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U.S. Department of Health and Human Services

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Agency Response Letter GRAS Notice No. GRN 000460

CFSAN/Office of Food Additive Safety

August 23, 2013

Madhu G. Soni, Ph.D.
Soni & Associates
749 46th Square
Vero Beach, FL 32968

Re: GRAS Notice No. GRN 000460

Dear Dr. Soni:

The Food and Drug Administration (FDA) is responding to the notice, dated February 5, 2013, that you submitted on behalf of Sabinsa Corporation (Sabinsa) 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 February 12, 2013, filed it on February 28, 2013, and designated it as GRAS Notice No. GRN 000460.

The subject of the notice is curcuminoids purified from turmeric (Curcuma longa L.) (curcuminoids). The notice informs FDA of the view of Sabinsa that curcuminoids is GRAS, through scientific procedures, for use as a flavor, flavor enhancer, or an ingredient in baked goods, soups, snack foods, imitation dairy products, and seasoning, at levels up to 20 milligrams (mg) per serving. Sabinsa does not intend curcuminoids for use in infant formula, toddler foods, or United States Department of Agriculture (USDA) regulated meat and poultry products.

As part of its notice, Sabinsa includes the report of a panel of individuals (Sabinsa’s GRAS panel) that evaluated the data and information that are the basis for Sabinsa’s GRAS determination. Sabinsa considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Sabinsa’s GRAS panel evaluated the identity, method of manufacture, product specifications, estimates of dietary exposure, as well as published safety studies conducted with curcuminoids. Based on this review, Sabinsa’s GRAS panel concluded that curcuminoids that meet established food grade specifications is GRAS under the conditions of its intended use.

Sabinsa describes the identity and composition of curcuminoids. Curcuminoids is an orange-yellow crystalline powder with a characteristic odor and taste. This preparation is > 95% curcuminoids, composed of curcumin (75-81%), bisdemethoxy curcumin (2.2-6.5%), and desmethoxy curcumin (15-22%). Sabinsa states that the term curcumin is commonly used to denote the mixture of curcuminoids found in the turmeric extract.

Sabinsa describes the method of manufacture for curcuminoids. The starting material is dried turmeric rhizomes that are ground into a coarse powder and pelletized, followed by an acetone or ethyl acetate extraction. The extract is filtered and the acetone or ethyl acetate is removed by distillation and then treated with isopropyl alcohol to remove other resinous material and precursors of curcuminoids. The resultant material is dried and powdered.

Sabinsa provides specifications for curcuminoids. The specifications include the composition described above for curcuminoids and limits for moisture (≤ 2%), residual solvents (acetone (≤ 30 mg/kilogram (kg)), isopropanol (≤ 15 mg/kg), ethyl acetate (≤ 50 mg/kg)), ash (≤ 1%), arsenic (≤ 1 mg/kg), lead (< 2 mg/kg), cadmium (< 1 mg/kg), mercury (< 0.1 mg/kg), and for microbial contaminants, including total plate count (< 5000 colony forming units (cfu) per gram (g)), yeast and mold (< 100 cfu/g), and Escherichia coli, Staphylococcus aureus, Salmonella, and Pseudomonas aeruginosa (negative/10g).

Sabinsa estimates dietary exposure to curcuminoids. Estimates are based on: 1) Market Research Corporation of America (MRCA) mean frequency of eating and the USDA mean portion size of 34 general food categories data (MRCA, 1965); and, 2) consumption data from the USDA Continuing Survey of Food Intake by Individuals (CSFII, 1994-1996) database. Sabinsa notes that these methods assume that the maximum amount of curcuminoids (20 mg per serving) is added to the entire intended food category. Using MRCA food consumption data, the estimated mean daily exposure to curcuminoids is 53.85 mg/person (p)/day (d) (0.90 mg/kg body weight (bw)/d), and the 90th percentile daily exposure was determined by multiplying the mean value by two (107.55 mg/p/d or 1.80 mg/kg bw/d). Based on USDA CSFII food consumption data, the mean and 90th percentile estimated dietary exposure of curcuminoids from the intended use in the food is 97.44 and 180.25 mg/p/d (1.62 and 3 mg/kg bw/d), respectively. Sabinsa states that the estimated daily exposure to curcuminoids from their natural presence in turmeric ranges from 24 to 200 mg/p/d (0.40 to 3.33 mg/kg bw/d).

Sabinsa discusses its safety assessment of curcuminoids including published studies utilizing rats, mice, dogs and humans. The notifier reviews many pharmacokinetic studies that showed a low systemic bioavailability of curcuminoids following oral administration to animals and humans, which the notifier notes could be explained by an efficient first-pass metabolism or intestinal biotransformation. In addition, the notifier reviews published subchronic studies including 90 day studies by the National Cancer Institute in rats (up to 3,500 mg curcuminoids/kg bw/d via gavage) and dogs (up to 1,000 mg curcuminoids/kg bw/d via gelatin capsule) where no biologically significant effects were observed at the highest dose tested. The notifier also discusses other published 90 day studies by the National Toxicology Program in mice (up to 7,700 mg/kg bw/d male and 9,280 mg/kg bw/d female) and rats (up to 2,587 mg/kg bw/d male and 2,760 mg/kg bw/d female) showing no gross or microscopic pathological changes at the highest dose tested. The notifier discusses published genotoxicity studies, from which they conclude, given the totality of the data, there is no evidence for the genotoxicity of curcuminoids.

The notifier discusses a published two-generation reproductive toxicity study, which was also reviewed by the Joint FAO/WHO Expert Committee on Food Additives (JECFA-2004), in which rats consumed diets containing approximately 160, 320, or 1100 mg/kg bw/d of curcuminoids. Sabinsa explains that the study showed a small body weight reduction in the F2 pups of the highest dose group (1100 mg/kg bw/d), resulting in JECFA determining an acceptable daily intake of curcuminoids of 3 mg/kg bw/d, utilizing a 100-fold safety factor, based on the intake of about 320 mg/kg/d; which was the mid-dose. Finally, the notifier discusses published clinical studies which showed that curcuminoids generally had no adverse effects and is not toxic even at very high levels (2000 mg/d for 120 days).

Standards of Identity

In the notice, Sabinsa states its intention to use curcuminoids 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.

Potential Labeling Issues

In describing the intended use of curcuminoids and in describing the information that Sabinsa relies on to conclude that curcuminoids is GRAS under the conditions of its intended use, Sabinsa raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act). Sabinsa describes clinical studies on physiological effects of curcuminoids that Sabinsa views as beneficial. Under section 403(a) of the FD&C Act, a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FD&C Act lays out the statutory framework for the use of labeling claims that characterize the level of a nutrient in a food or that characterize the relationship of a nutrient to a disease or health-related condition. If products that contain curcuminoids bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition, Labeling and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition. The Office of Food Additive Safety (OFAS) neither consulted with ONLDS on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about curcuminoids on the label or in labeling.

Potential Requirement for a Color Additive Petition

In its notice, Sabinsa describes curcuminoids as an orange-yellowish powder. As such, the use of curcuminoids in food products may constitute the use of a color additive under section 201(t)(1) of the FD&C Act 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,1 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 FD&C Act 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, β-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, ß-carotene is used for both purposes. Importantly, if the use of curcuminoids constitutes use as a color additive within the meaning of section 201(t)(1) of the FD&C Act and FDA's implementing regulations in 21 CFR 70.3(f) and (g), section 721(a) of the FD&C Act requires premarket review and approval of that use by FDA. Under section 402(c) of the FD&C Act, a food product that contains an unapproved color additive would be deemed adulterated.2

In its notice, Sabinsa states that the addition of curcuminoids to the various food products occurs at sufficiently low levels, and that it will not impart significant color to the resulting food products. Furthermore, Sabinsa states that curcuminoids is not intended to function as a color additive and that the incorporation of curcuminoids with its orange-yellowish color falls outside of the definition of color additive (21 CFR 70.3(g)). Importantly, FDA’s response to GRN 000460 does not include any comment by FDA about Sabinsa’s view of this issue. If, after receipt of this letter, Sabinsa has any specific questions about this issue, we recommend that Sabinsa contact the Division of Petition Review in OFAS.

Section 301(ll) of the FD&C Act

The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the 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 Sabinsa’s notice that curcuminoids is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing curcuminoids. Accordingly, this response should not be construed to be a statement that foods that contain curcuminoids, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).

Conclusions

Based on the information provided by Sabinsa, as well as other information available to FDA, the agency has no questions at this time regarding Sabinsa’s conclusion that curcuminoids is GRAS under the intended conditions. The agency has not, however, made its own determination regarding the GRAS status of the subject use of curcuminoids. As always, it is the continuing responsibility of Sabinsa 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 000460, 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



 



 

1The Secretary of the Department of Health and Human Services.

2We note that section 721(b)(4) of the FD&C Act provides that a color additive shall be deemed to be safe and suitable for the purpose of listing under section 721(b) of the FD&C Act 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 FD&C Act. Importantly, FDA’s response to GRN 000460 does not constitute a “finding of the Secretary” within the meaning of section 721(b)(4) of the FD&C Act.