Agency Response Letter
GRAS Notice No. GRN 000140

Zoraida DeFreitas, Ph.D.
Kemin Foods, L.C.
600 E. Court Ave., Suite A
Des Moines, IA 50309-2021

Re: GRAS Notice No. GRN 000140

Dear Dr. DeFreitas:

The Food and Drug Administration (FDA) is responding to the notice, dated November 14, 2003, 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 November 18, 2003, filed it on November 21, 2003, and designated it as GRAS Notice No. GRN 000140.

The subject of the notice is a mixture of the carotenoids lutein and zeaxanthin referred to by Kemin Foods, L.C. (Kemin) as "crystalline lutein." The notice informs FDA of the view of Kemin that crystalline lutein is GRAS, through scientific procedures, for use as an ingredient in baked goods and baking mixes, beverages and beverage bases, breakfast cereals, chewing gum, dairy product analogs, egg products, fats and oils, frozen dairy desserts and mixes, gravies and sauces, hard candy, infant and toddler foods (other than infant formula), milk products, processed fruits and fruit juices, soft candy, soups and soup mixes, and in medical foods intended as the sole item of the diet. The levels of crystalline lutein in the above listed food items range from 0.3 to 3.0 milligrams (mg) per eating occasion (Table 1).

Table 1
Food categories and use levels for crystalline lutein

Food Category	Proposed food use	Use level (mg crystalline lutein per RACC*)
Baked goods and baking mixes	Cereal and energy bars	2.0
	Crackers and crisp bread	2.0
Beverages and beverage bases	Bottled water	0.5
	Carbonated beverages	2.0
	Meal replacements	2.0
	Tea, ready-to-drink	0.6
Breakfast cereals	Instant & regular hot cereal	2.0
	Ready-to-eat-cereal	2.0
Chewing gum	Chewing gum	1.0
Dairy product analogs	Imitation milks	2.0
	Soy milks	1.5
Egg products	Liquid, frozen, dried egg substitutes	2.0
Fats and oils	Margarine-like spreads	1.5
	Salad dressings	1.5
Frozen dairy desserts and mixes	Frozen yogurt	1.0
Gravies and sauces	Tomato-based sauces	0.3
Hard candy	Hard candy	1.0
Infant** and toddler foods	Junior, strained, and toddler type baby foods	1.0
Soft candy	Chewy and nougat candy	1.0
	Fruit snacks	1.0
Soups and soup mixes	Canned soups	0.6
Milk products	Dry milk	3.0
	Fermented milk beverages	0.6
	Flavored milk & milk drinks	3.0
	Milk-based meal replacement	3.0
	Yogurt	3.0
Processed fruit and fruit juices	Energy, sport and isotonic drink	2.0
	Fruit-flavored drinks	2.0
	Fruit juice	2.0
	Nectars	2.0
	Vegetable juice	2.0
Medical foods	Medical foods	20 mg/day
*RACC is defined as "reference amounts customarily consumed per eating occasion" (21 CFR 101.12) **Kemin states the infant food category does not include infant formula.

For clarity, in the remainder of this letter FDA uses the term "crystalline lutein" to denote the mixture of the carotenoids lutein and zeaxanthin that is the subject of the notice and the term "lutein" to denote the principal component of this mixture.

Our use of "crystalline lutein" in this letter should not be considered an endorsement or recommendation of that term as an appropriate common or usual name for the purpose of declaring the substance in the ingredient statement of foods that contain that ingredient. 21 CFR 101.4 states that all ingredients must be declared by their common or usual name. In addition, 21 CFR 102.5 outlines general principles to use when establishing common or usual names for nonstandardized foods. Issues associated with labeling and the appropriate common or usual name of a food are the responsibility of the Office of Nutritional Products, Labeling, and Dietary Supplements.

As part of its notice, Kemin includes the report of a panel of individuals (Kemin's GRAS panel) who evaluated the data and information that are the basis for Kemin's GRAS determination. Kemin considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Kemin's GRAS panel evaluated estimates of dietary exposure, method of manufacture, product specifications, and published studies on crystalline lutein and related compounds. Based on this review, Kemin's GRAS panel concluded that crystalline lutein that meets appropriate food grade specifications and is manufactured in compliance with current good manufacturing practices is GRAS under the conditions of its intended use.

Kemin describes the method of manufacture for crystalline lutein. The process begins with marigold oleoresin, which is derived from the hexane extraction of dried marigold flower petals (Tagetes erecta). The oleoresin is extracted with a basic solution, organic solvent, and water yielding a crystalline product containing lutein and zeaxanthin. This product is then diluted with water, centrifuged, washed, and dried to form the final product, crystalline lutein. Kemin notes that crystalline lutein is packaged under nitrogen.

Kemin provides product specifications for crystalline lutein. These specifications include limits on lead, arsenic, pesticides, organic solvents, yeasts and molds, and microbiological contaminants. Kemin also provides specifications on the total carotenoids in crystalline lutein and the percentages of lutein and zeaxanthin. Kemin reports that crystalline lutein contains approximately 76 percent lutein by weight and approximately 7 percent zeaxanthin by weight (for a total of approximately 83 percent total carotenoids by weight).

Using its proposed use levels and data from the United States Department of Agriculture 1994-1996 Continuing Survey of Food Intakes by Individuals and 1998 Supplemental Children's Survey, Kemin estimates that the intake of crystalline lutein would be approximately 10 milligrams per person per day (mg/person/day) at the mean and approximately 18 mg/person/day at the 90th percentile. Based on the carotenoid composition of crystalline lutein, Kemin also estimates that the intake of lutein and zeaxanthin would be approximately 7mg/person/day (lutein) and 0.7 mg/person/day (zeaxanthin) at the mean and approximately 13 mg/person/day (lutein) and 1.2 mg/person/day (zeaxanthin) at the 90th percentile, respectively. Kemin notes that the average dietary intake of lutein and zeaxanthin from plant sources ranges from 2 to 4 mg/person/day. However, Kemin notes that there are no consumption data from which to reliably estimate the intake of lutein and zeaxanthin from dietary supplements.

Kemin discusses published studies conducted in humans and various animal species regarding the absorption, distribution, metabolism, excretion, bioavailability, toxicity and mutagenicity of crystalline lutein and its primary components, lutein and zeaxanthin. Kemin concludes that results of these studies show no toxic or adverse effects (including ocular damage) from the consumption of crystalline lutein or lutein and zeaxanthin from other sources. Kemin notes that carotenodermia⁽¹⁾ was reported in a study in which healthy subjects consumed 15 mg/person/day of lutein (from mixed ester forms extracted from marigold) for 4 months. Kemin notes, however, that carotenodermia is considered a harmless and reversible biological effect of high carotenoid intake, and that no signs of its occurrence have been reported in other populations (e.g., patients with cataracts or patients with age-related macular degeneration) following exposure 3 times per week for 13 months of approximately 25 mg/person/day of lutein.

Use of crystalline lutein in medical foods

In its notice, Kemin informs FDA that one intended use of crystalline lutein is 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 21CFR 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 Kemin's notice that crystalline lutein is 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 crystalline lutein 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 requirements for nutrition labeling, nutrient content claims, and health claims.

Potential requirement for a color additive petition

FDA notes that Kemin's crystalline lutein product has the potential to impart color in food products that contain it. As such, the use of crystalline lutein in food products may constitute the use of a color additive under section 201(t)(1) of the Federal Food, Drug and Cosmetic Act (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 crystalline lutein 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 conference on April 21, 2004, between representatives of FDA and Kemin, FDA requested that Kemin present its view on whether any of the intended uses of crystalline lutein would be exempt from the definition of color additive. In an amendment dated April 27, 2004, Kemin presented its reasons for concluding that all of the intended uses of crystalline lutein 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 000140 does not include any comment by FDA about Kemin's view on this issue. If, after receipt of this letter, Kemin has any specific questions about this issue, we recommend that Kemin 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) 418-3217.

Standards of identity

In the notice, Kemin states its intention to use crystalline lutein 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 permitted by the applicable standard of identity. If you have any questions about the use of crystalline lutein 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, 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) 436-2371.

Conclusions

Based on the information provided by Kemin, as well as other information available to FDA, the agency has no questions at this time regarding Kemin's conclusions that crystalline lutein 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 crystalline lutein. As always, it is the continuing responsibility of Kemin to ensure that food ingredients it markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements. In particular, we note that any use of crystalline lutein that constitutes 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).

Sincerely,    /s/ George H. Pauli, Ph.D. Acting Director Office of Food Additive Safety Center for Food Safety      and Applied Nutrition

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⁽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 (DHHS). The Secretary of DHHS 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 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 findings of the Secretary declaring that the substance is exempt from the definition of "food additive" because of its being generally recognized by qualified expert as safe for its intended use as provided in section 201(s) of the FFDCA. Importantly, FDA's response to GRN 000140 does not constitute a "finding of the Secretary" within the meaning of section 721(b)(4) of the FFDCA.