Agency Response Letter GRAS Notice No. GRN 000398
CFSAN/Office of Food Additive Safety
February 13, 2012
Kristen Dammann, Ph.D, R.D.
15407 McGinty Road West
Wayzata, MN 55391
Re: GRAS Notice No. GRN 000398
Dear Dr. Dammann:
The Food and Drug Administration (FDA) is responding to the notice, dated August 15, 2011, 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 August 16, 2011, filed it on August 18, 2011, and designated it as GRAS Notice No. GRN 000398.
The subject of the notice is vegetable oil and tall oil derived phytosterol and phytosterol ester formulations (PPEFs). The notice informs FDA of the view of Cargill, Incorporated (Cargill) that PPEFs 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; condiments and relishes; dairy product analogs; egg products; fats and oils; fish products; frozen dairy desserts and mixes; grain products and pastas; gravies and sauces; hard candy; herbs, seeds, spices, seasonings, blends, extracts, and flavorings; jams and jellies; whole and skim milk; milk products; nuts and nut products; processed fruits and fruit juices; processed vegetables and vegetables juices; snack foods; soft candy; and soups and soup mixes at levels of 0.5 or 1.0 gram (g)/serving. , 
Our use of "PPEFs" 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 in the Center for Food Safety and Applied Nutrition.
As part of its notice, Cargill includes the report of a panel of individuals (Cargill's GRAS panel) who evaluated the data and information that are the basis for Cargill's GRAS determination. Cargill considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Cargill's GRAS panel evaluated the composition and identity, methods of manufacture, product specifications, and estimates of dietary exposure; as well as published toxicological studies for PPEFs. Based on this review, Cargill's GRAS panel concluded that PPEFs, produced consistent with current good manufacturing practice and meeting purity and established food grade specifications, are GRAS under the conditions of its intended use.
Cargill describes PPEFs as a group of free and esterified phytosterols derived from vegetable oil and tall oil. The major phytosterols and phytostanols in PPEFs are sitosterol, sitostanol, campesterol, campestanol, stigmasterol, and brassicasterol. PPEFs are manufactured in the following forms: powdered, granular, pulp, emulsified, or oil.
Cargill describes the methods of manufacture for PPEFs that differs depending on the starting material, tall or vegetable oil, and the final product, phytosterol or phytosterol ester. Cargill states that all ingredients and processing aids used in the manufacture of PPEFs are in compliance with federal regulations. For the production of vegetable oil phytosterols, plant sterols are isolated from deodorizer distillate (a by-product of edible oil production) at high temperature and vacuum. The first step involves distilling the phytosterols to remove free fatty acids and other impurities. Next, the residual neutral oils (tri-, di-, and monoglycerides) undergo transesterification using sodium hydroxide and methanol to yield fatty acid methyl esters (FAME). The sterols are purified by steam stripping to remove any solvents, excess FAME, and minor impurities.
Phytosterols are also isolated from tall oil, a by-product of pine wood pulp manufacture, by saponification with caustic soda to obtain a mixture of free sterols and organic salts. The phytosterols separated from the residual organic salts are concentrated through several steam evaporation steps. The phytosterols are further concentrated by distillation and then crystallized using a mixture of organic solvents. The crystals are dried under vacuum to remove the solvents.
To produce phytosterol esters, vegetable oil or tall oil derived sterols are reacted with FAME in the presence of sodium methoxide (catalyst) under heat and vacuum. Methanol is produced as a by-product and removed during processing. The product is cooled and water is added to deactivate the catalyst, converting it to sodium hydroxide and methanol. Steam centrifugation is used to separate out the fatty acid soaps. Silica and bleaching clay are used to remove trace compounds and color bodies.
Cargill provides specifications for vegetable oil and tall oil phytosterols as well as for vegetable oil and tall oil phytosterol esters. Specifications for vegetable oil and tall oil phytosterols include total sterols (≥92% and ≥99%, respectively), moisture and volatiles (≤2% and ≤3%, respectively), lead (<0.1 milligram (mg)/kilogram (kg) for each), and sulphated ash (≤0.1 for each). Specifications for vegetable oil and tall oil phytosterol esters include total sterols (≥97%), phytosterol esters (≥91), free phytosterols (≤6%), acyl-glycerides (≤5%), acidity (≤0.2 mg/kg), lead (≤0.1 mg/kg), and loss on drying (≤0.1 mg/kg). Additionally, levels of residual solvents were analyzed and found to conform to the specifications (<1,000 mg/kg for ethanol and <40 mg/kg for methanol).
Cargill states that the results of a three-year stability study showed that PPEFs lots held at 25 °C and 60% relative humidity, remained within product specifications for sterol purity (≥88%). Tall oil phytosterols were also tested and found stable for a shelf-life of at least 59 months. The stability of phytosterol and phytosterol ester containing products was tested using a variety of food matrices. Cargill states that the food products tested had stable PPEFs content when analyzed.
Cargill provides an estimated daily intake of PPEFs based on its addition to foods in specified categories at the maximum use level. The consumption of the phytosterols was estimated using the National Center for Health Statistics' National Health and Nutrition Examination Surveys (CDC, 2006, USDA, 2009). The consumption of phytosterols, calculated for a total U.S. population mean all-user intake, was 6.6 g/person (p)/day (d) (0.1 mg/kg body weight (bw)/d). The 90th percentile all-users intake was 11.0 g/p/d (0.2 mg/kg bw/d). This calculation is based on the mean intake for all-person and all-users with the exception of infants, as the products are not intended to be consumed by infants.
Cargill discusses current published toxicological studies for PPEFs. Cargill states that dietary phytosterols are not very bioavailable, with absorption being approximately 5% of the dietary load. Cargill further reports that many published animal studies (including subchronic, reproductive, developmental, and teratogenic) are available and were reviewed with the highest no observed adverse effect level being 4200 mg vegetable oil phytosterols/kg bw/d, the highest level tested. In addition, Cargill states that published human clinical studies with exposures of up to 30 g/d phytosterols showed no adverse effects. Cargill discusses the safety of a variety of different vegetable oil and tall oil derived phytosterol ingredients that have been the subject of 11 previous GRAS notices (GRN Nos. 000039, 000048, 000053, 000061, 000112, 000176, 000177, 000181, 000206, 000250, and 000335). Finally, Cargill notes that phytosterols have been successfully reviewed by various scientific bodies world-wide, including Health Canada, European Scientific Committee on Food, and Food Standards Australia New Zealand.
Cargill concludes that based on the totality of the supporting information that PPEFs are GRAS under the intended conditions of use on the basis of scientific procedures.
Standards of Identity
In the notice, Cargill states its intention to use PPEFs 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.
Section 301(ll) of the Federal Food, Drug, and Cosmetics Act (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 Cargill's notice that PPEFs are GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing PPEFs. Accordingly, this response should not be construed to be a statement that foods that contain PPEFs, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Cargill, as well as other information available to FDA, the agency has no questions at this time regarding Cargill's conclusion that PPEFs are 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 PPEFs. As always, it is the continuing responsibility of Cargill 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 000398, 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
 On October 4, 2011, FDA received a communication from Cargill removing alcoholic beverages from the intended conditions of use.
 The notice dated August 15, 2011, listed food categories which could fall under either FDA's or United States Department of Agriculture's (USDA's) jurisdiction (e.g., fish products, gravies and sauces, and soups and soup mixes). On September 14, 2011, FDA received a communication from Cargill stating that the use of PPEFs in products under USDA's jurisdiction is excluded from this notice.