Food

Agency Response Letter GRAS Notice No. GRN 000141

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CFSAN/Office of Food Additive Safety

April 28, 2004

Mr. David R. Schoneker
Director, Global Regulatory Affairs
Colorcon
415 Moyer Boulevard
P.O. Box 24
West Point, PA 19486

Re: GRAS Notice No. GRN 000141

Dear Mr. Schoneker:

The Food and Drug Administration (FDA) is responding to the notice, dated December 11, 2003, submitted by the Law Offices of John B. Hallagan, P.C. on behalf of Colorcon 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 17, 2003, filed it on December 23, 2003, and designated it as GRAS Notice No. GRN 000141.

The subject of the notice is polyvinyl alcohol. The notice informs FDA of the view of Colorcon that polyvinyl alcohol is GRAS, through scientific procedures, for use in aqueous film coating formulations applied to dietary supplement products (i.e., tablets or capsules), where the coating formulation is up to four percent (by weight) of the tablet or capsule, and polyvinyl alcohol is up to 45 percent (by weight) of the coating formulation.

As part of its notice, Colorcon includes the report of a panel of individuals (Colorcon's GRAS panel) who evaluated the data and information that are the basis for Colorcon's GRAS determination. Colorcon considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Colorcon's GRAS panel evaluated estimates of dietary exposure, method of manufacture, product specifications, and published studies conducted with polyvinyl alcohol. Based on this review, Colorcon's GRAS panel concluded that polyvinyl alcohol, meeting food and pharmaceutical grade specifications and manufactured in compliance with current good manufacturing practices, is GRAS, through scientific procedures, for use in aqueous film coating formulations applied to dietary supplement products.

Colorcon describes polyvinyl alcohol as a white, odorless granular powder that is soluble in water and insoluble in aliphatic and aromatic hydrocarbons, esters, ketones, and oils. Polyvinyl alcohol is produced by polymerization of vinyl acetate with subsequent controlled hydrolysis of the resulting polyvinyl acetate. Sodium acetate, methanol, and methyl acetate are the primary expected impurities.

Colorcon provides specifications for polyvinyl alcohol, including limits on the maximum levels of heavy metals, lead, arsenic, residue on ignition, residual methyl acetate and methanol, and degree of hydrolysis. These specifications are in accordance with United States Pharmacopeia/ National Formulary standards and international specifications for pharmaceutical grade polyvinyl alcohol.

Colorcon estimates that the maximum daily intake of polyvinyl alcohol from its intended use in aqueous film coatings applied to dietary supplements would be 180 milligrams per person per day (mg/person/day) and that the maximum daily intake of polyvinyl alcohol from its current use in film coatings applied to pharmaceutical products is 180 mg/person/day, assuming that a person consumes a maximum of ten 1,000 mg dietary supplement tablets or capsules and ten 1,000 mg pharmaceutical tablets or capsules with polyvinyl alcohol film coating formulations per day. Therefore, Colorcon concludes that the total maximum daily intake of polyvinyl alcohol from its intended use in dietary supplements and from its current use in pharmaceutical products would be 360 mg/person/day, equivalent to 6 milligrams per kilogram body weight per day (mg/kg body weight/day) for a 60 kg person.

Colorcon discusses published studies conducted with polyvinyl alcohol in various animal species. Colorcon reports that acute and subchronic oral toxicity studies conducted in animals including rats, mice, and dogs and a two-generation reproductive toxicity study conducted in rats fed polyvinyl alcohol showed no adverse toxicological or reproductive effects. Colorcon also reports that genotoxicity studies conducted in vitro and in vivo with polyvinyl alcohol demonstrated no evidence of mutagenic or clastogenic effects. Colorcon concludes that these studies demonstrate that polyvinyl alcohol is not mutagenic, genotoxic, or carcinogenic by the oral route. In addition, Colorcon concludes that animal toxicology data support a no-observed-adverse-effect-level (NOAEL) for polyvinyl alcohol of 5,000 mg/kg body weight/day.

Colorcon also reports that polyvinyl alcohol is approved for use as an indirect food additive in products that are in contact with food, as a diluent in color additive mixtures for coloring shell eggs, and for use in several medical applications, including in coatings applied to pharmaceutical tablets. Furthermore, Colorcon reports that the Joint Food and Agriculture Organization/World Health Organization's (FAO/WHO) Expert Committee on Food Additives (JECFA) assigned an acceptable daily intake (ADI) to polyvinyl alcohol of 50 mg/kg body weight/day at its sixty-first meeting held in June 2003.

Based on the information provided by Colorcon, as well as other information available to FDA, the agency has no questions at this time regarding Colorcon's conclusion that polyvinyl alcohol 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 polyvinyl alcohol. As always, it is the continuing responsibility of Colorcon 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, 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,

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

cc: John B. Hallagan
The Law Offices of John B. Hallagan, P.C.
1620 I Street, NW
Suite 925
Washington, DC 20006

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