Agency Response Letter
GRAS Notice No. GRN 000086
Mr. John S. Eldred
Keller and Heckman LLP
1001 G Street, N.W
Suite 500 West
Washington, DC 20001
Re: GRAS Notice No. GRN 000086
Dear Mr. Eldred:
The Food and Drug Administration (FDA) is responding to the notice, dated October 19, 2001, that you submitted on behalf of Avebe b.a. (Avebe) 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 October 22, 2001, and designated it as GRAS Notice No. GRN 000086.
The subjects of the notice are coagulated potato protein in hydrolyzed and unhydrolyzed form (“potato protein preparations”). The notice informs FDA of the view of Avebe that potato protein preparations are GRAS, through scientific procedures, for use as a water binder in meat, sausage, and poultry, as a foaming aid in confectionary, bakery, and dairy products, and as an emulsifier in spreads, sauces, desserts, and dressings, at levels between 0.1 and 3.0 percent in the finished product. Avebe estimates the dietary exposure to potato protein preparations from the intended uses to be 1.9 grams per person per day.
Avebe describes three distinct potato protein preparations: coagulated potato protein (CPP), hydrolyzed potato protein (HPP), and hydrolyzed, clarified potato protein (HCP). CPP is manufactured from conventional potatoes that are washed in water and ground into a mass. Sulfite is added at this stage to prevent oxidation. Fibers and ground starch are then separated from the “fruit juice,” which contains the dissolved protein. The protein is precipitated by adjusting the pH of the juice and using steam to raise the temperature. The protein precipitate is collected by centrifugation or by drying, dispersed in dilute food-grade mineral acid, decanted, and washed with water. The pH may then be adjusted, followed by drying.
HPP and HCP are prepared from CPP by dispersion in water, adjustment of the pH, and addition of a food-grade protease. The hydrolysis reaction is stopped by heating the mixture to more than 85 degrees Celsius, to inactivate the protease. This mixture may then be dried to give partially solubilized potato protein (HPP). Alternatively, the mixture may be separated using a decanter and a separator into a fully soluble fraction (HCP) and a partially soluble fraction (HPP). Both fractions are then dried to give the final potato protein preparations.
Avebe provides identical specifications for the three potato protein preparations, with limits on water, dry matter, protein, ash, glycoalkaloids, total lysinoalanine, and free lysinoalanine content. Avebe also provides analyses of inorganic elements and microbial contaminants for the potato protein preparations. Avebe states that the potato protein preparations are within current safety limits for food ingredients, and that control points in the manufacturing process are adequate.
Avebe concludes that CPP is comparable to potato protein from boiled potatoes. This conclusion is based on Avebe’s determination that the manufacture of CPP does not change the primary amino acid sequence of the protein, and denaturation of the secondary and tertiary structure in CPP is comparable to effects on potato protein from boiling potatoes. Avebe also concludes that HPP and HCP are comparable to partially digested potato protein formed from eating cooked potatoes. This conclusion is based on Avebe’s determination that the hydrolysis of CPP by food-grade proteases to produce HPP and HCP is similar to enzymatic hydrolysis of potato protein during human digestion of potatoes.
Avebe provides unpublished amino acid composition data for the potato protein preparations. In addition, Avebe notes that the composition of essential amino acids in the potato protein preparations is comparable to that of potato, egg, and beef proteins.
Avebe describes generally available information about the presence in potatoes of the toxic glycoalkaloids, alpha-chaconine and alpha-solanine, collectively referred to as “TGA” or “solanine.” The levels of glycoalkaloids in commonly consumed varieties of potatoes range from 20 to 150 milligrams per kilogram (mg/kg), with an average level of 80 mg/kg. Using the average glycoalkaloid level and an average intake of potatoes of 61 g/person/day, Avebe estimates that the average glycoalkaloid intake from potatoes would be 4.9 mg/person/day. Avebe establishes a specification for glycoalkaloids of less than 150 mg/kg in the potato protein preparations as sold. Using the upper limit for glycoalkaloids in the potato protein preparations and the estimated daily intake of the potato protein preparations (1.9 g/person/day), Avebe estimates that the maximum intake of glycoalkaloids from use of the potato protein preparations would be 0.28 mg/person/day. Avebe concludes that the small increase in glycoalkaloid intake (approximately 5 percent) from the use of the potato protein preparations will not significantly increase risk to consumers.
Avebe discusses published information about lysinoalanine and its possible formation during the manufacturing of the potato protein preparations. Heat or alkali treatment of proteins during food processing is known to lead to structural changes and the formation of cross-links, such as lysinoalanine, in the proteins. Avebe refers to lysinoalanine cross-links in proteins as protein-bound lysinoalanine. When proteins that contain lysinoalanine cross-links are subsequently hydrolyzed to amino acids, free lysinoalanine is formed. It has been reported that lysinoalanine is in many proteinaceous foods (including heated milk, simulated cheese, cooked egg whites, cooked chicken, cooked corn products, acid casein, hydrolyzed vegetable protein, and whipping agents) that have been heated or cooked. Avebe concludes that protein bound lysinoalanine is a normal and ubiquitous constituent of the human diet.
Avebe discusses published toxicity studies conducted with free lysinoalanine in several species. In rats, renal cytomegaly was observed, with a no-observed-adverse-effect-level (NOAEL) of 30 mg lysinoalanine per kg of the diet or 1.5 milligrams per kilogram of body weight per day. No renal effects were observed, however, when free lysinoalanine was fed to other species (quail, mice, hamsters, rabbits, dogs, and monkeys). Based on the NOAEL in rats of 1.5 mg/kg bw/day and a safety factor of 1000, Avebe calculates an acceptable daily intake of 1.5 micrograms/kg bw/day for free lysinoalanine.
Avebe notes that the Select Committee on GRAS Substances (the Select Committee)(1) considered lysinoalanine toxicity in its evaluation of soy protein isolates (Ref. 1). The Select Committee’s report concludes that the levels of lysinoalanine in food-grade soy protein isolates pose no hazard to consumers but recommended that lysinoalanine levels be restricted in the specifications for food-grade soy protein products. Following this approach, Avebe includes limits for total (protein bound and free) lysinoalanine (less than 500 mg/kg) and free lysinoalanine (less than 10 mg/kg) in the specifications for its potato protein preparations. Using the upper limit for free lysinoalanine in the potato protein preparations and the estimated daily intake of the potato protein preparations (1.9 g/person/day), Avebe estimates that the maximum intake of free lysinoalanine from use of the potato protein preparations would be 19 micrograms/person/day (equivalent to 0.32 micrograms/kg bw/day).(2)
Avebe describes published information about the potential allergenicity of potato protein preparations. Avebe states that potatoes are generally considered a non-allergenic food, although raw potatoes and potato peelings and dust are known to elicit infrequent allergic responses. It is believed that the allergic responses are induced by specific undenatured potato proteins with structures similar to birch pollen and latex. Avebe cites a recent study that indicates that patatin, the main storage protein in potatoes, may be the allergenic component. Cooked potatoes, however, are usually well-tolerated, and evidence indicates that denaturation of potato protein leads to a decrease in allergenic potential. Avebe concludes that there is little reason for concern regarding allergenicity because potato allergies are not common, and because the potato protein preparations are denatured and equivalent to protein in cooked potatoes.
Based on the information provided by Avebe, as well as other information available to FDA, the agency has no questions at this time regarding Avebe’s conclusion that potato protein preparations (CPP, HPP, and HCP) 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 potato protein preparations. As always, it is the continuing responsibility of Avebe to ensure that food ingredients that the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements.
Under 21 CFR 101.100(a)(4), which requires that any products containing sulfites at or above 10 parts per million declare the presence of sulfites on the label, potato protein preparations treated with sulfites must declare the presence of sulfites on the label. Avebe’s notice states that the company will advise its customers of the levels of sulfites in the potato protein preparations so that the customers can comply with FDA’s sulfite ingredient declaration requirements.
During its evaluation of GRN 000086, 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 and additives 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 binders are regulated under the Federal Meat Inspection Act based on efficacy of use in meat products, including standardized meat products. FSIS advised that Avebe’s notice does not provide any data to support Avebe’s assertion that the potato protein preparations are suitable for use as binders in meat and poultry products. Specifically, FSIS pointed out that Avebe does not provide data establishing that the potato protein preparations are being used at the lowest level necessary to achieve the intended technical effects in the specific meat and poultry products to which application is desired.
The federal meat inspection regulations list specific binding additives for use below 3.5 percent of meat product formulation. FSIS has viewed the use of binders and extenders at levels greater than 3.5 percent as re-characterizing products. If Avebe provides data to FSIS establishing suitability and efficacy, FSIS would not object to the use of the potato protein preparations as binders in various non-standadized meat and poultry products provided the potato protein preparations do not exceed 3.5 percent of the product formulation. Currently, there are no allowances for the use of the potato protein preparations as binders in standardized meat and poultry products.
FSIS also advised that sulfiting agents are not permitted as direct additives to meat or poultry products. However, sulfiting agents may be present in meat and poultry food products as the result of being present in ingredients used in formulating processed meat and poultry food products. Therefore, FSIS does not object to the use of sulfites in the processing of the potato protein preparations.
FSIS requested that FDA advise Avebe to seek regulatory guidance from FSIS, Labeling and Consumer Protection Staff, about the use of the potato protein preparations in meat and poultry products. Avebe should direct such an inquiry to Dr. Robert Post, Director, Labeling and Consumer Protection Staff, Office of Policy, Program Development and Evaluation, Food Safety and Inspection Service, 300 12th Street SW, Room 602, Washington, DC 20250-3700. The telephone number of his office is (202) 205-0279 and the telefax number is (202) 205-3625.
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, /s/ Alan M. Rulis, Ph.D. Director Office of Food Additive Safety Center for Food Safety and Applied Nutrition |
1. Life Sciences Research Office, Federation of American Societies for Experimental Biology. 1979. Evaluation of the Health Aspects of Soy Protein Isolates as Food Ingredients.
| cc: | Dr. Robert Post, Director Labeling and Consumer Protection Staff Office of Policy, Program Development and Evaluation Food Safety and Inspection Service 300 12th Street, SW, Room 602 Washington, DC 20250-3700 |
(1)FDA commissioned the Select Committee on GRAS Substances through the Life Sciences Research Office of the Federation of American Societies for Experimental Biology as part of its comprehensive review of GRAS and prior sanctioned food ingredients.
(2)Since potato protein preparation would likely replace soy protein, FDA notes that there should be no significant increase in exposure to lysinoalanine from the use of the potato protein preparations
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