U. S. Food and Drug Administration
Center for Food Safety and Applied Nutrition
Office of Food Additive Safety
October 25, 2001

Gerhard Schmid, Ph.D.
Wacker Biochem Corporation
3301 Sutton Road
Adrian, MI 49221

Re: GRAS Notice No. GRN 000074

Dear Dr. Schmid:

The Food and Drug Administration (FDA) is responding to the notice, dated March 23, 2001, 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 Office of Food Additive Safety (OFAS; formerly the Office of Premarket Approval) received the notice on March 28, 2001 and designated it as GRAS Notice No. GRN 000074.

The subject of your notice is beta-cyclodextrin. The notice informs FDA of the view of Wacker Biochem Corporation (Wacker Biochem) that beta-cyclodextrin is GRAS, through scientific procedures, for use as a flavor carrier or protectant as described in the table below.

In the notice, Wacker Biochem reports that a panel of individuals (Wacker Biochem's GRAS panel) evaluated the data and information that are the basis for Wacker Biochem's GRAS determination. Wacker Biochem considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Wacker Biochem's GRAS panel evaluated published and unpublished data and information concerning the manufacture, intended use, and safety of beta-cyclodextrin and concluded that Wacker Biochem's beta-cyclodextrin product that meets appropriate food grade specifications and is manufactured in accordance with good manufacturing practices is generally recognized as safe.

Wacker Biochem's notice describes generally available information about the identity, characteristic properties, and functionality of beta-cyclodextrin. Beta-cyclodextrin (Chemical Abstracts Service Registry No. 7585-39-9) is a cyclic, alpha-(1-4) -linked maltooligosaccharide consisting of seven glucose units. Due to the three-dimensional arrangement of the glucose units, the inner side of the torus-like cyclodextrin molecule is less polar than the outer side. This property enables cyclodextrins to form inclusion complexes with various organic compounds and forms the basis for the applications of cyclodextrins in foods.

Wacker Biochem's notice describes generally available information about the method of manufacture of beta-cyclodextrin. Cyclodextrins (including alpha-, beta-, and gamma cyclodextrins) are formed when bacterial-derived amylolytic enzymes (cyclodextrin-glycosyltransferases (CGTase); EC 2.4.1.19; Chemical Abstracts Service Registry No. 9030-09-5) degrade starch by a cyclization reaction. Beta-cyclodextrin is physically isolated from the enzymatic reaction mixture by the addition of a suitable organic solvent (i.e., toluene), which forms an insoluble complex with the cyclodextrin.⁽¹⁾ Wacker Biochem's notice states that toluene is added as a complexant to precipitate formed beta-cyclodextrin. Beta-cyclodextrin manufactured by Wacker Biochem meets the specifications for food-grade beta-cyclodextrin in the Food Chemicals Codex (FCC) 4th edition, (First Supplement), including a lead specification of not more than one part per million.

Wacker Biochem's notice describes published studies conducted with beta-cyclodextrin. These studies include 52-week toxicity studies in rats and dogs, carcinogenicity studies in mice and rats, and a 3-generation reproductive toxicity study in rats with a teratology phase. Wacker Biochem notes that these data have previously been reviewed by the Joint Food and Agriculture Organization/World Health Organization's (FAO/WHO) Expert Committee on Food Additives (JECFA) (Refs. 1 and 2). JECFA considered the No Observed Adverse Effect Level (NOAEL) in a 1-year toxicity study in the dog was 1.25 percent beta-cyclodextrin in the diet (equal to 470 mg/kg body weight/day). JECFA applied a 100-fold safety factor to this NOAEL and allocated an acceptable daily intake (ADI) of 0-5 mg/kg body weight/day for beta-cyclodextrin, equivalent to 300 mg per person per day (mg/p/day) for a 60 kg person.

In an amendment dated August 31, 2001, Wacker Biochem informed FDA that beta-cyclodextrin has been marketed in the U.S. since 1996 and that the actual amount of beta-cyclodextrin that is being used in the food industry is less than 50 tons per year. This information, combined with the knowledge that the population of the U.S. is approximately 285 million persons, and an assumption that only 10 percent of that population are "eaters" of beta-cyclodextrin, leads to an estimate of dietary exposure of approximately 4 mg/p/day for mean consumers and 9 mg/p/day at the 90th percentile.

Based on the information provided by Wacker Biochem, as well as other information available to FDA, the agency has no questions at this time regarding Wacker Biochem's conclusion that beta- cyclodextrin 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 beta- cyclodextrin. As always, it is the continuing responsibility of Wacker Biochem 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 Office of Food Additive Safety's homepage on the Internet (at http://www.cfsan.fda.gov/~rdb/opa-gras.html).

References

1. WHO (1993). Safety evaluation of certain food additives and contaminants. WHO Food Additives Series 32:173-193, World Health Organization, Geneva

2. WHO (1996). Safety evaluation of certain food additives and contaminants. WHO Food Additive Series 35:257-268, World Health Organization, Geneva

⁽¹⁾As you discussed by telephone with OFAS representatives on July 13, 2001, the monograph for beta-cyclodextrin in the Food Chemicals Codex lists both toluene and trichloroethylene (TCE) as solvents that can be used. A study conducted by the National Toxicology Program reports that TCE is carcinogenic in B6C3F1 mice, causing increased incidences of hepatocellular carcinomas in males and females and increased incidence of hepatocellular adenomas in females. To minimize the potential that residues of TCE would be present in food products that contain beta-cyclodextrin, FDA recommends that TCE not be used. In that telephone conversation, you confirmed that Wacker Biochem does not use TCE.

Content last updated by lsk on 2001-OCT-27
Hypertext last updated by lsk on 2001-NOV-02