[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
