Agency Response Letter GRAS Notice No. GRN 000438
CFSAN/Office of Food Additive Safety
January 16, 2013
Raisio Nutrition Ltd., Benecol Division
P.O. Box 101 (Raisionkaari 55)
Re: GRAS Notice No. GRN 000438
Dear Mr. Wester:
The Food and Drug Administration (FDA) is responding to the notice, dated June 18, 2012, 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 July 11, 2012, filed it on August 1, 2012, and designated it as GRAS Notice No. GRN 000438.
The subject of the notice is plant stanol esters. The notice informs FDA of the view of Raisio Nutrition Ltd., Benecol Division (Raisio Nutrition) that plant stanol esters are GRAS, through scientific procedures, for use as an ingredient in baked goods and baking mixes, beverages and beverage bases, breakfast cereals; cheeses, coffee and tea, dairy product analogs, fats and oils, grain products and pastas, gravies and sauces, milk, milk products, processed fruits and fruit juices, processed vegetables and vegetable juices, soft candy, and soups and soup mixes at a level ranging between 0.5 to 2.0 grams (g) plant stanols per serving (provided as plant stanol esters).1
Our use of “plant stanol esters” 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. Title 21 CFR 101.4 states that 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 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, Raisio Nutrition includes the report of a panel of individuals (Raisio Nutrition’s GRAS panel) that evaluated the data and information that are the basis for Raisio Nutrition’s GRAS determination. Raisio Nutrition considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Raisio Nutrition’s GRAS panel evaluated the method of manufacture, product specifications, estimates of dietary exposure, as well as published and unpublished safety studies. Based on this review, Raisio Nutrition’s GRAS panel concluded that plant stanol esters that meet established food grade specifications are GRAS under the conditions of its intended use.
Plant stanol esters were the subject of Food Master File (FMF) 000626. GRN 000438 incorporates FMF 000626 by reference. FMF 000626 includes discussion of the chemical identity, structure and physical characteristics, method of manufacture, product specifications, purity and stability, and published and unpublished studies on plant stanol esters.
Raisio Nutrition discusses the composition of plant stanol esters. Plant stanols are esterified with fatty acids derived from vegetable oils. The plant stanol/plant sterol moiety of the plant stanol fatty acid ester blend has a composition of ≥ 94.0% by weight of total stanols (i.e., sitostanol and campestanol) and ≥ 6.0% by weight unsaturated sterols. Plant stanol esters are manufactured as either a creamy white powder or a pale yellow liquid.
Raisio Nutrition discusses the method of manufacture of plant stanol esters. The source material is commercially available plant sterols, derived from vegetable oil or wood sources (also referred to as tall oil sterols), or blends thereof. Plant stanols are prepared using palladium catalyzed hydrogenation methods currently employed by the food industry. The resulting plant stanols are then esterified with fatty acid alcohol esters isolated from vegetable oils, fats or their blends. The manufacturing process currently being employed by Raisio Nutrition in the production of plant stanol esters is consistent with what was previously described in FMF 000626. The only difference is the use of two additional processing aids (activated carbon and sodium acetate) in the saturation step to optimize the manufacturing process. Activated carbon is used to adsorb trace impurities from plant sterols prior to the saturation process, and sodium acetate is used as a buffering agent to adjust the pH. Both processing aids are removed during the filtration of the palladium catalyst and the esterification washing step, and are not present in the finished product. Raisio Nutrition also intends to produce powdered plant stanol esters by spray-drying and using food grade carriers (e.g., maltodextrin) and food grade proteins (e.g., sodium caseinate). The plant stanol esters are manufactured using current good manufacturing practices and use food grade starting materials and processing aids.
Raisio Nutrition provides specifications for both the liquid and powdered forms of plant stanol esters. Specifications for the liquid form include a minimum content of total stanols (≥ 56%), which is composed of a minimum of 68% sitostanol and a maximum of 32% campestanol. Specifications include limits on free sterols (≤ 3%), free fatty acids (≤ 0.1%), moisture (< 0.1%), lead (≤ 0.1 milligrams per kilogram (mg/kg)) and residual solvents (≤ 50 mg/kg). Specifications for the powdered form of plant stanol esters include a minimum content of total stanols (≥ 38%, wet weight), and limits on free sterols (≤ 3%), fatty acids (~ 29%), moisture (≤ 5%), and limits on microbial contaminants.
Raisio Nutrition estimates the daily intake of plant stanols based on the intended food uses and use levels in conjunction with food consumption data from the 2003-04 and 2005-06 National Health and Nutrition Examination Survey. On a users-only basis, the mean estimated daily intake (EDI) of plant stanols (from consumption of plant stanol esters) by the total U.S. population from intended uses is 5.02 g/person (p)/day (d) (92 mg/kg body weight (bw)/d), and the 90th percentile EDI is 8.82 g/p/d (186 mg/kg bw/d).
FMF 000626 provided a literature search up to the year 1999. Raisio Nutrition provides an updated scientific literature review on plant stanol esters covering the years 1999 through 2011 in GRN 000438. The notice discusses absorption, distribution, metabolism, and elimination information for plant stanol esters, and also points out that published studies have shown that plant stanol esters are not mutagenic or genotoxic. Studies published since 1999 evaluated subchronic toxicity, as well as reproductive and developmental toxicity with no toxic effects noted. A no observed adverse effect level was determined from the animal studies to be 8.5% plant stanol esters in the diet which corresponds to 4600 mg/kg bw/d. Furthermore, additional published in vitro and in vivo observations have shown that plant stanol esters are not estrogenic. The notifier also reviewed human studies showing no adverse effects, including studies in which individuals consumed up to 9 g of plant stanol esters for ten weeks or 2-3 g of plant stanol esters for 85 weeks. Finally, the notifier discusses the issue of fat soluble vitamin availability and the fact that a large body of published clinical data shows that plant stanol esters do not affect vitamin absorption.
Standards of Identity
In the notice, Raisio Nutrition states its intention to use plant stanol esters 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.
The Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) amends the Federal Food, Drug, and Cosmetic Act (FD&C Act) 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. Powdered plant stanol esters produced using food grade proteins (e.g., sodium caseinate derived from milk) may require labeling under FALCPA, because it may contain protein derived from milk. Although issues associated with labeling food are the responsibility of the ONLDS, issues associated with FALCPA exemptions are the responsibility of the Food Allergen Coordinator in the Office of Food Additive Safety.
Section 301(ll) of the FD&C Act
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FD&C Act to, among other things, add section 301(ll). 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 Raisio Nutrition’s notice that plant stanol esters are GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing plant stanol esters. Accordingly, this response should not be construed to be a statement that foods that contain plant stanol esters, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Raisio Nutrition and other information available to FDA, the agency has no questions at this time regarding Raisio Nutrition’s conclusion that plant stanol esters are GRAS under the intended conditions. The agency has not, however, made its own determination regarding the GRAS status of the subject use of plant stanol esters. As always, it is the continuing responsibility of Raisio Nutrition 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 000438, 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
1The notice dated June 27, 2012, listed food categories which could fall under either FDA's or United States Department of Agriculture's (USDA's) jurisdiction (e.g., gravies and sauces, and soups and soup mixes). On September 12, 2012, FDA received a communication from Intertek (on behalf of Raisio Nutrition) stating that the use of plant stanol esters in products under USDA's jurisdiction is excluded from this notice.