Food

Agency Response Letter GRAS Notice No. GRN 000578

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CFSAN/Office of Food Additive Safety

November 6, 2015

Gary Yingling
Morgan, Lewis & Bockius LLP
1111 Pennsylvania Avenue, NW
Washington, DC  20004

Re: GRAS Notice No. GRN 000578

Dear Mr. Yingling:

The Food and Drug Administration (FDA) is responding to the notice, dated April 14, 2015, that you submitted on behalf of DSM Food Specialties (DSM), 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 April 15, 2015, filed it on ,May 19, 2015 and designated it as GRAS Notice No. GRN 000578.

The subject of the notice is natamycin. The notice informs FDA of the view of DSM that natamycin is GRAS, through scientific procedures, for use as an antimycotic to prevent the growth of molds and yeasts in ready-to-drink tea beverages and fruit flavored drinks at use levels not to exceed 5 milligrams per kilogram (mg/kg) beverage.

Natamycin is a polyene macrolide with a molecular weight of 665.7; the CAS number is 7681-93-8. DSM describes natamycin as an off-white to cream colored crystalline powder that is tasteless and odorless.

DSM provides information about the manufacturing process for natamycin. A pure culture of the production strain Streptomyces natalensis (S. natalensis) CBS 700.57 is fermented under controlled conditions. During fermentation, natamycin is secreted to the broth. After fermentation, the broth containing insoluble natamycin is centrifuged to separate natamycin from most of the residual mycelia. For purification purposes, natamycin is then resuspended, recrystalized, filtered and washed, and then dried and milled into a powder. DSM states that all raw materials used in manufacturing natamycin are food grade and that the entire process is performed in accordance with current good manufacturing practices.

DSM provides specifications for natamycin. Specifications include purity (≥ 95%, anhydrous) as well as limits for arsenic (≤ 1 mg/kg), lead (≤ 2 mg/kg), mercury (≤ 1 mg/kg), water (6.0%-9.0%), and microbial contaminants. DSM describes the analytical tests performed to verify that natamycin meets the specifications in the Food Chemicals Codex (9th Edition). DSM states that natamycin is stable for three years when stored at < 20º C under dry conditions and protected from light.

DSM estimates the dietary exposure to natamycin based on current uses in cheeses (21 CFR 172.155), yogurt (GRN 0005171), and the intended uses in beverages described in GRN 000578. Two-day average food consumption data from the National Health and Nutrition Examination Survey (NHANES, 2007-2010) were used to generate dietary exposure estimates. The total dietary exposure estimates for natamycin are 1.4 mg per person per day (mg/p/d) at the mean (0.024 mg/kg body weight (bw)/d for a 60 kg individual) and 3.4 mg/p/d (0.057 mg/kg bw/d for a 60 kg individual) at the 90th percentile (2+ years). The previous cumulative dietary exposures from GRN 000517 were 0.61 mg/p/d at the mean (0.011 mg/kg bw/d for a 60 kg individual) and 1.3 mg/p/d (0.023 mg/kg bw/d for a 60 kg individual) at the 90th percentile (2+ years).

DSM states that S. natalensis is nonpathogenic and nontoxigenic. DSM also notes that it has used S. natalensis CBS 700.57 and isolates derived from this strain for large scale fermentation since 1960. DSM notes that GRN 000578 incorporates by reference all preclinical and clinical safety studies on natamycin that were discussed in GRN 000517. The studies incorporated by reference summarize the safety of consumption of natamycin from S. natalensis by addressing the safety of the source strain, continued use in food, metabolism, and toxicological studies conducted in animals, as well as safety and tolerance studies conducted in humans. DSM concludes that the findings of the safety studies support that natamycin is GRAS for the intended use. DSM states that no new safety studies have been discussed or referenced in GRN 000578.

Standards of Identity

In the notice, DSM states its intention to use natamycin in ready-to-drink teas, fruit flavored energy, sport and isotonic drinks, and fruit flavored drinks, for which standards of identity exist, located in 21 CFR 146 (canned fruit juices and beverages). 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

Section 403(k) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) provides that a food shall be deemed to be misbranded if it bears or contains any chemical preservative, unless it bears labeling stating that fact. Section 403(i)(2) of the FD&C Act provides that a food shall be deemed to be misbranded unless its label bears the common or usual name of each ingredient. Section 403(a) of the FD&C Act provides that a food shall be deemed to be misbranded if its labeling is false or misleading in any particular. DMS’s use of natamycin constitutes use as a preservative. Therefore, the ingredient statement on labels of food products that contain natamycin must comply with the labeling regulations that implement sections 403(k) and 403(i)(2) of the FD&C Act. For example, 21 CFR 101.22(j) requires that the food to which a chemical preservative is added bear a label declaration stating both the common or usual name of the ingredient and a separate description of its function. Further, food that is subjected to any form of preservation, except as provided in 21 CFR 101.95(c), may not be labeled as “fresh.” If DSM has any questions about the appropriate labeling of this food ingredient, DSM should contact the staff in the Office of Nutrition, Labeling, and Dietary Supplements.

Section 301(ll) of the FD&C Act

Section 301(ll) of the FD&C Act prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FD&C Act, 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 DSM’s notice that natamycin is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing natamycin. Accordingly, this response should not be construed to be a statement that foods that contain natamycin, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).

Conclusions

Based on the information provided by DSM, as well as other information available to FDA, the agency has no questions at this time regarding DSM’s conclusion that natamycin 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 natamycin. As always, it is the continuing responsibility of DSM 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 000578, 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 at www.fda.gov/grasnoticeinventory.   

Sincerely,

Dennis M.  Keefe, Ph.D.
Director
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition

(1)The subject of GRN 000517 is natamycin. GRN 000517 informed FDA of the view of DSM that natamycin is GRAS for use in yogurt. FDA responded in a letter dated November 21, 2014, stating that the agency had no questions at that time regarding DSM’s GRAS determination.

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