Agency Response Letter GRAS Notice No. GRN 000250
CFSAN/Office of Food Additive Safety
February 9, 2009
Clyde A. Takeguchi, Ph.D.
Phoenix Regulatory Associates, Ltd.
21525 Ridgetop Circle, Suite 240
Sterling, VA 20166
Re: GRAS Notice No. GRN 000250
Dear Dr. Takeguchi:
The Food and Drug Administration (FDA) is responding to the notice, dated April 11, 2008, that you submitted on behalf of Arboris LLC (Arboris) 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 April 30, 2008, filed it on May 5, 2008, and designated it as GRAS Notice No. GRN 000250.
The subject of the notice is plant sterols and stanols from pine trees (hereinafter referred to in this letter as pine tree phytosterols). The notice informs FDA of the view of Arboris that pine tree phytosterols are GRAS, through scientific procedures, for use as an ingredient in multiple food categories including margarine and vegetable based spreads, yogurt and yogurt-like products, milk-based juice beverages, ice cream and non-standardized ice cream products, cream cheese and cream cheese-like products, snack bars, salad dressings, standardized and non-standardized bread products, baked foods, beverages, dairy analogs, cheeses and cream, breakfast cereals, mayonnaise, pasta and noodles, sauces, salty snacks, processed soups, puddings, confections, vegetarian meat analogs, fruit/vegetable juices, vegetable oils, egg products, including egg whites and substitute egg products.1
Arboris incorporates by reference several GRAS notices regarding phytosterol and phytosterol esters (GRNs 000039, 000048, 000053, 000061, 000112, 000176, 000177, 000181, and 000206) and states that they intend for pine tree phytosterols to be used in accordance with the uses described in the incorporated GRAS notices.
Arboris states that pine tree phytosterols are white to off-white mixtures of sterols and stanols derived from pine tree tall oil.2 Arboris indicates that pine tree phytosterols will contain no less than 99 percent total phytosterols. Arboris compares the phytosterol content of its product to other tall oil derived phytosterol products, including the subjects of GRN 000039 and GRN 000112. The main components are β-sitosterol (70-80 percent), β-sitostanol (not more than 15 percent), and campesterol (not more than 15 percent), with lesser amounts of campestanol (not more than 5 percent), stigmasterol (not more than 2 percent), and other sterols (not more than 3 percent). Arboris notes that the distribution of sterols and stanols is similar in the products it manufactures to other tall oil phytosterol products that are currently on the market.
Arboris indicates that pine tree phytosterols are produced from tall oil derived from pine trees, primarily of the species Pinus elliottii and P. taeda. Arboris describes a multi-step process where tall oil, a by-product of wood pulp production, is first saponified with caustic soda, yielding a mixture of free sterols/stanols and soaps. This resulting mixture then undergoes wiped-film evaporation in two stages, followed by flash evaporation. Evaporated phytosterols (and other neutral components) are thermally distilled to remove non-sterol components. The crude phytosterols are then dissolved in solvent and further purified by crystallization, filtration, and washing steps. Hexane, ethanol, and water are used in the final purification processes. The resulting crystals are dried under vacuum to remove residual solvent and formed into pellets to obtain the finished product.
Arboris provides product specifications for pine tree phytosterols, including the minimum amounts of total phytosterols (not less than 99 percent) and limits for individual sterols and stanols as described above. Arboris also provides specifications for heavy metals, pesticides, polycyclic aromatic hydrocarbons, dioxins and dioxin-like PCBs, residual solvents and microorganisms.
Based on its review of estimated daily intakes (EDI) presented in previous GRAS notices, Arboris notes that the EDI of phytosterols, from all uses, is 7.3 grams per person per day (g/p/d) at the mean and 12.9 g/p/d at the 90th percentile. Arboris notes that the pine tree phytosterols that are the subject of GRN 000250 will be used in accordance with conditions of use previously described in completed GRAS notices and, as such, will substitute for other phytosterol ingredients without changing the cumulative exposure to phytosterols or phytosterol esters.
Arboris summarizes and compares the dietary intakes, sources, and metabolism of cholesterol and phytosterols. Arboris states that a review of the published literature supports their conclusion that there is no difference between vegetable and other plant derived phytosterols and those derived from pine tree oil in terms of safety. Arboris also notes the conclusions in the nine previous GRAS notices, and associated GRAS panel reports, where the use of phytosterols, phytostanols and phytosterol esters were determined to be safe for the intended uses in foods. Arboris states that it has reviewed the recent published literature on the safety of phytosterols in food and has concluded that the literature continues to support the safe use of phytosterols in foods.
Standards of Identity
In the notice, Arboris states its intention to use pine tree 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 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 Cosmetic Act (FFDCA)
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 Arboris' notice that pine tree phytosterols are GRAS for use in certain foods, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing pine tree phytosterols. Accordingly, this response should not be construed to be a statement that foods that contain pine tree phytosterols, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Arboris, as well as other information available to FDA, the agency has no questions at this time regarding Arboris' conclusion that pine tree 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 pine tree phytosterols. As always, it is the continuing responsibility of Arboris 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 000250, as well as a copy of the information in this notice that conforms to the information in the proposed GRAS exemption claim (proposed 21 CFR 170.36(c)(1)), is available for public review and copying via the FDA homepage at http://www.fda.gov. To view or obtain an electronic copy of the text of this 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.
Laura M. Tarantino, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
(1)GRN 000250 includes discussion of two products identified by Arboris as AS-2 and AS-4. The AS-2 product contains no less than 99 percent total phytosterols (consisting of β-sitosterol, β-sitostanol, campesterol, stigmasterol, campestanol, and other sterols), while the AS-4 product contains no less than 95 percent total of the same phytosterols, with the remainder consisting of minor components. On November 13, 2008, Arboris requested that the scope of GRN 000250 be limited to the AS-2 product.
(2)Sterols and stanols both have the same steroid ring structure as cholesterol; however, the B-ring of the steroid moiety is unsaturated in the 5, 6 position of sterols and saturated in stanols (FAO/WHO Joint Expert Committee on Food Additives Monographs 5 (2008)). Sitosterol and campesterol differ from sitostanol and campestanol, respectively, only by the double bond at the 5, 6 position. The use of the term phytosterols in this letter refers collectively to both sterol and stanol components.