U. S. Food and Drug Administration
Center for Food Safety and Applied Nutrition
Office of Food Additive Safety
January 21, 2003

Cynthia M. Schweitzer, Ph.D.
Cognis Corporation
5325 South Ninth Avenue
LaGrange, IL 60525

Re: GRAS Notice No. GRN 000110

Dear Dr. Schweitzer:

The Food and Drug Administration (FDA) is responding to the notice, dated July 17, 2002, that you submitted 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 July 22, 2002, filed it on July 25, 2002, and designated it as GRAS Notice No. GRN 000110.

The subject of the notice is a mixture of carotenoid xanthophyll esters that Cognis Corporation (Cognis) calls "lutein esters." The notice informs FDA of the view of Cognis that this mixture is GRAS, through scientific procedures, for use as an ingredient in baked goods and baking mixes, soy milk, beverages and beverage powders, frozen dairy desserts and mixes, processed fruit and vegetable products, egg products and egg substitutes, breakfast cereals (ready-to-eat and hot), fats and oils, hard candy, fruit snacks, and dairy products, and in medical foods intended as the sole item of the diet.

In discussing generally available information about the identity, composition, and manufacture of lutein esters, Cognis uses the term "lutein esters" in two ways. First, Cognis uses the term "lutein esters" as the common name for the ingredient that is the subject of its notice. This ingredient is a mixture of carotenoid xanthophyll esters, including esters of both lutein and zeaxanthin. Second, Cognis uses the term "lutein esters" as the name of the principal component of the mixture of carotenoid xanthophyll esters, and notes that the major chemical entity of this component is lutein dipalmitate. For clarity, in the remainder of this letter, FDA uses the term "lutein esters" to describe the mixture of carotenoid xanthophyll esters that is the subject of the notice and "esterified lutein" to describe the principal component of this mixture.

Cognis describes the method of manufacture for three lutein ester products - i.e., a concentrate, and two products that are prepared by diluting this concentrate. The concentrate is manufactured from marigold (Tagetes erecta) flowers that are dried, milled, and subjected to solvent extraction and filtration. The solvent is removed under vacuum. The residue is then purified in low molecular weight alcohol, and the product is concentrated under vacuum. The resulting concentrate is a granular, dark orange-brown solid containing a minimum of 60 percent lutein esters. Esterified lutein constitutes more than 93 percent of the total lutein esters in the concentrate and esterified zeaxanthin constitutes less than 7 percent of the total lutein esters in the concentrate. In addition, Cognis provides specifications for the concentrated form of its lutein ester product. Cognis notes that the patented manufacturing process uses current Good Manufacturing Practices.

Cognis prepares two commercial products from the concentrated form of its lutein ester product. One commercial product is a microencapsulated powder that is prepared by forming an emulsion, which is then dispersed with porcine gelatin under high speeds. The resulting paste is atomized at low temperatures to form beadlets that are dried. This powder is a six-fold dilution of the concentrate and, thus, contains a minimum of 10 percent lutein esters. The second commercial product is a liquid that Cognis prepares by diluting the concentrate with vegetable oil. The liquid product is a four-fold dilution of the concentrate and, thus, contains a minimum of 15 percent lutein esters. Cognis intends to use the powder or liquid form of lutein esters in a variety of food products as described in Table 1. In a letter dated December 5, 2002, Cognis notes that either the powder or liquid form of lutein esters may be used in any of the food products described in its notice, although the powder form is more suitable for some products and the liquid form is more suitable for other products. For example, the liquid form of lutein esters is suitable for products that have fat added during processing.

Cognis uses its proposed use levels, data from the United States Department of Agriculture (USDA) 1994-1996 Continuing Surveys of Food Intakes by Individuals, and the USDA carotenoid database to estimate that the intake of lutein esters from both dietary sources and Cognis' proposed uses would be approximately 12 milligrams per person per day (mg/person/day) at the mean and approximately 22 mg/person/day at the 90th percentile. Cognis also estimates that the intake of lutein esters from consumption of dietary supplements ranges from 0.5 to 12 mg/person/day. Therefore, Cognis estimates that the potential maximum intake of lutein esters (i.e., combined from the diet, the uses that Cognis proposes in conventional foods, and dietary supplements) would be 34 mg/person/day at the 90th percentile.

Cognis discusses published and unpublished studies conducted in humans and various animal species regarding the absorption, distribution, metabolism, excretion, bioavailability and toxicity of lutein esters. Cognis concludes that results of these studies show no toxic or adverse effects from the consumption of lutein esters and that long-term consumption of lutein esters is well tolerated. Cognis notes, however, that carotenodermia⁽¹⁾ was observed in one study in which subjects consumed supplements containing 30 mg/person/day of a mixed lutein esters product for 112 days. In contrast, Cognis notes that carotenodermia was not observed in an ongoing study in which subjects consumed supplements containing up to 40 mg/person/day of Cognis' lutein esters product for more than 90 days.

As part of its notice, Cognis includes the report of a panel of individuals (Cognis' GRAS panel) who evaluated the data and information that are the basis for Cognis' GRAS determination. Cognis considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Cognis' GRAS panel evaluated estimates of dietary exposure, published information on the safety and toxicity of lutein esters and related compounds, and other available data and information. Based on this review, Cognis' GRAS panel established an acceptable daily intake (ADI) of 40 mg/person/day of lutein esters (or lutein ester equivalents), a dose that has been administered without evidence of carotenodermia.

Use of lutein esters in medical foods

In its notice, Cognis informs FDA that one intended use of lutein esters is use in medical foods intended as the sole item of the diet. Section 5(b)(3) of the Orphan Drug Act defines a medical food as a food that is formulated to be consumed or administered enterally under the supervision of a physician and that is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation. Section 403(q) of the Federal Food, Drug, and Cosmetic Act (FFDCA) lays out the statutory framework for nutrition labeling of food products. Section 403(r) of the FFDCA lays out the statutory framework for health claims and nutrient content claims. Under section 403(q)(5)(A)(iv) of the FFDCA and FDA's implementing regulations in 21 CFR 101.9(j)(8), the requirements for nutrition labeling do not apply to medical foods as defined in section 5(b) of the Orphan Drug Act. Under section 403(r)(5)(A) and FDA's implementing regulations in 21 CFR 101.13(q)(4) and 21 CFR 101.14(f)(2), the requirements for nutrient content claims and health claims do not apply to medical foods as defined in section 5(b) of the Orphan Drug Act. For your information, FDA's response to Cognis' notice that lutein esters are GRAS for use in medical foods intended as the sole item of the diet does not address the question of whether any particular food product that contains lutein esters as an ingredient would be a medical food within the meaning of section 503(b) of the Orphan Drug Act and, thus, would be exempt from the requirements for nutrition labeling, nutrient content claims, and health claims.

Potential requirement for a color additive petition

In its notice, Cognis describes the concentrate that it uses to prepare its commercial lutein ester products as a granular, dark orange-brown solid. As such, the use of lutein esters in food products may constitute the use of a color additive under section 201(t)(1) of the FFDCA and FDA's implementing regulations in 21 CFR Part 70. Under section 201(t)(1) and 21 CFR 70.3(f), the term color additive means a material that is a dye, pigment, or other substance made by a process of synthesis or similar artifice, or extracted, isolated, or otherwise derived from a vegetable, animal, mineral, or other source, and that is capable (alone or through reaction with another substance) of imparting color when added or applied to a food; except that such term does not include any material which the Secretary,⁽²⁾ by regulation, determines is used (or intended to be used) solely for a purpose or purposes other than coloring. Under 21 CFR 70.3(g), a material that otherwise meets the definition of color additive can be exempt from that definition on the basis that it is used or intended to be used solely for a purpose or purposes other than coloring, as long as the material is used in a way that any color imparted is clearly unimportant insofar as the appearance, value, marketability, or consumer acceptability is concerned. Given the construct of section 201(t)(1) of the FFDCA and 21 CFR 70.3(f) and (g), the use of a substance that is capable of imparting color may constitute use as a color additive in addition to use as a food additive or GRAS substance. For example, beta-carotene is both approved for use as a color additive (21 CFR 73.95) and affirmed as GRAS for use as a nutrient supplement (21 CFR 184.1245); in some food products, beta-carotene is used for both purposes. Importantly, if the use of lutein esters constitutes use as a color additive within the meaning of section 201(t)(1) of the FFDCA and FDA's implementing regulations in 21 CFR 70.3(f) and (g), section 721(a) of the FFDCA requires premarket review and approval of that use by FDA. Under section 402(c) of the FFDCA, a food product that contains an unapproved color additive would be deemed adulterated.⁽³⁾

In a telephone conversation on December 17, 2002, between representatives of FDA and legal counsel to Cognis, FDA requested that Cognis present its view on whether any of the intended uses of lutein esters would be exempt from the definition of color additive. In an amendment dated January 8, 2003, Cognis' legal counsel presented Cognis' reasons for concluding that all of the intended uses of lutein esters would be exempt from the definition of color additive under section 201(t) of the FFDCA and FDA's implementing regulations in 21 CFR 70.3(f) and (g). Importantly, FDA's response to GRN 000110 does not include any comment by FDA about Cognis' view on this issue. If, after receipt of this letter, Cognis has any specific questions about this issue, we recommend that Cognis contact the Division of Petition Review (HFS-265), Office of Food Additive Safety, Center for Food Safety and Applied Nutrition, Food and Drug Administration, 5100 Paint Branch Parkway, College Park, MD 20740. You can reach this division by telephone at (202)418-3035.

Standards of identity

In its notice, Cognis states its intention to use lutein esters in several food categories, including foods for which standards of identity exist, located in Title 21 of the Code of Federal Regulations. 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. If you have any questions about the use of lutein esters in standardized foods that would be marketed in the United States, you should contact the staff in the Office of Nutritional Products, Labeling, and Dietary Supplements (ONPLDS), Division of Standards and Labeling Regulations (HFS-820), Center for Food Safety and Applied Nutrition, Food and Drug Administration, 5100 Paint Branch Parkway, College Park, MD 20740. You can reach this division by telephone at (301)436-2375.

Conclusions

Based on the information provided by Cognis, as well as other information available to FDA, the agency has no questions at this time regarding Cognis' conclusion that lutein esters are 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 lutein esters. As always, it is the continuing responsibility of Cognis to ensure that food ingredients that the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements. In particular, we note that any use of lutein esters that constitutes use as a color additive requires premarket review and approval by FDA.

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⁾A reversible condition described as a yellowing of the skin, especially the palms of the hands and the soles of the feet.

⁽²⁾The Secretary of the Department of Health and Human Services (DHSS). The Secretary of DHSS has delegated the authority for this provision of the FFDCA to FDA.

⁽³⁾We note that section 721(b)(4) of the FFDCA provides that a color additive shall be deemed to be safe and suitable for the purpose of listing under section 721(b) of the FFDCA while there is in effect a published finding of the Secretary declaring that the substance is exempt from the definition of "food additive" because of its being generally recognized by qualified experts as safe for its intended use as provided in section 201(s) of the FFDCA. Importantly, FDA's response to GRN 000110 does not constitute a "finding of the Secretary" within the meaning of section 721(b)(4) of the FFDCA