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

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: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule

establishing that all over-the-counter (OTC) drug products containing

colloidal silver ingredients or silver

[[Page 44654]]

salts for internal or external use are not generally recognized as safe

and effective and are misbranded. FDA is issuing this final rule

because many OTC drug 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: This regulation is effective September 16, 1999.

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

In the Federal Register of October 15, 1996 (61 FR 53685), FDA

published a proposed rule to declare that all OTC drug products

containing colloidal silver ingredients or silver salts are not

generally recognized as safe and effective, and are new drugs and

misbranded within the meaning of section 201(p) of the Federal Food,

Drug, and Cosmetic Act (the act) (21 U.S.C. 321(p)). Colloidal silver

is a suspension of silver particles in a colloidal base. In recent

years, colloidal silver preparations of unknown formulation have been

appearing in retail outlets. These products are labeled for numerous

disease conditions, many of which are serious diseases. The dosage form

of these colloidal silver products is usually oral, but product

labeling also contains directions for topical and, occasionally,

intravenous use.

FDA has not approved a new drug application (NDA) for any colloidal

silver product. None of the silver salts evaluated as part of FDA's OTC

drug review was found to be generally recognized as safe and effective

for its intended use(s). FDA is not aware of any substantial scientific

evidence that supports the use of OTC colloidal silver ingredients or

silver salts for disease conditions. The agency invited 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. Interested persons were invited to submit written comments

on the proposed regulation and on the agency's economic impact

determination by January 13, 1997.

In response to the proposal, the agency received 251 responses.

Copies of these comments are on public display in the Dockets

Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers

Lane, rm. 1061, Rockville, MD 20852. Additional information that has

come to the agency's attention since publication of the proposal is

also on public display in the Dockets Management Branch.

Based on the information set forth in the proposed rule, and after

consideration of the information submitted by the public comments (as

summarized as follows), FDA is declaring that all OTC drug products

containing colloidal silver ingredients or silver salts are not

generally recognized as safe and effective, and are new drugs and

misbranded within the meaning of section 201(p) of the act. Adequate

safety and effectiveness data have not been provided to establish

general recognition of the safety and effectiveness of colloidal silver

or silver salt ingredients for any OTC drug uses. The data submitted

did not include the required absorption, metabolism, tissue

distribution, accumulation, excretion, and pharmacodynamics (effect of

the drug at its action site) of silver in the body, both when taken

internally and applied externally, and of the effect of the particle

size of the silver on these systemic effects.

FDA is amending subpart E of part 310 (21 CFR part 310) to add

Sec. 310.548 for OTC drug products containing colloidal silver

ingredients or silver salts. The agency has expanded proposed

Sec. 310.548(a) to include some additional silver ingredients.

II. Public Comments and the Agency's Response

A. General Comments

1. Many comments agreed with the proposed rule. One of these

comments cautioned against the dangers of using untested drugs and

recalled that Laetrile misled unsuspecting people in search of a quick

cancer cure. Another comment provided personal experience as a victim

of argyria who had been disfigured for 40 years as a result of using

colloidal silver. This comment included an excerpt from a book that

recorded 114 cases of argyria compiled in the 1930's. The comment

contended that many marketers of colloidal silver deny the potential

for harm and often misquote or distort the historical articles dealing

with these products.

A physician, who was formerly a pharmacist, recounted his own

experience in reviewing cases of argyria. The victims had ingested

silver products in the 1940's and 1950's. The physician was concerned

that a product that does not have any rational use would lead to the

redevelopment of argryia as a clinical problem. Another physician/

ophthalmologist commented that colloidal silver is dangerous quackery.

The agency appreciates these comments in support of its proposal.

B. Comments on Safety and Effectiveness

2. One comment expressed concern that many different silver

products being marketed are inferior products and are not even true

colloids. Another comment stated that the vast majority of silver

products being sold are fraudulent products. The comment noted that it

had tested a number of these products and found that several actually

had no silver content, one did not contain the silver particle size as

stated on the label, and only one product exceeded all stated purity

and stability claims found on the label. The comment added that many of

the products were only duplicates of older colloidal silver products.

The comment considered these ``newer'' products as having the same

dangers, intermittent effectiveness, and lack of stability as the older

products. The comment contended that the vast majority of the colloidal

silver products it tested are totally useless, some were dangerous to

ingest, and some were possibly a threat to life. The comment stated

that it is a major problem to keep off the market these so-called

``colloidal silver'' products that contain significant amounts of

silver ions and silver salts. The comment suggested a revision of the

United States Pharmacopeia (USP) specifications for these products.

Another comment stated that many of the colloidal silver products

it analyzed are considered ``Bredig Sols'' (simple colloidal silver),

referring to Bredig, Heidelberg, 1893. The comment added that a pure

Bredig Sol is simply elemental silver in distilled water, while some

Bredig Sols are mixed with saline to make them isotonic. The comment

mentioned that the silver content in these products (a viable product

could contain 0.005 percent silver) is many magnitudes less than the

silver content of the products discussed by FDA in its safety and

effectiveness evaluation (61 FR 53685 at 53686). The comment contended

that the agency had not reviewed the Bredig Sols and disagreed with the

agency's assumptions that there is an analogous comparison between

colloidal silver proteins and other silver compounds to a simple Bredig

Sol.

[[Page 44655]]

These comments highlight the existing problems in trying to

establish whether any silver salts or colloidal silver ingredients can

be generally recognized as safe and effective. Because of the

acknowledged differences in silver content and particle size of the

silver in various products, it is difficult to draw conclusions from

clinical studies conducted on different silver products. The agency has

minimal manufacturing controls information on these products. The

agency does not have information that assures the strength, quality,

purity, and potency of various silver products used in clinical studies

and other reports included in the comments.

Concerning the comment suggesting a revision of USP specifications,

the proposed rule stated that none of the formerly recognized colloidal

silver preparations (e.g., colloidal silver iodide, strong (or mild)

silver protein, ammoniacal silver nitrate solution) has been official

in the USP or the National Formulary (N.F.) since 1975. It is

industry's responsibility to have these silver ingredients reinstated

in the USP or N.F. and to revise the specifications used in the former

compendial monographs. Concerning ``Bredig Sols,'' the comment did not

provide any specific safety and effectiveness data; thus, the agency is

not able to establish that such products are generally recognized as

safe and effective.

3. Several comments submitted information purporting to support the

safety of colloidal silver and other silver ingredients. The comments

contended that silver is nontoxic and has minimal side effects. One

comment stated that silver is poorly absorbed and not readily retained

in the body when taken orally. Another comment stated that colloidal

silver is harmless to the liver, kidneys, other internal organs, human

enzymes, and the eyes; contains no free radicals; and has no reaction

with other medications. Several comments mentioned that argyria, a blue

skin discoloration resulting from prolonged administration of silver

compounds and accumulation in the body, is the main side effect that

occurs. One comment explained that argyria occurs because a small

amount of the silver compound is absorbed and deposited in the skin,

where it is reduced by light to metallic silver; the resulting skin

discoloration persisting almost indefinitely, although there are no

associated toxic effects. The comment contended that colloidal silver

is the only known form of silver that is not deposited under the skin

even with large doses. Another comment added that most of the reported

cases of argyria resulted from the use of silver nitrate, various ionic

silver salts, or highly concentrated mild silver protein. The comment

concluded that the dilute, mild silver protein products marketed today

are similar to pre-1938 colloidal silver solutions and do not cause

argyria. The comment also discussed the levels of silver in the

majority of silver products marketed today and indicated that the

amount of silver ingested from these products and the diet are within

the Environmental Protection Agency's maximum daily exposure reference

dose of 350 micrograms per day for a 70 kilogram (kg) adult.

Another comment presented the results of several animal (rat)

studies involving acute or chronic administration of various amounts of

colloidal silver (mild silver protein in colloidal suspension),

approximately 1,500 parts per million (ppm), either by intravenous (IV)

injection or in drinking water. The IV studies included an initial

acute dose finding study followed by a chronic study (0.15 or 0.015

milligram (mg) per 1 milliliter (mL)). Two groups of four rats received

each dosage; two rats served as controls and received 1 mL of

physiological saline solution. Each rat received a total of 12

injections. The investigator reported that no abnormal clinical or

behavioral signs were observed after 12 days of treatment. In another

followup chronic IV rat study, three rats were injected with 1,500 ppm

colloidal silver three times per week for 4 weeks (a total of 18 mg per

300 gram (g) rat), and three rats served as controls. All treated and

control rats were weighed at the time of injection. At the completion

of the study, there were no differences in body weight and no clinical

signs or gross pathologic changes between the treated and control

groups. The drinking water study involved 15 rats fed 1.5 ppm mild

silver protein solution in their drinking water for 40 days. The rats

showed no clinical signs of gross pathological changes at the end of

the treatment period. Three rats received regular drinking water and

served as controls. The investigator stated that the data do not

provide information about the metabolic fate of the silver, but support

safety if extrapolated to humans because a 60-kg person would have to

be given 3,600 mg to receive an amount equivalent to the rats' highest

dose (18 mg/300 g rat).

The agency does not consider this information adequate to establish

general recognition of the safety of silver salts or colloidal silver

ingredients for OTC drug use. The comments themselves indicate that

ionic silver salts and highly concentrated mild silver protein clearly

are not safe for OTC use. The animal data indicate that mild silver

protein in colloidal suspension at low concentrations may be safe in

rats when administered in specific concentrations for up to 40 days.

Additional data are needed in humans on the absorption, metabolism,

tissue distribution, accumulation, excretion, and pharmacodynamics of

silver in the body, both when taken internally and applied externally,

and of the effect of the particle size of the silver on these systemic

effects. The agency concludes that a full pharmacologic profile that is

relevant to human use is needed.

4. Several comments submitted information purporting to support the

effectiveness of colloidal silver and other silver ingredients. One

comment provided a partial list of the more than 650 diseases that

colloidal silver has been used against and included a number of

testimonials. Another comment stated that silver will kill 650 disease

organisms, but it does not cure 650 diseases. The comment added that a

Bredig Sol of silver at 30 ppm is an effective germicide for both gram-

positive and gram-negative bacteria, fungi, yeasts, and viruses.

Another comment noted the antimicrobial and bacteriostatic effects of

diluted colloidal silver protein solutions. One comment provided a

number of case reports involving the use of a colloidal silver (200

ppm) suspension with protein and distilled water and a mild silver

protein cream to treat various conditions (e.g., rash, pain, and sore

gums).

Another comment, from a physician, described a double-blind

clinical study that he conducted using a commercial colloidal silver

product (concentration not provided) in 22 men ages 50 to 82, with a

mean age of 61.9 years. The physician obtained a brief medical history

from each man and did a rectal examination. The men reported that

nocturia (frequency of urination) ranged from one to five times a

night. The physician assumed that the men had benign prostatic

hypertrophy because of their age and the onset of symptoms in recent

years. Of the 22 men, 15 took colloidal silver and 7 took placebo

(colored water). The dose was 1 teaspoon (tsp) of the products morning

and evening, and the duration of the study was from 19 to 23 days, with

one exception of 10 days for a late entry. At the end of the study,

four men (all on the colloidal silver) reported considerable

improvement in the nocturia, with a reduction from 2 to 4 times to 1

time each night, while six other men (five on the colloidal silver)

noted some improvement in the nocturia. Two men with a history of

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transurethral resection of the prostate, who were on the colloidal

silver, did not report any improvement.

Subsequently, all of the men continued on colloidal silver (1 tsp

daily) for the next 8 weeks. The men were interviewed after about 4

more weeks, and each completed an American Urological Association (AUA)

Symptom Index representing symptoms at the time of the interview. The

men also completed an AUA index representing symptoms before starting

the colloidal silver. The AUA index is based on answers to seven

questions, graded from 0 (not at all) to 5 (almost always), with the

score being a sum of the answers to the questions. The one man who

reported improvement on placebo reported marked improvement on the

colloidal silver, with his nocturia decreasing from 2 to 3 times to 1,

and occasionally 0, time each night. His AUA index was 9+ at the

beginning and improved to a 3 at the last interview. One man moved, and

a followup was not obtained. Of the remaining 21 men, 16 reported

improvement of varying degrees. All reported decreased nocturia, with

five men recording an improvement of 2 or less on the AUA index and

nine men reporting an improvement of 3 to 10 on the AUA index. One man

reported that he had been taking a prescription drug for benign

prostatic hypertrophy before starting the colloidal silver. The last

two men had improvements of 14 and 18 on the AUA index, with nocturia

decreasing by 3 and 2 times, respectively. Five men reported no

improvement during the study. Two of these men had a history of

transurethral resection of the prostate, one had been taking a

prescription drug for this condition for the past 6 months and his

nocturia had already improved to 1 time each night, and the other two

had been having symptoms for 6 and 15 years, respectively, and had an

enlarged prostate when the study began. The physician noted that

because the four men with a tender prostate improved, it was reasonable

to suggest that the beneficial action of the colloidal silver was due

to its antibacterial activity. He hypothesized that there may be some

subclinical prostatitis in many men with benign prostatic hypertrophy,

and this might explain why the colloidal silver resulted in a

remarkable reduction in the men's symptoms. The physician concluded

that the results of this study merit further investigation by the

medical community.

The physician also commented on some other observations from about

50 men who had taken colloidal silver (most for symptoms of prostatism)

under his direction before, during, and after the study (a period of

about 6 months). Six noted clearing of acne or other infectious lesions

of the skin, three reported improvement of mucus in the throat and

associated cough of long duration, two indicated that irritation around

the anus had cleared, one stated that he had no summer colds for 3

months (which was unusual for him), eight reported improvement in nasal

discharge and sinus trouble (especially when using colloidal silver in

a nasal spray), two noted a reduction in upset stomach and abdominal

pain, and two reported that their sexual enjoyment and performance had

improved. The physician concluded that these observations suggested

some areas that needed to be investigated further.

The agency finds that the previous studies are not adequate and

well-controlled clinical studies of the type described in Sec. 314.126

(21 CFR 314.126) that need to be conducted. The studies have major

methodic flaws. There needs to be a clear statement of the objectives

of the investigation and a protocol containing a specific study design,

the method of subject selection (with inclusion and exclusion

criteria), the method of assigning subjects to treatment and control

groups, well-defined methods for measuring the subjects' responses, and

methods for analysis of the study results. Adequate measures need to be

taken to minimize bias on the part of the subjects, observers, and

analysts of the data, which is done by adequate blinding. The agency is

unable to determine the adequacy of the blinding in the physician's

study because the placebo was described as ``colored water.'' The

agency is not able to ascertain the degree of similarity or difference

that existed in the appearance of the colloidal silver product and the

placebo to determine how well the study was blinded. The studies need

replication by other investigators and need to follow Sec. 314.126.

Likewise, the conditions described in the case reports provided by one

comment need to be studied in adequate and well-controlled clinical

trials. Finally, the information that silver will kill 650 disease

organisms and that a Bredig Sol of silver at 30 ppm is an effective

germicide for both gram-positive and gram-negative bacteria, fungi,

yeasts, and viruses needs to be related to in vivo treatment for

specific disease conditions. The agency concludes that the data and

information submitted are not sufficient to establish general

recognition of effectiveness for colloidal silver or other silver

ingredients for any specific OTC condition.

C. The Grandfather Clauses of the Act

5. One comment claimed that the silver products marketed today are

the same as the more dilute mild silver protein products marketed pre-

1938 that did not cause argyria. The comment made the following

recommendation: FDA should set guidelines of the acceptable levels of

the solutions and the dosage based on current EPA safety standards and

what was available pre-1938, so that a ``grandfathered'' standard is

implemented. Another comment stated that not approving its colloidal

silver product as a grandfathered colloidal silver would be to deprive

the public of the use of an extremely safe and effective product

already in use for 4 years.

The ``grandfather exemption'' was discussed in detail in the

proposed rule (61 FR 53685 to 53686). None of the comments provided any

evidence to show that the composition and the labeling of colloidal

silver or silver salt drug products have remained unchanged since 1938

or 1962. Without such evidence, the products cannot qualify for either

grandfather exemption, and there is no need to set any guidelines as

requested by one comment.

D. Freedom of Choice

6. A number of comments included individual testimonials or

expressions of belief that colloidal silver benefited their health and

that of their family members or friends. A few comments mentioned

benefits experienced by pets. Many of the comments stated that the

proposed rule would deny them the freedom of choice to select their own

drugs.

FDA's statutory mandate includes protection and promotion of the

public health by ensuring that drugs are not only safe but also

effective for their intended use. The Commissioner of Food and Drugs'

decision on the status of Laetrile, published in the Federal Register

of August 5, 1977 (42 FR 39788), expresses the agency's position on

freedom of choice with respect to ensuring that drugs are not only

safe, but also effective. That statement reads in part:

In passing the 1962 Amendments to the act--the amendments that

require that a drug be proved effective before it may be marketed--

Congress indicated its conclusions that the absolute freedom to

choose an ineffective drug was properly surrendered in exchange for

the freedom from the danger to each person's health and well-being

from the sale and use of worthless drugs * * *. To the extent that

any freedom

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has been surrendered by the passage of the legislation which bans

from the marketplace drugs that have not been proven to be

effective, that surrender was a rational decision which has resulted

in the achievement of a greater freedom from the dangers to health

and welfare represented by such drugs.

Agency regulations in 21 CFR 330.10(a)(4)(ii) state that the

standards for effectiveness for an OTC drug that is generally

recognized as effective include a requirement for controlled clinical

investigations. Isolated case reports, random experience, and reports

lacking the details that permit scientific evaluation are not

considered adequate to establish effectiveness. Testimonials from

consumers cannot be considered as adequate proof of effectiveness or

safety. None of the comments presented any evidence of safety or

effectiveness beyond personal experience.

In the absence of data demonstrating that the ingredients present

in OTC drug products containing colloidal silver ingredients or silver

salts are generally recognized as safe and effective, these ingredients

cannot be included in an OTC drug product. After the effective date of

the final regulation, any such OTC drug product initially introduced or

initially delivered for introduction into interstate commerce (unless

it is the subject of an approved NDA, of which there currently are

none) that is not in compliance with this regulation will be subject to

regulatory action.

E. The Dietary Supplement Health and Education Act (DSHEA)

7. Several comments, from consumers, stated that the specific

product they used did not make any claims and might be considered a

dietary supplement. None of the comments provided any labeling or

specifics about the products they used.

This final rule addresses products marketed as OTC drugs. A product

that is not intended for OTC ``drug'' use in accord with section

201(g)(1) of the act would not be subject to this final rule. A product

containing silver could, under certain circumstances, be marketed as a

dietary supplement if it meets the definition in section 201(ff) of the

act and other applicable requirements. Among other things, such a

product's label must state that the product is a dietary supplement and

meet other labeling requirements of the act. (See, e.g., section

403(q), (r), and (s) of the act (21 U.S.C. 343(q), (r), and (s)).) It

must also meet the safety requirements of the act. (See, e.g., 21

U.S.C. 342(a), (f), and (g).) FDA may take regulatory action against a

product marketed as a dietary supplement when authorized to do so by

the act.

A dietary supplement containing colloidal silver or silver salts

may not be labeled in whole or in part for topical use. Section

201(ff)(2)(A)(i) of the act requires that a dietary supplement is a

product that is ``intended for ingestion.'' The term ingestion has been

addressed by the court in United States v. Ten Cartons, Ener-B Nasal

Gel, 888 F. Supp. 393 (E.D.N.Y.), aff'd, 72 F.3d 285 (2d Cir. 1995). A

topical product could not be a dietary supplement.

III. Analysis of Impacts

FDA has examined the impacts of the final rule under Executive

Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).

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). 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 the rule on small

entities.

Title II of the Unfunded Mandates Reform Act (2 U.S.C. 1501 et

seq.) requires that agencies prepare a written statement and economic

analysis before proposing any rule that may result in an expenditure in

any one year by State, local, and tribal governments, in the aggregate,

or by the private sector, of $100 million (adjusted annually for

inflation). As the agency stated in the proposed rule, this rulemaking

is not expected to pose a significant impact on small business because

only a limited number of products are affected (61 FR 53685 at 53687).

The agency believes that this final rule is consistent with the

principles set out in the Executive Order and in these two statutes.

The purpose of this final rule is to establish that all 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. The agency's Drug Listing System

identifies a multitude of silver-containing products. These products

may contain silver, silver ion, silver chloride, silver cyanide, silver

iodide, silver oxide, or silver phosphate.

All of these manufacturers are considered small entities, using the

U.S. Small Business Administration designation for this industry (750

employees).

Manufacturers will no longer be able to market OTC drug products

containing any silver ingredients after the effective date of the final

rule. While the manufacturers may incur a loss of revenue from some of

these products, some silver products for internal use may be able to

continue to be marketed as dietary supplements, provided they meet,

among other regulatory requirements applicable to dietary supplements,

the definition of dietary supplements in section 201(ff) of the act and

meet the labeling requirements of section 403 of the act.

Manufacturers have been aware of the possible effects on the status

of these OTC silver drug products since October 1996 and have not

submitted adequate safety and effectiveness data to the agency. Since

publication of the 1996 proposal and with the 30-day implementation

date after publication of the final rule, manufacturers should have

ample time to deplete most of their remaining stock of OTC drug

products containing the affected ingredients.

The agency has considered a longer effective date for this final

rule. However, manufacturers have not submitted the necessary data, and

safety and effectiveness have not been established for the ingredients

included in this final rule. Consumers will benefit from the removal

from the marketplace of OTC drug products containing ingredients for

which safety and effectiveness have not been established. If consumers

purchase these products marketed as dietary supplements and if the

product bears a statement claiming a benefit related to a classical

nutrient deficiency disease and discloses the prevalence of such

disease in the United States, describes the role of a nutrient or

dietary ingredient intended to affect the structure or function of the

body in humans, characterizes the documented mechanism by which a

nutrient or dietary supplement acts to maintain such structure or

function, or describes general well-being from consumption of a

nutrient or dietary ingredient, then the labeling will have to inform

them that ``This statement has not been evaluated by the Food and Drug

Administration. This product is not intended to diagnose, treat, cure,

or prevent any disease.'' (See 21 U.S.C. 343(r)(6).)

While this final rule may cause manufacturers to discontinue

marketing or reformulate or relabel some products, these manufacturers

have known for some time that if adequate data were not submitted to

support safety and effectiveness, cessation of marketing of the current

OTC drug products would be required, in any event, when the final

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rule was published and became effective.

The analysis shows that this final rule is not economically

significant under Executive Order 12866 and that the agency has

considered the burden to small entities. Thus, this economic analysis,

together with other relevant sections of this document, serves as the

agency's final regulatory flexibility analysis, as required under the

Regulatory Flexibility Act. Finally, this analysis shows that the

Unfunded Mandates Reform Act does not apply to the final rule because

it would not result in an expenditure in any one year by State, local,

and tribal governments, in the aggregate, or by the private sector, of

$100 million.

IV. Paperwork Reduction Act of 1995

This final rule contains no collections of information. Therefore,

clearance by the Office of Management and Budget under the Paperwork

Reduction Act of 1995 is not required.

V. 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.

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, 21 CFR part

310 is amended as follows:

PART 310--NEW DRUGS

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

follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f,

360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262,

263b-263n.

2. Section 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, silver ion, silver chloride, silver

cyanide, silver iodide, silver oxide, and silver phosphate.

(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 as set forth in part 312

of this chapter.

(d) After September 16, 1999, any such OTC drug product containing

colloidal silver or silver salts initially introduced or initially

delivered for introduction into interstate commerce that is not in

compliance with this section is subject to regulatory action.

Dated: July 14, 1999.

Margaret M. Dotzel,

Acting Associate Commissioner for Policy.

[FR Doc. 99-21253 Filed 8-16-99; 8:45 am]

BILLING CODE 4160-01-F