Agency Response Letter GRAS Notice No. GRN 000387

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CFSAN/Office of Food Additive Safety

December 19, 2011

Edward A. Steele
EAS Consulting Group, LLC
1940 Duke Street, Suite 200
Alexandria, VA 22314

Re: GRAS Notice No. GRN 000387

Dear Mr. Steele:

The Food and Drug Administration (FDA) is responding to the notice, dated June 17, 2011, that you submitted on behalf of Cognis Corporation, Nutrition and Health (Cognis) 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 June 20, 2011, filed it on July 6, 2011, and designated it as GRAS Notice No. GRN 000387.

The subject of the notice is plant-derived esterified and non-esterified sterols and stanols (phytosterols). The notice informs FDA of the view of Cognis that phytosterols are GRAS, through scientific procedures, for use as an ingredient in the following food categories at levels ranging from 500 milligrams (mg) to 2000 mg phytosterols per reference amount customarily consumed (RACC):

Food Category Use-level (mg/RACC)
Baked Goods and Baking Mixes 500
Beverages and Beverage Bases 500
Breakfast Cereals 500
Cheeses 500
Coffee and Tea 500
Dairy Product Analogs 1000
Fats and Oils 500
Frozen Dairy Desserts and Mixes 500
Grain Products and Pastas 500
Gravies and Sauces 500
Milk (fluid and powdered) 1000
Milk Products: Cocoa and Chocolate Beverages 500
Milk Products: Cream 500
Milk Products: Cultured Dairy Drinks 2000
Milk Products: Meal Replacement Drinks 500
Milk Products: Milk-based Drinks and Flavored Milk 1000
Milk Products: Yogurt 2000
Plant Protein Products 500
Processed Fruits and Fruit Juices: Fruit Juices and Smoothies 1000
Processed Fruits and Fruit Juices: Powdered Fruit-Flavored Beverages 500
Processed Vegetables and Vegetable Juices 1000
Snack Foods 500
Soft Candy 500
Soups and Soup Mixes 500

As part of its notice, Cognis includes the report of a panel of individuals (Cognis' GRAS panel) who evaluated the data and information that are the basis for Cognis' GRAS determination. Cognis considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Cognis' GRAS panel evaluated the specifications and manufacturing processes, regulatory status, stability studies, intake from natural presence in food, intended use, estimated daily intake, and safety of phytosterols. According to Cognis' GRAS panel, phytosterols, produced consistent with current good manufacturing practices (cGMPs) and meeting appropriate food-grade specifications, are safe for use as food ingredients at the proposed use levels under the intended conditions of use.

Cognis describes several different phytosterol formulations. The manufacturing process varies slightly for each formulation. Cognis states that the phytosterols are produced under cGMPs. Cognis provides chemical and microbial specifications for each of the formulations. Cognis identifies the principal sterol and stanol components in each of the formulations and states that all formulations meet purity specifications proposed by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) for phytosterols, phytostanols, and their esters that requires purities of at least 95% for free sterols on a total free sterol/stanol basis and 55% for sterol esters on a sterol/stanol basis.

Cognis provides information about the methods of manufacture of phytosterols. The non-esterified phytosterols are isolated either from deodorizer distillate, a by-product of edible oil production, or from tall oil, a by-product of wood pulp manufacture. The phytosterols are purified by distillation, extraction, crystallization, and washing. Raw materials and processing aids are detailed in the notice and include: vegetable oil distillate, sodium hydroxide, sulfuric acid, methanol, hexane, diatomaceous earth, and aluminum calcium silicates. These substances are either GRAS for their intended uses and use levels or are approved for use as solvents in processing food.

Phytosterol esters are obtained by esterification of free plant sterols with food-grade fatty acids from vegetable oil. The plant sterols are derived either from deodorizer distillate or from tall oils. The fatty acids are derived from sunflower or rapeseed oil. The fatty acids are heated under nitrogen in a reaction vessel. The free sterols are added and the mixture is slowly heated under vacuum. The raw sterol ester is further refined using molecular distillation under a vacuum and then deodorized. Other components of the formulations include sodium caseinate, glucose syrup, gum arabic, silicon dioxide, sodium ascorbate, mixed tocopherol, and ascorbyl palmitate. These substances are either GRAS or approved food additives for their intended uses.

Cognis discusses an estimate of dietary intake for phytosterols based on their addition to the specified food categories at maximum use levels. Consumption data from the National Center for Health Statistics' National Health and Nutrition Examination Surveys were used to estimate intake. The mean intake of phytosterols, calculated for eaters only, was 4.0 grams/person/day (g/p/d) (or 77 mg/kilogram body weight (kg bw)/d). The 90th percentile eaters only intake was 6.8 g/p/d (159 mg/kg bw/d).

Cognis discusses the safety of phytosterols, reviewing previous GRAS notices for phystosterols (GRNs 000039, 000048, 00053, 00061, 000112, 000176, 000177, 000181, 000206, 000250, and 000335), where FDA had no questions regarding the conclusions that phytosterols were GRAS for the intended uses. The most recent notice (GRN 000335) was evaluated by FDA in 2010. Cognis states that it has reviewed recent published literature on phytosterols in food (searches were conducted for publications through June 2011) and concluded that there are no studies that raise any safety concerns. Based on this review, Cognis concludes that phytosterols are safe under the conditions of their intended use.

The notifier also discusses international evaluations of the safety of phytosterols in food. The Scientific Panel of the European Food Safety Authority, JECFA, and the Food Standards Australia and New Zealand all concluded that the addition of phytosterols to food is safe.

Standards of Identity

In the notice, Cognis states its intention to use phytosterols 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 added lawfully 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 Cosmetic 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 Cognis' notice that phytosterols are GRAS for use in conventional foods, excluding meat and poultry products, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing phytosterols. Accordingly, this response should not be construed to be a statement that foods containing phytosterols, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).


Based on the information provided by Cognis, as well as other information available to FDA, the agency has no questions at this time regarding Cognis' conclusion that phytosterols 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 phytosterols. As always, it is the continuing responsibility of Cognis 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 000387, 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

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

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