[Federal Register: April 29, 1999 (Volume 64, Number 82)] [Notices] [Page 23083-23086] From the Federal Register Online via GPO Access [wais.access.gpo.gov] [DOCID:fr29ap99-58] ----------------------------------------------------------------------- DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. 98N-1109] Mercury Compounds in Drugs and Food; Request for Data and Information AGENCY: Food and Drug Administration, HHS. ACTION: Notice; followup request for data and information. ----------------------------------------------------------------------- SUMMARY: The Food and Drug Administration (FDA) is announcing a followup to its call-for-data, which was published in the Federal Register of December 14, 1998 (63 FR 68775), to identify food and drug products that contain intentionally introduced mercury compounds, e.g., mercurous chloride, mercuric chloride, phenylmercuric acetate, thimerosal (hereinafter referred to as the December 1998 call-for-data notice). The agency is seeking both quantitative and qualitative information about the mercury compounds in these food and drug products. The agency is requesting this information as part of the implementation of the Food and Drug Administration Modernization Act of 1997 (FDAMA). DATES: Submit data and information by June 1, 1999. Submit written general comments by June 1, 1999. [[Page 23084]] ADDRESSES: Submit written comments and information to the particular subject office as follows: 1. General comments on this call-for-data to the Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. 2. Information on human drug products to the Division of Over-the- Counter (OTC) Drug Products (HFD-560), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. 3. Information on human biological products to the Division of Vaccine and Related Products Applications (HFM-475), Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852. 4. Information on veterinary drug products to the Division of Epidemiology and Surveillance (HFV-210), Center for Veterinary Medicine, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. 5. Information on food products, including dietary supplements, to the Office of Special Nutritionals (HFS-456), Center for Food Safety and Applied Nutrition, Food and Drug Administration, 200 C St. SW., Washington, DC 20204. FOR FURTHER INFORMATION CONTACT: For human drug products: Gerald M. Rachanow, Center for Drug Evaluation and Research (HFD-560), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-2222. For human biological products: Robert A. Yetter, Center for Biologics Evaluation and Research (HFM-10), Food and Drug Administration, 1401 Rockville, MD 20852, 301-827-0373. For veterinary drug products: William C. Keller, Center for Veterinary Medicine (HFV-210), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-6641. For food and dietary supplement products: Sharon A. Ross, Center for Food Safety and Applied Nutrition (HFS-456), Food and Drug Administration, 200 C St. SW., Washington, DC 20204, 202-205-5343. SUPPLEMENTARY INFORMATION: I. Background FDAMA (Pub. L. 105-115) was enacted on November 21, 1997. Section 413 of FDAMA, entitled ``Food and Drug Administration Study of Mercury Compounds in Drugs and Food,'' requires FDA to: (1) Compile a list of drugs and foods that contain intentionally introduced mercury compounds, and (2) provide a quantitative and qualitative analysis of the mercury compounds in this list. FDAMA requires the agency to compile the list and provide the analysis within 2 years after the date of its enactment. The statute does not differentiate whether the mercury compound is present in the products as an active or an inactive ingredient. Therefore, FDA is requesting data and information on any mercury compounds, present as active or as inactive ingredients, in any human or veterinary drug (prescription or OTC) product, any human biological products, or any food product, including dietary supplements. II. Mercury Compounds in Human Drug Products There are several different types of mercury compounds that have been used in human drug products. Inorganic mercury salts used include mercurous chloride (calomel) and mercuric chloride (bichloride of mercury). Organic aryl mercury compounds used include phenylmercuric acetate and phenylmercuric nitrate. Some of these mercury compounds (e.g., phenylmercuric acetate and phenylmercuric nitrate) have been used as both active and inactive ingredients. Some mercury-containing drug products have been marketed by prescription and others have been marketed OTC only. FDA has already evaluated the safety and effectiveness of many of the OTC uses of mercury compounds as part of its OTC drug review. Many mercury compounds used as active ingredients in OTC drug products have been found to be not generally recognized as safe (GRAS) and effective and are classified as new drugs. These mercury ingredients are listed in Sec. 310.545(a) (21 CFR 310.545(a)). FDA included a table of these ingredients in the December 1998 call-for-data notice (see Table 1, 63 FR 68775 at 68776). FDA has also considered mercury compounds as inactive ingredients in OTC ophthalmic drug products. Section 349.50(c)(3) of the final monograph for OTC ophthalmic drug products (21 CFR 349.50(c)(3)) states: For ophthalmic drug products containing mercury compounds used as a preservative. ``This product contains (name and quantity of mercury-containing ingredient) as a preservative. Do not use this product if you are sensitive to'' (select one of the following: ``mercury'' or ``(insert name of mercury-containing ingredient) or any other ingredient containing mercury).'' The agency is aware that mercury compounds (e.g., phenylmercuric acetate and thimerosal) are used as a preservative in OTC nasal solution products, prescription ophthalmic drug products, and biological products including vaccines, immunoglobulins, antivenins, and skin test antigens. Phenylmercuric nitrate is also present in some oral homeopathic drug products and may be present in other homeopathic drug products. Therefore, homeopathic drug products are included in this call-for-data. III. Mercury Compounds in Veterinary Drug Products Currently, there are no approved veterinary drug products that contain a mercury compound as an active ingredient. There is some limited use, however, of mercury compounds in veterinary drug products. These products are all unapproved OTC products for use in nonfood species. For instance, older textbooks may contain an indication for red mercuric iodide petrolatum as a compounded counterirritant. An aqueous formulation of red mercuric iodide is commercially marketed with that indication. Mercurochrome is currently marketed for treating bacterial diseases of ornamental fish. The potential exists for some limited use of mercury compounds as inactive ingredients, such as preservatives, particularly in unapproved products. IV. Mercury Compounds in Food Products The agency has limited information on the intentional addition of mercury-containing compounds to food products. Under section 201(s) of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 321(s)), an ingredient used in food or as food must be an approved food additive or it must be GRAS for its intended food use. Currently, FDA has not approved any mercury-containing compounds as food additives and does not consider any mercury-containing compounds to be GRAS. Substances that are ``dietary ingredients'' as defined in section 201(ff) of the act are exempt from the food additive provisions of the act under section 201(s)(6). Under the act, dietary supplement ingredients subject to section 201(ff) do not require FDA's premarket scrutiny or approval. Additionally, ingredients subject to this section of the act do not need to be registered with FDA. Consequently, FDA has no listing of mercury-containing compounds that are used as dietary ingredients in dietary supplements. [[Page 23085]] The agency is aware that some categories of products marketed as dietary supplements in the United States may contain a source of added mercury. Products similar to those that are used as traditional medicines in other countries may sometimes be marketed as dietary supplements in the United States. For example, mercury-containing compounds are used in traditional Chinese medicines. The Chinese Herbal Materia Medica (Ref. 1) reports that cinnabar (mercuric sulfide; cinnabaris or zhu sha in Mandarin Chinese) and calomel (mercurous chloride; calomelas or qing fen in Mandarin Chinese) have been widely used as a sedative and detoxicant and to treat constipation and edema, respectively. The California Department of Health Services reported that 5 of 260 traditional Chinese medicines available in the retail marketplace, which they examined, listed cinnabar as an ingredient on the label (Ref. 2). In this study, 35 of 251 products that were screened for mercury content were found to contain significant quantities of mercury (Refs. 2 and 3). Additionally, the study showed that most of the products that contained significant quantities of mercury did not list mercury sources on the label. Therefore, it is not possible to determine whether the mercury in these products is intentionally added or is present as an unintended ingredient or contaminant. Other than this limited information, FDA is not aware of other uses of mercury in dietary supplements. V. References The following references have been placed on display in the Dockets Management Branch (address above) and may be seen by interested persons between 9 a.m. and 4 p.m., Monday through Friday. 1. Bensky, D., A. Gamble, and T. Kaptchuk, Chinese Herbal Medicine Materia Medica, 8th Ed., Eastland Press, Inc., Seattle, pp. 573-574 and 638-639, 1992. 2. Ko, R. J., and A. Au, 1997-1998 Compendium of Asian Patent Medicines, California Department of Health Services, Food and Drug Branch, Sacramento, 1998. 3. Ko, R. J., ``Adulterants in Asian Patent Medicines,'' New England Journal of Medicine, 339:847, 1998. VI. Call-for-Data and Information In order to prepare the list and provide the analysis required by section 413 of FDAMA, the agency is requesting all manufacturers of any food, including dietary supplement, and human or veterinary drug product (prescription or OTC), and human biological products containing any intentionally introduced mercury compounds, whether used as an active or inactive ingredient, to provide FDA the following information for each product: 1. The commercial name of the product that contains the mercury compound; 2. The chemical name (USAN or established name, if one exists) of the mercury compound(s) present in the drug product; the Chemical Abstract Service (CAS) registry (Reg.) number (No.) and the CAS preferred chemical name of the mercury compound(s) present in the food or dietary supplement product; 3. The quantitative amount of the mercury compound present in the product. State as either quantity per dosage unit or per quantity of product (e.g., ounce or gram). State whether amount is calculated on a weight to weight (w/w) or weight to volume (w/v) basis, where applicable; 4. State the purpose of the mercury compound in the product. If an active ingredient, state the pharmacologic use(s) of the product. If an inactive ingredient, state the function (e.g., preservative). 5. Provide a copy of the product's labeling; and 6. Estimate the amount of the mercury compound used annually in manufacturing the product. VII. Response to Date and Need for Additional Information To date, FDA has received a limited number of responses to the December 1998 call-for-data notice. The information received indicates that mercury compounds are being used as a preservative at very low concentrations: (1) Phenylmercuric acetate in three nasal spray products, (2) phenylmercuric nitrate in one water for injection product and in one veterinary ophthalmic ointment, and (3) thimerosal in 10 nose drop/spray products, 5 eye products, 2 ear products, and 20 injectable products (e.g., toxoids, vaccines, and antivenins). The information also indicates that various mercury compounds are being used as active ingredients in over 200 oral homeopathic drug products. The agency is aware that mercury compounds are present in many other drug products. The agency's Drug Listing System (DLS) identifies over 200 nasal spray/solution products and 5 eye products containing phenylmercuric acetate; over 20 rectal (ointment and suppository) products, 1 eye product. and 3 oral homeopathic products containing phenylmercuric nitrate; over 100 nasal spray/solution, eye, and topical products containing thimerosal; and several hundred oral homeopathic drug products containing ammoniated mercury, mercurius chloride, mercuric chloride, mercuric sulfide red, mercuric sulfate, mercury, mercurius auratus, and mercurius solubilis. The information submitted to date indicates that other mercury compounds are also being used in oral homeopathic drug products, e.g., black mercuric sulfide, mercuric cyanide, mercurous iodide, mercuric iodide, mercury ammonium chloride, mercuric oxide, and Hahnemann's soluble mercury. The agency is especially concerned about the amount of phenylmercuric nitrate that has been present in some rectal products and needs to be informed whether these products still contain this preservative or have been reformulated. The agency is aware that some of the information in its DLS system is outdated because some of the listed products may have been reformulated to delete the mercury preservative. In the absence of updated information, the agency will have to use the information available to it to compile the list of drugs that contain intentionally introduced mercury compounds and to do the quantitative and qualitative analysis of the mercury compounds in this list. Some products in the DLS may no longer be marketed, while manufacturers have not provided information to DLS on other products. Accordingly, the agency is again requesting all affected manufacturers to provide the information requested in section VI of this document. This information is needed for the agency to provide accurate information in response to FDAMA. The agency has received inquiries about the applicability of this information request to biological products. This request encompasses all human biological products. To date, the agency has received five responses concerning biological products. VIII. Followup Request for Data and Information Affected manufacturers should, on or before June 1, 1999, submit the data and information requested in section VI of this document. Two copies of the data and information are to be submitted, except that individuals may submit one copy. Data and information should be addressed to the appropriate FDA centers (Drug Evaluation and Research, Biologics Evaluation and Research, Veterinary Medicine, or Food Safety and Applied Nutrition) (addresses above). All submitted data and information on the quantitative amount of the mercury compound present in the product (unless the information appears in product labeling) and the amount of the [[Page 23086]] mercury compound used annually in manufacturing the product will be handled as confidential by the agency under 21 CFR 20.61. General comments on this call-for-data should be addressed to the Dockets Management Branch (address above). General comments are to be identified with the docket number found in brackets in the heading of this document. Received general comments may be seen in the Dockets Management Branch between 9 a.m. and 4 p.m., Monday through Friday. Dated: April 21, 1999. William K. Hubbard, Acting Deputy Commissioner for Policy. [FR Doc. 99-10697 Filed 4-28-99; 8:45 am] BILLING CODE 4160-01-F