Agency Response Letter GRAS Notice No. GRN 000208
CFSAN/Office of Food Additive Safety
November 20, 2007
David R. Joy
Keller and Heckman LLP
1001 G Street, N.W.
Suite 500 West
Washington, DC 20001
Re: GRAS Notice No. GRN 000208
Dear Mr. Joy:
This letter corrects a propagated error in the letter issued to you on January 25, 2007, in response to GRAS Notice No. 000208. In that letter, in the middle of the sixth paragraph (now the seventh paragraph in this letter), an unpublished acute study of the fermentation broth is cited. The broth is erroneously described as containing the organism. This letter repeats the text of our letter dated January 25, 2007, with the exception of the description of the fermentation broth, which is corrected.
The Food and Drug Administration (FDA) is responding to the notice, dated July 27, 2006, that you submitted on behalf of Mitsubishi-Kagaku Foods Corporation (Mitsubishi-Kagaku) 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 31, 2006, filed it on August 3, 2006, and designated it as GRAS Notice No. GRN 000208.
The subject of the notice is erythritol produced through fermentation of glucose by a microorganism known as Trichosporonoides megachiliensis. The notice informs FDA of the view of Mitsubishi-Kagaku that erythritol is GRAS, through scientific procedures, for use as a flavor enhancer, formulation aid, humectant, nutritive sweetener, stabilizer and thickener, sequestrant, and texturizer in a variety of foods as described in Table 1 (below).
|Food||Level of Use|
|Reduced and low-calorie and non-carbonated beverages; Dairy drinks (chocolate and flavored milks)||3.5 percent|
|Frozen dairy desserts (regular ice cream, soft serve, sorbet); Puddings (instant, phosphate set); Yogurt (regular and frozen)||10 percent|
|Bakery fillings (fruit, custard, cream, pudding); Cakes and cookies (regular and dietetic)||15 percent|
|Fat-based cream used in modified fat/calorie cookies, cakes, and pastries; Chewing gum; Soft candies (non-chocolate, plain chocolate, chocolate coated)||60 percent|
|Hard candies (including pressed candy, mints, and cough drops)||99 percent|
|Sugar substitutes (carrier)||100 percent|
Mitsubishi-Kagaku's erythritol is manufactured by pure culture fermentation of glucose using the non-toxic and non-pathogenic microorganism T. megachiliensis. The fermentation broth is heated to kill the culture organisms, and dead cells are separated from the broth by filtration. The supernatant is passed first through ion-exchange resins to remove salts, impurities, and colorants, and then through activated charcoal. The resulting solution is further purified through ultrafiltration, concentrated, crystallized, centrifuged, washed, and air-dried. The resulting erythritol is at least 99.5% pure by high-performance liquid chromatography analysis, and complies with the specifications for erythritol set forth in the Food Chemicals Codex (FCC), 5th Edition(1) (2003). Mitsubishi-Kagaku includes a summary analysis of five batches of its product that are in compliance with the FCC specifications.
Mitsubishi-Kagaku's notification incorporates by reference GRAS Affirmation Petition GRP No. 7G0422 and also relies on data and information previously submitted to FDA to support its evaluation of GRN 000076. Mitsubishi-Kagaku and the notifier for GRN 000076 (Cerestar Holding B.V.; Cerestar) were joint petitioners for GRP 7G0422, which requested that FDA affirm as GRAS certain food uses of erythritol produced using either of the microorganisms T. megachiliensis or Moniliella pollinis. Cerestar subsequently submitted GRN 000076 to the agency and included expanded uses of erythritol produced using only the microorganism M. pollinis.2 FDA had no questions about Cerestar's determination that the intended uses of erythritol (produced using M. pollinis) are GRAS.
Mitsubishi-Kagaku's current notification, GRN 000208, states that erythritol produced using T. megachiliensis is GRAS under the same conditions of use (Table 1) as described in GRN 000076. Mitsubishi-Kagaku considers that the estimated exposure of erythritol from the intended uses in GRN 000208 is therefore identical to the exposure calculated in GRN 000076. Mitsubishi-Kagaku notes that, in FDA's response to GRN 000076, the agency indicated that its own calculations of the estimated daily intake for erythritol under the conditions of use in GRN 000076 are 13 grams per person per day (g/p/d) at the mean and 30 g/p/d at the 90th percentile.
Mitsubishi-Kagaku states that a panel of individuals evaluated the data and information that were the basis for Cerestar's GRAS determination (Cerestar's GRAS panel). Cerestar's GRAS panel had previously published a review accompanying an entire issue of the journal Regulatory Toxicology and Pharmacology in 1996 on the safety of erythritol. The published studies in this issue included acute, subchronic, and chronic oral toxicity studies in rats, mice, and dogs, teratogenicity, reproductive, genotoxicity, and metabolic studies, as well as human tolerance studies. Members of Cerestar's GRAS panel were also among the authors of a published 1998 review article on the safety of erythritol. Mitsubishi-Kagaku notes that Cerestar's GRAS panel subsequently reviewed information on expanded levels of use of the ingredient as described in GRN 000076. In addition to the evidence described above, Mitsubishi-Kagaku provides (by reference to GRP 7G0422) an unpublished acute toxicity study in which erythritol fermentation broth (filtered to remove T. megachiliensis) was fed to rats. Finally, Mitsubishi-Kagaku notes that erythritol (including that produced by T. megachiliensis) has been evaluated as a food ingredient by both the Joint FAO/WHO Expert Committee on Food Additives and the Scientific Committee on Food of the European Union and that neither organization considered it necessary to establish an acceptable daily intake limiting erythritol consumption.
Standards of Identity
In the notice, Mitsubishi-Kagaku states its intention to use erythritol 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.
Based on the information provided by Mitsubishi-Kagaku, as well as other information available to FDA, the agency has no questions at this time regarding Mitsubishi-Kagaku's conclusion that erythritol (produced by T. megachiliensis) 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 erythritol. As always, it is the continuing responsibility of Mitsubishi-Kagaku 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 000208, 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 on the homepage of OFAS (on the Internet at http://www.cfsan.fda.gov/~lrd/foodadd.html).
Laura M. Tarantino, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
(1)The FCC monograph for erythritol mentions both T. megachiliensis and Moniliella pollinis
(2)Cerestar cites the erythritol monograph published in the second supplement to the fourth edition of the FCC. Mitsubishi-Kagaku relies on the monograph published in the fifth edition, which is essentially identical but contains some minor changes in the descriptions of the tests associated with the specification.