Agency Response Letter
GRAS Notice No. GRN 000192

Iris Meiri-Bendek
Enzymotec Ltd.
P.O. Box 6
Migdal HaEmeq
ISRAEL, 23106

Re: GRAS Notice No. GRN 000192

Dear Ms. Meiri-Bendek:

The Food and Drug Administration (FDA) is responding to the notice, dated January 31, 2006, 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 2, 2006, filed it on February 6, 2006, and designated it as GRAS Notice No. GRN 000192.

The subject of the notice is high 2-palmitic acid vegetable oil⁽¹⁾ (prepared by enzymatic modification of palm stearin). The notice informs FDA of the view of Enzymotec Ltd. (Enzymotec) that high 2- palmitic acid vegetable oil is GRAS, through scientific procedures, for use in term and pre-term infant formulas at levels up to 70% of total fat, to replace all added fat in baby and toddler foods (including meat and poultry products), and to replace all added fat in processed foods in general (excluding meat and poultry products).

As part of its notice, Enzymotec includes the report of a panel of individuals (Enzymotec's GRAS panel) who evaluated the data and information that are the basis for Enzymotec's GRAS determination. Enzymotec considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Enzymotec's GRAS panel discusses composition, manufacture, specifications, exposure, and safety data (including absorption, distribution, metabolism, and excretion studies; preclinical sub-chronic studies, chronic, and reproductive studies; and clinical studies). Enzymotec's GRAS panel considers that high 2-palmitic acid vegetable oil, meeting appropriate food-grade specifications and manufactured in accordance with good manufacturing practice, is GRAS based on scientific procedures under the conditions of its intended use in foods.

Our use of "high 2-palmitic vegetable 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. 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 non-standardized foods. Issues associated with labeling and the appropriate common or usual name of a food are the responsibility of the Office of Nutritional Products, Labeling, and Dietary Supplements.

High 2-palmitic acid vegetable oil is prepared by the enzymatic modification of palm stearin (composed mainly of tripalmitin) to yield an ingredient that more closely resembles human milk triglycerides in its fatty acid positional distribution relative to traditional vegetable oils. High 2- palmitic acid vegetable oil is a colorless and flavorless product. Its consistency ranges from turbid liquid to paste at room temperature.

The manufacturing process for the formation of high 2-palmitic acid vegetable oil has two steps. The first step involves the randomization of palm stearin fatty acids by treatment with the chemical catalyst, sodium methoxide. The mixture then undergoes neutralization and a bleaching process similar to that used for traditional vegetable oils.

The second step in the manufacturing process is an enzymatic transesterification reaction. The high 2-palmitic acid vegetable oil is produced by enzymatic esterification of randomized palm stearin with fatty acids (primarily oleic acid) from either palm kernel oil or high oleic sunflower oil. The palmitic acid residues on the palm stearin triglycerides are replaced by oleic acid residues at the sn-1 and sn-3 positions, leaving the sn-2 fatty acids (primarily palmitic acid as well as some oleic acid) unaltered. Enzymotec states that this process uses a safe and suitable immobilized GRAS lipase enzyme preparation from Aspergillus oryzae carrying a gene encoding a lipase from Thermomyces laguninosus (the subject of GRN 000043). The immobilization process is carried out in accordance with good manufacturing practice using materials approved for food use. Following reaction and separation of the catalyst, the oil is distilled to remove excess free fatty acids (primarily oleic acid). The oil next undergoes bleaching and steam distillation/deodorization processes. Enzymotec states that the oil is then mixed with permitted antioxidants.

Enzymotec states that potential residues from the manufacturing process include protein, sorbitan oleate, methanol, and epichlorhydrin, but that all residues were below the limits of detection. Enzymotec also states that residues of methanol, epichlorhydrin (used in the production of the immobilized enzyme), and 1,3-dichloro-2-propanol (formed by reaction of water with epichlorhydrin), if present, would be removed under the conditions (elevated temperature, vacuum) of the distillation and deodorization processes.

The predominant triacylglycerols in the high 2-palmitic acid vegetable oil are 1,3-dioleoyl-2- palmitoylglycerol; 1,2-dipalmitoyl-3-oleoylgIycerol; and triolein. The fatty acid composition of the high 2-palmitic acid vegetable oil is predominantly oleic and palmitic acids, with lesser amounts of other fatty acids. Enzymotec provides specifications (expressed as a percentage of total fatty acids) for fatty acids: oleic acid (42 - 60%), palmitic acid (25 - 42%), stearic acid (1 - 6%), and linoleic acid (6 - 17%). In addition, Enzymotec specifies that 62 - 70% of the palmitic acid is esterified at the sn-2 position of the glycerol backbone. Enzymotec also provides the results of batch analyses of several lots to show that the product meets their specifications. According to these analyses, palmitic acid represents approximately 60 - 66% of all the fatty acids found at the sn-2 position.

High 2-palmitic acid vegetable oil is intended to replace vegetable oils in infant formula up to a level of 70% of total fat, to replace all added fat in baby and toddler foods (including meat and poultry products), and to replace all added fat in processed food products in general (excluding meat and poultry products). Enzymotec notes that high 2-palmitic acid vegetable oil cannot replace all the fat in infant formula since it is limited with respect to essential fatty acids like linolenic acid.

Use of high 2-palmitic acid vegetable oil is also limited in baby and toddler foods, because most of these types of foods do not contain significant amounts of added fat. In foods intended for general consumption, use of high 2-palmitic acid vegetable oil is self-limiting based on its technological properties such as melting temperature.

Enzymotec provides estimates of intake of high 2-palmitic acid vegetable oil from all proposed food uses, prepared using the United States Department of Agriculture (USDA) 1994-1996 Continuing Survey of Food Intakes by Individuals (USDA CSFII 1994-1996) and the 1998 Supplemental Children's Survey (USDA CSFII 1998). On an eaters-only basis, the estimated intake of high 2-palmitic acid vegetable oil for young infants (0-5 months; 87.6% eaters) that would be consuming infant formula is 22 grams (g)/person (p)/day(d) at the mean and 36 g/p/d at the 90th percentile. On an eaters-only basis, the estimated intake of high 2-palmitic acid vegetable oil by all ages (99.3% eaters) fiom all proposed food uses was 35 g/p/d at the mean and 66 g/p/d at the 90th percentile.

The notice contains a review of triacylglycerol biochemistry, as well as summaries of relevant studies. Enyzmotec considers the safety of its high 2-palmitic acid vegetable oil to be supported by a number of published studies on another high 2-palmitic acid vegetable oil that is similar in fatty acid content and positional distribution. This ingredient was the subject of GRN 000131, submitted by Loders Croklaan B.V. (Loders Croklaan). GRN 000192 includes a comparison of the composition of these two high 2-palmitic acid vegetable oils to that of human milk, with respect to fatty acid content and positional distribution. GRN 000192 also cites a number of published studies with Loders Croklaan's high 2-palmitic acid vegetable oil, including absorption studies in Sprague-Dawley rats, a clinical study in infants comparing the absorption of palmitic acid from formula-based diets versus human milk, and other animal and human studies. Enzymotec conducted a comparative metabolic study in rats and reports that its high 2-palmitic acid vegetable oil exhibited absorptive and metabolic patterns similar to Loders Croklaan's high 2-palmitic acid vegetable oil.

Enzymotec's GRAS panel concludes that Ezymotec's high 2-palmitic acid vegetable oil is well absorbed and metabolized into normal body metabolites, that sn-2 esterified palmitic acid is a normal constituent of human milk, and that the intake of high 2-palmitic acid vegetable oil will not increase the current saturated fatty acid intake or significantly affect cholesterol or lipoprotein levels in humans.

In the notice, Enzymotec states its intention to use high 2-palmitic acid vegetable 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.

During its evaluation of GRN 000192, FDA consulted with the Labeling and Consumer Protection Staff of the Food Safety and Inspection Service (FSIS) of the United States Department of Agriculture (USDA). Under the Federal Meat Inspection Act and the Poultry Products Inspection Act, FSIS is responsible for determining the efficacy and suitability of food ingredients in meat and poultry 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 Enzymotec to seek regulatory guidance fiom FSIS, Labeling and Consumer Protection Staff, about the use of high 2-palmitic vegetable oil in meat and poultry products. Enzymotec should direct such an inquiry to Dr. Robert Post, Director, Labeling and Consumer Protection Staff, Office of Policy, Program, and Employee Development, Food Safety and Inspection Service, 1400 Independence Ave., S.W., Suite 602, Annex, Washington, DC 20250-3700. The telephone number for that office is (202) 205-0279 and the telefax number is (202) 205-3625.

Under section 412 of the Federal Food, Drug, and Cosmetic Act (FFDCA), a manufacturer of a new infant formula must make a submission to FDA, providing required assurances about the formula, at least 90 days before the formula is marketed. As part of that submission, the manufacturer of the infant formula must provide a quantitative formulation that lists the amount of every ingredient used in the formula. Enzymotec should be aware that FDA's response to Enzymotec's GRAS notice does not alleviate the responsibility of any infant formula manufacturer who intends to market an infant formula that contains high 2-palmitic vegetable oil to make the submission required by section 412.

Based on the information provided by Enzymotec, as well as other information available to FDA, the agency has no questions at this time regarding Enzymotec's conclusion that high 2-palmitic vegetable 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 high 2-palmitic vegetable oil. As always, it is the continuing responsibility of Enzymotec 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 000192, 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)(l)), is available for public review and copying on the homepage of the Office of Food Additive Safety (on the Internet at http://www.cfsan.fda.gov/-lrd/foodadd.html).

Sincerely,

Laura M. Tarantino, Ph.D.
Director
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition

cc: Dr. Robert Post, Director
Labeling and Consumer Protection Staff
Office of Policy, Program and Employee Development
Food Safety and Inspection Service
1400 Independence Ave., SW, Suite 602, Annex
Washington, DC 20250-3700

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⁽¹⁾Throughout the notice, Enzymotec refers to the ingredient that is the subject of GRN 000192 by the trade name "InFat™ " and the common or usual name of "high 2-palmitic acid vegetable oil," referring to the content of palmitic acid at the sn-2 position of the glycerol backbone.