Agency Response Letter GRAS Notice No. GRN 000293
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CFSAN/Office of Food Additive Safety
December 22, 2009
Kohjin Co., Ltd.
1-21, Nihombashi-Muromachi 4 Chome
Chou-ku, Tokyo, 103-0022
Re: GRAS Notice No. GRN 000293
Dear Mr. Uchida:
The Food and Drug Administration (FDA) is responding to the notice, dated June 25, 2009, 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 June 29, 2009, filed it on July 02, 2009, and designated it as GRAS Notice No. GRN 000293.
The subject of the notice is L-glutathione. The notice informs FDA of the view of Kohjin Co., Ltd. (Kohjin) that L-glutathione is GRAS, through scientific procedures, for use as a food ingredient as shown in Table 1, at levels ranging from 5 to 743 milligrams per serving (mg/serving).
|Food Category||Level of L-Glutathione (mg/serving)|
|Baked Goods and Baking Mixes||100 to 133|
|Beverages and Beverage Bases||300 to 360|
|Breakfast Cereals||50 to 183|
|Coffee and Tea||100|
|Condiments and Relishes||10|
|Dairy Product Analogs||50 to 100|
|Gelatins, Puddings, and Fillings||30 to 400|
|Grain Products and Pastas||30|
|Gravies and Sauces (meatless)||10|
|Hard Candy||100 to 300|
|Milk Products||10 to 743|
|Plant Protein Products||100|
|Processed Fruits and Fruit Juices||200 to 225|
|Processed Vegetables and Vegetable Juices||100|
|Soft Candy||100 to 400|
|Soups and Soup Mixes||10 to 100|
As part of its notice, Kohjin includes the report of a panel of individuals (Kohjin's GRAS panel) who evaluated the data and information that are the basis for Kohjin's GRAS determination. Kohjin considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Based on their review, Kohjin's GRAS panel concluded that L-glutathione, that meets food grade specifications and is manufactured in accordance with good manufacturing practices, is GRAS under the conditions of its intended use.
Kohjin provides information about the identity of L-glutathione. Kohjin states that L-glutathione (gamma-L-Glutamyl-L-cysteinylglycine) is a white crystalline powder, soluble in water and is isolated from the torula yeast Candida utilis.1
Kohjin describes the method of manufacture for L-glutathione as a standard fermentation of a non-genetically modified torula yeast strain. Kohjin states that an aseptically collected seed culture is added to the fermenter where conditions such as temperature, pressure, pH, and rate of aeration are controlled to achieve optimum conditions. Once the fermentation process is completed, L-glutathione is extracted from the yeast culture by heating the resulting yeast/media suspension followed by rapid cooling and centrifugation. After this centrifugation step, additional purification processes are performed to obtain the resulting L-glutathione solution that is concentrated under reduced pressure, followed by crystallization with ethanol. L-glutathione crystals are collected by centrifugation and further dried under reduced pressure to remove any remaining solvent. Kohjin states that L-glutathione is produced in accordance with current good manufacturing practices.
Kohjin provides physical and chemical specifications for L-glutathione. Specifications include: lead (≤ 1 parts per million, (ppm)) and arsenic (≤ 1 ppm). Analyses were presented for residual ethanol (≤ 1650 ppm), as well as for microbial contaminants. The specifications are consistent with those established by the Japan Food Sanitation Act and the Japanese Pharmacopeia, 15th Ed. and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).(2)
Kohjin estimates the daily intake of L-glutathione for its intended use. Based on the intended use levels and data available from the National Center for Health Statistics' 2003–2004 National Health and Nutrition Examination Survey, Kohjin estimates on an all-user basis, the mean intake of L-glutathione to be 448 milligrams per person per day (mg/p/d) and the 90th percentile intake to be 961 mg/p/d. Kohjin also estimates the cumulative consumption of L-glutathione, based on the background dietary intake and the intended uses to be approximately one gram per person per day.
Kohjin discusses published studies that describe absorption, distribution, metabolism, and excretion of L-glutathione, as well as safety data on L-glutathione, including acute and subchronic oral toxicity studies, in vitro mutagenicity/genotoxicity, developmental toxicity studies; and short- and long-term animal and human studies. Based on the data and publicly available information, Kohjin concludes that L-glutathione is safe under the intended conditions of use.
Standards of Identity
In the notice, Kohjin states its intention to use L-glutathione 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.
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 the use of labeling claims that characterize the level of a nutrient in a food or that characterize the relationship of a nutrient to a disease or health-related condition. In describing the intended use of L-glutathione and in describing the information that Kohjin relies on to conclude that L-glutathione is GRAS under the conditions of its intended use, Kohjin raises a potential issue under these labeling provisions of the FFDCA. If products that contain L-glutathione bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition, Labeling, and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition. The Office of Food Additive Safety neither consulted with ONLDS on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about L-glutathione on the label or in labeling.
Section 301(ll) of the FFDCA
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FFDCA to, among other things, add section 301(ll). 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 Kohjin's notice that L-glutathione is GRAS for use in various food products, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing L-glutathione. Accordingly, this response should not be construed to be a statement that foods that contain L-glutathione, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Kohjin, as well as other information available to FDA, the agency has no questions at this time regarding Kohjin's conclusion that L-glutathione 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 L-glutathione. As always, it is the continuing responsibility of Kohjin 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 000293, 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 via the FDA home page at http://www.fda.gov. To view or obtain an electronic copy of the text of the 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.
Mitchell A. Cheeseman, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
(1)Dried torula yeast (Candida utilis) may be safely used in food provided the total folic acid content of the yeast does not exceed 0.04 milligram per gram of yeast, under 21 CFR 172.896.
(2)Impurities: Guideline for Residual Solvents: Q3C(RC): Current Step 4 Version: Parent Guideline dated 17 July 1997, revised at ICH 2005.