[Federal Register: December 14, 1998 (Volume 63, Number 239)]
[Notices]
[Page 68775-68777]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr14de98-67]

-----------------------------------------------------------------------

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; request for data and information.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is announcing a call-
for-data to identify food and drug products that contain intentionally
introduced mercury compounds, e.g., mercurous chloride, mercuric
chloride, phenylmercuric acetate, thimerosal. The agency is seeking
both quantitative and qualitative information about the mercury
compounds in these food and drug products. This request is part of the
implementation of the Food and Drug Administration Modernization Act of
1997 (FDAMA).

DATES: Submit data and information by March 15, 1999. Submit written
general comments by March 15, 1999.

ADDRESSES: Submit written 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. Submit 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. Submit
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. Submit
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 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

[[Page 68776]]

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 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)) (see Table 1 of this document).

        Table 1.--Mercury Ingredients Listed in 21 CFR 310.545(a)
------------------------------------------------------------------------
             Rulemaking and Ingredients                    Paragraph
------------------------------------------------------------------------
Dandruff/seborrheic dermatitis/psoriasis drug         310.545(a)(7)
 products (Docket No. 82N-0214)
  Mercury oleate
External analgesic drug products: Poison ivy/poison   310.545(a)(10)(vii
 oak/poison sumac drug products (Docket No. 78N-       )
 301P)
  Merbromin (mercurochrome)
  Mercuric chloride (bichloride of mercury, mercury
   chloride)
Laxative drug products: Stimulant laxatives (Docket   310.545(a)(12)(iv)
 No. 78N-036L)
  Calomel (mercurous chloride)
Skin bleaching drug products (Docket No. 78N-0065)    310.545(a)(17)
  Mercury, ammoniated
Skin protectant drug products: Poison ivy/poison oak/ 310.545(a)(18)(vi)
 poison sumac drug products (Docket No. 78N-021P)
  Merbromin (mercurochrome)
  Mercuric chloride (bichloride of mercury, mercury
   chloride)
Ophthalmic drug products: Anti-infective (Docket No.  310.545(a)(21)(ii)
 80N-0145)
  Mercuric oxide, yellow
First aid antiseptic drug products (Docket No. 75N-   310.545(a)(27)(i)
 183F)
  Ammoniated mercury
  Calomel (mercurous chloride)
  Merbromin (mercurochrome)
  Mercufenol chloride (ortho-chloromercuriphenol,
   ortho-hydroxyphenylmercuric chloride)
  Mercuric chloride (bichloride of mercury, mercury
   chloride)
  Mercuric oxide, yellow
  Mercuric salicylate
  Mercuric sulfide, red
  Mercury
  Mercury oleate
  Mercury sulfide
  Nitromersol
  Para-chloromercuriphenol
  Phenylmercuric nitrate
  Thimerosal
  Vitromersol
  Zyloxin
Antimicrobial diaper rash drug products (Docket No.   310.545(a)(27)(ii)
 75N-183D)
  Para-chloromercuriphenol
  Any other ingredient containing mercury
Vaginal contraceptive drug products (Docket No. 80N-  310.545(a)(28)
 0280)
  Phenylmercuric acetate
  Phenylmercuric nitrate
  Any other ingredient containing mercury
------------------------------------------------------------------------

    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 and prescription ophthalmic drug products.
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

[[Page 68777]]

veterinary drug products. These products are all unapproved OTC
products for use in nonfood species. For instance, older text books 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 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.
    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, 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) 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. Request for Data and Information

    Affected manufacturers should, on or before March 15, 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,
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 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: December 7, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-33053 Filed 12-11-98; 8:45 am]
BILLING CODE 4160-01-F