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U.S. Department of Health and Human Services

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Agency Response Letter GRAS Notice No. GRN 000283

CFSAN/Office of Food Additive Safety

September 4, 2009

Raymond C. Dobert, Ph.D.
Monsanto Company
800 North Lindbergh Blvd
St. Louis, MO 63167

Re: GRAS Notice No. GRN 000283

Dear Dr. Dobert:

The Food and Drug Administration (FDA) is responding to the notice, dated February 25, 2009, 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 February 26, 2009, filed it on March 3, 2009, and designated it as GRAS Notice No. GRN 000283.

The subject of the notice is stearidonic acid (SDA) soybean oil. The notice informs FDA of the view of Monsanto Company (Monsanto) that SDA soybean oil is GRAS, through scientific procedures, for use as an ingredient in baked goods and baking mixes, breakfast cereals and grains, cheeses, dairy product analogs, fats and oils, fish products, frozen dairy desserts and mixes, grain products and pastas, gravies and sauces, meat products, milk products, nuts and nut products, poultry products, processed fruit juices, processed vegetable products, puddings and fillings, snack foods, soft candy, and soups and soup mixes, at levels that will provide 375 milligrams (mg) of SDA per serving.1

21 CFR 101.4 states that all ingredients must be declared by their common or usual name. In addition, 21 CFR 102.5 outlines general principles to use when establishing common or usual names for nonstandardized foods. Our use of “SDA soybean 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. 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 (ONLDS) in the Center for Food Safety and Applied Nutrition.

As part of its notice, Monsanto includes the report of a panel of individuals (Monsanto’s GRAS panel) who evaluated the data and information that are the basis for Monsanto’s GRAS determination. Monsanto considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Monsanto’s GRAS panel evaluated estimates of dietary exposure, method of production, and product specifications. as well as published studies. Based on this review, Monsanto’s GRAS panel concluded that SDA soybean oil that meets its established food grade specifications is GRAS under the conditions of its intended use.

Monsanto describes the identity of SDA soybean oil. The oil is obtained from a bioengineered soybean. Monsanto states that SDA soybean oil is compositionally different from conventional soybean oil. SDA soybean oil contains 15 to 30 percent SDA and 5 to 8 percent gamma-linolenic acid (GLA), neither of which is present in conventional soybean oil. SDA soybean oil also contains slightly higher levels of alpha-linolenic acid (ALA) and palmitic acid than conventional soybean oil. SDA soybean oil contains lower levels of oleic acid and linoleic acid (LA) than those present in conventional soybean oil. Monsanto notes that the variability in the oil’s fatty acid composition, notably the SDA concentration, is due to natural variation in growing conditions for the soybean.

Monsanto discusses the biosynthetic pathway of SDA in the bioengineered soybean. SDA biosynthesis involves the introduction of two desaturase genes that encode for the proteins Primula juliae delta 6-desaturase and Neurospora crassa delta 15-desaturase. Conventional soybeans lack delta 6-desaturase; delta 6-desaturase is required for the production of SDA in soybeans. Addition of the delta 15-desaturase with temporal expression similar to the delta 6-desaturase increases the flux of ALA to SDA. The delta 15-desaturase also lowers LA levels, thus lowering the substrate pool for GLA production. Monsanto notes that the introduced desaturases are the only non-soybean genes expressed in the bioengineered soybean.2

SDA soybean oil is processed using conventional industry standard processing methods. The soybean meat is first mechanically separated from the hulls. The resulting soybean meat is then flaked and solvent extracted with iso-hexane/hexane to yield crude soybean oil and soybean meal. The crude oil is degummed and bleached, and further purified through filtration and steam distillation. Anti-oxidants, primarily TBHQ, are added at the end of processing to inhibit oxidation of the oil. All processing aids used in the manufacture of SDA soybean oil are used in compliance with appropriate federal regulations.

Monsanto states that stability of SDA soybean oil was determined with respect to peroxide value and fatty acid content. SDA soybean oil maintains a peroxide value similar to that of conventional soybean oil under similar storage conditions. Monsanto notes that SDA oil is stable when stored under nitrogen, as is typical for soybean oil, for as long as nine months.

Monsanto provides specifications for SDA soybean oil with comparison to the specifications set forth in the Food Chemicals Codex (FCC), 6th Edition, for conventional soybean oil. Specifications include fatty acid composition, stability, limits for free fatty acids (< 0.1 percent), lead (< 0.1 milligrams/kilogram), peroxide value (< 10 milliequivalents/kilogram), unsaponifiable matter (< 1.5 percent), and water (< 0.1 percent).

Monsanto estimates the per capita consumption of SDA soybean oil from all intended food uses using the intended use levels in conjunction with food consumption data included in the National Health and Nutrition Examination Surveys (1999-2002). The current intake of fat, trans-fat, and fatty acids in the diet as well as intake following the addition of 20 or 30 percent SDA soybean oil to the intended food uses was calculated. SDA soybean oil was either added to foods or used as a replacement for unhydrogenated oil (including soybean oil, ‘not further specified’ oil, corn oil, cottonseed oil, peanut oil, sunflower oil, coconut oil, olive oil, canola oil, or palm oil). Monsanto notes that in order to achieve 375 milligrams SDA per serving of food, target foods need to have 1.8 g of 20 percent SDA soybean oil or 1.3 grams of 30 percent SDA soybean oil per serving of food.

Monsanto estimates, on a per capita basis, mean and 90th percentile intakes of 20 percent SDA soybean oil to be 10.1 and 19.6 grams per day (g/day), respectively (0.18 and 0.38 grams per kilogram body weight per day (g/kg bw/day), respectively). Monsanto also estimates per capita mean and 90th percentile intakes of 30 percent SDA soybean oil to be 7.6 and 14.8 g/day, respectively (0.10 and 0.30 g/kg bw/day, respectively). Monsanto estimates the per capita mean and 90th percentile intakes of SDA to be 2.1 g/day and 4.1 g/day, respectively. Estimated intakes of SDA were similar for 20 or 30 percent SDA soybean oil due to the constant use level of SDA per serving.

Monsanto discusses the known biochemical pathways through which SDA soybean oil is metabolized after absorption into the body. The fatty acids (FA) of SDA soybean oil may undergo beta-oxidation to produce acetyl-CoA, or they may be elongated to form long chain fatty acids such as eicosapentaenoic acid (EPA). Monsanto describes published studies that discuss the FA elongation conversion rate in humans as being as high as 3:1 SDA to EPA; this equates to 0.73 g/day at the mean, and 1.4 g/day at the 90th percentile for the intended food uses.

Monsanto discusses published animal studies for SDA soybean oil, in which rats received up to 4 g/kg bw/day; no toxicologically significant effects were observed. Monsanto also cites other published animal studies where rats, guinea pigs, and dogs consumed SDA oil derived from sources other than soybean at up to 2.1 g/kg bw/day with no toxicologically significant effects observed. In addition, no reproductive or developmental effects were seen in a published study in which rats received up to 4 g/kg bw/day. Furthermore, Monsanto describes a published study in humans where SDA soybean oil, consumed at 3.66 g/d for 16 weeks, did not affect physiological or blood chemistry endpoints. Other published studies in which humans consumed SDA oil derived from non-soybean sources, showed no adverse effects at levels up to 1.875 g/day.

Standards of Identity

In the notice, Monsanto states its intention to use SDA soybean oil in several food categories, 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.

Potential Labeling Issues

Under section 403(a) of the Federal Food, Drug, and Cosmetic Act (FFDCA), a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FFDCA lays out the statutory framework for the use of labeling claims that characterize the level of a nutrient in a food or that characterize the relationship of a nutrient to a disease or health-related condition. In describing the intended use of SDA soybean oil and in describing the information that Monsanto relies on to conclude that SDA soybean oil is GRAS under the conditions of its intended use, Monsanto raises a potential issue under these labeling provisions of the FFDCA. If products that contain SDA soybean oil bear any claims on the label or in labeling, such claims are the purview of ONLDS. The Office of Food Additive Safety neither consulted with ONLDS on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about SDA soybean oil on the label or in labeling.

Allergen Labeling

The Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) amends the FFDCA to require that the label of a food that is or contains an ingredient that bears or contains a “major food allergen” declare the presence of the allergen (section 403(w)). FALCPA defines a “major food allergen” as one of eight foods or food groups (i.e., milk, eggs, fish, Crustacean shellfish, tree nuts, peanuts, wheat, and soybeans) or a food ingredient that contains protein derived from one of those foods. Issues associated with labeling food are the responsibility of ONLDS.

Use in Meat, Poultry, and Egg Products

During its evaluation of GRN 000283, FDA consulted with the Risk and Innovations Management Division of the Food Safety and Inspection Service (FSIS) of the United States Department of Agriculture. Under the Federal Meat Inspection Act, the Poultry Products Inspection Act, and the Egg Products Inspection Act, FSIS is responsible for determining the efficacy and suitability of food ingredients in meat, poultry, and egg products as well as prescribing safe conditions of use. Suitability relates to the effectiveness of the ingredient in performing the intended purpose of use and the assurance that the conditions of use will not result in an adulterated product, or one that misleads consumers.

FSIS requested that FDA advise Monsanto to seek regulatory guidance from FSIS about the use of SDA soybean oil in meat and poultry products. Monsanto should direct such an inquiry to Dr. John M. Hicks, Jr., Risk and Innovations Management Division, Office of Policy and Program Development, Food Safety and Inspection Service, United States Department of Agriculture, George Washington Carver Center (GWCC), 5601 Sunnyside Ave., Mailstop 5271, Beltsville, MD 20705-5271. The telephone number for that office is (391) 504-0884 and the telefax number is (301) 504-0876.

Section 301(ll) of the FFDCA

The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FFDCA to, among other things, add section 301(ll). Section 301(ll) of the FFDCA prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FFDCA, 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 Monsanto’s notice that SDA soybean oil is GRAS for use in certain foods, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing SDA soybean oil. Accordingly, this response should not be construed to be a statement that foods that contain SDA soybean oil, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).

Conclusions

Based on the information provided by Monsanto, the agency has no questions at this time regarding Monsanto’s conclusion that SDA soybean 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 SDA soybean oil. As always, it is the continuing responsibility of Monsanto 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 000283, 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 via the FDA home page at http://www.fda.gov. To view or obtain an electronic copy of the text of the letter, follow the hyperlinks from the “Food” topic to the “Food Ingredients and Packaging” section to the “Generally Recognized as Safe (GRAS)” page where the GRAS Inventory is listed.

Sincerely,

Mitchell A. Cheeseman, Ph.D.
Acting Director
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition


 

cc: John M. Hicks, Jr. DVM, MPH
Risk and Innovations Management Division
Office of Policy and Program Development
Food Safety and Inspection Service
United States Department of Agriculture
George Washington Carver Center (GWCC)
5601 Sunnyside Ave., Mailstop 5271
Beltsville, MD 20705-5271



 



 

1Reference amounts customarily consumed (21 CFR 101.12)

2Monsanto states that Neurospora crassa is considered a non-pathogenic organism and is found in foods worldwide. Monsanto also notes that Primula juliae is a member of the Primula (Primrose) genus that includes plants that are commonly used as sources of GLA for human uses.