[Federal Register Volume 61, Number 200 (Tuesday, October 15, 1996)]
[Proposed Rules]
[Pages 53685-53688]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-26371]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. 96N-0144]


Over-the-Counter Drug Products Containing Colloidal Silver 
Ingredients or Silver Salts

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to 
establish that all over-the-counter (OTC) drug products containing 
colloidal silver ingredients or silver salts for internal or external 
use are not generally recognized as safe and effective and are 
misbranded. FDA is issuing this proposal because many products 
containing colloidal silver ingredients or silver salts are being 
marketed for numerous serious disease conditions and FDA is not aware 
of any substantial scientific evidence that supports the use of OTC 
colloidal silver ingredients or silver salts for these disease 
conditions.

DATES: Written comments by January 13, 1997; written comments on the 
agency's economic impact determination by January 13, 1997. FDA is 
proposing that any final rule that may issue based on this proposal 
become effective 30 days after its date of publication in the Federal 
Register.

ADDRESSEES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Bradford W. Williams, Center for Drug 
Evaluation and Research (HFD-310), Food and Drug Administration, 7520 
Standish Pl., Rockville, MD 20855, 301-594-0063.

SUPPLEMENTARY INFORMATION:

I. Background

    Colloidal silver is a suspension of silver particles in a colloidal 
base. Historically, a number of colloidal silver/silver colloidal salts 
have been marketed in the United States. Some of these colloidal silver 
products were recognized as official articles in the United States 
Pharmacopeia (U.S.P.) and the National Formulary (N.F.). Colloidal 
silver iodide (Ref. 1) contained not less than 18 percent and not more 
than 22 percent silver, with the product diluted for local use to 
concentrations from 0.05 to 10 percent. Strong silver protein (Ref. 1) 
contained not less than 7.5 percent and not more than 8.5 percent 
silver, with the product diluted for local use to concentrations from 
0.5 to 10 percent. The 10th edition of the N.F. had a cautionary note 
for these products that stated: ``Caution: Solutions of Colloidal 
Silver Iodide should be freshly prepared and should be dispensed in 
amber-colored bottles,'' and ``Caution: Strong Silver Protein Solutions 
should be freshly prepared and should be dispensed in amber-colored 
bottles.''
    Mild silver protein (Ref. 2) contained not less than 19 percent and 
not more than 23 percent silver, with the product diluted for local use 
to concentrations from 0.1 to 5 percent. The 12th edition of the N.F. 
had a cautionary note, which stated: ``Caution: Solutions of Mild 
Silver Protein should be freshly prepared or contain a suitable 
stabilizer, and should be dispensed in amber-colored bottles.''
    Ammoniacal silver nitrate solution (Ref. 2) contained 28.5 to 30.5 
percent silver, was made extemporaneously, and was used locally without 
dilution. Silver nitrate solution (Ref. 3) was made extemporaneously 
and was used locally at strengths from 0.1 to 10 percent.
    None of these formerly recognized colloidal silver preparations has 
been official in the U.S.P. or the N.F. since 1975. Moreover, of the 
silver salts evaluated as part of the agency's OTC drug review thus 
far, none was found to be generally recognized as safe and effective 
for its intended use(s). These included silver nitrate as an astringent 
(58 FR 27636, May 10, 1993) and as a smoking deterrent (58 FR 31236, 
June 1, 1993) and mild silver protein as an ophthalmic anti-infective 
(57 FR 60416, December 18, 1992). Silver acetate was also evaluated as 
a smoking deterrent and found not to be generally recognized as safe 
and effective (58 FR 31236).

II. Recent Developments

    In recent years, colloidal silver preparations of unknown 
formulation have been appearing in retail outlets. These products are 
labeled for numerous disease conditions, including human 
immunodeficiency virus (HIV), acquired immune deficiency syndrome 
(AIDS), cancer, tuberculosis, malaria, lupus, syphilis, scarlet fever, 
shingles, herpes, pneumonia, typhoid, exanthematic typhus, tetanus, 
variola, scarlatina, erysipelas, rheumatism, candida, staphylococcus 
and streptococcus infections, tonsillitis, parasites, fungus, bubonic 
plague, cholera, chronic fatigue, acne, warts, Meniere's disease 
(syndrome), whooping cough, enlarged prostate, perineal eczema, 
hemorrhoids, impetigo, ringworm, recurrent boils, burns, and 
appendicitis.
    Several marketers of these products use a labeling brochure that 
refers to colloidal silver as a treatment or cure for 650 diseases 
(Ref. 4). Some colloidal silver products have been promoted using 
reprints of articles, taken from magazines and newspapers, that make 
claims of extensive health benefits for colloidal silver, similar to 
the claims listed above. The articles have also been shipped with 
colloidal silver products, when the products were ordered through the 
mail (Ref. 5). The dosage form of these colloidal silver products is 
usually oral, but product labeling also contains directions for topical 
and, occasionally, intravenous use.
    In October 1994, FDA issued Health Fraud Bulletin #19 (Ref. 6) to 
address the emerging marketing of colloidal silver products offered for 
serious disease conditions. In that bulletin, the agency stated that it 
was ``not aware of any substantial scientific evidence which 
demonstrates that any OTC colloidal silver solution is useful to 
prevent or treat any serious disease condition.'' The bulletin 
explained that FDA has not approved a new drug application (NDA) for a 
colloidal silver product. In addition, the bulletin stated no data or 
information has been submitted to FDA to document an exemption from the 
new drug provisions of the Federal Food, Drug, and Cosmetic Act (the 
act) under the 1938 or 1962 grandfather provisions. The bulletin 
referred to 21 CFR 314.200(e)(2), which sets forth the type of evidence 
necessary to support an exemption under a grandfather provision.

III. The ``Grandfather'' Exemption

    Some marketers of various colloidal silver preparations claim their 
products are exempt from the ``new drug'' provisions of section 201(p) 
of the act (21 U.S.C. 321(p)) under the ``grandfather'' provisions of 
the 1938 act and the 1962 amendments to the act. The marketers 
frequently claim that their products were marketed before 1938, that 
only insubstantial changes have been made in product formulation and 
labeling since that time, and that

[[Page 53686]]

the products' current labeling contains the same representations for 
use as those contained in the labeling used before 1938.
    To qualify for exemption from the ``new drug'' definition under the 
1938 ``grandfather'' clause, the drug product must have been subject to 
the Food and Drugs Act of 1906, before June 25, 1938, and at such time 
its labeling must have contained the same representations concerning 
the conditions of its use (section 201(p)(1) of the act). Under the 
1962 ``grandfather'' clause, a drug product that, preceding October 9, 
1962, (1) Was commercially used or sold in the United States, (2) was 
not a ``new drug'' as defined in the 1938 act, and (3) was not covered 
by an approved NDA under the 1938 act, would not be subject to the 
added requirement of effectiveness ``when intended solely for use, 
under conditions prescribed, recommended, or suggested in the labeling 
with respect to such drug.'' (Pub. L. 87-781, sec. 107(c)(4), 76 Stat. 
788, note following 21 U.S.C. 321.)
    FDA does not believe that any of the currently marketed products 
qualify for the exemption, because the currently marketed silver 
products do not appear to be the same as the silver products marketed 
in the early 1900's. Unlike the silver preparations that were once 
compendial articles, these new colloidal silver preparations, based on 
their labeling and/or product analysis, appear to contain less silver 
than the products marketed historically. Many of the products FDA has 
sampled lack an ingredient declaration. Samples of some products 
analyzed by FDA laboratories contained as little as 0.01 percent 
silver. Analyses showed potency varied from 15.2 percent to 124 percent 
of the amount of silver declared on the labels. However, FDA has not 
analyzed the majority of the products on the market and, thus, is 
unable to state their actual silver content.
    Any person seeking to show that a drug comes within a grandfather 
exemption must prove every essential fact necessary for invocation of 
the exemption. (See United States v. An Article of Drug * * * ``Bentex 
Ulcerine,'' 469 F.2d 875, 878 (5th Cir. 1972), cert. denied, 412 U.S. 
938 (1973).) Furthermore, the grandfather clause will be strictly 
construed against one who invokes it. (See id.; United States v. Allan 
Drug Corp., 357 F.2d 713, 718 (10th Cir.), cert. denied, 385 U.S. 899 
(1966).) A change in the composition or labeling of the product 
precludes the applicability of the grandfather exemption. (See USV 
Pharmaceutical Corp. v. Weinberger, 412 U.S. 655, 663 (1973).)

IV. Evidence of Safety and Effectiveness

    FDA is not aware of any body of data that supports the use of 
colloidal silver for the various conditions listed in the labeling 
(Refs. 4 and 5) used with currently marketed products.
    The 1939 book, ``Argyria, The Pharmacology of Silver'' (Ref. 7), 
discussed the history and pharmacophysiologic effects of silver 
administration. It included a summary chapter on the negative effects 
of argyria, a permanent ashen-grey discoloration of the skin, 
conjuctiva, and internal organs, resulting from the silver salts. The 
book also included an index that listed proprietary silver compounds 
marketed at that time.
    Goodman and Gilman described colloidal silver use in earlier 
editions of The Pharmacological Basis of Therapeutics (Refs. 8 and 9). 
But in the 1980 edition (Ref. 10), Goodman and Gilman stated:
    Claims that mild silver protein penetrates tissue at the site of 
application because chloride ion does not precipitate the silver are 
misleading. The large-carrier protein molecule penetrates poorly. 
Fortunately, the colloidal silver preparations are now in a deserved 
oblivion.
    Goodman and Gilman (Ref. 10) also stated that the indiscriminate 
use of colloidal silver solutions, especially in the prophylaxis and 
treatment of respiratory tract infections, probably does more harm than 
good. They mentioned that there is no acceptable evidence that the 
routine use of silver solutions for the prophylaxis of colds is at all 
efficacious, and cases of argyria have resulted from this practice.
    Remington's Pharmaceutical Sciences (Ref. 11) and The Dispensatory 
of the United States of America (Ref. 12) state that long-term use of 
silver preparations could lead to argyria. Concerns about the side 
effects of argyria may have contributed to reduced medical usage of 
colloidal silver products.
    The Dispensatory of the United States of America (Ref. 12) also 
stated that there is no justification for the internal use of colloidal 
silver either theoretically or practically.
    Recently, Fung and Bowen (Ref. 13) reviewed the basic chemistry, 
pharmacokinetics, pharmacology, clinical toxicology, and case reports 
of adverse events of OTC silver-containing medicinal products, 
including colloidal silver proteins. They concluded that silver has no 
known physiologic function and that the risk of using these products 
exceeds any unsubstantiated benefit.
    Fung and Bowen reported that, after ingestion, up to 10 percent of 
silver salts may be absorbed. Silver is deposited in many organs. The 
highest concentrations are found in the skin, liver, spleen, and 
adrenal glands, with lesser deposits in the muscle and brain. Argyria 
is the most commonly reported adverse event and results from 
accumulation of silver deposits in the skin below the epidermis. 
Argyria is effectively irreversible.
    As noted in section I. of this document, a number of silver salts 
were evaluated as part of FDA's OTC drug review, and none was found to 
be generally recognized as safe and effective for its intended use(s). 
Accordingly, FDA concludes at this time that no colloidal silver 
ingredients or silver salts are generally recognized as safe and 
effective for OTC use.

V. The Agency's Proposal

    FDA is proposing to declare all OTC drug products containing 
colloidal silver ingredients or silver salts as not generally 
recognized as safe and effective, misbranded, and new drugs within the 
meaning of section 201(p) of the act. FDA proposes to amend subpart E 
of part 310 (21 CFR part 310) by adding new Sec. 310.548 for OTC drug 
products containing colloidal silver ingredients or silver salts. The 
agency invites any interested parties to collect and submit any 
existing data and information that support the safety and effectiveness 
of colloidal silver ingredients or silver salts for any of the uses not 
already evaluated under the OTC drug review. Safety data should be in 
accord with Sec. 330.10(a)(4)(i) (21 CFR 330.10(a)(4)(i)) and 
effectiveness data in accord with Sec. 330.10(a)(4)(ii). The agency 
will evaluate these data and determine if any colloidal silver 
ingredients or silver salts should not be included in new Sec. 310.548.

VI. 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. National Formulary, 10th ed., pp. 517 and 520, Rockville, MD, 
1955.
    2. National Formulary, 12th ed., pp. 354-355, Rockville, MD, 
1965.
    3. The Pharmacopeia of the United States, 16th ed., pp. 643-644, 
Rockville, MD, 1960.
    4. Labeling brochure for ``Colloidal Silver.''
    5. Reprints of articles and labeling that accompanied samples of 
colloidal silver shipped through the mail.
    6. Food and Drug Administration, Health Fraud Bulletin #19, 
``Colloidal Silver,'' October 7, 1994.
    7. Hill, W. B., and D. M. Pillsbury, Argyria, The Pharmacology 
of Silver, The Williams & Wilkins Co., Baltimore, 1939.

[[Page 53687]]

    8. The Pharmacological Basis of Therapeutics, Goodman and 
Gilman, 4th ed., p. 1050, 1970.
    9. The Pharmacological Basis of Therapeutics, Goodman and 
Gilman, 5th ed., pp. 930, 931, 999, and 1000, 1975.
    10. The Pharmacological Basis of Therapeutics, Goodman and 
Gilman, 6th ed., pp. 976-977, 1980.
    11. Remington's Pharmaceutical Sciences, 16th ed., pp. 351, 727, 
and 1111, 1980.
    12. The Dispensatory of the United States of America, 25th ed., 
pp. 1234-1236, 1960.
    13. Fung, M. C., and D. L. Bowen, ``Silver Products for Medical 
Indications: Risk-benefit Assessment,'' Clinical Toxicology, March 
1996.

VII. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this proposed rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the proposed 
rule is not a significant regulatory action as defined by the Executive 
Order and so is not subject to review under the Executive Order.
    Under the Regulatory Flexibility Act, if a rule has a significant 
impact on a substantial number of small entities, an agency must 
analyze regulatory options that would minimize any significant impact 
of a rule on small entities. Early finalization of the regulatory 
status of colloidal silver ingredients and silver salts will benefit 
consumers by the early removal from the marketplace of products for 
which safety and effectiveness have not been established. This will 
result in a direct economic savings and public health protection to 
consumers. In addition, other approved products may be available to 
treat the conditions. This particular rulemaking for OTC colloidal 
silver and silver salts drug products is not expected to pose a 
significant impact on small business because only a limited number of 
products, the agency estimates fewer than 30, would be covered by this 
rulemaking. A number of silver ingredients have already been covered in 
earlier rulemakings in the OTC drug review, and none were found safe 
and effective for OTC human use. Under the Regulatory Flexibility Act 
(5 U.S.C. 605(b)), the Commissioner of Food and Drugs certifies that 
this proposed rule will not have a significant economic impact on a 
substantial number of small entities. No further analysis is required.
    The agency invites public comment regarding any substantial or 
significant economic impact that this rulemaking would have on OTC drug 
products containing colloidal silver ingredients or silver salts. 
Comments regarding the impact of this rulemaking on OTC drug products 
containing colloidal silver ingredients or silver salts should be 
accompanied by appropriate documentation. The agency is providing a 
period of 90 days from the date of publication of this proposed rule 
for comments on this subject to be developed and submitted. The agency 
will evaluate any comments and supporting data that are received and 
will reassess the economic impact of this rulemaking in the preamble to 
the final rule.

VIII. Environmental Impact

    The agency has determined under 21 CFR 25.24(c)(6) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

IX. Request for Comments and Data

    Interested persons may, on or before January 13, 1997 submit to the 
Dockets Management Branch (address above) written comments and data in 
response to the proposed rule. Written comments on the agency's 
economic impact determination may be submitted on or before January 13, 
1997. Three copies of all comments or objections are to be submitted, 
except that individuals may submit one copy. Comments and data should 
be identified with the docket number found in brackets in the heading 
of this document and may be accompanied by a supporting memorandum or 
brief. Received comments and data may be seen in the office above 
between 9 a.m. and 4 p.m., Monday through Friday.

List of Subjects in 21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 310 be amended as follows:

PART 310--NEW DRUGS

    1. The authority citation for 21 CFR part 310 continues to read as 
follows:

    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 512-
516, 520, 601(a), 701, 704, 705, 721 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 
360b-360f, 360j, 361(a), 371, 374, 375, 379e); secs. 215, 301, 
302(a), 351, 354-360F of the Public Health Service Act (42 U.S.C. 
216, 241, 242(a), 262, 263b-263n).

    2. New Sec. 310.548 is added to subpart E to read as follows:


Sec. 310.548  Drug products containing colloidal silver ingredients or 
silver salts offered over-the-counter (OTC) for the treatment and/or 
prevention of disease.

    (a) Colloidal silver ingredients and silver salts have been 
marketed in over-the-counter (OTC) drug products for the treatment and 
prevention of numerous disease conditions. There are serious and 
complicating aspects to many of the diseases these silver ingredients 
purport to treat or prevent. Further, there is a lack of adequate data 
to establish general recognition of the safety and effectiveness of 
colloidal silver ingredients or silver salts for OTC use in the 
treatment or prevention of any disease. These ingredients and salts 
include, but are not limited to, silver proteins, mild silver protein, 
strong silver protein, silver chloride, and silver iodide.
    (b) Any OTC drug product containing colloidal silver ingredients or 
silver salts that is labeled, represented, or promoted for the 
treatment and/or prevention of any disease is regarded as a new drug 
within the meaning of section 201(p) of the Federal Food, Drug, and 
Cosmetic Act (the act) for which an approved application or abbreviated 
application under section 505 of the act and part 314 of this chapter 
is required for marketing. In the absence of an approved new drug 
application or abbreviated new drug application, such product is also 
misbranded under section 502 of the act.
    (c) Clinical investigations designed to obtain evidence that any 
drug product containing colloidal silver or silver salts labeled, 
represented, or promoted for any OTC drug use is safe and effective for 
the purpose intended must comply with the requirements and procedures 
governing the use of investigational new drugs set forth in part 312 of 
this chapter.
    (d) After (date 30 days after date of publication of the final rule 
in the Federal Register), any such OTC drug product containing 
colloidal silver or silver salts initially introduced or

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initially delivered for introduction into interstate commerce that is 
not in compliance with this section is subject to regulatory action.

    Dated: October 9, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-26371 Filed 10-11-96; 8:45 am]
BILLING CODE 4160-01-F