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Agency Response Letter GRAS Notice No. GRN 000585

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See also Generally Recognized as Safe (GRAS).

CFSAN/Office of Food Additive Safety

January 29, 2016

Eric F. Greenberg
Cellresin Technologies, LLC
303 East Wacker Drive
Suite 1020
Chicago, Illinois 60601

Re: GRAS Notice No. GRN 000585

Dear Mr. Greenberg:

The Food and Drug Administration (FDA) is responding to the notice, dated June 4, 2015, that you submitted on behalf of Cellresin Technologies, LLC (Cellresin) 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 June 8, 2015, filed it on July 9, 2015, and designated it as GRAS Notice No. GRN 000585. In response to questions raised by FDA, Cellresin provided amendments to the notice and additional information in a letter dated November 4, 2015.

The subject of the notice is 1-methylcyclopropene(1-MCP) and alpha-cyclodextrin complex (1-MCP complex). The notice informs FDA of the view of Cellresin that 1-MCP complex is GRAS, through scientific procedures, for use as an ethylene inhibitor in food packaging substrates for fruits and vegetables, including flexible films, lidding films, labels, inserts, and paper and paperboard, at levels in the mid-parts per billion (ppb) range (volume (v)/volume) in the package headspace.

Cellresin states that the subject of the notice is a complex of 1-methylcyclopropene (CAS Registry number 3100-04-7) and alpha-cyclodextrin (CAS Registry number 10016-20-3). 1-MCP is an inhibitor of ethylene, which occurs in most fruits and vegetables and is involved in ripening, among other processes. 1-MCP competitively inhibits ethylene at the receptor sites of the plant, thereby blocking further maturation.

Cellresin describes the method of manufacture for 1-MCP complex. 3-chloro-2-methylpropene is added to a reaction mixture of hexamethyldisilazane and sodium amide in mineral oil, producing 1-MCP gas. The gas is scrubbed and combined with an aqueous solution of alpha-cyclodextrin, forming a crystalline 1-MCP and alpha-cyclodextrin complex that is separated from the solution. Water is removed under vacuum and the product is washed with methanol followed by methyl formate. Finally, heated air or nitrogen is used to evaporate the residual water and solvents.

Cellresin gives specifications for the resulting 1-MCP complex, including a typical content of 1-methylcyclopropene (5%), moisture content (< 8%), and limits for 1-chloro-2-methylpropene (1-CMP) and 3-chloro-2-methylpropene (3-CMP) (< 0.05% for each), which result from the manufacture of 1-MCP.

Cellresin discusses the dietary exposure to 1-MCP from the intended use. Cellresin estimates the dietary concentration of 1-MCP based on estimates of annual consumption of tomatoes and fruit, an average daily diet consists of 3 kilograms (kg) of food per day, and a residual 1-MCP concentration of 4 micrograms (μg) per kg in treated foods. Cellresin calculates that the dietary concentration of 1-MCP to be 0.5 ppb.[1] Cellresin states that this represents an over-estimate of actual 1-MCP exposure and that the intended use described in GRN 000585 is substitutional for current uses of 1-MCP as a fumigant and will not add to current dietary exposure to 1-MCP from consumption of fruits and vegetables. In addition, Cellresin states that some fruits and vegetables are cooked prior to consumption, which Cellresin expects will remove any residual 1-MCP. Cellresin calculates the dietary concentration of 1-CMP and 3-CMP to be 3.5 x 10-5 ppb, based on a residual concentration of 0.017% of each in 1-MCP.

Cellresin summarizes the safety of 1-MCP (the key ingredient of the 1-MCP complex) as an ethylene inhibitor in food packaging substrates by relying primarily on the safety data evaluated for its approval by government agencies and scientific authoritative bodies including the US Environmental Protection Agency (EPA), European Food Safety Authority (EFSA), Canadian Pest Management Regulatory Agency, and Food and Agriculture Organization (FAO) of the United Nations.[2] Cellresin states that no evidence of mutagenicity was found in the data reviewed by these organizations, and that both oral and inhalation[3] toxicology studies identified no adverse effects at exposure levels many orders of magnitude above Cellresin’s estimates of exposure. Finally, Cellresin cites the firm’s estimate of dietary exposure relative to FDA’s Threshold of Exemption for food contact substances. FDA has set a 0.5 ppb threshold level below which substances unintentionally migrating from food packaging require a more limited set of data to establish safety and a full food additive petition is not necessary. While 1-MCP is intended to enter the food in order to exert its technical effect and does not qualify for this exemption, Cellresin views the fact that the firm’s estimate of dietary exposure is comparable to the food contact threshold as additional evidence supporting the safety of the intended use. Cellresin also notes that exposure to the carcinogenic impurities (1-CMP and 3-CMP) present in 1-MCP complex would be more than a thousand times lower than exposure to 1-MCP. Based on Cellresin’s consideration of all the data and information, the firm concludes that 1-MCP is GRAS under the conditions of its intended use.

Section 301(ll) of the Federal Food, Drug, and Cosmetic Act (FD&C Act)

The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the Federal Food Drug and Cosmetic Act (FD&C Act) to, among other things, add section 301(ll). 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 Cellresin’s notice that 1-MCP complex is GRAS for use as an ethylene inhibitor in food packaging substrates for fruits and vegetables, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing 1-MCP complex. Accordingly, this response should not be construed to be a statement that foods that contain 1-MCP complex, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).

Conclusions

Based on the information provided by Cellresin, as well as other information available to FDA, the agency has no questions at this time regarding Cellresin’s conclusion that 1-MCP complex 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 1-MCP complex. As always, it is the continuing responsibility of Cellresin 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 000585, 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] OFAS notes that this estimate of dietary concentration is equivalent to 0.1 μg/person/day if the assumption of a 3 kg/day diet is excluded from the notifier’s calculation.

[2] 1-MCP received approval for use by these authorities. Cellresin notes that 1-MCP is registered as a plant growth regulator by US EPA and has received a tolerance exemption.

[3] The release of 1-MCP is adjusted by changes in the physical package structure and the amount of 1-MCP contained in the package structure. Moisture released from the respiring plant material causes 1-MCP to be released from the package structure.

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