U. S. Food and Drug Administration
Center for Food Safety and Applied Nutrition
Office of Food Additive Safety
February 4, 2002

David R. Joy
Keller and Heckman LLP
1001 G Street, N.W.
Washington, DC 20001

Re: GRAS Notice No. GRN 000092

Dear Mr. Joy:

The Food and Drug Administration (FDA) is responding to the notice, dated December 5, 2001, that you submitted on behalf of Mitsubishi Chemical Corporation (Mitsubishi) 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 December 6, 2001, filed it on December 12, 2001, and designated it as GRAS Notice No. GRN 000092.

The subject of the notice is sucrose fatty acid esters. The notice informs FDA of the view of Mitsubishi that sucrose fatty acid esters are GRAS, through scientific procedures, for use in beta-carotene color preparations intended for use in orange-colored beverages such as soft drinks and juice beverages as an emulsifier at a maximum level of 2 per cent of the beta-carotene color preparation.

FDA has evaluated the information that Mitsubishi discusses in its GRAS notice as well as other data and information that are available to the agency. As discussed more fully below, the notice does not provide a sufficient basis for a determination that sucrose fatty acid esters are GRAS under the conditions of their intended use.

Data and information that Mitsubishi presents to support its GRAS determination

Sucrose fatty acid esters are a mixture of mono-, di-, and tri-esters of sucrose with fatty acids. The fatty acids are derived from edible vegetable or hydrogenated edible vegetable oils and fats. Sucrose fatty acid esters are intended for use to emulsify beta-carotene, which is a water-insoluble carotenoid, in a concentrated color preparation. The sucrose fatty acid esters are intended to be a part of the concentrated beta-carotene color preparation that would be added to beverages such as soft drinks and juice beverages.

Sucrose fatty acid esters are manufactured by inter-esterification of sucrose with methyl esters of fatty acids in the presence of food-grade solvents such as ethyl acetate, methyl ethyl ketone, dimethyl sulfoxide, or isobutanol, as specified in 21 CFR 172.859 and the Food Chemicals Codex, first supplement to the 4th edition. The ratio of fatty acid methyl ester to sucrose establishes the degree of esterification, and the final product meets all relevant specifications currently established in 21 CFR 172.859 and in the Food Chemicals Codex, first supplement to the 4th edition.⁽¹⁾

Mitsubishi estimates the daily intake of sucrose fatty acid esters as a result of its intended use. Mitsubishi assumes that the maximum level of use would be 2 per cent in beta-carotene color preparations, that 6 parts per million of pure beta-carotene is needed to color a beverage, and that the beverage has a specific gravity of 1 gram per milliliter. Based on these assumptions, Mitsubishi estimates that a 240 milliliter serving of beverage would contain approximately 0.6 milligrams of sucrose fatty acid esters.⁽²⁾

Mitsubishi notes that the Joint Food and Agriculture Organization/World Health Organization's (FAO/WHO) Expert Committee on Food Additives (JECFA) has determined that the acceptable daily intake (ADI) for sucrose fatty acid esters is 30 milligrams per kilogram body weight (mg/kg bw). According to Mitsubishi, JECFA determined this ADI by first applying a 50-fold safety factor to a no observed effect level from a two year feeding study in rats (which would result in an ADI of 0-40 mg/kg bw), and then limiting the ADI to 30 mg/kg bw because available human tolerance studies show that sucrose esters have the potential to induce laxative effects at doses exceeding 30 mg/kg bw per day.

Mitsubishi describes certain unpublished studies that JECFA evaluated and includes copies of JECFA toxicological monographs pertaining to sucrose fatty acid esters.⁽³⁾ Mitsubishi also includes a copy of an unpublished manuscript discussing the two year feeding study in rats and informs FDA that this manuscript has been accepted for publication.⁽⁴⁾

FDA's evaluation of the data and information in Mitsubishi's notice

As discussed in the GRAS proposal, a GRAS substance is distinguished from a food additive on the basis of the common knowledge about the safety of the substance for its intended use. There are two aspects to this common knowledge. First, the data and information relied on to establish safety must be generally available. Second, there must be a basis to conclude that there is consensus among qualified experts about the safety of the substance for its intended use. Neither aspect is, by itself, sufficient to satisfy the common knowledge element of the GRAS standard. To our knowledge, most of the safety studies that JECFA relied on in reaching its conclusion are not generally available to the public. Even if the single study that has been evaluated for publication becomes available in the near future, FDA has previously expressed the opinion that a time gap following the publication of safety data is appropriate before those data could satisfy the GRAS standard (39 FR 34194; September 23, 1974):

[G]eneral recognition of safety through scientific procedures does require that the scientific evidence on the basis of which this status is achieved has been published in the literature or otherwise widely disseminated throughout the scientific community knowledgeable about the safety of food ingredients, and that this evidence has indeed become common knowledge among such scientists. Accordingly, there will be at least some gap between the gathering of the scientific knowledge necessary to provide the toxicological underpinning for general recognition of safety and the dissemination to and assimilation by the scientific community of this material that is necessary for general recognition of safety to exist.

Furthermore, were a single report to become publicly available, it is not clear to FDA that the body of evidence pertaining to sucrose fatty acid esters is publicly available. Although JECFA applied a safety factor to the rat study that is described in the unpublished manuscript, JECFA both evaluated other studies and requested studies in addition to the rat study described in the unpublished manuscript. For example, JECFA requested metabolic studies on representative individual sucrose esters, studies on individual sucrose esters to determine the likely sites and degree of hydrolysis, and a well designed and conducted tolerance study in humans. In addition, JECFA factored the human tolerance study into its calculation of the ADI. Thus, JECFA placed great value on studies other than the two year rat feeding study.

Thus, the generally available JECFA toxicological monograph is an opinion based on data and information that are not generally available. This toxicological monograph does not satisfy both aspects of the common knowledge standard.

Conclusions

FDA has evaluated the data and information in GRN 000092 as well as other available information. Given that Mitsubishi's determination that sucrose fatty acid esters are safe for their intended use is based on data and information that are not generally available, the notice does not provide a sufficient basis for a determination that sucrose fatty acid esters are GRAS under the conditions of intended use.

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 homepage of the Office of Food Additive Safety (on the Internet at http://www.cfsan.fda.gov/~lrd/foodadd.html).

⁽¹⁾FDA notes that its regulation for sucrose fatty acid esters lists the sources of the fatty acids as edible tallow or hydrogenated edible tallow or edible vegetable oils. FDA also notes that the Food Chemicals Codex, first supplement to the 4th edition describes the fatty acid source as the methyl and ethyl esters of edible fatty acids or as edible naturally-occurring vegetable oils.

⁽²⁾FDA notes that a 240 milliliter serving is approximately the same as the mean daily intake for eaters-only in the 1989-1991 3-day USDA Continuing Survey of Food Intakes by Individuals.

⁽³⁾Each of JECFA's toxicological monographs pertaining to sucrose fatty acid esters lists the studies that JECFA evaluated.

⁽⁴⁾JECFA applied a 50-fold safety factor to the rat study that is the subject of this manuscript.

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