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U.S. Department of Health and Human Services

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Agency Response Letter GRAS Notice No. GRN 000134

CFSAN/Office of Food Additive Safety
January 8, 2004

Kohei Yamamoto
Kyowa Hakko USA, Inc.
767 Third Avenue, 19th Floor
New York, NY 10017

Re: GRAS Notice No. GRN 000134

Dear Mr. Yamamoto:

The Food and Drug Administration (FDA) is responding to the notice, dated June 26, 2003, 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 7, 2003, filed it on July 14, 2003, and designated it as GRAS Notice No. GRN 000134.

In its notice, Kyowa Hakko refers to the subject of GRN 000134 as "CSPHP" as an abbreviation for "C-fraction soy protein hydrolyzate with bound phospholipids." The notice informs FDA of the view of Kyowa Hakko that this mixture is GRAS, through scientific procedures, for use as an ingredient in baked goods and baking mixes, breakfast cereals, dairy product analogs, fats and oils, grain products and pastas, health beverages, meat products, milk products, plant protein products, processed fruits and fruit juices, processed vegetables and vegetable juices, and soups and soup mixes at varying levels.

In the view of FDA, "C-fraction soy protein hydrolyzate with bound phospholipids" does not adequately describe the substance because "C-fraction" is an unfamiliar term that is potentially confounding when used without explanation, the term "bound" is inconsistent with the chemical nature of the substance as a mixture, and the substance "phospholipid" is more accurately and completely described as "enzyme-modified lecithin." The subject of the notice appears to be a simple 4 to 1 mixture of two ingredients, soy peptones (or partially hydrolyzed soy protein) and enzyme-modified lecithin. FDA has previously affirmed the GRAS status of peptones produced from a variety of protein sources, including soy, based on a history of safe use as nutrient supplements, processing aids, and surface-active agents (21 CFR 184.1553). Also, FDA has affirmed the GRAS status of enzyme-modified lecithin for use as an emulsifier based on scientific procedures. In essence, GRN 134 describes a new use of a specific mixture of these two ingredients. Because FDA considers that CSPHP is not an adequately descriptive term, for the purpose of this letter FDA refers to the subject of the notice as soy peptones and enzyme-modified lecithin.

As part of its notice, Kyowa Hakko reports that a panel of individuals (Kyowa Hakko's GRAS panel) has evaluated the data and information that are the basis for Kyowa Hakko's GRAS determination. Kyowa Hakko considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food.

Kyowa Hakko reports that the mixture separates in the gastrointestinal tract into its components - i.e., partially hydrolyzed soy protein and enzyme-modified lecithin. To support its view that soy peptones and enzyme-modified lecithin are GRAS for their intended use, Kyowa Hakko describes published and unpublished studies and other information regarding the mixture of the two ingredients, soy protein (including soy isoflavones and trypsin inhibitors that are components of soy protein), enzyme-modified lecithin, and substances that are related to enzyme-modified lecithin (i.e., lecithin and lysolecithin).

Kyowa Hakko describes the soy component. Kyowa Hakko considers that the partially hydrolyzed soy protein complies with 21 CFR 184.1553 (peptones). Under 21 CFR 184.1553, peptones include "polypeptides, oligopeptides, and amino acids produced by partial hydrolysis of ... soy protein isolate." The starting material that is hydrolyzed (i.e., soy protein isolate) is a source of the soy protein that is the subject of an authorized health claim on the association between soy protein and reduced risk of coronary heart disease (21 CFR 101.82; 64 FR 57711; October, 26, 1999). Partially hydrolyzed soy protein contains the isoflavones genistein, daidzein and glycetein at levels that are within the range contained in soy protein isolate (as described in the rulemaking that authorized the health claim for soy protein). Kyowa Hakko acknowledges that isoflavones have been investigated for safety and concludes that the data generated from studies conducted with these components have been inconclusive. Kyowa Hakko concludes the consumption of soy isoflavones from the soy component of the mixture is not expected to induce adverse health effects. Kyowa Hakko discusses trypsin inhibitors contained in soy protein isolate and concludes the processing of soy protein to make the hydrolyzed ingredient significantly reduces levels of trypsin inhibitors.

Kyowa Hakko also describes the lecithin component. Commercial preparations of lecithin are a complex mixture primarily composed of phospholipids, triglycerides, fatty acids and carbohydrates. The removal of most triglycerides and fatty acids results in a product known as "de-oiled lecithin". Treatment of lecithin with pancreatin (an enzyme preparation that contains phospholipase A2 activity) or with isolated phospholipase A2 hydrolyzes one of the ester bonds between glycerol and a fatty acid at the 2-position of glycerol, producing one molecule of a lysophospholipid known as lysolecithin and one molecule of fatty acid from each molecule of lecithin; the resulting product is commonly referred to as "enzyme-modified lecithin." FDA has affirmed that enzyme-modified lecithin is GRAS for use as an emulsifier with no limitation other than good manufacturing practice (21 CFR 184.1063). Under 21 CFR 184.1063, enzyme-modified lecithin contains lysolecithin at a level of 50 to 80 mole percent of total phosphatides; the enzyme-modified lecithin manufactured by Kyowa Hakko complies with 21 CFR 184.1063.

Kyowa Hakko describes published and unpublished studies conducted with its mixture of soy peptones and enzyme-modified lecithin, including published short-term studies conducted in rats, an unpublished 90-day oral toxicity study conducted in rats, an unpublished study conducted to evaluate mutagenic potential, and published studies conducted in humans to evaluate potential benefits. Kyowa Hakko concludes that the no-observed-effect level (NOEL) in the 90-day oral toxicity study was the highest dose tested (i.e., 4.5 grams per kilogram body weight per day), that its mixture has no mutagenic potential in bacterial assays in the presence or absence of metabolic activation, and that studies conducted in humans to evaluate the potential beneficial effects of soy peptones and enzyme-modified lecithin were not associated with adverse effects.

Kyowa Hakko describes a published 22-month study conducted in rats to evaluate the ability of a semi-purified diet containing soy protein to support normal growth and development in rats and published studies conducted in humans to evaluate the potential benefits of soy protein. Kyowa Hakko concludes that these studies support the safety of soy peptones because soy protein isolate, like peptides derived from soy protein isolate, is degraded to amino acids in the gastrointestinal tract.

Kyowa Hakko discusses published information concerning the absorption, distribution, metabolism and excretion of lecithin and lysolecithin. Lysolecithin is reported to be the predominant phospholipid in the human small intestine. In humans, lecithin produced in the bile and provided by the diet is most likely converted to lysolecithin prior to absorption by the enterocyte and transfer from the blood to other tissues. In laboratory animals, lysolecithin has been reported to be completely and rapidly absorbed from the small intestine and distributed to a number of tissues. Absorbed lysolecithin is metabolized by direct acylation to lecithin, hydrolysis to form glycero-3-phosphocholine (GPC) and water-soluble products, or transesterification to yield lecithin and GPC. Small amounts of lysolecithin have been reported to be excreted in the feces.

Kyowa Hakko describes published studies conducted with enzyme-modified lecithin or with lysolecithin. Kyowa Hakko describes effects seen in these studies and its reasons for concluding that these effects do not raise a safety concern. For example, nephrocalcinosis that was observed in Colworth-Wistar rats fed high doses of enzyme-modified lecithin has been reported to be a common and spontaneous occurrence in Colworth-Wistar rats fed purified diets, and decreased hemoglobin levels in female rats fed high doses of enzyme-modified lecithin were seen at a mid-point, but not at the end, of a 13-week study. Kyowa Hakko also reports that it found no significant adverse effects in an unpublished 90-day toxicity study conducted in Wistar rats administered enzyme-modified lecithin.

Kyowa Hakko provides the individual food categories and intended use levels for its blend of soy peptones and enzyme-modified lecithin (Table 1), based on the addition of 3 grams per serving. Based on these food categories and use levels, Kyowa Hakko estimates that the intake of the 4 to 1 mixture of soy peptones and enzyme-modified lecithin would be 14 grams per person per day (g/p/d) at the mean and 19 g/p/d at the 90th percentile.

Table 1
Summary of proposed food categories and intended use levels
Food CatagorySpecific FoodsUse Level
percent (w/w)
Baked goods and Baking mixesBreads6
Rolls6
Bagels5.5
English muffins5.5
Breakfast cerealsReady-to-eat cereals5.5 - 20
Dairy product analogsSoy/imitation milks1.3
Fats and oilsMargarines21.4
Salad dressings10
Grain products and pastasHealth bars7.5
Health beveragesMeal replacements1.3
Meat productsMeat patty with soy protein5.5
Milk productsFlavored milk drinks1.3
Milk based meal replacements1.3
Yogurt (regular and frozen)2.1- 42.9
Plant protein productsMeat alternatives2.1- 42.9
Processed fruits and fruit juicesFruit juice1.3
Nectars1.3
Fruit-flavored drinks1.3
Processed vegetables and vegetable juicesVegetable/tomato juice1.3
Soups and soup mixesPrepared soups, dry soup mixes, and condensed soups1.2

Potential labeling issues

Under section 403(a) of the Federal Food, Drug, and Cosmetic Act (FFDCA), a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FFDCA lays out the statutory framework for a health claim. In describing the intended use of soy peptones and enzyme-modified lecithin and in describing the information that Kyowa Hakko relies on to conclude that these uses are GRAS under the intended conditions of use, Kyowa Hakko raises potential labeling issues under these provisions of the FFDCA. These labeling issues consist of Kyowa Hakko's assertion that the mixture has physiological effects that Kyowa Hakko views as "beneficial." If products that contain the mixture bear any claims about such benefits on the label or in labeling, such claims are the purview of the Office of Nutritional Products, Labeling, and Dietary Supplements (ONPLDS) in the Center for Food Safety and Applied Nutrition (CFSAN). The Office of Food Additive Safety (OFAS) neither consulted with ONPLDS on these labeling issues nor evaluated the information in your notice to determine whether it would support any claims made on the label or in labeling.

Use in meat and poultry products

During its evaluation of GRN 000134, 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 advised that Kyowa Hakko seek regulatory guidance about the use of these ingredients in meat and poultry products from Dr. Robert Post, Director, Labeling and Consumer Protection Staff, Office of Policy, Program Development and Evaluation, Food Safety and Inspection Service, 1400 Independence Ave., S.W., Suite 602, Annex, Washington, DC 20250-3700. The telephone number for his office is (202)205-0279 and the telefax number is (202)205-3625.

Conclusions

Based on the information provided by Kyowa Hakko, as well as the information in GRN 000134 and other information available to FDA, the agency has no questions at this time regarding Kyowa Hakko's conclusion that a mixture of soy peptones and enzyme-modified lecithin 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 this mixture. As always, it is the continuing responsibility of Kyowa Hakko 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, as well as a copy of the information in your notice that conforms to the information in proposed 21 CFR 170.36(c)(1), 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.
Acting 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 Development and Evaluation
     Food Safety and Inspection Service
     Independence Ave., S.W., Suite 602, Annex
     Washington, DC 20250-3700