[Federal Register Volume 64, Number 82 (Thursday, April 29, 1999)]
[Notices]
[Pages 23083-23086]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-10697]


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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.

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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.

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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.

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    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

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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