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U.S. Department of Health and Human Services

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Agency Response Letter GRAS Notice No. GRN 000076

CFSAN/Office of Food Additive Safety

September 11, 2001


Diane B. McColl
Hyman, Phelps, & McNamara, P.C.
700 13th St. NW
Washington, DC 20005-5929

Re: GRAS Notice No. GRN 000076

Dear Ms. McColl:

The Food and Drug Administration (FDA) is responding to the notice, dated April 30, 2001, that you submitted on behalf of Cerestar Holding, B. V. (Cerestar) 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)). FDA received the notice on April 30, 2001 and designated it as GRAS Notice No. GRN 000076.

The subject of the notice is erythritol. The notice informs FDA of the view of Cerestar 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). Based on these conditions of use, Cerestar informs FDA that the estimated daily intake (EDI) of erythritol would be one gram per person per day (g/p/d) at the mean and 4 g/p/d at the 90th percentile.(1)

Erythritol is a naturally occurring four-carbon sugar alcohol. Its chemical name is 1,2,3,4-butanetetrol and its Chemical Abstracts Service Registry Number (CAS Reg. No.) is 149-32-6. It has a sweetness of about 60-80 percent that of sucrose. Erythritol is manufactured using the fermentative conversion of glucose to erythritol by a non-toxicogenic and non-pathogenic organism, Moniliella pollinis. The fermented broth is heated to kill the microorganisms, crystallized, washed, redissolved and purified using an ion exchange resin. The erythritol solution is purified further by ultrafiltration and recrystallization. The resulting erythritol is at least 99.5 percent pure and complies with the specifications for erythritol set forth in the Food Chemicals Codex, 4th edition Second Supplement (2000).(2)

 

Table 1
Conditions of Use Proposed by Cerestar
FoodLevel of use
Reduced- and low-calorie carbonated 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

In its notice, Cerestar describes the deliberations of a panel of individuals (Cerestar's GRAS panel) who evaluated the data and information that are the basis for its GRAS determination. Cerestar considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Cerestar's notice includes two reviews published by members of its GRAS panel (the 1996 panel report and the 1998 interpretive review) and an unpublished report authored by its GRAS panel (the May 2000 panel report).

In the 1996 panel report, Cerestar's GRAS panel concludes that the use of erythritol in certain foods (sugar substitutes, hard candies, soft candies, reduced- and low-calorie beverages, fat-based cream for use in cookies, cakes, and pastries, dietetic cookies, wafers and chewing gum) is GRAS based on scientific procedures. In the 1998 interpretive review, Cerestar's GRAS panel provides a comprehensive review of the data and information, already summarized in the 1996 panel report, in anticipation of a review by JECFA (the Joint Food and Agriculture Organization/World Health Organization's (FAO/WHO) Expert Committee on Food Additives).(3)

The published reviews included in Cerestar's GRAS notice describe studies in rats, dogs, and humans (including diabetics). From these studies, Cerestar's GRAS panel concludes that most ingested erythritol is rapidly absorbed via the small intestine. Cerestar's GRAS panel also concludes that this absorbed erythritol is excreted unchanged in the urine 24 hours after a single oral dose. Cerestar's GRAS panel concludes that any unabsorbed erythritol undergoes microbial fermentation to volatile fatty acids in the colon. Cerestar's GRAS panel further concludes that erythritol is well-tolerated by humans and produces no meaningful gastrointestinal or renal effects when ingested with food and beverages at levels providing up to one gram per kilogram body weight per day (g/kg bw/day), corresponding to a daily intake of 60 g/day (i.e., for a 60 kg adult).

The published reviews included in Cerestar's GRAS notice also describe acute, subchronic, chronic, carcinogenicity, reproductive toxicity, teratogenicity, and mutagenicity studies conducted with erythritol. From these toxicological studies, Cerestar's GRAS panel concludes that erythritol is without carcinogenic and teratogenic potential, and does not exhibit mutagenic or clastogenic activity in vitro. Cerestar's GRAS panel reports that no reproductive or developmental toxicological effects were observed at doses up to 8 g/kg bw/day in mice or at doses representing up to 100 g/kg of feed in rats.

In the May 2000 panel report, Cerestar's GRAS panel discusses dietary exposure to erythritol for uses that were expanded compared to those described in both the 1996 panel report and in a GRAS affirmation petition (GRP 7G0422) that is pending at FDA. Cerestar's GRAS panel also discusses the toxicological significance of some effects that were described in the previous reports and considers the handling of dietary erythritol by the renal system of young children. Cerestar's GRAS panel unanimously concludes that its detailed analysis of the data and information provides no evidence that erythritol would be associated with adverse health effects under the conditions of its intended use.

Based on the information provided by Cerestar, as well as other information available to FDA, the agency has no questions at this time regarding Cerestar's conclusion that erythritol 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 Cerestar 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,
   /s/
Alan M. Rulis, Ph.D.
Director
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition



 


(1) As we discussed with you by telephone on July 24, 2001, FDA does not concur with the methodology used by Cerestar to estimate the dietary intake of erythritol. FDA's own calculations of the EDI for erythritol under the conditions of use proposed by Cerestar are 13 g/p/d at the mean, and 30 g/p/d at the 90th percentile.

(2) In an addendum to the notice, Cerestar informed FDA that the lead specification for erythritol manufactured by Cerestar is 0.1 milligrams per kilogram (mg/kg; equivalent to 0.1 parts per million). This limit is 10-fold lower than that specified in the Food Chemicals Codex (1 part per million).

(3) In 2000, as part of its 53rd meeting, JECFA published a technical report (Series No. 896) and a toxicological monograph (Series No. 44) on erythritol. The monograph discusses the studies reviewed by Cerestar's GRAS panel with comments on the EDI and the toxicological significance of the effects, such as laxation, observed with high intake levels of erythritol. In the monograph, JECFA establishes an Acceptable Daily Intake (ADI) of "not specified." JECFA describes "ADI not specified" as a term applicable to a food component of very low toxicity for which the total dietary intake of the substance does not, in the opinion of the Committee, represent a hazard to health.