions of use, we did not consider whether section 301(ll) or any of its exemptions apply to foods containing monoglycerides. Accordingly, our response should not be construed to be a statement that foods containing monoglycerides, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).

Conclusions

Based on the information that Apeel Sciences provided, as well as other information available to FDA, we have no questions at this time regarding Apeel Sciences’s conclusion that monoglycerides are GRAS under its intended conditions of use. This letter is not an affirmation that monoglycerides are 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 000648 is accessible to the public at www.fda.gov/grasnoticeinventory.

Sincerely,

Dennis M. Keefe, Ph.D.
Director
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition

 

[1] Mono- and diglycerides has been affirmed GRAS for use in food (21 CFR 184.1505). The GRAS affirmation defines mono- and diglycerides as a mixture of glycerol mono- and diesters, and minor amounts of triesters, that are prepared from fats or oils or fat-forming acids that are derived from edible sources. The most prevalent fatty acids include lauric, linoleic, myristic, oleic, palmitic, and stearic.

[2] The CIR refers to monoglyerides as glyceryl monoesters.

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