| Public Health Service Food and Drug Administration |
| Dallas District 4040 North Central Expressway Dallas, Texas 75204·3128 |
Department of Health and Human ServicesJanuary 13, 2010
2010-DAL-WL-05
WARNING LETTER
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
Peter Bianchi, Chief Executive Officer
Innovative Beverage Group, Inc.
5833-B West View Dr.
Houston, TX 77055
Dear Mr. Bianchi:
The Food and Drug Administration (FDA) has reviewed the regulatory status of the ingredients declared on the label of your beverage product, "Drank." Your product is adulterated under section 402(a)(2)(C) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. 342(a)(2)(C)] because it bears or contains melatonin, which is an unapproved food additive. The regulations pertaining to the general provisions for food additives are located in Title 21, Code of Federal Regulations (21 CFR), Part 170. You can find copies of the Act and these regulations through links in FDA's home page at http://www.fda.gov.
Any substance intentionally added to a conventional food, such as the beverage product "Drank," must be used in accordance with a food additive regulation, unless the substance is the subject of a prior sanction or is generally recognized as safe (GRAS) among qualified experts for its use in foods. There is no food additive regulation in effect that provides for the safe use of melatonin, and we are not aware of any information to indicate that melatonin is the subject of a prior sanction. Likewise, we are not aware of any basis to conclude that melatonin is GRAS for use in conventional foods.
FDA's regulations in 21 CFR Part 170 describe criteria for eligibility for classification of a food ingredient as GRAS. Under 21 CFR 170.30(a), general recognition of safety must be based only on the views of qualified experts. The basis of such views may be either (1) scientific procedures or (2) in the case of a substance used in food prior to January 1, 1958, through experience based on common use in food. Section 170.30(a) further states that general recognition of safety requires common knowledge about the substance throughout the scientific community knowledgeable about the safety of substances directly or indirectly added to food.
FDA's regulations in 21 CFR Part 170 define "[c]ommon use in food" and establish criteria for eligibility for classification as GRAS through experience based on common use in food. Under 21 CFR 170.3(f), "[c]ommon use in food means a substantial history of consumption of a substance for food use by a significant number of consumers." Under 21 CFR 170.30(c)(1), "[g]eneral recognition of safety through experience based on common use in food prior to January 1, 1958, shall be based solely on food use of the substance prior to January 1, 1958, and shall ordinarily be based upon generally available data and information." Importantly, however, the fact that a substance was added to food before 1958 does not, in itself, demonstrate that such use is safe, unless the pre-1958 use is sufficient to demonstrate to qualified experts that the substance is safe when added to food.
Similarly, FDA's regulations in 21 CFR Part 170 define "scientific procedures" and establish criteria for eligibility for classification as GRAS through scientific procedures. Under 21 CFR 170.3(h), "[s]cientific procedures include those human, animal, analytical, and other scientific studies, whether published or unpublished, appropriate to establish the safety of a substance." Under 21 CFR 170.30(b), "[g]eneral recognition of safety based upon scientific procedures shall require the same quantity and quality of scientific evidence as is required to obtain approval of a food additive regulation for the ingredient." Section 170.30(b) further states that general recognition of safety through scientific procedures is ordinarily based upon published studies, which may be corroborated by unpublished studies and other data and information.
FDA's regulations in 21 CFR Part 170 define "safe" and "safety." Under 21 CFR 170.3(i), "[s]afe or safety means that there is a reasonable certainty in the minds of competent scientists that the substance is not harmful under the intended conditions of use." The regulation provides that, in determining safety, the following factors are to be considered: (1) The probable consumption of the substance and of any substance formed in or on food because of its use; (2) the cumulative effect of the substance in the diet, taking into account any chemically or pharmacologically related substance or substances in such diet; and (3) safety factors which, in the opinion of qualified experts, are generally recognized as appropriate. Such safety factors ordinarily are established through extensive testing in animals to determine whether consumption of the ingredient produces adverse effects when consumed chronically (i.e., on a daily basis over the course of a lifetime1).
Melatonin (5-Methoxy-N-acetyltryptamine, CAS Reg. No. 73-31-4) is a neurohormone that is used for medicinal purposes, primarily for treatment of sleep-related disorders. Various credible sources and reports in the scientific literature, some of which we will refer to below, describe information on melatonin that would raise safety concerns about its use as a food ingredient.
• In a study published in 2001 (Anisimov et al., Journal of Gerontology: Biological Sciences, 56A:B311-B323, 2001), melatonin was reported to increase spontaneous malignant tumor incidence when administered orally to female CBA mice, although it increased the life span of these animals. Based on this observation, the authors advised caution regarding use of melatonin as an anti-aging drug.
• A recently published study (Wiechmann et al., Experimental Eye Research, 86:241-250, 2008) shows melatonin, administered orally, to be toxic to retinal photoreceptor cells of male and female Fischer 344 (non-pigmented) rats and male pigmented LongeEvans rats, depending on the conditions of exposure to light. In their conclusion, the authors cautioned that chronic exposure to natural or artificial light and simultaneous intake of melatonin may potentially contribute to a significant loss of photoreceptor cells in the aging retina.
• Melatonin is the subject of a monograph prepared by the Natural Standard,2 an international research collaboration that gathers and reviews data on complementary and alternative therapies. The safety assessment that the monograph provides is with respect to the medicinal use of melatonin. The monograph states that, based on available studies and clinical use, melatonin is generally regarded as safe at recommended doses for short-term use only and describes various safety concerns about its use, some of which we mention here. The monograph states that melatonin may cause drops in blood pressure, as observed in animals and in preliminary human research and caution is advised in patients already on anti-hypertensive medications. The monograph states that preliminary research suggests that regular use of melatonin may increase atherosclerotic plaque buildup in humans and animals. The monograph states that hyperglycemia has been reported in patients with type-1 diabetes, and low doses of melatonin have reduced glucose tolerance and insulin sensitivity. The monograph states that gynecomastia has been reported in men, as well as decreased sperm count (both of which resolved with cessation of melatonin). It also states that decreased sperm motility has been reported in rats and humans. The monograph states that there are limited studies regarding use of melatonin in children (younger than 18 years) and safety has not been established. It further states that melatonin should not be used in children without consultation with a physician. The monograph states that melatonin use should be avoided in women who are pregnant or attempting to become pregnant, based on possible hormonal effects, including alterations of pituitary-ovarian function and potential inhibition of ovulation or uterine contractions. It also states that high levels of melatonin during pregnancy may increase the risk of developmental disorders.
In light of these safety concerns, the use of melatonin in the beverage product "Drank" does not satisfy the criteria for GRAS status outlined above. Further, FDA is not aware of any other exemption from the food additive definition that would apply to melatonin for use as an ingredient in a conventional food, such as a beverage product. Therefore, melatonin used in this manner is a food additive under section 201(s) of the Act and is subject to the provisions of section 409 of the Act (21 U.S.C. 348). Under section 409, a food additive is required to be approved by FDA for its intended use prior to marketing. Melatonin is not an approved food additive for use in beverages. Therefore, the product "Drank," a beverage containing melatonin, is adulterated within the meaning of section 402(a)(2)(C) of the Act.
You should take prompt action to correct this violation and prevent its future recurrence. Failure to do so may result in enforcement action without further notice. The Act authorizes the seizure of illegal products and injunctions against manufacturers and distributors of those products. We want you to be aware that FDA did not conduct an all inclusive review of the labeling or ingredients for your product "Drank" or other products you manufacture or distribute. It is the responsibility of a manufacturer to ensure that foods the firm markets are safe nd otherwise in compliance with all applicable legal and regulatory requirements.
Please advise this office in writing within fifteen (15) days from your receipt of this letter as to the specific steps you have taken to correct the violation noted above and to assure that similar violations do not occur. Your response should include any documentation necessary to show that correction has been achieved. If you cannot complete all corrections before you respond, please explain the reason for your delay and the date by which each such item will be corrected and documented.
Please send your reply to Ronda Loyd-Jones, Compliance Officer, Food and Drug Administration, Dallas District Office, 4040 North Central Expressway Suite 300, Dallas, Texas 75204. If you have questions about this letter, you may contact Ronda Loyd-Jones at 214-253-5242.
Sincerely,
/s/
Reynaldo R. Rodriguez
Director Dallas District
11. Toxicological Testing of Food Additives, which is available at http://vm.cfsan.fda.gov/~dms/opa-tg1.html.
2 http://www.naturalstandard.com/naturalstandard/monographs/monoframeset.asp?monograph=/monograph
s/herbssupplements/melatonin.asp&natientVersion=/monographs/herbssupplements/patient-melatonin.asp
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