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CFSAN/Office of Food Additive Safety
June 5, 2002
Diane B. McColl
Hyman Phelps and McNamara, P.C.
700 Thirteenth Street, N.W.
Washington, DC 20005
Re: GRAS Notice No. GRN 000082
Dear Ms. McColl:
The Food and Drug Administration (FDA) is responding to the notice, dated August 23, 2001, that you submitted on behalf of INEOS Fluor Limited (INEOS Fluor) 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 September 4, 2001, and designated it as GRAS Notice No. GRN 000082.
The subject of the notice is 1,1,1,2-tetrafluoroethane (HFC-134a; hereinafter HFC-134a). The notice informs FDA of the view of INEOS Fluor that HFC-134a is GRAS, through scientific procedures, for use as an extraction solvent in the production of food flavors and flavorings. INEOS Fluor estimates that, under the intended conditions of use, intake of HFC-134a through the diet will be approximately 0.00044 milligrams (mg) per kilogram (kg) body weight per day (0.0264 mg/person/day).
At room temperature and pressure, HFC-134a (CAS No. 811-97-2, C2F4H2) is a colorless gas with a faint ethereal odor. Crude HFC-134a is produced by the reaction of trichloroethylene with hydrogen fluoride in the presence of chromium-based catalysts. Crude HFC-134a is fed into a two-stage process where it undergoes further purification in discrete batches. INEOS Fluor has established specifications for food-grade HFC-134a, including specifications on chlorofluoroethanes and fluoroethanes that could result from the manufacturing process. INEOS Fluor states that HFC-134a is 99.9 to 100 percent pure by gas chromatography.
HFC-134a is intended to be used as an extraction solvent for the production of a variety of flavors and flavorings used in food. Flavor extracts are prepared from plant materials (including fruits, vegetables, and spices, as well as other natural seasonings and flavorings), which are continuously washed with liquid HFC-134a under pressure at ambient temperature, for a length of time suitable for extracting the particular flavor. Residual HFC-134a levels are reduced to within the specification limit (300 parts-per-million weight in weight or 300 mg/kg) by further evaporation of the extract.
As part of its notice, INEOS Fluor includes a report of a panel of individuals (INEOS Fluor's GRAS panel) who evaluated the data and information that are the basis for INEOS Fluor's GRAS determination. INEOS Fluor considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. INEOS Fluor's GRAS panel discussed the chemistry and manufacturing process for HFC-134a, specifications for food-grade material, its intended use in food processing, and studies conducted with HFC-134a in animals and humans. INEOS Fluor's GRAS panel considers that HFC-134a, meeting appropriate food-grade specifications and manufactured in accordance with current good manufacturing practices, is GRAS based on scientific procedures under the conditions of intended use as an extraction solvent in the production of food flavors and flavorings.
INEOS Fluor reports the results of published and unpublished animal and human studies conducted with HFC-134a. These studies include acute, subchronic, chronic, and developmental toxicity studies in animals as well as acute and subchronic studies in humans. Most of the studies reported by INEOS Fluor involved an inhalation route of exposure.(1) Inhalation studies that provide for systemic exposure can be used to qualitatively characterize systemic toxicity. One 52-week study conducted in rats used an oral route of exposure. INEOS Fluor’s GRAS panel concludes that these studies demonstrate no developmental toxicity and suggest the absence of genotoxic potential.
INEOS Fluor reports that a published chronic study conducted in rats using an inhalation route of exposure showed a statistically significant higher mean relative testes weight in male rats exposed to 50,000 parts-per-million (ppm) HFC-134a and that this effect correlated with an increased incidence of Leydig cell hyperplasia and benign Leydig cell tumors. INEOS Fluor also reports that no adverse effects were observed in rats exposed to 10,000 ppm HFC-134a in the same study. After careful consideration of the evidence in the current literature and other information, INEOS Fluor concludes that the increases in Leydig cell hyperplasia and in the incidence of benign Leydig cell tumors are of no relevance to humans exposed to trace quantities of HFC-134a from its intended use as a food flavor extract solvent.(2)
Based on the information provided by INEOS Fluor, as well as other information available to FDA, the agency has no questions at this time regarding INEOS Fluor’s conclusion that HFC-134a is GRAS for use as an extraction solvent in the production of food flavors and flavorings. The agency has not, however, made its own determination regarding the GRAS status of the subject use of HFC-134a. As always, it is the continuing responsibility of INEOS Fluor 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 the 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).
Alan M. Rulis, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
(1) INEOS Fluor notes that metered dose inhalers (MDIs) that use HFC-134a as a propellant deliver 75 mg HFC-134a per inhalation dose and that it is not unusual for individuals using MDIs to require multiple inhalations per day.
(2)As FDA discussed with you and other representatives of INEOS Fluor on November 30, 2001, and January 25, 2002, regarding the increased incidence of benign Leydig cell tumors associated with inhalation of the solvent, FDA does not agree with all of the arguments put forth by INEOS Fluor that the Leydig cell tumors reported in the study are not relevant to humans. However, it is not necessary to definitively resolve this disagreement with regard to this notice in light of the extremely low exposure that would result from the intended use of HFC-134a. FDA also notes that INEOS Fluor’s basis for considering its intended use of HFC-134a to be safe should not be extrapolated to other reports of Leydig cell tumors from this or other substances.