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CFSAN/Office of Premarket Approval*
December 4, 2000
Ms. Sandra J.P. Dennis
Morgan, Lewis & Bockius, LLP
1800 M Street, N.W.
Washington, D.C., 20036
Re: GRAS Notice No. GRN 000056
Dear Ms. Dennis:
The Food and Drug Administration (FDA) is responding to the notice, dated August 11, 2000, that you submitted on behalf of Kao Corporation (Kao) 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 Office of Premarket Approval (OPA) received this notice on August 11, 2000 and designated it as GRAS Notice No. GRN 000056.
The subject of the notice is diacylglycerol (DAG) oil. The notice informs FDA of Kao's view that DAG oil is GRAS, through scientific procedures, for use as a substitute for vegetable oils in cooking oil and in the commercial formulation of margarine for home use. As discussed more fully below, OPA consulted with the Office of Nutritional Products, Labeling, and Dietary Supplements (ONPLDS) in the Center for Food Safety and Applied Nutrition (CFSAN) regarding the intended use of DAG oil in margarine, which is subject to a food standard (21 CFR 166). As we discussed with you by telephone, it is ONPLDS' view that DAG oil may not lawfully be used in standardized margarine. Related products such as spread are not subject to a food standard. Therefore, in evaluating your notice, we also considered that an intended use of DAG oil could be as a substitute for vegetable oils in the commercial formulation of spread for home use.
The notice describes generally available information about the identity, characteristic properties, and functionality of DAG. DAG is composed of greater than 80 percent diacylglycerol as a mixture of 1,3-diglyceride and 1,2-diglyceride at a ratio of 7:3. A published study shows that this composition of fat is readily hydrolyzed to monoglycerides and fatty acids in the gastrointestinal tract. The main metabolic product is 1-monoglyceride, which is further hydrolyzed into free fatty acids and glycerol, while the minor product 2-monoglyceride is re-esterified into triglycerides. The diglyceride content of plant-derived oils and fats can be as much as 15 percent content by weight. FDA has affirmed that monoglycerides and diglycerides are GRAS when used in food at levels not to exceed current good manufacturing practice for a variety of technical effects, such as an emulsifier, stabilizer, thickener, and texturizer (21 CFR 184.1505).
The notice describes the method of manufacture of DAG, which includes the enzyme-catalyzed esterification of fatty acids derived from natural edible plant oils and either monoacylglycerol or glycerol. Component fatty acids are derived from edible oils including soybean oil, rapeseed oil, corn oil and olive oil. The main fatty acid constituents of DAG are oleic acid (C18:1), linoleic acid (C18:2) and linolenic acid (C18:3). The notice provides specifications for food-grade DAG, including a lead specification of less than 0.5 ppm.
The notice cites generally available information to support Kao's conclusion that the consumption of monoglycerides and diglycerides from currently consumed foods is in the range of 1-10 grams/person/day. Kao estimates that the expected additional consumption of monoglycerides and diglycerides, at the 90th percentile level, from its proposed use would range from approximately 6 grams per person per day to approximately 16 grams per person per day.
The notice describes studies conducted with DAG, including published absorption and metabolism studies; unpublished acute, subchronic and chronic toxicity studies; and an unpublished mutagenicity study. It also describes published and unpublished clinical trials designed to study the effects of DAG on circulating lipid levels.
The notice includes the findings of a panel of individuals (Kao's GRAS panel) who evaluated the data and information that are the basis for Kao's GRAS determination. Kao considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Kao's GRAS panel concluded that the available data and information demonstrate that DAG is GRAS, through scientific procedures, under the conditions of its intended use in food. Kao considers this conclusion to be consistent with the findings of the Joint Food and Agriculture Organization/World Health Organization Expert Committee on Food Additives and the Federation of American Societies for Experimental Biology regarding diglycerides in general. Kao also considers this conclusion to be consistent with the specific approval of DAG as Food for Specified Health Use by the Ministry of Health and Welfare in Japan in May 1998 for use as a cooking oil.
Section 403(a) of the Federal Food, Drug, and Cosmetic Act (FFDCA) provides that a food is misbranded if its labeling is false or misleading in any particular manner. Section 403(r) of the FFDCA lays out the statutory framework for a health claim. In describing the intended use of diacylglycerol oil and in describing the information that Kao relies on to conclude that diacylglycerol is GRAS under the conditions of its intended use, Kao raises an issue under these labeling provisions of the FFDCA. This issue consists of physiological effects of diacylglycerol oil that Kao views as "beneficial." These issues are the purview of the ONPLDS in CFSAN. OPA neither consulted with ONPLDS on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about diacylglycerol on the label or in labeling.
OPA did consult with ONPLDS regarding the common or usual name that Kao proposes. Kao believes that "DAG" is an appropriate name because the letters represent the essential portions of the substance's name, D (di) A (acyl) G (glycerol), and because randomized diacylglycerol of fatty acids is the main component of DAG oil. ONPLDS advises that their general approach is that an ingredient should be declared using a common or usual term or terms. For this particular food ingredient, ONPLDS comments that it is not clear that the consumer would recognize diacylglycerol by the term "DAG." While the ingredient is "new," ONPLDS recommends that Kao use both the chemical term "diacylglycerol" and the abbreviation "DAG." After some period of time, when DAG is more recognized, DAG could then stand alone. If you or Kao have any questions about the common or usual name that would be used to identify diacylglycerol oil in the ingredient statement of food products that would be marketed in the United States, OPA suggests that you or Kao contact the Division of Standards and Labeling Regulations, ONPLDS, CFSAN, HFS-820, 200 C Street S.W., Washington, DC 20204. You can reach this division by telephone at (202)205-4168.
As we mentioned above, 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. Standards of identity regarding margarine are described in 21 CFR Part 166 (Margarine). OPA consulted with ONPLDS regarding the use of DAG in margarine. Under 21 CFR 166.110 (a)(1), margarine may be produced from "edible fats and/or oils," of vegetable or animal origin, "which may have been subjected to an accepted process of physico-chemical modification." DAG is composed of diglycerides, not vegetable oil. Diglycerides are found in standard margarine as emulsifiers, but they are not intended as the primary ingredient. Since DAG is derived from edible vegetable oils, ONPLDS investigated the possibility that DAG could be used as an edible fat or oil "which was subjected to an accepted process of physico-chemical modification." After reviewing Federal Register publications on this issue from 1977 to the present, ONPLDS concluded that "accepted processes" referred to hydrogenation and partial hydrogenation methods. Therefore, the process used by Kao of extracting fatty acids from edible oils and re-esterifying them to produce diglycerides is not in accordance with the intent of "an accepted process" statement in the standard of identity for margarine. Because DAG is not an edible vegetable or animal oil that has undergone an accepted process of physio-chemical modification, it may not lawfully be used in standardized margarine. If you have any questions about the use of diacylglycerol oil in standardized margarine that would be marketed in the United States, OPA suggests that you contact the Division of Standards and Labeling Regulations, ONPLDS, CFSAN.
Based on the information provided by Kao, as well as other information available to FDA, the agency has no questions at this time regarding Kao's conclusion that diacylglycerol 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 diacylglycerol oil. As always, it is the continuing responsibility of Kao Corporation 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, as well as a copy of the information in your notice that conforms to the information in proposed 21 CFR 170.36(c)(1), is available for public review and copying on the Office of Premarket Approval's homepage on the Internet (at http://www.cfsan.fda.gov/~lrd/foodadd.html).
Alan M. Rulis, Ph.D.
Office of Premarket Approval
Center for Food Safety and Applied Nutrition
* The Office of Premarket Approval became the Office of Food Additive Safety on June 18, 2001.