December 16, 1999

Mr. Kiyoshi Matsumoto
Sankyo Co., Ltd.
7-12, Ginza 2-Chome
Chuo-ku, Tokyo 104-8113
Japan

Re: GRAS Notice No. GRN 000027

Dear Mr. Matsumoto:

The Food and Drug Administration (FDA) is responding to your letter, dated July 5, 1999, that Mr. Edward Steele of the consulting firm AAC transmitted on your behalf. Your letter requests that FDA convert the filed GRAS affirmation petition GRP 6G0420 to a GRAS notice 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 this conversion request on July 14, 1999, and designated it as GRAS Notice No. GRN 000027.

The subject of your conversion request is dextranase enzyme preparation from Chaetomium gracile (dextranase EP). The conversion request informs FDA of the view of Sankyo Co., Ltd., that dextranase EP is GRAS, through scientific procedures, for use as a processing aid in cane and beet sugar.

Data and information that Sankyo relies on to support Sankyo's GRAS determination

GRAS Petition GRP 6G0420 describes (1) published information about the technical effect of the enzyme dextranase; (2) published information about the source of dextranase EP, C. gracile; (3) information about the fermentation of C. gracile, which involves standard microbiological techniques; (4) published and unpublished information about the purification and characterization of dextranase EP, including the ultrafiltration process that separates the enzyme preparation from the fermentation biomass, concentrates the enzyme preparation, and reduces the concentration of low molecular weight components of the fermentation medium; (5) the use of sterilizing microfiltration that would remove any spores of C. gracile from the dextranase EP; and (6) a report, published in the Annual Report of Sankyo Research Laboratories, that describes 5 week and 26 week oral toxicity studies conducted with dextranase EP. In addition, GRP 6G0420 includes an estimate of dietary exposure to total organic solids in dextranase EP, from the consumption of sugar, of 20 ng/person/day (equivalent to 7 parts per trillion (ppt) in the diet). This estimate includes an assumption that most of the organic solids in dextranase EP are removed from sugar as part of the sugar refining process. According to GRP 6G0420, dextranase EP meets the specifications for enzyme preparations provided in the Food Chemicals Codex (4th ed., 1996).

FDA's evaluation of the available data and information regarding dextranase EP

FDA has evaluated the information in GRP 6G0420 as well as other data and information that are available to the agency.

For your information, dextranase EP used as a processing aid in the production of sugar would also be expected to be found in the molasses. Molasses is consumed both as and in human food. We estimated the dietary exposure to total organic solids in the dextranase EP, from the consumption of both sugar and molasses. Because much of the organic solids that are removed from sugar as part of the sugar refining process remain in the molasses, we estimate that dietary exposure to dextranase EP could be as much as 100-fold higher than the estimate that is provided in GRP 6G0420 - i.e., as much as 2 µg/person/day (equivalent to 700 ppt in the diet).

Ordinarily, a source microorganism that is used to manufacture a food grade enzyme preparation is nontoxigenic or is a nontoxigenic strain of a microorganism that is known to be capable of producing toxins.⁽¹⁾ The source of dextranase EP is a fungus [C. gracile] that is known to produce the mycotoxin chaetochromin (Refs. 1 through 4). In FDA's view, the available data and information do not establish that the production strain is "a nontoxigenic strain." However, GRP 6G0420 includes the results of analytical and in vitro cytotoxicity tests that gave no indication that the tested samples of dextranase EP contain chaetochromins. These test results indicate that dextranase EP derived from the production strain can be manufactured in a way such that the enzyme preparation does not contain chaetochromins.

Role of Current Good Manufacturing Practices

In FDA's view, certain steps in the fermentation of the source microorganism or the purification of the enzyme preparation may be critical from the perspective of either preventing mycotoxin synthesis or preventing carryover of synthesized mycotoxins to the final enzyme preparation. For example, toxicogenic fungi are known for their ability to switch between the toxicogenic and non-toxicogenic phenotype (Ref. 5), and suboptimal growth conditions, such as those that occur at the end of the growth phase, may trigger mycotoxin synthesis. Alternatively, synthesized chaetochromins could remain within the biomass rather than being released into the fermentation medium. It is Sankyo's continuing responsibility to assure that food containing sugar products that have been processed with dextranase EP does not contain mycotoxins at levels that could raise a safety concern.

Conclusions

As FDA discussed in the GRAS proposal, notice to the Center for Food Safety and Applied Nutrition that a substance is GRAS for use in human food does not encompass use of that substance in animal feed. Given that byproducts of sugar processing are often used in animal feed, we have sent the Center for Veterinary Medicine (CVM) a copy of this letter. If you wish to inform CVM that dextranase EP may reasonably be expected to become a component of animal feed, the contact is Dr. George Graber, Center for Veterinary Medicine (HFV-220), Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855. You can also reach Dr. Graber by telephone at (301)827-6651 or by telefax at (301)827-1484.

In accordance with the interim policy discussed in the GRAS proposal (62 FR 18938 at 18954), FDA has not committed any resources to review of GRP 6G0420 since July 14, 1999, the date that we received your conversion request. At this time, we request that you formally withdraw GRP 6G0420.

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 Premarket Approval's homepage on the World Wide Web.

References

1. S. Udagawa. 1984. "Taxonomy of Mycotoxin-Producing Chaetomium." In Toxicogenic Fungi, pp. 139-147. H. Kurata and Y. Ueno, eds. Elsevier.

2. S. Sekita, K. Yoshihira, S. Natori, S. Ugadawa, T. Muroi, Y. Sugiyama, and H. Kurata. 1981. Mycotoxin production by Chaetomium spp. and related fungi. Can. J. Microbiol., 37:766-772.

3. K. Koyama and S. Natori. 1987. Chaetochromins B, C and D, bis(naphto-gamma-pyrone) derivatives from Chaetomium gracile. Chemical and Pharmaceutical Bulletin (Tokyo), 35(2):578-584.

4. K. Koyama and S. Natori. 1989. Biosynthesis of Chaetochromin A, a Bis(naphto- -pyrone), in Chaetomium spp. Chem. Pharm. Bull., 37(8):2022-2025.

5. D.H. Griffin. 1994. Fungal Physiology. 2nd edition. Wiley-Liss, N. York.

⁽¹⁾For example, see the description of the source organism in 21 CFR 173.110, 173.120, 173.130, 173.135, 173.140, 173.150, 173.160, 173.170, 184.1012, 184.1372, 184.1387, 184.1388, 184.1685(a)(2), 184.1685(a)(3), 184.1685(a)(4), 184.1924, and 184.1985.

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