Oral Health Care Drug Products for Over-the-Counter Human Use; Tentative Final Monograph for Oral Antiseptic Drug Products; Proposed Rule DEPARTMENT OF HEALTH AND HUMAN SERVICES

SUMMARY: The Food and Drug Administration (FDA) is issuing a notice of

proposed rulemaking in the form of a tentative final monograph that

would establish conditions under which over-the-counter (OTC) oral

antiseptic drug products (drug products used to help decrease the

chance of infection in wounds in the mouth) are generally recognized as

safe and effective and not misbranded. FDA is issuing this notice of

proposed rulemaking after considering the report and recommendations of

the Advisory Review Panel on OTC Oral Cavity Drug Products and public

comments on an advance notice of proposed rulemaking that was based on

those recommendations. This proposal is part of the ongoing review of

OTC drug products conducted by FDA.

DATES: Written comments, objections, or requests for oral hearing on

the proposed regulation before the Commissioner of Food and Drugs by

August 8, 1994. Because new testing procedures for OTC oral antiseptic

drug products are included in this tentative final monograph, the

agency is allowing a period of 180 days for comments and objections

instead of the normal 60 days. New data by February 9, 1995. Comments

on the new data by April 10, 1995. Written comments on the agency's

economic impact determination by August 8, 1994.

ADDRESSES: Written comments, objections, new data, or requests for oral

hearing to the Dockets Management Branch (HFA-305), Food and Drug

Administration, rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug

Evaluation and Research (HFD-810), Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857, 301-594-5000.

SUPPLEMENTARY INFORMATION: In the Federal Register of May 25, 1982 (47

FR 22760), FDA published, under Sec. 330.10(a)(6) (21 CFR

330.10(a)(6)), an advance notice of proposed rulemaking to establish a

monograph for OTC oral health care drug products, together with the

recommendations of the Advisory Review Panel on OTC Oral Cavity Drug

Products (Oral Cavity Panel), which was the advisory review panel

responsible for evaluating data on the active ingredients in this drug

class. Interested persons were invited to submit comments by August 23,

1982. Reply comments in response to comments filed in the initial

comment period could be submitted by September 22, 1982. In the Federal

Register of July 30, 1982 (47 FR 32953), in response to a request for

an extension of time, the comment period and reply comment period for

OTC oral health care drug products were extended to November 22, 1982

and December 22, 1982, respectively.

In the Federal Register of December 28, 1982 (47 FR 57739), the

reply comment period was extended to January 21, 1983.

In accordance with Sec. 330.10(a)(10), the data and information

considered by the Panel were put on public display in the Dockets

Management Branch (address above), after deletion of a small amount of

trade secret information.

In response to the advance notice of proposed rulemaking, 11 drug

manufacturers, 3 professional organizations, 4 health professionals,

and 1 individual consumer submitted comments. Copies of the comments

received are on public display in the Dockets Management Branch

(address above).

FDA is issuing the tentative final monograph for OTC oral health

care drug products in several segments. This document is the third

segment to be published, and it contains the agency's responses to

comments on OTC oral antiseptic drug products and to comments on the

drug or cosmetic status of certain oral antiseptic ingredients and

claims. The first segment of the tentative final monograph covering OTC

oral health care anesthetic/analgesic, astringent, debriding agent/oral

wound cleanser, and demulcent drug products was published in the

Federal Register of January 27, 1988 (53 FR 2436). The second segment,

an amendment to the tentative final monograph to include OTC relief of

oral discomfort drug products, was published in the Federal Register of

September 24, 1991 (56 FR 48302). Another part of the OTC oral health

care drug products rulemaking involves antiplaque and antiplaque-

related products. The agency published a call-for-data for OTC

antiplaque ingredients in the Federal Register of September 19, 1990

(55 FR 38560). The data received in response to that call-for-data are

currently being evaluated by the Dental Products Panel. The Panel's

recommendations to the agency regarding the safety and effectiveness of

antiplaque and antiplaque-related drug products will be published in an

advance notice of proposed rulemaking in a future issue of the Federal

Register.

The advance notice of proposed rulemaking, which was published in

the Federal Register on May 25, 1982 (47 FR 22760), was designated as a

``proposed monograph'' in order to conform to terminology used in the

OTC drug review regulations (21 CFR 330.10). Similarly, the present

document is designated as a ``tentative final monograph.'' In this

tentative final monograph (proposed rule) to amend part 356 (21 CFR

part 356) (proposed in the Federal Register of January 27, 1988, 53 FR

2436), FDA states for the first time its position on the establishment

of a monograph for OTC oral antiseptic drug products. Final agency

action on this matter will occur with the publication at a future date

of a final monograph, which will be a final rule establishing a

monograph for OTC oral health care drug products and will include oral

antiseptic drug products.

This proposal constitutes FDA's tentative adoption of the Oral

Cavity Panel's conclusions and recommendations on OTC oral antiseptic

drug products, as modified on the basis of the comments received and

the agency's independent evaluation of that report. Modifications have

been made for clarity and regulatory accuracy and to reflect new

information. Such new information has been placed on file in the

Dockets Management Branch (address above). These modifications are

reflected in the following summary of the comments and FDA's responses

to them.

The OTC drug procedural regulations (21 CFR 330.10) provide that

any testing necessary to resolve the safety or effectiveness issues

that formerly resulted in a Category III classification, and submission

to FDA of the results of that testing or any other data, must be done

during the OTC drug rulemaking process before the establishment of a

final monograph. Accordingly, FDA does not use the terms ``Category I''

(generally recognized as safe and effective and not misbranded),

``Category II'' (not generally recognized as safe and effective or

misbranded), and ``Category III'' (available data are insufficient to

classify as safe and effective, and further testing is required) at the

final monograph stage. In place of Category I, the term ``monograph

conditions'' is used; in place of Categories II or III, the term

``nonmonograph conditions'' is used. This document retains the concepts

of Categories I, II, and III at the tentative final monograph stage.

The agency advises that the conditions under which the drug

products that are subject to this monograph would be generally

recognized as safe and effective and not misbranded (monograph

conditions) will be effective 12 months after the date of publication

of the final monograph in the Federal Register. On or after that date,

no OTC drug product that is subject to the monograph and that contains

a nonmonograph condition, i.e., a condition that would cause the drug

to be not generally recognized as safe and effective or to be

misbranded, may be initially introduced or initially delivered for

introduction into interstate commerce unless it is the subject of an

approved application. Further, any OTC drug product subject to this

monograph that is repackaged or relabeled after the effective date of

the monograph must be in compliance with the monograph regardless of

the date the product was initially introduced or initially delivered

for introduction into interstate commerce. Manufacturers are encouraged

to comply voluntarily with the monograph at the earliest possible date.

In the advance notice of proposed rulemaking for OTC oral health

care drug products (47 FR 22760), the agency suggested that the

conditions included in the monograph (Category I) be effective 6 months

after the date of publication of the final monograph in the Federal

Register and that the conditions excluded from the monograph (Category

II) be eliminated from OTC drug products effective 6 months after the

date of publication of the final monograph, regardless of whether

further testing was undertaken to justify their future use. Experience

has shown that relabeling of products covered by the monograph is

necessary in order for manufacturers to comply with the monograph. New

labels containing the monograph labeling have to be written, ordered,

received, and incorporated into the manufacturing process. The agency

has determined that it is impractical to expect new labeling to be in

effect 6 months after the date of publication of the final monograph.

Experience has shown also that if the deadline for relabeling is too

short, the agency is burdened with extension requests and related

paperwork.

In addition, some products will have to be reformulated to comply

with the monograph. Reformulation often involves the need to do

stability testing on the new product. An accelerated aging process may

be used to test a new formulation; however, if the stability testing is

not successful, and if further reformulation is required, there could

be a further delay in having a new product available for manufacture.

The agency wishes to establish a reasonable period of time for

relabeling and reformulation in order to avoid an unnecessary

disruption of the marketplace that could not only result in economic

loss, but also interfere with consumers' access to these products.

Therefore, the agency is proposing that the final monograph be

effective 12 months after the date of its publication in the Federal

Register. The agency believes that within 12 months after the date of

publication most manufacturers can order new labeling and reformulate

their products and have them in compliance in the marketplace.

If the agency determines that any labeling for a condition included

in the final monograph should be implemented sooner than the 12-month

effective date, a shorter deadline may be established. Similarly, if a

safety problem is identified for a particular nonmonograph condition, a

shorter deadline may be set for removal of that condition from OTC drug

products.

In the event that new data submitted to the agency during the

allotted 12-month comment and new data period are not sufficient to

establish ``monograph conditions'' for OTC oral antiseptic drug

products, the final rule will declare these products to be new drugs

under section 201(p) of the Federal Food, Drug, and Cosmetic Act (the

act) (21 U.S.C. 321(p)), for which new drug applications approved under

section 505 of the act (21 U.S.C. 355) and 21 CFR part 314 are required

for marketing. That rule would also declare that in the absence of an

approved new drug application, these products would be misbranded under

section 502 of the act (21 U.S.C. 352). The rule will then be

incorporated into 21 CFR part 310, subpart E--Requirements for Specific

New Drugs or Devices, instead of into an OTC drug monograph in part

356.

All ``OTC Volumes'' cited throughout this document refer to the

submissions made by interested persons pursuant to the call-for-data

notices published in the Federal Registers of January 30, 1973 (38 FR

2781) (dental drug products) and July 20, 1973 (38 FR 19444) (oral

health care drug products) or to additional information that has come

to the agency's attention since publication of the advance notice of

proposed rulemaking. The volumes are on public display in the Dockets

Management Branch (address above).

I. The Agency's Tentative Conclusions on the Comments

A. General Comments on Oral Antiseptic Ingredients

1. Several comments objected to the recommendation of the majority

of the Oral Cavity Panel that only one Category III indication is

appropriate for oral antiseptics, i.e., for the treatment of sore mouth

and sore throat. One comment contended that antiseptic mouthwashes are

not intended to be used primarily in the treatment of sore mouth and

sore throat. Two comments maintained that the Oral Cavity Panel's

recommendations that antiseptic mouthwashes be used solely for this

indication is inconsistent with the commonly accepted purpose of these

products. Another comment stated that the use of oral antiseptics

solely for the treatment of sore mouth or sore throat, as the Panel

recommended, would result in a disservice to consumers by depriving

them of safe, familiar products upon which they depend. A number of

comments discussed the use of oral antiseptic ingredients to reduce

dental plaque, gingivitis, or both.

The agency notes that the Oral Cavity Panel used the term

``antimicrobial agent'' to describe an ingredient that kills

microorganisms or prevents or inhibits their growth and reproduction.

In this tentative final monograph, in order to be consistent with

terminology proposed in the tentative final monograph for OTC first aid

antiseptic drug products in the Federal Register of July 22, 1991 (56

FR 33644), the agency is proposing to replace the Panel's term

``antimicrobial'' with the term ``antiseptic.''

The Oral Cavity Panel only reviewed antiseptic ingredients for sore

mouth and sore throat claims and did not specifically evaluate the

effectiveness of oral antiseptics to inhibit plaque formation. Although

data on plaque reduction as a measure of the effectiveness of OTC oral

antiseptics were presented to that Panel, it did not accept such data

because it believed that ``the rationality of plaque reduction as a

criterion of effectiveness of antimicrobial agents for use in the mouth

and throat is highly debatable, and evidence of the validity of the

method is scant'' (47 FR 22760 at 22840 to 22842). The Panel was not

charged with reviewing drug products used to treat dental or

periodontal diseases, and it did not address ingredients with

antiplaque claims.

Because no advisory review panel reviewed the safety and

effectiveness data on particular ingredients, including oral

antiseptics, for antiplaque or gingivitis indications, the agency

announced a call-for-data for ingredients contained in products bearing

antiplaque and antiplaque-related claims in the Federal Register of

September 19, 1990 (55 FR 38560). A substantial amount of information

has been submitted to the agency pursuant to that call-for-data. The

safety and effectiveness data submitted to the agency for various

antiplaque and antiplaque-related ingredients are currently being

evaluated by the Dental Products Panel. That Panel will advise the

Commissioner of Food and Drugs on the promulgation of a monograph

establishing conditions under which oral antiseptic drugs for

antiplaque and antiplaque-related use are generally recognized as safe

and effective and not misbranded.

In the call-for-data, the agency stated that, in order to be

eligible for review under the OTC drug review procedures, an ingredient

must have been marketed in a product with the relevant indication to a

material extent and for a material time (21 U.S.C. 321(p)(2)). The

agency specifically requested information demonstrating such marketing.

The marketing data submitted to the agency by various manufacturers

includes data on ingredients marketed in the United States, as well as

data on ingredients that have only been marketed in other countries.

Agency policy currently requires ingredients to have been marketed in

the United States as of a certain date (December 4, 1975) to be

eligible for consideration in the OTC drug review. Because of the

passage of time, some antiplaque ingredients have entered the

marketplace since 1975 and have been marketed for a number of years.

The agency is reevaluating its policy for eligibility in the OTC drug

review in relation to the statutory language ``used to a material

extent and for a material time'' within the meaning of 21 U.S.C.

321(p)(2). The agency is also reevaluating its longstanding policy that

foreign marketing alone is not an adequate basis for an ingredient to

be considered in the OTC drug review. The agency's conclusions on these

matters will affect many other therapeutic categories of drugs in

addition to antiplaque products. For example, the agency is currently

reviewing petitions to include sunscreens and phytomedicines marketed

only in Europe in the OTC drug review. The ultimate review status of

some of the antiplaque ingredient(s) is dependent on the resolution of

this broader policy, which will be discussed in a future issue of the

Federal Register.

The agency agrees with the comments that more than one indication

may be appropriate for oral antiseptics. Although the Oral Cavity

Panel's recommended indication for temporary relief of sore throat and

sore mouth remains in Category III in this tentative final monograph,

the agency is proposing a Category I indication for oral antiseptics

used to help in the prevention of infection in minor sore mouth

conditions. The agency is also requesting additional data to support

the Panel's recommended Category III indication. (For a further

discussion regarding the indications for OTC oral antiseptic drug

products, see section I.K., comment 22.)

2. Two comments maintained that the safety of oral antiseptics is

well established. One of the comments noted that the Oral Cavity Panel

had initially placed oral antiseptic active ingredients in Category I

for safety, but after questions were raised about the carcinogenic,

teratogenic, and mutagenic potential of these ingredients, the Panel

placed them in Category III. Maintaining that the chemical nature and

the extensive scientific history of oral antiseptics do not lead to the

conclusion that these materials are carcinogenic, teratogenic, or

mutagenic, the comment noted that the review of quaternary ammonia

compounds written for the Panel by one of its members concludes that

quaternary ammonia compounds are safe for use in the oral cavity. The

comment also quoted the following from the tentative final monograph

for OTC topical antimicrobial drug products published in the Federal

Register of January 6, 1978 (43 FR 1210 at 1238 and 1239):

The Commissioner disagrees with the Panel that carcinogenicity,

mutagenicity, or teratogenicity studies must be completed. The

Commissioner concludes that, in the absence of any data suggesting

that * * * has any carcinogenic, mutagenic, or teratogenic

potential, testing for these properties should not be required.

The comment contended that ``the parallel with oral antiseptics is

striking and conclusive.''

Both comments disagreed with the Panel that long-term use of oral

antiseptics could cause harmful shifts of the oral flora, arguing that

no such effects have been reported for this class of products and the

available evidence suggests that their occurrence is unlikely. As an

example, one comment stated that fungal overgrowth leading to thrush

(candidiasis or moniliasis) that is commonly associated with the

administration of broad spectrum antibiotics is one type of floral

shift that could be troublesome. However, the comment asserted that

there is no basis for supposing that frequent or even abusive use of

OTC antiseptic mouthwashes could lead to thrush because part of the

testing procedure for active antiseptic ingredients has been an in

vitro test showing effectiveness against the fungus Candida albicans,

which is the organism principally responsible for thrush.

Regarding the Oral Cavity Panel's suggestion that antiseptic

mouthwashes could selectively eliminate ``beneficial'' organisms from

the mouth, opening the way to the adverse effects of pathogenic flora,

the comment asserted that in ``all the literature of the microbial

etiology of oral disease there are no reports stating or implying such

an adverse shift of oral flora.'' In support of this statement, the

comment cited reviews by Socransky (Ref. 1) and Loesche (Ref. 2). The

comment also cited a report by Volpe et al. (Ref. 3) that no harmful

floral shift resulted when mouthwashes containing cetylpyridinium

chloride, benzethonium chloride, or hexachlorophene were used.

The comment stated that members of the Nonprescription Drug

Manufacturers Association (NDMA) Task Group (formerly known as The

Proprietary Association Task Group) estimate that, over a period of 10

years, its companies have conducted studies of antiseptic mouthwashes

involving over 5,000 subjects for intervals ranging from 1 week to 1

year. Professional supervision and examination have demonstrated no

instances of adverse effects resulting from floral shifts. The comment

asserted that this is conclusive evidence of the safety of oral

antiseptics.

The comment noted that another example of an occasional and

undesirable effect of the prolonged use of antibiotics is lingua nigra

or black hairy tongue. Maintaining that this condition is associated

with Candida and with members of the related genera, Actinomyces,

Nocardia, and Streptomyces, the comment asserted that because in vitro

testing of oral antiseptics by the NDMA Task Group included proof of

effectiveness against Actinomyces as well as Candida, there is no

reason to believe that black hairy tongue would result from any use of

oral antiseptics.

The Oral Cavity Panel evaluated the adverse effects of antiseptic

ingredients contained in oral health care drug products from the

following two standpoints: (1) Short-term use to treat sore mouth and

sore throat and (2) long-term use for cleansing, elimination of mouth

odors, and other purposes where no symptoms of a disease exist (47 FR

22760 at 22848). The Panel did not consider OTC oral health care drug

products appropriate for prophylactic use to prevent the development of

symptoms or disease states of the mouth and throat (47 FR 22778). It

concluded that antiseptic ingredients should be used for oral health

care only when specific symptoms (e.g., sore throat or sore mouth) are

present to justify the need for a specific product whose effectiveness

has been established (47 FR 22834).

Although the Oral Cavity Panel placed no oral antiseptics in

Category I, it placed 25 antiseptic ingredients in Category III for

effectiveness. Additionally, the Panel determined that 16 of those 25

ingredients are safe for short-term use in the oral cavity. It did not

determine that any antiseptic ingredients are safe (i.e., Category I)

for long-term use in the oral cavity. Ingredients considered by the

Panel to be safe for short-term use as OTC antiseptics in the oral

cavity (i.e., Category III for effectiveness and Category I for safety)

include phenol, carbamide peroxide in anhydrous glycerin, ethyl

alcohol, and hydrogen peroxide. Ingredients placed in Category III for

safety and effectiveness by the Panel include cetylpyridinium chloride,

domiphen bromide, and povidone-iodine. The Panel also recommended

labeling for oral antiseptics in OTC oral health care drug products

that includes a warning restricting use to not more than 2 days (47 FR

22850).

The Panel did not clearly distinguish between the use of oral

antiseptic ingredients in mouthwashes (long-term) and oral first aid

products (short-term). The agency believes that many of these

ingredients were placed in Category III for safety by the Panel because

the ingredients are used in mouthwashes that are recommended by

manufacturers for long-term use on a daily basis. (For a discussion of

the time limits for use of oral antiseptics, see section I.K., comment

25.) The agency believes that the Panel's concerns are not necessarily

relevant to the short-term use of these ingredients (i.e., up to 7

days). For example, the Panel stated that ''extensive clinical

observations also indicate that PVP-I [povidone-iodine] is generally

nonirritating and nonsensitizing when applied to the skin and mucous

membranes`` (47 FR 22760 at 22884) and that dequalinium chloride has a

low degree of toxicity similar to other quaternary ammonia compounds

(quats) (47 FR 22760 at 22867). Nevertheless, the Panel placed

povidone-iodine and dequalinium chloride in Category III for safety.

The Panel recognized the safety of the commercially available

concentrations of domiphen bromide, but stated that because controlled

studies had not been done on the effects of domiphen bromide when used

on a long-term basis, its safety could not be assumed (47 FR 22868 and

22869).

Accordingly, the agency concludes that the assessment of short-term

safety of oral antiseptics should be determined on an individual basis

based upon customary use (see section I.E., comment 8; section I.G.,

comment 12; and section I.I., comment 15). The agency invites comment

on the safety of specific ingredients for use on a short-term basis.

When OTC oral antiseptics are indicated for short-term use and

there is an absence of data suggesting that the ingredients evaluated

by the Oral Cavity Panel have any carcinogenic, mutagenic, or

teratogenic activities, the agency agrees with the Panel that the

sponsor of a product should not be expected to conduct studies to

obtain data on their tumorigenicity, mutagenicity, or teratogenicity.

Such studies are often conducted by the National Cancer Institute and

other agencies when necessary. The agency notes that benzethonium

chloride is currently being evaluated for carcinogenic potential in the

National Toxicology Program (NTP). (See section I.C., comment 5.)

The safety of long-term daily usage of OTC oral antiseptic

ingredients in the oral cavity will be evaluated by the Dental Products

Panel as part of its safety and effectiveness review of OTC antiplaque

ingredients and will be discussed in a subsequent segment of the

rulemaking for OTC oral health care drug products, to be published in a

future issue of the Federal Register. (See section I.A., comment 1.)

References

(1) Socransky, S. S., ``Microbiology of Periodontal Disease--

Present Status and Future Considerations,'' Journal of

Periodontology, 48:497-504, 1977.

(2) Loesche, W. J., ``Chemotherapy of Dental Plaque

Infections,'' Oral Sciences Review, 9:65-107, 1976.

(3) Volpe, A. R. et al., ``Antimicrobial Control of Bacterial

Plaque and Calculus and the Effects of the Agents on Oral Flora,''

Journal of Dental Research, 48:832-841, 1969.

3. Several comments and two reply comments disagreed with the Oral

Cavity Panel's recommendation that OTC oral health care drug products

containing pharmacologically active concentrations of antimicrobial

ingredients should not be used to achieve a cosmetic effect, such as a

reduction of mouth odor (47 FR 22760 at 22844). The comments contended

that the use of ingredients in cosmetic mouthwash products is outside

the scope of the OTC drug review procedure, which is limited to drug

actions and drug claims. Arguing that the Panel's recommendation

advocates the position that the regulatory classification of a product

is dependent solely on the ingredient it contains, the comments

maintained that it is a well-established regulatory policy that the

intended use of a product determines whether it is regulated as a drug

or as a cosmetic and that the intended use is determined by the

manufacturer's representations and labeling claims. The comments stated

that claims for the reduction or suppression of mouth odor and for oral

cavity cleansing or refreshing are cosmetic claims. To support their

contentions, many of the comments cited the definitions of ``drug'' and

``cosmetic'' in sections 201(g) and 201(i) of the act (21 U.S.C. 321(g)

and 321(i)), the legislative history of the act, and prior case law.

Some comments also quoted the following statement delivered to the Oral

Cavity Panel in 1974 by the then FDA chief counsel:

Generally, a product label will be the determining factor as to

how a product will be classified, i.e., a drug or cosmetic. The

overall safety of a product will also be a major factor in such

classification. For example: The claim ``kills germs that cause

odor,'' would be considered a cosmetic claim; the claim ``kills

germs that cause disease'' would be considered a drug claim * * *.

(Ref. 1)

Several comments stated that the agency has a long-standing policy

that cosmetics containing antimicrobial ingredients or other

pharmacologic agents are not drugs unless drug claims are made for

them. Some of the comments pointed out that FDA's policy concerning

drug versus cosmetic status has been stated in many documents,

including the procedural regulations governing the OTC drug review (37

FR 9464 to 9475) and official trade correspondence, and that the policy

was restated in the tentative final monograph for OTC antiperspirant

drug products, published in the Federal Register of August 20, 1982 (47

FR 36492), and in the report of the Advisory Review Panel on OTC

Contraceptives and Other Vaginal Drug Products (Vaginal Panel),

published in the Federal Register of October 13, 1983 (48 FR 46694).

Many comments pointed out that in both the OTC antiperspirant drug

products rulemaking and the OTC topical antimicrobial drug products

rulemaking, the FDA agreed that a product that contains antimicrobial

ingredients to reduce microbial flora solely for the purpose of

cleansing or reducing odor is a cosmetic and not a drug and that such

cosmetic uses are outside the scope of OTC drug monographs. Concluding

that the Oral Cavity Panel's recommendations are without legal

foundation and are contrary to the provisions of the act and the legal

precedents established for more than 40 years, the comments requested

that FDA reject the Panel's recommendations and adhere to the

traditional drug/cosmetic distinctions.

One comment stated that the Oral Cavity Panel appeared to base its

proposal to delete all cosmetic indications for antimicrobial mouthwash

products on the finding that topical antimicrobials as a class are

unsafe and ineffective. Asserting that action to be contrary to the

substantial scientific evidence presented to that Panel and to the

Advisory Review Panels on OTC Topical Antimicrobial Drug Products (the

Antimicrobial I and II Panels), the comment stated that antimicrobial

ingredients, used appropriately, are no less safe than other

ingredients commonly used as cosmetics. A reply comment added that

there are extensive scientific data demonstrating the effectiveness of

an antimicrobial mouthwash in suppressing mouth odor.

Another reply comment agreed with the Panel that cosmetic claims

are not acceptable as ``indications'' for the OTC oral health care drug

products rulemaking insofar as cosmetic claims are not drug

indications. However, the reply comment stated that this should not

preclude truthful and nonmisleading information about the cosmetic

usefulness in the product's labeling and mentioned antidandruff

shampoos and anticaries toothpastes as two examples of OTC products

with both drug and cosmetic claims. The reply comment argued that dual

claims should be permitted for an OTC oral health care drug product,

e.g., that it refreshes or deodorizes the mouth (a cosmetic claim) and

aids in the temporary relief of discomfort due to occasional sore

throat or sore mouth (a drug claim), just as such dual claims are

permitted for antidandruff shampoos, which are represented to clean

hair (a cosmetic claim) and to prevent dandruff (a drug claim), and for

anticaries toothpastes, which are represented to clean teeth and to

prevent tooth decay.

The comments requested that the agency recognize the following

phrases as cosmetic claims for OTC oral health care products and,

therefore, consider them as outside the scope of the OTC drug review:

``Kills germs that cause bad breath,'' ``mouth refreshment,'' ``clean

feeling,'' ``control of mouth odor,'' ``control of bad breath,'' ``an

aid to the daily care of the mouth,'' and ``causing the mouth to feel

clean.'' Two comments argued that terms such as ``antimicrobial,''

``antiseptic,'' ``kills germs,'' ``kills germs by millions on

contact,'' ``antibacterial,'' and other synonymous phrases can be

properly used to describe cosmetic functions, i.e., cleansing or

refreshing and deodorizing, without creating drug connotations. The

comments stated that when used in connection with oral hygiene and

deodorizing representations, such claims are cosmetic claims because

the context in which they appear connotes cosmetic purposes only. These

comments concluded that mouthwashes, rinses, and gargles labeled solely

with traditional cosmetic claims for cleansing, refreshing, or

deodorizing the mouth or breath are subject to regulation only as

cosmetics and not as drugs.

The Oral Cavity Panel stated that claims for the suppression of

mouth odor in the labeling of OTC antiseptic health care products are

drug claims because they are linked to a drug action, i.e.,

antimicrobial activity (47 FR 22760 at 22844). Concluding that such

claims ``* * * indicate that a product is used for cosmetic purposes

but imply that the product exerts a therapeutic effect'' (47 FR 22857),

the Panel classified claims for the suppression of mouth odor as well

as claims for the cleansing or freshening of the mouth in Category II.

The act provides the statutory definitions that differentiate a

drug from a cosmetic. A ``drug'' is defined as an article ``intended

for use in the diagnosis, cure, mitigation, treatment, or prevention of

disease'' or ``intended to affect the structure or any function of the

body * * *,'' (21 U.S.C. 321(g)(1)(B) and 321(g)(1)(C)). A

``cosmetic,'' on the other hand, is defined as an article intended to

be ``* * * applied to the human body or any part thereof for cleansing,

beautifying, promoting attractiveness, or altering the appearance * *

*'' (21 U.S.C. 321(i)(1)). The agency agrees with the comments that the

intended use of a product is the primary determining factor as to

whether it is a drug, a cosmetic, or both. This intended use may be

inferred from the product's labeling, promotional material,

advertising, and any other relevant factor. (See, e.g., National

Nutritional Foods Ass'n v. Mathews, 557 F.2d 325, 334 (2d Cir. 1977).)

In determining whether a product is a drug or a cosmetic, the

intended use may be established from the type and amount of

ingredient(s) present, as well as the product's labeling. For example,

in some instances, the mere presence of certain therapeutically active

ingredients could make a product a drug even in the absence of drug

claims. In these cases, the intended use would be implied because of

the known or recognized drug effects of the ingredient (e.g., fluoride

in a dentifrice). However, in other instances, the presence of an

ingredient (e.g., an antimicrobial), in and of itself, does not make a

product a drug when no drug claim is made.

The agency does not agree with the Panel that claims for the

suppression of mouth odor in the labeling of an oral product containing

an antiseptic ingredient necessarily makes that product a drug. Oral

products that contain antiseptic ingredients are considered

``cosmetics,'' and not ``drugs,'' if only deodorant (or other cosmetic)

claims are made for the products. The agency stated in the tentative

final monograph for OTC first aid antiseptic drug products (56 FR 33644

at 33648) that the mere presence of an antimicrobial ingredient in a

product labeled for deodorant use, with the ingredient identified only

in the ingredient list and no reference to its antimicrobial properties

stated elsewhere in the labeling, would not cause the product to be

considered a drug. Claims such as ``mouth refreshment,'' ``clean

feeling,'' ``control of mouth odor,'' ``control of bad breath,'' and

``for causing the mouth to feel clean'' are considered cosmetic claims

in accordance with section 201(i) of the act and are not included in

this tentative final monograph.

However, any broader claims that represent or suggest a therapeutic

use for the product would subject it to regulation as a drug. For

example, the agency considers the phrase ``an aid to daily care of the

mouth'' to be a drug claim because it implies that the product exerts a

therapeutic benefit. The agency also considers terms such as

``antibacterial,'' ``antimicrobial,'' ``antiseptic,'' or ``kills

germs'' in the labeling of oral products to imply that the product will

have a therapeutic effect. The agency concludes that such statements

would constitute a drug claim for the product because consumers would

perceive the intended effect to be achieved by a drug action. Likewise,

any of the cosmetic statements mentioned above could become part of a

drug claim if additional statements are included. For example, cosmetic

claims such as ``control of mouth odor'' and ``for causing the mouth to

feel clean'' become drug claims when therapeutic terms are added as

follows: (1) ``antimicrobial for control of mouth odor,'' or (2)

``kills germs to help the mouth feel clean.'' Furthermore, use of the

term ``active ingredient(s)'' in the labeling of these products would

imply that the product possesses a drug-like property and, thus, would

cause the product to be considered a drug.

Products marketed only as cosmetics are not subject to this

rulemaking, but are subject to the provisions of sections 601 and 602

of the act (21 U.S.C. 361 and 362) relating to adulteration and

misbranding of cosmetics. The final OTC drug monograph for these

products will cover only the drug use of the active ingredients listed

therein. The concentration range, limitations, warnings, and directions

established for the ingredients in the monograph may not apply to the

use of the same ingredients in products intended solely as cosmetics.

However, some of these factors may be considered by the agency in

determining the safety of an ingredient for cosmetic uses. Those

products intended for both drug and cosmetic use will be required to

conform to the requirements of the final monograph. However, such

products, in addition to bearing the indications allowed for OTC oral

health care drug products, may also be labeled for cosmetic uses, such

as deodorancy or cleansing, in conformity with section 602 of the act

and the provisions of 21 CFR parts 701 and 740.

In accordance with the revised labeling requirements for OTC drug

products, it is the agency's view that cosmetic claims may not appear

within the boxed area designated ``APPROVED USES.'' As discussed in the

final rule on the agency's ``exclusivity policy'' (51 FR 16258 at 16264

(paragraph 14)), cosmetic terminology is not reviewed and approved by

FDA in the OTC drug monographs and therefore could not be placed in the

box. Cosmetic claims may appear elsewhere in the labeling, should

manufacturers choose the labeling alternative provided in

Sec. 330.1(c)(2)(i) or (c)(2)(iii) for labeling drug/cosmetic products.

Although the agency does not specifically prohibit commingled drug and

cosmetic labeling in other than the indications section, such claims

should be appropriately described so that consumers will more readily

be able to differentiate the drug aspects from the cosmetic aspects of

such labeling. If commingled drug and cosmetic labeling claims are

confusing or misleading, the product's labeling could be misleading

within the meaning of the act and misbranded under sections 502(a) and

602(a) of the act (21 U.S.C. 352(a) and 362(a)).

Reference

(1) Summary Minutes of the Advisory Review Panel on OTC Oral

Health Care Drug Products, June 13 and 14, 1974, OTC Vol. 130PA2,

Dockets Management Branch.

B. Comment on Alcohol

4. One comment expressed confusion regarding the Oral Cavity

Panel's discussion and conclusions on ethyl alcohol (47 FR 22760 at

22871 to 22873). As an example, the comment mentioned that the Panel

considered ethyl alcohol to be safe for use in the oral cavity while

also stating that ``Ethyl alcohol above 20 percent is considered to be

an irritant * * *.'' Pointing out that the Panel also mentioned 70

percent alcohol (47 FR 22873), the comment questioned if it was

permissible to use 70 percent alcohol as a solvent. The comment also

wondered how the Panel determined that ``The quantity [of alcohol]

absorbed from the mouth and throat is not significant,'' (47 FR 22872).

The comment concluded that, because it appears that the Panel's report

lacks sufficient proof of safety and effectiveness of alcohol in

concentrations over 20 percent and because of the high vulnerability of

elderly people and children to alcohol, oral health care products

containing more than 20 percent alcohol should not be permitted to stay

on the market.

The agency reviewed the Oral Cavity Panel's discussion regarding

ethyl alcohol (alcohol) as an active ingredient in OTC oral health care

drug products and did not find any statement concerning alcohol above

20 percent being considered an irritant. However, in a report on OTC

agents for the relief of oral discomfort published concurrently with

the Oral Cavity Panel's report in the Federal Register of May 25, 1982

(47 FR 22712), the Dental Panel stated that alcohol above 20 percent is

an irritant to the dental pulp and, therefore, concentrations above 20

percent should not be used in agents for the relief of toothache in an

open tooth cavity (47 FR 22712 at 22726).

The Oral Cavity Panel concluded that alcohol is safe for use as an

OTC oral antimicrobial ingredient (47 FR 22760 at 22872). However, the

Panel did not clearly define a safe concentration of alcohol. The Panel

also stated that commercially available mouthwashes contain alcohol as

a solvent in concentrations up to 35 percent, but that concentrations

above 35 percent cause burning of the mucous membranes (47 FR 22872).

The Panel specifically stated that concentrations of alcohol that kill

bacteria, e.g., 70 percent alcohol, cause burning and intense

discomfort and are too irritating when applied to inflammations of the

mucous membranes of the oral cavity (47 FR 22873). For the above

reasons and because alcohol has a marked potential for abuse, the Panel

recommended that the quantity of alcohol used as a solvent in

pharmaceutical preparations should be limited to 35 percent.

In its report on OTC agents for the relief of oral discomfort (47

FR 22712 at 22737), the Dental Panel accepted the safety of 1.5 percent

phenol in 70 percent alcohol for direct application to the gums for up

to 7 days. That Panel concluded that up to 70 percent alcohol was an

appropriate vehicle for 5 to 20 percent benzocaine with a maximum

dosage of 1 milliliter (mL) and that compound benzoin tincture (74 to

80 percent alcohol) and benzoin tincture (75 to 83 percent alcohol)

were safe for occasional application to small areas of the oral mucosa

regardless of the high alcohol content (47 FR 22746).

The Oral Cavity Panel considered alcohol ineffective as an

antimicrobial ingredient at concentrations below 70 percent (47 FR

22872 to 22873). However, that Panel also postulated that the lower

concentrations of alcohol used as a solvent for an antimicrobial

ingredient could act synergistically with the antimicrobial ingredient

to produce an enhanced antimicrobial effect. The Panel concluded that

there were insufficient data from controlled studies to establish the

effectiveness of alcohol alone as an antiseptic ingredient for the

treatment of symptoms such as sore mouth and sore throat, and the Panel

placed it in Category III.

In the advance notice of proposed rulemaking for OTC alcohol drug

products for topical antimicrobial use (47 FR 22324), the Advisory

Review Panel on OTC Miscellaneous External Drug Products (Miscellaneous

External Panel) stated that the ``irritant action of alcohols is

particularly marked on mucosa. The more concentrated the alcohol, the

more pronounced are its irritant effects.'' That Panel recommended

caution in the topical use of 60 to 95 percent alcohol and 50 to 91.3

percent isopropyl alcohol on the mucous membranes (47 FR 22324 at

22327) and placed the indication ``For application to mucous

membranes'' in Category II (47 FR 22332). In the tentative final

monograph for OTC first aid antiseptic drug products, the agency

discussed this indication and stated that the use of alcohol on the

mucous membranes of the mouth and throat would be addressed in the

rulemaking for OTC oral health care drug products (56 FR 33644 at

33656).

The agency is aware of a recent study (Ref. 1) indicating that men

and women using mouthwashes with 25 percent or higher alcohol content

on a regular long-term basis have a slightly increased risk of oral and

pharyngeal cancers. Moreover, the risk rose with longer and more

frequent mouthwash use. After adjusting for tobacco and alcohol

consumption, men had a 40-percent higher risk and women had a 60-

percent higher risk of these cancers, compared to those who did not use

a mouthwash product. Although these findings do not firmly establish

the risk relationship between use of an alcohol-containing mouthwash

product and these cancers, they show a need to look further at this

relationship. The agency is also aware of three earlier studies

demonstrating an apparent association between long-term mouthwash use

and an increased risk of oral and pharyngeal cancers (Refs. 2, 3, and

4). Although these studies may have no bearing on the safety of the

short-term use of drug products containing alcohol, the agency believes

that serious consideration must be given to the results of these

studies to determine whether there is a need to limit the amount of

alcohol permitted in oral health care drug products.

In 1992, the agency sent letters to two manufacturers' associations

requesting data and information on the relationship between alcohol-

containing drug products and oral and pharyngeal cancers and the extent

of alcohol in OTC oral health care drug products (Refs. 5 and 6). In

response, the associations jointly submitted a list of OTC mouthwashes,

their alcohol content, and their 1990 sales data (Ref. 7), a reanalysis

(Ref. 8) of the study on the association between the use of alcohol-

containing mouthwashes and oral/pharyngeal cancer (Ref. 1) discussed

previously, and a review (Ref. 8) of related medical and scientific

literature pertaining to the etiology of oral cancer. The agency is

currently evaluating the data and information submitted.

The agency notes that alcohol is used as a solvent in many OTC oral

health care drug products currently on the market. When alcohol is

included in oral antiseptic products, the agency believes that the

amount of alcohol absorbed from topical application of the product to

the mouth and throat to be insignificant. Such products are usually

formulated as mouthwashes (oral rinses) or gargles and are retained in

the mouth for a short period of time (usually 1 minute or less) and

then spit out, or are applied as very small amounts of the product to

discreet areas of the oral mucosa. However, the agency believes that

alcohol should be included in OTC oral health care drug products only

if the alcohol is necessary to dissolve the active ingredient(s).

The agency is currently evaluating the use of alcohol in all OTC

drug products. On December 17, 1992 (Ref. 9), the OTC Drugs Advisory

Committee discussed the use of alcohol in OTC drug products for oral

ingestion and recommended to the agency that such products should not

contain more than the minimum amount of alcohol needed as a solvent for

the active ingredient, for preservative purposes, or for taste

enhancement. The Committee specifically recommended the following:

1. For persons 12 years of age and above, a maximum alcohol

concentration up to and including 10 percent volume-to-volume;

2. For children age 6 to under 12, a maximum alcohol concentration

up to and including 5 percent volume-to-volume; and

3. For children under 6 years of age, a maximum alcohol

concentration up to and including 0.5 percent volume-to-volume.

Based on the Committee's recommendations, the agency published a

proposed rule on OTC drug products intended for oral ingestion that

contain alcohol in the Federal Register of October 21, 1993 (58 FR

54466). That proposal would establish a maximum concentration limit for

alcohol as an inactive ingredient in OTC drug products intended for

oral ingestion.

In conclusion, the agency is evaluating the use of alcohol in all

OTC drug products, is investigating a possible link between the regular

use of alcohol-containing mouthwashes and oral and pharyngeal cancers,

and is considering limiting the amount of alcohol permitted in such

products. Although the agency is not proposing in this tentative final

monograph to limit the amount of alcohol used as a solvent in OTC oral

health care drug products, it urges all manufacturers to limit the

alcohol content of all OTC drug products to the smallest amount

compatible with the dissolution of the active ingredient(s).

References

(1) Blot, W. J. et al., ``Mouthwash Use and Oral Conditions in

the Risk of Oral and Pharyngeal Cancer,'' Cancer Research, 51:3044-

3047, 1991.

(2) Wynder, E. L. et al., ``Oral Cancer and Mouthwash Use,''

Journal of the National Cancer Institute, 70:255-260, 1983.

(3) Blot, W. J., D. M. Winn, and J. F. Fraumeni, ``Oral Cancer

and Mouthwash,'' Journal of the National Cancer Institute, 70:251-

253, 1983.

(4) Weaver, A., S. M. Fleming, and D. B. Smith, ``Mouthwash and

Oral Cancer: Carcinogen or Coincidence?'' Journal of Oral Surgery,

37:250-253, 1979.

(5) Letter from W. E. Gilbertson, FDA, to E. E. Kavanaugh,

Cosmetic, Toiletry and Fragrance Association, coded LET 17, Docket

No. 81N-0033, Dockets Management Branch.

(6) Letter from W. E. Gilbertson, FDA, to J. D. Cope,

Nonprescription Drug Manufacturers Association (NDMA) coded LET 16,

Docket No. 81N-0033, Dockets Management Branch.

(7)Comment No. LET25, Docket No. 81N-0033, Dockets Management

Branch.

(8) Comment No. 53, Docket No. 81N-0033, Dockets Management

Branch.

(9) Summary Minutes of the Nonprescription Drugs Advisory

Committee Meeting, December 16 and 17, 1992, OTC Vol. 13CTFM.

C. Comment on Benzethonium Chloride

5. One comment disagreed with the Oral Cavity Panel's

classification of benzethonium chloride in Category III for safety. The

comment criticized the Panel's statement that ``Adequate data on

absorption and attainment of toxic blood levels and the metabolic fate

of quats [quaternary ammonium compounds] are not available'' (47 FR

22760 at 22860). The comment contended that information on the

absorption of benzethonium chloride is available and that submissions

to the Panel (Refs. 1 and 2) contained extensive data on the absorption

and distribution of benzethonium chloride in chickens and in pregnant

rats and their fetuses.

The comment also objected to the Oral Cavity Panel's statement that

``No data are available on the mutagenic, tumorigenic, or teratogenic

effects of benzethonium chloride when used in mouthrinses or gargles

for long-term use on a daily basis for oral health care'' (47 FR

22860). The comment contended that five studies submitted to the Panel

(Refs. 3 through 7) show that tumorigenicity and teratogenicity of

benzethonium chloride are not a problem. The comment mentioned several

other studies that were available to the Panel and supposedly further

substantiate that benzethonium chloride is not a teratogen and does not

impede fertility or adversely affect postnatal survival of pups (Refs.

8 through 12).

The comment pointed out that the Oral Cavity Panel made several

comments in its discussion of benzalkonium chloride (47 FR 22760 at

22858 to 22860) indicating concerns similar to those raised regarding

benzethonium chloride, but the Panel still placed benzalkonium chloride

in Category I for safety. The comment stated that it could not

understand how the Panel could conclude that benzalkonium chloride is

safe while concluding that benzethonium chloride is not safe, when the

supporting data for benzalkonium chloride were not as extensive. Adding

that 88 million units of a mouthrinse containing benzethonium chloride

have been used without any serious toxicity reported, the comment noted

that out of this large population of users, some must have been

pregnant. The comment contended that this use experience further

supports the rat and rabbit fertility and teratogenicity studies. The

comment requested that benzethonium chloride be reclassified in

Category I for safety.

Although acknowledging that quats are, in general, nonirritating

and nontoxic in their effective dosage ranges, the Oral Cavity Panel

was concerned about the effect of long-term, daily use of these

compounds. The Panel stated that adequate data are not available on:

(1) The absorption and attainment of toxic blood levels and the

metabolic fate of the quats and (2) the cumulative effects from

continued use on a day-to-day basis over the span of years or a

lifetime as would be the case when these ingredients are incorporated

in mouthwashes (47 FR 22760 at 22860). The Panel was also concerned

about the absence of data on the mutagenic, tumorigenic, or teratogenic

effects of quats when used on a long-term daily basis in the oral

cavity. The Oral Cavity Panel placed most of the quats it evaluated in

Category III for safety. Nevertheless, in spite of these concerns, the

Panel recommended that benzalkonium chloride and cetalkonium chloride

be considered safe for OTC use in the oral cavity.

Regarding the comment's contention that the Oral Cavity Panel was

inconsistent in its evaluation of benzethonium chloride and

benzalkonium chloride, the agency cannot determine from the Panel's

discussion of the two ingredients (47 FR 22760 at 22858 to 22861) what

caused the Panel to recommend that one ingredient was safe and the

other not safe. However, the Panel made its safety decisions based upon

an assumption that oral antiseptics were used on a long-term daily

basis. As discussed above, the agency is proposing in this tentative

final monograph that data relating to the long-term safety of oral

antiseptics is not relevant to the determination of safety for short-

term use in the oral cavity (see section I.A., comment 2). Therefore,

the agency agrees with the Panel's safety evaluation of benzalkonium

chloride and is proposing that benzalkonium chloride is safe for short-

term use as an oral antiseptic.

The agency has reevaluated the data submitted to the Oral Cavity

Panel as well as new information regarding the safety of benzethonium

chloride and concludes that benzethonium chloride should remain in

Category III. The agency agrees with the Panel that the studies

originally submitted to the Panel (Refs. 1 through 7) do not support

the safety of benzethonium chloride.

Regarding the data on absorption and attainment of adequate blood

levels and the metabolic fate of quats, the data referred to by the

comment (Refs. 1 and 2) do not answer the Panel's concerns. The most

meaningful data presented on absorption were contained in the rat

maternal and fetal absorption study (Ref. 2). Low levels of C14

were detected in maternal blood and urine following oral dosing of

pregnant rats with C14 labeled benzethonium chloride. After 15

days of dosing with 1.125 milligrams/kilogram (mg/kg) per day labeled

benzethonium chloride, 1.5 nanogram/gram of the labeled compound was

detected in maternal blood. The urinary level of labeled benzethonium

chloride found in this group was 28 nanograms per milliliter (mL).

These data suggest poor absorption, but there is no correlation with

toxic blood levels. Furthermore, the metabolic fate of benzethonium is

unknown and is not addressed in any of the studies mentioned by the

comment.

Two studies demonstrate that subcutaneous injection of benzethonium

chloride produces fibrosarcomas at the injection site in rats (Ref. 6),

but not in mice (Ref. 4). Another study demonstrates that this

ingredient is cytotoxic (Ref. 7). These data indicate that benzethonium

chloride is a weak carcinogen according to the classification scheme

proposed by Grasso and Golberg (Ref. 13).

In one study, rats were injected with the maximally tolerated dose

of 3 mg/kg and three lower doses twice weekly for 1 year (Ref. 6). Two

hundred animals were treated; 80 were in the high dose group. The study

also included 120 each in negative and vehicle control groups.

Observation continued for 6 months after termination of treatment.

Cumulative data from all dose groups show a 16-percent incidence of

tumors at the injection site in males and a 10-percent incidence in

females. No injection site tumors were noted in the vehicle control

animals; one injection site tumor was observed in the negative control

group. At other tested sites, tumor incidence numbers of the treated

animals were not different from the control groups. However, there was

a clear dose-related effect at the injection site. As stated above,

these data indicate that benzethonium chloride is a weak carcinogen.

The teratology studies (Refs. 9, 10, and 12) indicate that

benzethonium chloride has very slight teratogenic potential. Effects on

the fetus are largely related to the retardation of growth, which is

also evident in the dams. Maternal effects also influence fetal

viability, especially evident in rabbits (Ref. 12). Increased

ossification variations were significant only in the high dose groups

(i.e., 35.6 mg/kg/day) in rats (Ref. 10). Effects at lower doses that

were apparent in one study (Ref. 9) might be attributed to variability

as evidenced by the difference in the two control groups of one of the

other studies (Ref. 10). The reproductive capacity of rats does not

appear to be affected, although weight gains are affected in both

parents (Ref. 8).

The agency does not believe that sufficient data and information

are available at this time to categorize benzethonium chloride as safe

for use in the oral cavity and invites further comments and data on

this matter. The agency is aware that the NTP has undertaken studies to

characterize and evaluate the toxicological potential, including

carcinogenicity, of benzethonium chloride in laboratory animals. The

results of these studies may aid the agency in its determinations

regarding the safety of benzethonium chloride. At this time,

benzethonium chloride remains in Category III for safety in this

tentative final monograph.

References

(1) Research Report No. 23-19, ``A Study to Determine

Radioactive Residue Levels in Eggs, Tissues, and Excreta from Laying

Hens Which Were Fed C14-Hyamine 1622 Sanitized Water,'' Comment

No. C00009, Docket No. 81N-0033, Dockets Management Branch.

(2) ``Rat Maternal and Fetal Absorption of C14-Benzethonium

Chloride (C1414-BTC),'' Comment No. C00009, Docket No. 81N-

0033, Dockets Management Branch.

(3) Finnegan, J. K. et al., ``Pharmacologic Observations on Two

Quaternary Ammonium Germicides,'' Comment No. C00009, Docket No.

81N-0033, Dockets Management Branch.

(4) Kirschstein, R. L., ``Toxicology and Carcinogenicity of

Preservatives Used in the Preparation of Biological Products,''

Comment No. C00009, Docket No. 81N-0033, Dockets Management Branch.

(5) ``Six Month Toxicity Study with BTC and ZnCl 2 on

Rats,'' Comment No. C00009, Docket No. 81N-0033, Dockets Management

Branch.

(6) ``Toxicology and Carcinogenesis of Various Chemicals Used in

the Preparation of Vaccines,'' Comment No. C00009, Docket No. 81N-

0033, Dockets Management Branch.

(7) ``Final Report, Contract PH-43-67-677, Project C-173,''

Comment No. C00009, Docket No. 81N-0033, Dockets Management Branch.

(8) ``Project 75-1343, Segment I Rat Fertility Study,'' Comment

No. C00009, Docket No. 81N-0033, Dockets Management Branch.

(9) ``Project 75-1344, Segment II Rat Teratology Study,''

Comment No. C00009, Docket No. 81N-0033, Dockets Management Branch.

(10) ``Project 76-1495A, Segment II Rat Teratology Study,''

Comment No. C00009, Docket No. 81N-0033, Dockets Management Branch.

(11) ``Project 75-1345, Segment III Rat Peri and Post Natal

Study,'' Comment No. C00009, Docket No. 81N-0033, Dockets Management

Branch.

(12) ``Project 75-1346, Segment II Rabbit Teratology Study,''

Comment No. C00009, Docket No. 81N-0033, Dockets Management Branch.

(13) Grasso, P., and L. Golberg, ``Subcutaneous Sarcoma as an

Index of Carcinogenic Potency,'' Food and Cosmetic Toxicology,

4:297-320, 1966.

D. Comments on Boric Acid

6. One comment stated that the Oral Cavity Panel's discussion on

the safety and effectiveness of boric acid as an antimicrobial

ingredient (47 FR 22760 at 22850) should be considered arbitrary

because it is based on a limited search of the literature and a minimum

effort to evaluate this literature. The comment contended that the

Panel's statements that ``absorption of boric acid occurs readily from

the mucous membranes of the mouth, throat * * * '' and that ``it is

also absorbed from the surface of the vagina, the lining of the

conjunctival sac * * *'' (47 FR 22850) are not mentioned in the

discussion of this ingredient in the paper by George (Ref. 1) which the

Panel cited as the source of this information. The comment added that

the only statement this author makes regarding mucous membrane

absorption of boric acid is an inference taken from another reference

(Ref. 2), which in turn provided no chemical or laboratory evidence to

support the previous statements.

The comment also objected to the Oral Cavity Panel's statement

``Death has occurred from ingestion of less than 5 grams (g) [of boric

acid] in infants and from 5 to 20 g in adults,'' (47 FR 22760 at

22850), stating that these reported lethal doses are found in review

articles and appear repeatedly as a result of frequent cross-

referencing from publications used in the medical field. The comment

contended that the only absolute statement on a toxic dose of boric

acid appeared in a 1906 New York Medical Bulletin which discussed an

autopsy report on a 62-year-old man who had ingested 15 g of boric acid

on prescription for a bladder infection; however, no conclusion was

made that boric acid was the cause of death. The comment added that the

published reports on poisonings by boric acid resulted from special

circumstances, i.e., in the course of therapeutic treatments, erroneous

use of boric acid in place of other substances in hospitals, or similar

misuse, and usually only estimated dosages were reported. Although the

comment stated that boric acid should not be used indiscriminately, it

contended that the Panel made an inadequate study of the literature

concerning the safety of boric acid. The comment added that the only

carefully controlled clinical study on the ingestion of borax and boric

acid by humans was a study by Wiley, published in 1904 (Ref. 3). The

comment expressed surprise that this reference was not cited by the

Panel and has not been cited by other authors who have conducted a

literature review on boric acid. The comment reported that this study,

conducted by the ``poison squad'' who eventually made up the staff of

FDA, involved ingestion of borax or boric acid at varying dosages up to

5 g per day (as a single dose) for periods up to 50 days. The comment

claimed that no fatalities or chronic irreversible pathological

conditions were observed in any of the participants.

The comment also expressed concern about the Oral Cavity Panel's

classification of boric acid in Category II for effectiveness (47 FR

22760 at 22850) on what it considered a minimum effort to investigate

and evaluate the literature. For example, the comment mentioned that

the Panel cited a paper by Novak and Taylor (Ref. 4). In this study,

the investigators found that concentrations higher than 2 percent boric

acid may inhibit phagocytosis. The comment contended that although the

Panel acknowledged this finding, it ignored the absence of this action

at lower concentrations. The comment also referred to another paper by

these same authors (Ref. 5), which discusses the antibacterial action

of boric acid. The comment stated that this article appeared in the

same journal immediately following the article by Novak and Taylor but

was not cited by the Panel in its list of references on boric acid. The

comment concluded that the references cited as evidence to support the

Panel's conclusions on effectiveness are limited to one reference,

which is general in nature with no primary references or data

presented.

The agency has reviewed the article by George (Ref. 1) cited in the

Oral Cavity Panel's report and the reference cited therein (Ref. 2) and

agrees with the comment that these references do not present adequate

evidence to support the Panel's conclusion that boric acid is absorbed

from mucous membranes. Although the literature contains many incidences

of boric acid toxicity resulting from the absorption of the drug after

application to abraded skin or from ingestion, there is a lack of data

and information on the degree of absorption of boric acid from mucous

membranes (Refs. 6 through 9).

The agency agrees with the comment that the human lethal doses used

in the Oral Cavity Panel's report appear in review articles and other

biomedical publications as a result of cross-referencing from older

literature. However, because most reports of poisoning with boric acid

are due to accidental ingestion of the drug, exact doses cannot be

determined; thus, varying human lethal doses, such as 15 to 30 g in

adults and 3 to 6 g in children, are reported in the literature (Refs.

8, 9, and 10).

The agency notes that the study by Wiley (Ref. 3) was conducted to

determine the effects of borax and boric acid upon digestion and

overall human health. At the end of this study, Wiley reported that the

continuous administration of borax and boric acid created disturbances

of appetite, digestion, and health.

As more reports of the toxic effects of boric acid appeared and

more effective antiseptics were developed, the Vaginal Panel noted that

this ingredient fell into disfavor except for a few minor uses (48 FR

46694 at 46712). This may have been due in part to the findings of

Novak and Taylor (Ref. 4) who suggested that normal phagocytosis is

inhibited by boric acid in concentrations greater than 2 percent, thus

counteracting the drug's antibacterial action.

The agency reviewed the second study by Novak and Taylor (Ref. 5)

and notes that this in vitro study was designed to determine the

bacteriostatic action of boric acid, in the presence of tears, against

three species of bacteria commonly found in minor eye infections. The

authors reported that boric acid in concentrations from 0.5 to 2

percent was bacteriostatic against the three species of bacteria

tested. However, the agency does not consider this in vitro study to be

a valid substitute for a well-controlled clinical study in the intended

target population. The agency believes that the Panel did not include

this study in the list of references cited for boric acid because it

did not consider the study relevant to the efficacy of this ingredient

in OTC oral health care drug products. The agency concludes that this

study does not support the effectiveness of boric acid for antiseptic

use in OTC oral health care drug products.

The agency points out that the Oral Cavity Panel's discussion

concerning the safety and effectiveness of boric acid was not intended

to include all available information on the subject, but was intended

to be representative of the available data. The Panel members selected

the studies to be cited according to their best scientific judgment at

that time. In addition, because the comment did not submit new data or

information that offer evidence contrary to the Panel's conclusion and

other information that exists in the literature (as discussed above),

the agency is proposing in this tentative final monograph that boric

acid remain in Category II (not safe and not effective) as an

antiseptic agent in OTC oral health care drug products.

References

(1) George, A. J., ``Toxicity of Boric Acid through Skin and

Mucous Membranes,'' Food and Cosmetic Toxicology, 3:99-101, 1965.

(2) Gleason, M. N. et al., ``Borate Section III, Therapeutics

Index'' in ``Clinical Toxicology of Commercial Products: Acute

Poisoning (Home & Farm),'' The Williams and Wilkins Co., Baltimore,

p. 122, 1957.

(3) Wiley, H. W., ``1. Boric Acid and Borax,'' in ``Influence of

Food Preservatives and Artificial Colors on Digestion and Health,''

U. S. Department of Agriculture, Bureau of Chemistry-Bulletin No.

84, pp. 254-255, 1904.

(4) Novak, M., and W. I. Taylor, ``Phagocyticidal and

Antibacterial Action of Boric Acid,'' Journal of the American

Pharmaceutical Association (Scientific Edition), 40:428-430, 1951.

(5) Novak, M., and W. I. Taylor, ``Antibacterial Action of Boric

Acid in Lacrima (Tears),'' Journal of the American Pharmaceutical

Association (Scientific Edition), 40:430-432, 1951.

(6) Pfeiffer, C. C. et al., ``Boric Acid Ointment: A Study of

Possible Intoxication in the Treatment of Burns,'' Journal of the

American Medical Association, 128:266-274, 1945.

(7) Goldbloom, R. B., and A. Goldbloom, ``Boric Acid Poisoning--

Report of Four Cases and a Review of 109 Cases from the World

Literature,'' The Journal of Pediatrics, 43:631-643, 1953.

(8) Kingma, H., ``The Pharmacology and Toxicology of Boron

Compounds,'' Canadian Medical Association Journal, 78:620-622, 1958.

(9) McNally, W. D., and C. A. Rust, ``The Distribution of Boric

Acid in Human Organs in Six Deaths Due to Boric Acid Poisoning,''

Journal of the American Medical Association, 90:382-383, 1928.

(10) Valdes-Dapena, M. A., and J. B. Arey, ``Boric Acid

Poisoning: Three Fatal Cases with Pancreatic Inclusions and a Review

of the Literature,'' Journal of Pediatrics, 61:531-546, 1962.

7. Referring to the Oral Cavity Panel's statement that ``Boric acid

is used as a pharmaceutical necessity for buffering as well as for an

active ingredient (Ref. 1)'' (47 FR 22760 at 22850), one comment stated

that the cited reference discusses only the use of boric acid as a

pharmaceutical necessity, but not as a buffer or as an active

ingredient. The comment contended that the Panel's statement as written

gives the connotation that the buffering action of boric acid and its

use as an active ingredient are both cited in the reference. The

comment recommended that the statement be amended to read ``Boric acid

is used as a pharmaceutical necessity (Ref. 1) for buffering * * *.''

The comment is correct in stating that the cited pages of the

National Formulary (Ref. 1) discuss the use of boric acid as a

pharmaceutical necessity, but the cited pages do not discuss its use as

a buffer or as an active ingredient. The agency notes, however, that

boric acid is discussed as a buffering agent on pages 935 to 936 of the

same reference (Ref. 2), and that these pages should have been included

as part of the citation. The agency also agrees with the comment that

the National Formulary does not discuss the use of boric acid as an

active ingredient.

References

(1) ``National Formulary,'' 14th ed., American Pharmaceutical

Association, Washington, pp. 776-777, 1975.

(2) ``National Formulary,'' 14th ed., American Pharmaceutical

Association, Washington, pp. 935-936, 1975.

E. Comments on Cetylpyridinium Chloride

8. Two comments contended that cetylpyridinium chloride at

concentrations of up to 0.1 percent is safe for use as an OTC

antiseptic agent and should be placed in Category I. The first comment

described the results of various safety testing (e.g., acute toxicity,

oral mucosal and eye irritation, subchronic, and teratology studies) on

cetylpyridinium chloride alone and on cetylpyridinium chloride in

combination with domiphen bromide. The comment also submitted a safety

report (Ref. 1) prepared from data available through August, 1982. The

comment stated that, in all these studies, there have been no

remarkable pathologic findings and thus 0.045 percent cetylpyridinium

chloride is safe for OTC oral use as a single ingredient and in

combination with 0.005 percent domiphen bromide.

The other comment stated that cetylpyridinium chloride is the

active ingredient in a commercially available mouthwash that has been

used by millions of consumers for over 40 years and that the product

continues to be the subject of an approved application based on the

established safety of the product. The comment summarized the safety

data that had been submitted to the Oral Cavity Panel, including long-

term usage studies involving acute and subacute toxicity exposure to

cetylpyridinium chloride and related compounds in humans and animals

(Ref. 2). The comment contended that these studies failed to reveal

evidence of any teratogenic effects and added that in studies involving

life time exposure of mice and rats to benzalkonium chloride, a

representative quat, no evidence of carcinogenic or mutagenic potential

was found. The comment concluded that these experimental data, in

conjunction with the extremely low order of toxicity seen in the more

than four decades of human use, reinforce and justify the National

Cancer Institute's (NCI) apparent lack of concern regarding the

carcinogenicity and mutagenicity of cetylpyridinium chloride and other

quats.

The comment added that the safety of cetylpyridinium chloride is

further substantiated by the infrequent number of adverse drug

experience reports, particularly when considered in relation to the

extensive usage of products containing this ingredient. For example,

marketing studies in 1979 indicated that one mouthwash product was used

by approximately 13 million consumers and that 500,000 people had used

the product more or less continuously for a 10-year period. The comment

stated that, in the 20-year period between 1963 and 1982, there were

only 110 drug experience reports, an average of 5.5 reports per year.

The comment contended that these reports show that cetylpyridinium

chloride is safe because it has not been associated with any

deleterious effects of a significant nature when routinely used as an

oral hygiene product. The comment also submitted the results of several

clinical evaluations of irritation and/or allergic reactions of mucous

membrane and skin surface exposure to cetylpyridinium chloride-

containing solutions (Ref. 3). The comment concluded that the drug

experience reports and clinical evaluations support a Category I

classification of cetylpyridinium chloride for safety.

As part of FDA's Drug Efficacy Study Implementation (DESI) program,

mouthwash products containing povidone-iodine, cetylpyridinium

chloride, and other ingredients were reviewed by the National Academy

of Sciences-National Research Council, Drug Efficacy Study Group (NAS-

NRC/DESG) and found ineffective for claims relating to antimicrobial,

antiseptic, germicidal, and analgesic uses (35 FR 12423). In a

subsequent notice published in the Federal Register of December 2, 1971

(36 FR 23000), the agency stated that because of the implementation of

the OTC drug review, mouthwash and gargle products reviewed under the

DESI program would now be under the purview of the OTC drug review;

thus, final agency action on these products would be deferred pending

evaluation of the data and information concerning such products under

the OTC drug review.

The agency believes that many of the oral antiseptic ingredients

reviewed by the Oral Cavity Panel, including cetylpyridinium chloride,

were placed in Category III for safety because they were used

commercially in mouthwashes that were recommended for long-term use on

a daily basis. The agency believes that the Panel's concerns regarding

the safety of the long-term OTC use of oral antiseptic ingredients are

not necessarily relevant to the short-term OTC use of these ingredients

(see section I.A., comment 2).

The Oral Cavity Panel discussed the results of several

cetylpyridinium chloride toxicity studies in its report (47 FR 22760 at

22865). According to the Panel, the LD50 of cetylpyridinium

chloride is 250 kg/mg subcutaneously, 6 mg/kg intraperitoneally, 30 mg/

kg intravenously, and 200 mg/kg orally. When 50 mg/kg cetylpyridinium

chloride in water was administered daily for 60 days to rats, no toxic

effects or alterations in the rate of growth were noted. Doses of 5 to

10 mg/kg administered through the esophagus showed no toxic effects

over a 6-day period.

The Panel noted that a 1:3,000 (0.033 percent) solution of

cetylpyridinium chloride is irritating to the mucous membranes of the

conjunctiva, but not to the skin (47 FR 22865). It also stated that a

1:200 (0.5 percent) alcoholic or aqueous solution of cetylpyridinium

chloride does not cause skin irritation. The Panel added that

percutaneous absorption of cetylpyridinium chloride is not believed to

be significant. However, the agency notes that the presence of the

cetyl group on the basic quat molecule increases the lipid solubility

of the molecule and, thus, cetylpyridinium chloride has a potential for

increased absorption and irritation (47 FR 22865).

The agency has reviewed its adverse reaction files covering 1969 to

August 1993 (Ref. 4). During those years, 249 cases of adverse

reactions were associated with the use of products containing

cetylpyridinium chloride. None of the adverse reaction reports could be

attributed solely to cetylpyridinium chloride. Of these cases, 10 had a

serious outcome (e.g., death, coma, or hospitalization). Two reports

involved children under 4 years of age who died after ingesting unknown

amounts of a mouthwash containing cetylpyridinium chloride and 14

percent alcohol. In both cases, alcohol was the most likely cause of

death.

Four adverse reaction reports described coma as an outcome. Two

involved young children (3 and 4 years old) who lapsed into comas after

ingesting unknown amounts of a mouthwash product containing

cetylpyridinium chloride and 14 percent alcohol. As is the case with

the deaths described above, these comas are more likely due to alcohol

ingestion than cetylpyridinium chloride ingestion. One adverse reaction

report in which coma is listed as the outcome involved an individual

who ingested 44 cetylpyridinium chloride-containing lozenges, became

gradually and imperceptively unconscious, and caused a head-on

automobile collision. Another report described a middle-aged male with

a history of alcoholism who was hospitalized in a coma after possibly

ingesting a mouthwash containing cetylpyridinium chloride.

Two anaphylactic-type reactions were reported. One was determined

to be an allergic reaction to bisulfites. The other was not clear-cut

because the subject had experienced several similar anaphylactic-like

attacks, only one of which followed use of a cetylpyridinium chloride-

containing product.

Two cases reported the hospitalization of people who had severe

allergic-type reactions. One report described a 21-year-old female with

swelling in her throat, a sensation of feeling hot and flushed,

followed by dyspnea, dysphagia, angioedema of the face (especially the

eyelids), hands, and feet, and near faintness following the ingestion

of one cetylpyridinium chloride lozenge. Another case report described

a young male (8 years old) with a burning sensation, redness, and

swelling on areas of the skin (chin and neck) where a cetylpyridinium

chloride-containing mouthwash was spilled during gargling.

The most frequently reported less serious events are as follows: 26

cases of stomatitis, 13 reports of pain, 12 reports of taste

perversion, 10 cases of nausea, 9 cases of contact dermatitis, 9 cases

of pharyngitis, 8 cases of malaise, and 7 cases of allergic responses.

Other less frequently reported reactions included rash, tooth caries,

dry mouth, and rhinitis.

The agency believes that the information contained in its adverse

reaction files regarding cetylpyridinium chloride demonstrates that the

ingredient can be safely used in an OTC drug product. None of the

adverse reaction reports could be attributed solely to cetylpyridinium

chloride. All reports involved products containing many ingredients in

addition to cetylpyridinium chloride. In addition, other drugs (e.g.,

alcohol) were implicated in the most serious cases.

The agency believes that the information contained in its adverse

reaction files, 30 years of safe marketing of an OTC mouthwash

containing cetylpyridinium chloride (NDA 14-598), and the safety data

evaluated by the Oral Cavity Panel are sufficient to conclude that

0.025 to 0.1 percent cetylpyridinium chloride is safe as an OTC oral

antiseptic when labeled for short-term use (not to exceed 7 days).

However, the agency is concerned that using cetylpyridinium chloride

where excessive gum irritation or bleeding exists could increase the

absorption and systemic load of the ingredient and possibly lead to

some of the toxicological effects discussed by the Oral Cavity Panel

(e.g., neuromuscular blocking of nicotinic and muscarinic receptors)

(47 FR 22760 at 22865). Therefore, the agency is proposing labeling

that would caution consumers not to use a product containing

cetylpyridinium chloride if excessive gum irritation or bleeding exists

unless directed to do so by a doctor or dentist as follows: ``Do not

use this product if gums are irritated or bleeding unless directed to

do so by a doctor or dentist.'' This labeling will be included in the

final monograph for OTC oral antiseptics if cetylpyridinium chloride

becomes Category I in that rulemaking. The agency requests comment

regarding this proposed labeling.

Data on the combination of cetylpyridinium chloride and domiphen

bromide are discussed in section I.L., comments 30 and 31.

References

(1) Comment No. C00013, Docket No. 81N-0033, Dockets Management

Branch.

(2) OTC Vol. 130167.

(3) Attachment C, Comment No. C00015, Docket No. 81N-0033,

Dockets Management Branch.

(4) Food and Drug Administration, Center for Drug Evaluation and

Research, Adverse Reaction Summary Listing for Cetylpyridinium

Chloride for the years 1969 to August 1993, OTC Vol. 13CTFM, Docket

No. 81N-0033, Dockets Management Branch.

9. Two comments contended that 0.025 to 0.1 percent cetylpyridinium

chloride is an effective antiseptic agent and should be placed in

Category I. One comment stated that complete proof of the ability of

cetylpyridinium chloride to kill bacteria in vitro had been submitted

to the Oral Cavity Panel (Ref. 1) and that this proof had been accepted

at the time by the Panel. The comment also discussed several tests

(Ref. 2) purporting to demonstrate the effectiveness of 0.045 percent

cetylpyridinium chloride in combination with 0.005 percent domiphen

bromide and stated that these tests supported the antiseptic

effectiveness of cetylpyridinium chloride. The other comment discussed

data from seven in vitro studies designed to demonstrate the antiseptic

activity of cetylpyridinium chloride (Ref. 3). The comment stated that

two of these studies fulfilled the in vitro guidelines established by

the Oral Cavity Panel (47 FR 22760 at 22890 to 22893) and that the

other five studies demonstrated complementary activity against other

test organisms (Ref. 3). The comment also summarized a number of in

vivo studies designed to demonstrate the antimicrobial activity of

cetylpyridinium chloride. The comment mentioned that all of these in

vitro and in vivo studies had been submitted to the Oral Cavity Panel.

That Panel discussed in vitro and in vivo testing protocol

guidelines for upgrading oral antiseptic ingredients to Category I (47

FR 22760 at 22890 to 22893). The in vitro studies submitted by the

second comment (Ref. 3) do not fulfill the guidelines recommended by

the Panel. For example, in one study (Ref. 4), the protocol closely

resembled that recommended by the Panel. However, the incubation

conditions used to prepare the test cultures were unlike those

recommended by the Panel, and some culture conditions were not

specified (i.e., whether the cultures were grown aerobically or

anaerobically). The test method used in this study was also different

from the method recommended by the Panel in that culture tubes that

showed no growth after 48 hours incubation were not transferred to 90

mL of sterile inactivating media and further incubated for 1 week. In

another study where the protocol was similar to that recommended by the

Panel (Ref. 5), a product containing cetylpyridinium chloride was used

as the test material, but cetylpyridinium chloride alone was not

tested. Therefore, there is no way of knowing whether or not other

ingredients in the test product affected its antimicrobial activity.

Several other in vitro studies (Refs. 6 through 9) tested the

antiseptic effectiveness of cetylpyridinium chloride and

cetylpyridinium chloride-containing products against organisms other

than those recommended by the Panel. One study (Ref. 10) tested the

effectiveness of several mouthwash formulations against pooled human

saliva. Critical killing times against the organisms in the saliva were

determined, but specific organisms were not identified.

Fifteen of the in vivo studies submitted were based upon plaque

reduction. The Panel had considered using plaque reduction as a

criterion for antiseptic activity in the oral cavity, but discarded it

(47 FR 22760 at 22840). The Panel did not accept plaque reduction as a

criterion for determining the effectiveness of oral antiseptics, and

the agency agrees. A subsequent segment of the rulemaking for OTC oral

health care drug products will cover plaque-related claims and

ingredients used for the reduction of plaque. (See section I.A.,

comment 1 and section I.M., comment 32.)

The agency believes that the other in vivo studies submitted (Ref.

3) are not adequate to demonstrate the effectiveness of cetylpyridinium

chloride in reducing the bacterial population of the oral cavity. These

studies were not designed to demonstrate the antibacterial activity of

the ingredient cetylpyridinium chloride alone. They were designed to

demonstrate the antibacterial activity of products such as commercial

mouthwashes or lozenges containing cetylpyridinium chloride and other

ingredients that could affect the antibacterial activity of the

product. The complete formulations of these products were not

identified, and the antiseptic activity of the ingredient

cetylpyridinium chloride was not compared to the activity of a placebo

containing all of the ingredients in the commercial product except for

the cetylpyridinium chloride. Therefore, any antiseptic activity

demonstrated in those studies cannot be solely attributed to the

presence of cetylpyridinium chloride. In order to demonstrate

antiseptic activity of cetylpyridinium chloride, studies must be

designed with one arm consisting of the ingredient cetylpyridinium

chloride alone to demonstrate that cetylpyridinium chloride decreases

the number of microorganisms in the oral cavity. In addition, the

agency is not aware of any data from clinical studies demonstrating a

therapeutic benefit from the OTC use of cetylpyridinium chloride as an

antiseptic in the oral cavity. Data on the combination of

cetylpyridinium chloride and domiphen bromide are discussed in section

I.L., comments 30 and 31.

The agency concludes that additional data are needed to establish

the effectiveness of cetylpyridinium chloride as an oral antiseptic to

help prevent infection in the oral cavity. The agency believes that the

Panel's proposed in vitro and in vivo testing guidelines and its

discussion of clinical studies represent a good starting point for the

design of studies to upgrade a Category II or Category III oral

antiseptic ingredient to Category I. (See section I.M., comment 33 for

a further discussion of testing guidelines.) However, the agency notes

that specific testing guidelines for upgrading ingredients to monograph

status are not included in the tentative final monograph. (See part II.

paragraph A.2.--Testing of Category II and Category III conditions.)

All such testing should be designed using the most current technology

available. The agency will meet with industry representatives or other

interested parties at their request to discuss testing protocols. Any

party interested in conducting studies should request a meeting at its

earliest convenience.

References

(1) OTC Vols. 130007 through 130011, 130089, 130090, and 130167

through 130171.

(2) Comment No. C00013, Docket No. 81N-0033, Dockets Management

Branch.

(3) Comment No. C00015, Docket No. 81N-0033, Dockets Management

Branch.

(4) Project Report No. M-75-03, OTC Vol. 130167.

(5) Project Report No. M-77-03, OTC Vol. 130167.

(6) Project Report No. M-76-05, OTC Vol. 130167.

(7) Myers, G. E., J. K. Logan, and V. J. Mitchell,

``Microbiological Problems in Oral Hygiene,'' OTC Vol. 130167.

(8) ``An In-Vitro Evaluation of Cepacol,'' OTC Vol. 130167.

(9) Hicks, G. F., L. L. Nisonger, and I. Ruchman, ``Germicidal

Effects of Various Combinations of Cetyl Pyridinium Chloride Against

Antibiotic-Resistant Staphylococci,'' OTC Vol. 130167.

(10) ``Comparison of the Antibacterial Activity of Colgate

100, Listerine, Lavoris,

Micrin, and Cepacol,'' OTC Vol. 130167.

F. Comments on Chlorophyllin Copper Complex

10. One comment complained that the Oral Cavity Panel's discussion

of chlorophyllin under the heading ``Antimicrobial Agents'' (47 FR

22760 at 22866 to 22867) contains inaccurate and misleading statements

about other properties of the ingredient. The comment specifically

objected to the statement that chlorophyllin ``has fallen into disuse

over recent years since it has not been demonstrated that it is an

effective deodorant'' and added that support for this statement was one

unidentified reference to a study in which ingested chlorophyll

decreased halitosis in dogs but had no effect on the odor in the dogs'

coats (hair).

The comment maintained that 15 laboratory and human clinical

studies demonstrating the deodorancy effectiveness of chlorophyll were

submitted to the Panel (Ref. 1). Emphasizing that chlorophyllin has not

fallen into disuse as a deodorant, the comment asserted that

chlorophyllin is widely used in hospitals and nursing homes as a

deodorant for ostomy patients and incontinent patients. The comment

cited an article by Young and Beregi (Ref. 2) to support the wide use

of chlorophyllin as an aid in controlling odors of incontinent

patients. The comment suggested that ``a less frequent but pertinent''

indication for chlorophyllin is to reduce odor from cancer of the oral

cavity.

The agency notes that chlorophyllin copper complex is the name

adopted for chlorophyllin by the United States Adopted Names Council

(Ref. 3). Therefore, chlorophyllin copper complex is the name used for

this ingredient in this tentative final monograph.

The agency agrees with the comment that chlorophyllin copper

complex is appropriate for use in hospitals and nursing homes as an

internal deodorant for ostomy patients and incontinent patients. In the

final monograph for OTC deodorant drug products for internal use

published in the Federal Register of May 11, 1990 (55 FR 19862), the

agency concluded that chlorophyllin copper complex (100 to 200 mg

daily) is generally recognized as safe and effective for OTC (internal)

use in controlling ostomy odors and in controlling the odors of fecal

and urinary incontinence. The agency considers the local deodorancy

effect of chlorophyllin copper complex when used topically in the oral

cavity to be a cosmetic rather than a drug effect and, as such, would

not be subject to the rulemaking for OTC oral health care drug

products. (For a discussion of the cosmetic uses of OTC oral health

care drug products, see section I.A., comment 3.) However, if a product

containing this ingredient makes a claim that the product ``reduces

odor from cancer of the oral cavity,'' this claim would need to be

supported by data from appropriate studies in patients with cancer of

the oral cavity.

References

(1) OTC Vol. 130015.

(2) Young, R. W., and J. S. Beregi, Jr., ``Use of Chlorophyllin

in the Care of Geriatric Patients,'' Journal of the American

Geriatrics Society, 28:46, 1980.

(3) ``USAN and the USP Dictionary of Drug Names,'' United States

Pharmacopeial Convention, Inc., Rockville, MD, p. 136, 1993.

11. Noting that the Oral Cavity Panel had classified chlorophyllin

solely as an ``antimicrobial agent,'' one comment stated that its

antibacterial properties are less significant than its healing effects.

The comment asserted that the data submitted to the Panel emphasized

that chlorophyllin is primarily a healing agent that acts to relieve

discomfort due to minor irritations, inflammation, and other lesions by

encouraging tissue repair and reducing inflammation. The comment

contended that there should be a classification for ingredients, such

as chlorophyllin, that encourage repair of minor irritations or

inflammation. Acknowledging that there might be some problems with

using the term ``healing agents'' for OTC drug products, the comment

suggested using the term ``tissue-repair agents'' for products

containing this ingredient. The comment referred to the statement in

the Panel's report that no data were submitted or are available from

controlled studies to substantiate a wound healing claim (47 FR 22760

at 22867) and argued that its own submission to the Panel contained

many controlled studies on the wound healing effects of chlorophyllin.

The agency has reviewed the submissions on chlorophyllin copper

complex made to the Oral Cavity Panel (Refs. 1 and 2) as well as

submissions made to the Advisory Review Panel on OTC Dentifrice and

Dental Care Drug Products (Dental Panel) (Refs. 3 and 4). Although no

antiseptic claims appear in the labeling of chlorophyllin copper

complex-containing products submitted to these panels, the submissions

contain data purporting to show the bacteriostatic effectiveness of

water-soluble chlorophyllins as well as data to support the wound

healing claims (Refs. 1 and 3). The Oral Cavity Panel evaluated the

data submitted in support of the antiseptic effectiveness of

chlorophyllin copper complex, and the Dental Panel evaluated the data

submitted to support the wound healing claims.

The Oral Cavity Panel concluded that chlorophyllin copper complex

is safe, but that there are insufficient data available to permit final

classification of its effectiveness as an OTC antiseptic active

ingredient for topical use on the mucous membranes of the mouth and

throat (47 FR 22760 at 22866). Because no additional data were

submitted to the agency in support of the antiseptic effectiveness of

chlorophyllin copper complex, the agency concludes that the Panel's

Category III classification is appropriate. Therefore, in this

tentative final monograph, the agency is proposing a Category III

classification for chlorophyllin copper complex as an OTC oral health

care antiseptic ingredient.

In its report on OTC oral mucosal injury drug products published in

the Federal Register of November 2, 1979 (44 FR 63270), the Dental

Panel concluded that water-soluble chlorophyllins are safe, but that

there were insufficient effectiveness data available to permit final

classification of water-soluble chlorophyllins as oral wound healing

agents (44 FR 63270 at 63286). Therefore, the Dental Panel classified

water-soluble chlorophyllins in Category III. In response to the

publication of the Panel's report, the agency received no comments

regarding chlorophyllin copper complex as an OTC oral wound healing

agent. Therefore, in the tentative final monograph for OTC oral mucosal

injury drug products published in the Federal Register of July 26, 1983

(48 FR 33984), the agency accepted the Panel's evaluation and proposed

a Category III classification for chlorophyllin copper complex as an

oral wound healing agent. Again, the agency received no comments

regarding chlorophyllin copper complex in response to the publication

of the tentative final monograph for OTC oral mucosal injury drug

products. Accordingly, in the final rule for OTC oral wound healing

agents published in the Federal Register of July 18, 1986 (51 FR

26112), the agency concluded that there was insufficient evidence to

support the effectiveness of chlorophyllin copper complex as an oral

wound healing agent. Therefore, chlorophyllin copper complex is

considered a nonmonograph oral wound healing ingredient.

References

(1) OTC Vol. 130015.

(2) OTC Vol. 130088.

(3) OTC Vol. 080043.

(4) OTC Vol. 080168.

G. Comments on Domiphen Bromide

12. One comment requested that the agency approve domiphen bromide

at concentrations of up to 0.1 percent for safety. The comment

described the results of various safety testing (e.g., acute toxicity,

oral mucosal and eye irritation, subchronic, and teratology studies) on

domiphen bromide alone and on domiphen bromide in combination with

cetylpyridinium chloride. The comment also included a safety report

(Ref. 1) prepared from data available through August 1982. The comment

stated that, in all these studies, there have been no remarkable

pathologic findings and thus up to 0.1 percent domiphen bromide is safe

for OTC oral use as a single ingredient.

As stated in section I.A., comment 2, the agency believes that many

of the oral antiseptic ingredients reviewed by the Oral Cavity Panel,

including domiphen bromide, were placed in Category III for safety

because they were used commercially in mouthwashes that were

recommended for long-term use on a daily basis. The agency believes

that the Panel's concerns regarding the safety of the long-term OTC use

of oral antiseptic ingredients are not necessarily relevant to the

short-term OTC use of these ingredients.

The agency has reevaluated the data submitted to the Oral Cavity

Panel regarding the safety of domiphen bromide in light of labeling

that would limit use of oral antiseptic drug products to 7 days or

less. The Panel noted in its discussion of domiphen bromide (47 FR

22760 at 22868 to 22869) that ``the concentrations of domiphen bromide

used in commercial lozenges and mouthwashes appear to be nontoxic.'' It

cited several studies in which no toxicity could be demonstrated.

According to the Panel, the intravenous LD50 was determined to be

18 mg/kg for rats, 31 mg/kg for mice, and 11 to 12 mg/kg for rabbits.

An oral LD50 (species unspecified) could not be determined because

marked diarrhea resulted, but it was suspected to be above 800 mg/kg/

day. The intraperitoneal LD50 was 40 to 45 mg/kg for rats and 10

to 20 mg/kg for guinea pigs. One study (Ref. 2) discussed in the

Panel's report concluded that clinical use of a mouthwash containing

0.01 percent domiphen bromide two to six times daily for up to 52 weeks

resulted in no apparent toxicity.

The Panel noted that only six adverse reactions were reported

between 1958 and 1970 for a lozenge product containing domiphen bromide

(47 FR 22869). These included one complaint of lack of effectiveness,

two cases of burns on the tongue, one case of soreness of the mouth,

one case of fungal growth after use of the product, and one case of

chalk-like taste. The agency has reviewed its adverse reaction files

covering 1969 to May 1993. During those years, no adverse event reports

associated with domiphen bromide were received.

The agency tentatively concludes that the safety data evaluated by

the Oral Cavity Panel, 30 years of safe marketing of an OTC mouthwash

product containing domiphen bromide (NDA 14-598), and the lack of

adverse event reports in its files are sufficient to conclude that up

to 0.1 percent domiphen bromide is safe as an OTC oral antiseptic when

labeled for short-term use (not to exceed 7 days). However, when this

ingredient is used in conjunction with cetylpyridinium chloride as an

oral antiseptic (see section I.E., comment 8), the agency is concerned

that using domiphen bromide where excessive gum irritation or bleeding

exists could increase the absorption and systemic load of the

ingredient and possibly lead to some of the toxicological effects

discussed by the Oral Cavity Panel (e.g., convulsions, central nervous

system depression followed by death due to the curare-like action of

quats) (47 FR 22760 at 22869). Therefore, the agency is proposing

labeling that would caution consumers not to use a product containing

domiphen bromide if excessive gum irritation or bleeding exists unless

directed to do so by a doctor or dentist as follows: ``Do not use this

product if gums are irritated or bleeding unless directed to do so by a

doctor or dentist.'' This labeling will be included in the final

monograph for OTC oral antiseptics if domiphen bromide becomes Category

I in that rulemaking. The agency requests comment regarding this

proposed labeling.

Data on the combination of cetylpyridinium chloride and domiphen

bromide are discussed in section I.L., comments 30 and 31.

References

(1) Comment No. C00013, Docket No. 81N-0033, Dockets Management

Branch.

(2) Kutscher, A. H., and J. Budowsky, ``Observations on the

Clinical Use of Bradosol,'' Oral Surgery, Oral Medicine, and Oral

Pathology, 7:873-875, 1954.

13. One comment requested that the agency approve 0.05 percent

domiphen bromide for effectiveness. The comment stated that

effectiveness was proven in tests against three organisms, and that the

results of these tests were included in the comment (Ref. 1) and had

been reported to the Oral Cavity Panel (Ref. 2). The comment added that

the protocol for these studies was reviewed and approved by the Panel.

The comment mentioned that, in several votes taken over a period of

more than 3 years, the Panel placed domiphen bromide in Category I. The

comment added that, at its next-to-last meeting, the Panel rescinded

its action and placed domiphen bromide, along with all other antiseptic

ingredients, in Category III for effectiveness. The comment argued that

the Panel's decision was ill-advised and urged the agency to give

monograph status to domiphen bromide.

The agency believes that there are not enough data to conclude that

domiphen bromide is an effective oral antiseptic. The effectiveness

studies (Refs. 1 and 2) were conducted according to the July 12, 1977,

version of tentative guidelines developed and submitted to the Panel by

the NDMA (formerly known as The Proprietary Association) (Ref. 3).

Those guidelines were under consideration by the Oral Cavity Panel, but

were subsequently revised as described in the Panel's 1982 report (47

FR 22760 at 22890 to 22893). A notable revision made by the Panel was

to increase the inoculum of test culture; the 1977 NDMA guidelines

provided for a 1 mL aliquot of a 1 to 4 dilution of inoculum added to

10 mL of the mouthwash product or active ingredient, while the Panel's

final guidelines specified 1 mL of undiluted culture in 9 mL of product

or active ingredient. The Panel also proposed additional in vitro

testing that included a determination of the minimum inhibitory

concentration (MIC) of the antiseptic agent, and testing of freshly

obtained clinical isolates from mouth and throat infections to provide

updated, relevant data on the susceptibility of these isolates to the

antiseptic agent (47 FR 22760 at 22890 to 22891). Since publication of

the Panel's report, no such data for domiphen bromide have been

provided to the agency. In addition, the agency is not aware of any

data from clinical studies demonstrating a therapeutic benefit from the

OTC use of domiphen bromide in the oral cavity. The agency concludes

that additional data are necessary to establish the effectiveness of

domiphen bromide as an oral antiseptic to help prevent infection in the

oral cavity.

The agency believes that the Panel's 1982 proposed testing

guidelines and its discussion of clinical studies represent a good

starting point for the design of studies to upgrade a Category II or

Category III oral antiseptic ingredient to Category I. (See section

I.M., comment 33 for a further discussion of testing guidelines.) Since

testing requirements are subject to change over time because of

technological advancements, the agency notes that specific testing

guidelines for upgrading ingredients to monograph status are not

included in the tentative final monograph. (See part II. paragraph

A.2.--Testing of Category II and Category III conditions.) All such

testing should be designed using the most current technology available.

The agency will meet with industry representatives or other interested

parties at their request to discuss testing protocols. Any party

interested in conducting studies should request a meeting at its

earliest convenience.

References

(1) Comment No. C00013, Docket No. 81N-0033, Dockets Management

Branch.

(2) OTC Vol. 130134.

(3) OTC Vol. 130131.

H. Comment on Phenol

14. One comment requested that the agency classify 1.4 to 1.5

percent phenol in Category I as an antiseptic mouthwash. The comment

stated that until its next-to-last meeting, the Oral Cavity Panel

believed that the antiseptic capability of a mouthwash could be

demonstrated through the use of in vitro and in vivo studies, but that

the Panel arbitrarily decided to reverse its long-standing position

without additional evidence. The comment further stated it had

presented documentation to the Panel prior to its reversal that phenol

met the requirements of both the in vitro and in vivo protocols. The

comment resubmitted the same studies it had submitted to the Panel and

requested that the agency accept these data (Ref. 1).

The agency has evaluated the studies submitted to the Panel and

concludes that they are not adequate to establish the effectiveness of

phenol as an OTC oral antiseptic. The comment's data include one in

vitro study and two in vivo efficacy studies. No data from clinical

studies were submitted to the agency to demonstrate a therapeutic

benefit from the OTC use of phenol in the oral cavity.

The in vitro study was conducted according to the July 12, 1977,

NDMA tentative guidelines that had been submitted to the Panel (Ref.

2). Those guidelines were under consideration by the Oral Cavity Panel

at the time the comment's studies were conducted, but were subsequently

revised as described in the Panel's report (47 FR 22760 at 22890). A

notable revision made by the Panel was to increase the inoculum of test

culture; the 1977 NDMA guidelines provided for a 1 mL aliquot of a 1 to

4 dilution of inoculum added to 10 mL of the product or active

ingredient, while the Panel's final guidelines specified 1 mL of

undiluted culture in 9 mL of product or active ingredient. The Panel

also proposed additional in vitro testing that included a determination

of the MIC of the antiseptic agent, and testing of freshly obtained

clinical isolates from mouth and throat infections to provide updated,

relevant data on the susceptibility of these isolates to the antiseptic

agent (47 FR 22760 at 22890 to 22891). No such data were provided for

phenol following the Panel's final recommendations.

The two in vivo studies were also designed following tentative

guidelines (Ref. 3) under consideration by the Panel. According to

those guidelines, an oral antiseptic ingredient that reduced the

accumulation of dental plaque was considered to reduce microorganisms,

and thus was deemed an oral antiseptic. The Panel had originally

considered this in vivo method, based on plaque reduction on the teeth

and periodontal tissues, as a criterion for antiseptic activity in the

oral cavity, but subsequently discarded it, stating that the method was

inexact and had no rational basis because dental plaque is not a

disease per se (47 FR 22760 at 22840). There was considerable

discussion of this issue by the Panel, and in making its final

determination, the Panel relied upon the opinions of consultants and

statisticians who are experts in the field, as well as on the expertise

of the Panel members (47 FR 22840 to 22842). In its final report, the

Panel did not accept plaque reduction as a criterion for determining

effectiveness of antiseptic agents, and the agency agrees. A subsequent

segment of the rulemaking for OTC oral health care drug products will

cover plaque-related claims and ingredients. (See section I.M., comment

32.)

The agency disagrees with the comment that the Oral Cavity Panel

arbitrarily reversed its position regarding in vitro and in vivo

studies. Rather, after careful deliberations, the Panel modified its

tentative in vitro guidelines, and replaced its tentative in vivo

guidelines with others it believed were more appropriate. The agency

believes that the Panel's proposed testing guidelines and its

discussion of clinical studies represent a good starting point for the

design of studies to upgrade a Category II or Category III oral

antiseptic ingredient to Category I. (See section I.M., comment 33 for

a further discussion of testing guidelines.) However, the agency notes

that specific testing guidelines for upgrading ingredients to monograph

status are not included in the tentative final monograph. (See part II.

paragraph A.2.--Testing of Category II and Category III conditions.)

All such testing should be designed using the most current technology

available. The agency will meet with industry representatives or other

interested parties at their request to discuss testing protocols. Any

party interested in conducting studies should request a meeting at its

earliest convenience.

References

(1) Comment No. C00014 and OTC Vol. 130131, Docket No. 81N-0033,

Dockets Management Branch.

(2) Letter from J. D. Cope, NDMA (formerly The Proprietary

Association), dated July 15, 1977, OTC Vol. 130PA3.

(3) Letter from J. D. Cope, NDMA (formerly The Proprietary

Association), dated February 23, 1977, OTC Vol. 130110-B.

I. Comments on Povidone-Iodine

15. Three comments objected to the Oral Cavity Panel's conclusion

that there are insufficient data available to permit classification of

povidone-iodine as safe for OTC topical antimicrobial use on the mucous

membranes of the mouth and throat. One comment (Ref. 1) stated that

most of the safety concerns raised by the Oral Cavity Panel had been

fully addressed by data submitted earlier to several other OTC drug

rulemakings: (1) Topical antimicrobial drug products, (2) contraceptive

and other vaginal drug products, (3) topical acne drug products, and

(4) antifungal drug products. The comment contended that had the data

and testimony to these other panels been considered by the Oral Cavity

Panel, many safety concerns would have been resolved and duplicative

efforts precluded. Another comment maintained that the Panel's

conclusion that there are insufficient data available to permit

classification of povidone-iodine as safe for antiseptic use on the

mucous membranes of the mouth and throat is in error. A third comment

mentioned that a commercially available mouthwash containing povidone-

iodine has been marketed under an approved new drug application (NDA)

(NDA 10-290) for a quarter century without reports of any significant

adverse effects related to this product.

One comment contended that clinical and experimental studies have

shown that povidone-iodine can reduce infection in wounds or surgical

procedures without impairing wound healing or causing adverse

reactions. The comment submitted several studies to support its

statement (Refs. 2 through 9). Another comment also submitted data to

establish that povidone-iodine preparations do not inhibit normal wound

healing (Refs. 10, 11, and 12). The comment stated that the concern as

to whether povidone-iodine accelerates or delays wound healing was

addressed in detail in the Antimicrobial II Panel's report on the

antifungal use of povidone-iodine, published in the Federal Register of

March 23, 1982 (47 FR 12480 at 12545).

One comment submitted three studies (Refs. 13, 14, and 15), one of

which (Ref. 13) was also submitted by another comment, designed to

demonstrate that no carcinogenic or mutagenic effects are associated

with the use of povidone-iodine. Another comment submitted data

regarding the capability of povidone-iodine to alter DNA in living

cells. These data were also presented to the Vaginal Panel in 1978

(Refs. 15 and 16). A third comment maintained that all data relevant to

the mutagenic potential of povidone-iodine had been considered by the

Vaginal Panel, which concluded that povidone-iodine is not

carcinogenic, teratogenic, or mutagenic. The comment submitted a review

of the available data (Ref. 17).

One comment discussed the Oral Cavity Panel's statement that

``chronic, indiscriminate use of PVP-I [povidone-iodine] has been

associated with iodism, an increase in protein-bound iodine, and

altered thyroid function,'' (47 FR 22760 at 22883). The comment agreed

that indiscriminate use of any substance may cause harm and stated that

one of the functions of proper OTC drug labeling is to instruct the

consumer with appropriate directions so that indiscriminate use of

pharmaceutical products can be avoided. The comment submitted FDA

approved labeling (from NDA 10-290) (Ref. 18) for a commercially-

available product and noted that the labeling should eliminate concerns

about chronic, indiscriminate use of the product. The comment added

that application of povidone-iodine to mucosal tissue does not affect

normal thyroid function and stated that data had been submitted to FDA

in support of this contention (Ref. 19).

One comment indicated that the Oral Cavity Panel's basis for the

following statement was misdirected: ``The toxic effects of PVP-I

[povidone-iodine] are due to the release of free iodine and since the

release occurs slowly, its toxicity and irritancy is low,'' (47 FR

22883). The comment agreed with the Panel that the toxicity and

irritancy of povidone-iodine is low; however, the comment maintained

that the low toxicity and irritancy exhibited by povidone-iodine is due

to the kinetics of the available iodine dynamic equilibrium as well as

the physical and chemical properties of the iodine moiety in povidone-

iodine rather than the slow release of free iodine as suggested by the

Panel.

One comment stated that povidone-iodine has been the subject of

extensive scientific study for decades and that the medical literature

contains approximately 4,000 references, including extensive long-term

feeding studies in animals and humans. The comment pointed out the Oral

Cavity Panel reported that povidone-iodine is nontoxic and that the

free iodine released from povidone-iodine has low toxicity and

irritancy (47 FR 22760 at 22883). The comment mentioned that the Panel

also stated that ``Povidone is practically nontoxic,'' ``povidone is

not metabolized,'' and ``the greatest portion [of povidone] is excreted

unchanged by the kidney.'' The comment submitted a toxicology review of

data to show no biologically significant toxicity or other adverse

effects of povidone-iodine following oral administration (Refs. 20

through 23). The comment contended that povidone-iodine is completely

safe for use on either a short- or long-term basis.

One comment stated that the rate of absorption of povidone and

iodine from the povidone-iodine complex through intact skin, vaginal

mucosa, and the peritoneal cavity has been shown to be insignificant or

virtually nonexistent. The comment submitted data to support its

statement (Refs. 20, 24, 25, and 26). Citing ``dental academicians,''

the comment contended that a valid comparison can be made between the

histology and function of the vaginal mucosa and the oral mucosa. One

comment asserted that the safety concerns raised by the Oral Cavity

Panel regarding the use of povidone-iodine in the oral cavity are based

upon uses of povidone-iodine solution that are not relevant to the use

of low concentrations of povidone-iodine in the oral cavity. For

example, the comment noted that the Panel's concern about the behavior

of povidone-iodine after parenteral administration is not pertinent to

the safety of oral health care drug products used topically on the

mouth and throat (47 FR 22760 at 22883 to 22884). Another comment

stated that because the oral mucosa and the peritoneum are very

different histologically and functionally, studies on the peritoneum

cited by the Oral Cavity Panel cannot be applied to the use of

povidone-iodine in the oral cavity.

The agency has considered the data submitted in support of the

safety of povidone-iodine, the Oral Cavity Panel's discussion of the

safety of povidone-iodine (47 FR 22760 at 22883 to 22884), and the

other advisory panels' evaluations of the safety of povidone-iodine.

Based on this information, FDA concludes that povidone-iodine should be

classified in Category I for safety as an OTC antiseptic ingredient for

short-term (i.e., no more than 7 days) topical use on the mucous

membrane of the mouth and throat.

As stated elsewhere in this document (see section I.A., comment 2),

the agency believes that many of the oral antiseptic ingredients

reviewed by the Panel, including povidone-iodine, were placed in

Category III for safety because they were used commercially in

mouthwashes that were recommended for long-term use on a daily basis.

The agency believes that the Oral Cavity Panel's concerns regarding the

safety of the long-term OTC use of oral antiseptic ingredients are not

necessarily relevant to the short-term OTC use of these ingredients. In

its discussion of povidone-iodine (47 FR 22760 at 22884), the Panel

stated that extensive clinical observations indicated that povidone-

iodine is generally nonirritating and nonsensitizing when applied to

skin and mucous membranes. The Panel concluded that although povidone-

iodine may be safe for occasional application to the mucous membranes,

there were insufficient data to establish its safety for long-term

daily use.

The Oral Cavity Panel's concern about povidone-iodine's effect on

wound healing was based upon a statement in the Antimicrobial I Panel

report on antimicrobial drug products published in the Federal Register

of September 13, 1974 (39 FR 33102) that ``conflicting data [had been

presented] concerning the role of PVP-iodine use on the rate of wound

healing.'' Some data presented to the Antimicrobial I Panel suggested

that povidone-iodine had no effect on the rate of wound healing, while

other data suggested a delay in wound healing after povidone-iodine use

in animal model studies (39 FR 33102 at 33131). In its evaluation of

povidone-iodine as a topical antifungal ingredient, the Antimicrobial

II Panel relied on new data as well as the recommendations of the

Antimicrobial I Panel. In its report, the Antimicrobial II Panel

specifically addressed the effects of povidone-iodine on wound healing

(47 FR 12480 at 12545), concluded that povidone-iodine has no adverse

effects on wound healing, and determined that 10 percent povidone-

iodine is safe for OTC use as an antifungal agent. In the tentative

final monograph for OTC first aid antiseptic drug products, the agency

evaluated additional new data regarding the effect of povidone-iodine

on wound healing and concluded that this ingredient does not delay

wound healing (56 FR 33644 at 33662). The agency has no reason to

believe that the mechanism for wound healing in the oral cavity is

significantly different from the mechanism for skin wound healing.

Therefore, the agency believes that the data discussed above are

applicable to wound healing in the oral cavity. The agency tentatively

concludes that povidone-iodine does not inhibit normal wound healing in

the oral cavity.

In the tentative final monograph for OTC first aid antiseptic drug

products (56 FR 33644 at 33661 to 33662), the agency discussed data

from published and unpublished studies to show that povidone-iodine

does not alter thyroid function. The agency reviewed the data and

agreed that thyroid disfunction does not occur from topical use of

povidone-iodine. In addition, studies following the application of

povidone-iodine to the mucous membranes (vagina) and intact and damaged

skin in humans and animals reported protein-bound iodine elevations,

but no alterations in thyroid function. The agency concluded that 0.5

to 5 percent povidone-iodine is safe for OTC use as a topical first aid

antiseptic.

The agency also agrees with one comment that the currently

available information indicates that povidone-iodine is not mutagenic

or carcinogenic. In its evaluation of povidone-iodine as a topical

antifungal ingredient, the Antimicrobial II Panel relied on new safety

data as well as the recommendations of the Antimicrobial I Panel (39 FR

33102 at 33129). In its report, the Antimicrobial II Panel specifically

discussed data on the mutagenicity potential of povidone-iodine (47 FR

12480 at 12545) and concluded that povidone-iodine has no significant

mutagenic or carcinogenic capabilities. That Panel determined that 10

percent povidone-iodine is safe for OTC use as an antifungal agent. The

Vaginal Panel reviewed a povidone-iodine migration and absorption study

in three experimental animal species using radioactively tagged

povidone-iodine (48 FR 46694 at 46705). Although there was evidence of

absorption of iodine from the vagina into the systemic circulation, the

experiments showed little or no flow of radioactively tagged povidone

into the uterus from the vagina. Stating that ``the weight of evidence

is sufficient to conclude that povidone-iodine does not have a

significant mutagenic or carcinogenic effect'' (48 FR 46694 at 46705),

that Panel classified povidone-iodine as Category I for the relief of

minor vaginal irritations. In addition, the agency has searched the

scientific literature covering 1982 through May 1993, and has not found

any information indicating that povidone-iodine might be mutagenic or

carcinogenic.

The agency has reviewed its adverse reaction files covering 1970 to

August 1993 (Ref. 26). During those years there were no cases of

adverse reactions associated with the use of povidone-iodine as an oral

antiseptic. There were numerous cases of adverse reactions associated

with the use of topical products containing povidone-iodine, e.g.,

first aid antiseptics or surgical scrubs. Of these cases, 20 were

classified as serious. Five deaths occurred. However, each death

occurred after the professional use of povidone-iodine as a health care

antiseptic in a hospital setting (i.e., (1) use as surgical scrub on a

patient who had previously been exposed to multiple radiographic

examinations, (2) use to sterilize the peritoneal cavity after surgery,

(3) administration concurrent with an electrolyte solution by enema and

subsequently through a nasogastric tube, and (4) continuous irrigation

of a hip wound). The other serious case reports involved chest pain,

contact dermatitis, or chemical burns resulting from the preoperative

use of povidone-iodine solutions as health-care antiseptics. These

cases resulted in prolonged hospitalizations and/or disability (e.g.,

loss of vision or burns of varying degrees). The most frequently

reported events included: reports of rash, reports of contact

dermatitis, reports of application site reactions, reports of

vaginitis, and reports of pain. Other less frequently reported

reactions (i.e., 1 or 2 reports per reaction) included conjunctivitis,

anaphylactic shock, iodism, rhinitis, and dry skin. The agency notes

that the majority of these cases were the result of povidone-iodine

products being used by health care professionals on people who were in

the hospital for surgery or who were otherwise compromised. In

addition, the povidone-iodine concentration in the products used in

these cases was 5 to 10 percent, which is much higher than its

concentration in oral antiseptic products (0.5 percent). The agency

does not believe that these reports are relevant to the use of

povidone-iodine as an oral antiseptic product used in small amounts in

the oral cavity for a limited period of time (i.e., up to 7 days).

The agency believes that the information contained in its adverse

reaction files and the safety data evaluated by the Oral Cavity Panel

are sufficient to conclude that 0.5 percent povidone-iodine (i.e., the

concentration evaluated by the Oral Cavity Panel) is safe as an OTC

oral antiseptic for short-term use (not to exceed 7 days).

References

(1) Comment No. C00020, Docket No. 81N-0033, Dockets Management

Branch.

(2) Bradley, S. G., ``A Review on Some Microbiological Aspects

of Povidone-Iodine (PVP-I),'' Addendum 20, Comment No. C00020,

Docket No. 81N-0033, Dockets Management Branch.

(3) Prince, H. N. et al., ``Drug Resistance Studies with Topical

Antiseptics,'' Journal of Pharmaceutical Sciences, 67:1629-1630,

1973.

(4) Eitzen, H. E., ``Efficacy of Povidone-Iodine (PVP-I),''

Addendum 22, Comment No. C00020, Docket No. 81N-0033, Dockets

Management Branch.

(5) Gilmore, O. J. A., and P. J. Sanderson, ``Prophylactic

Interparietal Povidone-Iodine in Abdominal Surgery,'' British

Journal of Surgery, 62:792-799, 1975.

(6) Eitzen, H. E. et al. ``A Microbiological In-Use Comparison

of Surgical Hand-Washing Agents,'' The Journal of Bone and Joint

Surgery, Incorporated, 61-A:403-406, 1979.

(7) Steere, A. C., and G. F. Mallison, ``Handwashing Practices

for the Prevention of Nosocomial Infections,'' Annals of Internal

Medicine, 83:683-690, 1975.

(8) Morgan, W. J., ``Povidone-Iodine Spray for Wounds Sutured

the Accident Department,'' Addendum 26, Comment No. C00020, Docket

No. 81N-0033, Dockets Management Branch.

(9) Carchman, R. A., ``The Effects of Povidone-Iodine on Wound

Healing,'' Addendum 27, Comment No. C00020, Docket No. 81N-0033,

Dockets Management Branch.

(10) Fischer, E., and Z. Paster, ``A Study of the Effect of

Polydine on Wound Healing,'' Appendix 10, Comment No. C00019, Docket

No. 81N-0033, Dockets Management Branch.

(11) Gilmore, O. J. A., ``A Reappraisal of the Use of

Antiseptics in Surgical Practice,'' Annals of the Royal College of

Surgeons of England, 59:93-103, 1977.

(12) Gilmore, O. J. A., and C. Reid, ``A Study of the Effect of

Povidone-iodine on Wound Healing,'' Postgraduate Medical Journal,

53:122-125, 1977.

(13) Schwartz, S. L., ``Evaluation of the Safety of Povidone and

Crospovidone,'' Addendum 16, Comment No. C00020, Docket No. 81N-

0033, Dockets Management Branch.

(14) ``Studies on Testing of Povidone-Iodine U.S.P. XIX for

Mutagenic Effects in Mice and Chinese Hamsters,'' Comment No.

C00019, Docket No. 81N-0033, Dockets Management Branch.

(15) Merkle, J., and H. Zeller, ``Absence of Povidone-Iodine-

Induced Mutagenicity in Mice and Hamsters,'' Journal of

Pharmaceutical Sciences, 68:100-102, 1979.

(16) Kessler, F. K. et al., ``Assessment of Somatogenotoxicity

of Povidone-Iodine Using Two In Vitro Assays,'' Addendum 15, Comment

No. C00020, Docket No. 81N-0033, Dockets Management Branch.

(17) Brusick, D. J., ``A Review of the Genotoxic Effects of

Povidone-Iodine,'' Attachment B, Comment No. C00010, Docket No. 81N-

0033, Dockets Management Branch.

(18) Attachment A, Comment No. C00010, Docket No. 81N-0033,

Dockets Management Branch.

(19) ``Serum Fodides and Thyroid Function; Betadine Mouthwash/

Gargle (Povidone-Iodine),'' Attachment C, Comment No. C00010, Docket

No. 81N-0033, Dockets Management Branch.

(20) Borzelleca, J. F., ``A Review of the Basic Toxicology of

Povidone-Iodine,'' Addendum 4, Comment No. C00020, Docket No. 81N-

0033, Dockets Management Branch.

(21) ``Toxicology Summary of PVP,'' Addendum 17, Comment No.

C00020, Docket No. 81N-0033, Dockets Management Branch.

(22) Blecher, L. et al., ``Polyvinylpyrrolidone,'' Addendum 18,

Comment No. C00020, Docket No. 81N-0033, Dockets Management Branch.

(23) Digenis, G. A., ``Behavior of Povidone-Iodine in the

Vaginal Vault of the Rat, Dog, and Sheep,'' Addendum 11, Comment No.

C00020, Docket No. 81N-0033, Dockets Management Branch.

(24) Istin, M., ``Study of the Urinary, Biliary, and Fecal

Excretion of C14 by Rats Treated with Labeled

Polyvinylpolypyrrolidone (PVPP-C14) by Gastric Intubation,''

Addendum 12, Comment No. C00020, Docket No. 81N-0033, Dockets

Management Branch.

(25) Ingbar, S. H., ``Studies of the Effects of Surgical

Scrubbing with PVP-I,'' Addendum 13, Comment No. C00020, Docket No.

81N-0033, Dockets Management Branch.

(26) Food and Drug Administration, Center for Drug Evaluation

and Research, Adverse Reaction Summary Listing for Povidone-iodine

for the years 1970 to August 1993, OTC Vol. 13CTFM, Docket No. 81N-

0033, Dockets Management Branch.

16. Two comments objected to the Oral Cavity Panel's conclusion

that there is insufficient evidence available to classify povidone-

iodine in Category I as an effective oral antiseptic. One comment

stated that a commercial mouthwash has been marketed under an approved

NDA for a quarter century and that reports of clinical studies

involving thousands of patients had been submitted to the Panel.

The comments objected to the Panel's statement that the ``* * *

slow release [of povidone-iodine] also raises doubts about its

effectiveness, since the active ingredient is elemental iodine,'' (47

FR 22760 at 22883). One comment stated that the Panel's speculation on

the release of iodine and its impact on the effectiveness of povidone-

iodine is unfounded. The comment added that the effectiveness of

povidone-iodine solution as a topical microbicide is proven in the

hundreds of studies submitted or referenced to the Panel. The comment

contended that the Panel did not develop an independent viewpoint

regarding the effectiveness of povidone-iodine but relied upon the

Antimicrobial I Panel's evaluation. The comment argued that the issues

raised by the Antimicrobial I Panel were fully answered by the data

submitted in response to that Panel's report.

Another comment stated that the efficacy of the povidone-iodine

complex is independent of the initial content of free iodine and that

biocidal effect is determined by iodine liberated from the complex

during the reaction with amino acids of the proteins of bacteria,

fungi, etc. The comment mentioned that substantial data submissions to

the Antimicrobial I Panel and other panels showed that iodine is freely

released from the complex and that the rate of iodine release is

controlled by tissue demand. The comment submitted data regarding the

rate of release and germicidal activity of povidone-iodine (Refs. 1, 2,

and 3). The comment stated that the studies established that: (1) The

biocidal activity of the complex is independent of the initial free

iodine content; (2) the clinical effectiveness of the complex is caused

by the amount of available iodine; (3) the iodine becomes effective by

oxidation or iodizing reaction of amino acids of the proteins of

bacteria, fungi, etc.; (4) the iodine is liberated from the povidone-

iodine complex at a rate in the milliseconds time range; and (5) within

the acidity levels studied (i.e., those levels relevant to the field of

medicine, between pH 3 and 5), no significant change with regard to the

rapidity of iodine release from the povidone-iodine complex could be

observed. The comment concluded that there are sufficient data

available to establish the effectiveness of povidone-iodine for use as

an OTC oral antiseptic.

As part of FDA's DESI program, mouthwash products containing

povidone-iodine, cetylpyridinium chloride, and other ingredients were

reviewed by the NAS-NRC/DESG and found ineffective for claims relating

to antimicrobial, antiseptic, germicidal, and analgesic uses (35 FR

12423). In a subsequent notice published in the Federal Register of

December 2, 1971 (36 FR 23000), the agency stated that because of the

implementation of the OTC drug review, mouthwash and gargle products

reviewed under the DESI program would now be under the purview of the

OTC drug review; thus, final agency action on these products would be

deferred pending evaluation of the data and information concerning such

products under the OTC drug review.

The agency has reviewed the data submitted regarding the

availability of iodine from the povidone-iodine complex and considered

the data discussed in the tentative final monograph for OTC topical

acne drug products, published in the Federal Register of January 15,

1985 (50 FR 2172 at 2173 to 2174) and in the tentative final monograph

for OTC first aid antiseptic drug products (56 FR 33644 at 33661). The

agency agrees with the comment that the issues regarding the

availability of iodine from povidone-iodine complex and the stability

of the complex have been resolved for this ingredient. However, the

agency has determined that further studies are needed to demonstrate

the effectiveness of povidone-iodine for OTC topical use in the oral

cavity to help prevent infection.

As discussed in section I.K., comment 27, the agency believes that

0.5 percent povidone-iodine is an effective oral antiseptic for

professional use when used for the preparation of the oral mucosa prior

to injection, dental surgery, or tooth extraction by a health care

professional. However, the data discussed in that comment do not

support OTC use of povidone-iodine as an OTC oral antiseptic. The data

demonstrate that applying povidone-iodine according to the specialized

professional labeling directions proposed in Sec. 356.80(c)(3) of this

tentative final monograph results in a decrease of bacteremia after

oral surgery or tooth extraction. They did not demonstrate a

therapeutic benefit from using povidone-iodine as an OTC oral rinse.

Although the gingival mucosa surrounding the operation sites were

sampled prior to and immediately after surgery or tooth extraction, the

studies did not demonstrate a decrease in the number of oral bacteria

over an extended period of time, and the organisms affected by the

povidone-iodine treatment were not completely identified. These studies

do not demonstrate the effectiveness of povidone-iodine when used as an

OTC oral rinse. In addition, the agency is not aware of any data from

clinical studies demonstrating a therapeutic benefit from the OTC use

of povidone-iodine in the oral cavity.

The agency believes that the Panel's proposed in vitro and in vivo

testing guidelines and its discussion of clinical studies represent a

good starting point for the design of studies to upgrade a Category II

or Category III oral antiseptic ingredient to Category I. (See section

I.M., comment 33 for a further discussion of testing guidelines.)

However, the agency notes that specific testing guidelines for

upgrading ingredients to monograph status are not included in this

monograph. (See part II. paragraph A.2.--Testing of Category II and

Category III conditions.) All such testing should be designed using the

most current technology available. The agency will meet with industry

representatives or other interested parties at their request to discuss

testing protocols.

References

(1) Appendix 2, Comment No. C00019, Docket No. 81N-0033, Dockets

Management Branch.

(2) Appendix 3, Comment No. C00019, Docket No. 81N-0033, Dockets

Management Branch.

(3) Appendix 4, Comment No. C00019, Docket No. 81N-0033, Dockets

Management Branch.

17. One comment objected to the Oral Cavity Panel's statement (47

FR 22760 at 22882) that ``There is some disagreement concerning the

chemical nature of povidone-iodine. Some believe that it is a specific

chemical entity; others claim that it is merely a complex. The

prevalent consensus is that povidone-iodine is a complex of povidone

and elemental iodine.'' Maintaining that there is no disagreement among

qualified scientists concerning the chemical nature of povidone-iodine,

the comment stated that povidone-iodine is a specific chemical entity

that is defined in the Official Compendia and the scientific

literature. Referring to the ``United States Pharmacopeia (U.S.P.) XX''

description of povidone-iodine as ``* * * a complex of iodine with

povidone'' (Ref. 1), the comment contended that the fact that povidone-

iodine is described as a complex does not contradict its existence as a

chemical entity. The comment stated that a ``complex'' is formed by the

``bonding of two or more compounds, resulting in a new chemical entity

having properties distinguishable from those of the component parts.''

According to the comment, data in the public record demonstrate that

povidone-iodine is a well-defined chemical entity that retains the full

antimicrobial spectrum of iodine without the noxious chemical and

physical properties of elemental iodine, thereby providing a stable,

essentially nonirritating and nontoxic compound.

Another comment agreed with the Oral Cavity Panel's recognition of

the ``prevailing consensus'' that povidone-iodine is a complex composed

of povidone and iodine. However, this comment felt that the Panel may

have been unaware of the nature of povidone-iodine, and contended that

this lack of awareness may have affected other considerations

concerning the source of the complex's effectiveness, the rate of

iodine release, and the complex's effect on the rate of healing. The

comment included a detailed chemical description of povidone-iodine and

of povidone-iodine's activity (Ref. 2).

One comment asserted that the Panel's misunderstanding of the

nature of povidone-iodine is indicated by its statement that ``Povidone

is available as a series of aggregates having mean molecular weights

ranging from 10,000 to 700,000 daltons,'' (47 FR 22760 at 22883).

Stating that the U.S.P. XX described povidone as a series of products

rather than a series of aggregates (Ref. 1), the comment maintained

that the povidone product used in the synthesis of povidone-iodine does

not spread over the broad range of molecular weights described by the

Panel but has a molecular weight average of less than 40,000. The

comment added that this specificity in molecular weight must be

recognized when considering the properties of the povidone used to

synthesize povidone-iodine.

The agency has reviewed the literature and believes that povidone-

iodine is a well-defined chemical. Povidone-iodine is described in

``U.S.P. XXII'' (Ref. 3) and in ``Martindale, The Extra Pharmacopeia''

(Ref. 4) as a complex of iodine with povidone (2-pyrrolidinone, 1-

ethenyl-, homopolymer or 1-vinyl-2-pyrrolidinone polymer) that contains

not less than 9 percent and not more than 12 percent of available

iodine calculated on a dried basis. ``U.S.P. XXII'' (Ref. 3) provides

standards for the purity and acceptability of iodine, povidone, and

povidone-iodine. Other references describe povidone-iodine as iodine

compounded or complexed with povidone (Refs. 5 and 6).

Regarding the Panel's statement that ``Povidone is * * * a series

of aggregates * * *'' (47 FR 22760 at 22883), the agency notes that

``U.S.P. XXII'' describes povidones as a ``synthetic polymer consisting

essentially of linear 1-vinyl-2-pyrrolidinone groups, the degree of

polymerization of which results in polymers of various molecular

weights,'' (Ref. 3). Povidone is produced commercially as a series of

products having mean molecular weights ranging from about 10,000 to

about 700,000 (Ref. 6), and the Panel correctly described the range of

molecular weights of povidone available. However, it neglected to point

out that povidone having an average molecular weight of 40,000 is used

in the preparation of povidone-iodine (Ref. 6). For the above reasons,

the agency concludes that there is little or no disagreement regarding

the chemical nature of povidone-iodine.

References

(1) ``The United States Pharmacopeia XX,'' United States

Pharmacopeial Convention, Inc., Rockville, MD, p. 647, 1980.

(2) Comment No. C00020, Docket No. 81N-0033, Dockets Management

Branch.

(3) ``The United States Pharmacopeia XXII--The National

Formulary XVII,'' United States Pharmacopeial Convention, Inc.,

Rockville, MD, pp. 1118-1119, 1989.

(4) Reynolds, J. E., editor, ``Martindale, The Extra

Pharmacopoeia,'' 29th ed., The Pharmaceutical Press, London, p.

1187, 1989.

(5) Gardner, W., E. I. Cooke, and R. W. I. Cooke, ``Handbook of

Chemical Synonyms and Trade Names,'' CRC Press, Inc., Cleveland, p.

576, 1978.

(6) Gennaro, A. R., editor, ``Remington's Pharmaceutical

Sciences,'' 18th ed., Mack Publishing Co., Easton, PA, pp. 1169 and

1307, 1990.

18. Two comments maintained that several of the Oral Cavity Panel's

statements in its discussion of povidone-iodine (47 FR 22760 at 22882

to 22885) showed a basic misunderstanding of the behavior of povidone-

iodine in solution. One comment requested that the Panel's introductory

discussion of povidone-iodine be rewritten to properly reflect the

chemical and physical properties of povidone-iodine and that the

information provided should accurately describe the product used in the

formulation of OTC oral health care antimicrobial preparations.

The comment asserted that the Panel's statement which reads ``The

iodine that can be released in its free form from povidone-iodine is

approximately 10 percent of the labeled iodine content of the complex''

(47 FR 22883) is misleading. The comment noted that povidone-iodine

powder contains about 10 percent available iodine and a 10-percent

aqueous solution of povidone-iodine provides 1 percent titratable

iodine, all of which is available for germicidal use.

The comment indicated that the following statement made by the

Panel is in error: ``Freshly prepared solutions of povidone-iodine do

not give a blue color with starch as do tinctures and other solutions

of elemental iodine. Solutions that have been standing for some time do

give a blue color'' (47 FR 22883). The comment referred to the two

identification tests required by the U.S.P. for povidone-iodine

solution (Ref. 1) and stated that identification test A requires a blue

color upon mixture of a povidone-iodine solution with starch TS (test

solution), and test B requires that no blue color be produced. Stating

that test B detects the presence of uncomplexed free iodine, the

comment asserted that properly manufactured povidone-iodine solutions

conform to these U.S.P. standards and do not deteriorate and release

free iodine vapor under normal storage conditions, as the Panel's

quoted statement implies.

The comment objected to the following statement in the Panel's

discussion of povidone-iodine: ``The addition of sodium bicarbonate

makes aqueous solutions less acidic, but also less stable,'' (47 FR

22760 at 22883), and noted that ``a current In-Process Revision of the

U.S.P.'' provides for a pH range of 2.0 to 6.5. Citing the

``Pharmacopeial Forum'' (Ref. 2), the comment stated that this pH range

reflects the range of values found in commercial formulations and is

consistent with adequate stability, germicidal activity, and dermal

safety. Noting that product stability is fully regulated under Current

Good Manufacturing Practice (CGMP) regulations found in 21 CFR parts

210 and 211, the comment maintained that its povidone-iodine mouthwash

gargle product is stable, has a documented shelf-life stability, and is

labeled with an expiration date.

Citing the Panel's statement ``When an aqueous solution is applied

topically, a slow release of free iodine occurs which exerts

antimicrobial action'' (47 FR 22760 at 22883), the comment asserted

that the activity of povidone-iodine solution is not the result of a

slow, ``trickle type'' of release of free iodine, but occurs because

iodine is available in the course of a continuous, dynamic equilibrium

reaction. The comment added that the dynamic equilibrium results in the

immediate availability of all the iodine present in the solution at

virtually the same rate as for tincture of iodine. The comment

maintained that data submitted to the Oral Cavity Panel, the

Antimicrobial I Panel, and the rulemaking for OTC topical acne drug

products demonstrate that all of the iodine present in an aqueous

solution of povidone-iodine is instantly (i.e., within milliseconds)

available upon application to the tissue site; therefore, the Panel's

reference to a ``slow release of free iodine'' is incorrect.

The second comment maintained that a key factor in the availability

of elemental iodine from the povidone-iodine complex is the ability of

the complex to keep the antimicrobial iodine in reserve and supply it

only on demand. The comment stated that when there is no iodine demand,

the level of free iodine is kept quite low, contrary to the Panel's

statement regarding the continuous ``slow-release'' of iodine. The

comment contended that at equilibrium the concentration of iodine is

low, but as the iodine is depleted from the solution, it is replaced

instantaneously from the available pool. Thus, the comment concluded

that the rate of release of iodine is not variable, but is always the

same and that the germicidal activity of povidone-iodine is not

affected until the entire pool is depleted. The comment submitted data

describing the structure and the kinetics of iodine release from the

povidone-iodine complex (Refs. 3 and 4) and purporting to confirm the

in vitro microbiological consequences of the release mechanism (Ref.

5).

The agency considers the following statement made by the Panel in

its discussion of povidone-iodine to be unclear and undocumented:

``Freshly prepared solutions * * * do not give a blue color * * *'' (47

FR 22760 at 22883). The agency agrees with the comments that properly

manufactured povidone-iodine solution must comply with the appropriate

U.S.P. standards that include two identification tests: one in which

the formation of a blue color confirms the presence of available iodine

in the povidone-iodine solution, and the other in which the lack of a

blue color confirms that free iodine is not being released into the

atmosphere (Ref. 6). The absence of free iodine in the atmosphere is

indicative that the vapor pressure of povidone-iodine solution is

virtually zero in contrast to the high vapor pressure demonstrated by

iodine tincture.

Regarding the Panel's statement that ``The addition of sodium

bicarbonate makes aqueous solutions [pH 2.0] less acidic, but also less

stable'' (47 FR 22760 at 22883), the agency notes that the U.S.P.

specifies a pH range between 1.5 and 6.5 for povidone-iodine topical

solutions (Ref. 6). Therefore, a povidone-iodine topical solution

should be stable for its shelf life at any pH between 1.5 and 6.5. The

agency also agrees with the comment that issues regarding stability

would be governed by the CGMP regulations (21 CFR parts 210 and 211).

These regulations require a written testing program to assess the

stability of finished products and to determine appropriate storage

conditions and an expiration date. Section 211.137(a) (21 CFR

211.137(a)) requires that products bear an expiration date supported by

appropriate stability testing. However, Sec. 211.137(g) provides that

expiration dating requirements are not enforced for human OTC drug

products if their labeling does not bear dosage limitations and they

have been shown to be stable for at least 3 years by appropriate

stability data.

The agency has reviewed the data submitted on the kinetics of

iodine released from the povidone-iodine complex in solution (Refs. 3

and 4) and discussed the data in the tentative final monograph for OTC

topical acne drug products (50 FR 2172 at 2173 and 2174) and in the

tentative final monograph for OTC topical antifungal drug products

published in the Federal Register of December 12, 1989 (54 FR 51136 at

51143 and 51144). The agency agrees with the comment that all of the

iodine in a povidone-iodine solution is immediately available and that

the rate of iodine release from the povidone-iodine complex is neither

slow nor variable.

Regarding the comment's statement that povidone-iodine powder

contains 10 percent available iodine and that a 10-percent solution of

povidone-iodine contains 1 percent available iodine, the agency notes

that ``U.S.P. XXII'' states that povidone-iodine powder contains not

less than 9 percent and not more than 12 percent available iodine (Ref.

6). Earlier compendia (e.g., ``U.S.P. XIX'' (Ref. 7)) characterized a

10-percent povidone-iodine solution as equivalent to 1 percent

available iodine.

Regarding the data submitted to confirm the in vitro

microbiological consequences of the povidone-iodine complex's release

mechanism (Ref. 5), the agency discusses the oral antimicrobial

effectiveness of povidone-iodine in section I.I., comment 16.

One comment requested that the introductory portion on povidone-

iodine in the Panel's report should be rewritten to reflect these

corrections. Although the agency acknowledges some ambiguities in the

Panel's introductory discussion of povidone-iodine (47 FR 22760 at

22882 to 22885), it does not see a need to rewrite that discussion. The

agency believes that the above response should add to and clarify the

Panel's discussion of the chemical and physical nature of povidone-

iodine in solution.

References

(1) Comment No. C00010, Docket No. 81N-0033, Dockets Management

Branch.

(2) ``Pharmacopeial Forum,'' The United States Pharmacopeial

Convention, Inc., Rockville, MD, p. 2343, September and October,

1982.

(3) Schenck, H. U. et al., ``Structure of Povidone-Iodine,'' in

``Current Chemotherapy and Infectious Disease,'' Vol. I, American

Society of Microbiology, Washington, pp. 477-478, 1980.

(4) Ditter, W., D. Horn, and E. Luedekke, ``Thermodynamic and

Kinetic Examinations Concerning the Complex Binding State and the

Rate of Liberation of Iodine from Aqueous Iodine-PVP-Solutions,'' in

Comment No. C00020, Docket No. 81N-0033, Dockets Management Branch.

(5) Marcus Research Laboratory Inc., Chemists, ``Povidone-Iodine

U.S.P., Chemistry, Microbiology, and Toxicology,'' in Comment No.

C00020, Docket No. 81N-0033, Dockets Management Branch.

(6) ``United States Pharmacopeia XXII-The National Formulary

XVII,'' United States Pharmacopeial Convention, Inc., Rockville, MD,

p. 1119, 1989.

(7) ``United States Pharmacopeia XIX,'' United States

Pharmacopeial Convention, Inc., Rockville, MD, p. 396, 1975.

J. Comments on Dosages for Oral Antiseptic Ingredients

19. One comment stated that the dosage level of 0.025 percent

eucalyptol, as recommended in the Oral Cavity Panel's majority report

on antimicrobial agents (47 FR 22760 at 22873), is incomplete. The

comment contended that the dosage should read 0.025 to 0.1 percent

concentration, the range reviewed by the Panel and correctly listed in

the Panel's evaluation of eucalyptol as an anesthetic/analgesic (47 FR

22827).

The agency has reviewed the administrative record regarding the

Panel's evaluation of eucalyptol as an antimicrobial agent and notes

that one product submitted to the Panel contained eucalyptol at a

concentration of 0.025 percent (Ref. 1), while another submitted

product contained 0.091 percent eucalyptol (Ref. 2). The Panel also

reviewed data on products containing eucalyptol used as an anesthetic/

analgesic ingredient in the same dosage range (i.e., 0.025 to 0.091

percent) and apparently rounded off the 0.091 percent dose in the data

to 0.1 percent in its report. Therefore, the agency agrees with the

comment that the proposed dosage range for eucalyptol as an antiseptic

agent should also have read 0.025 to 0.1 percent. However, because

eucalyptol is classified as Category III as both an oral health care

antiseptic and anesthetic/analgesic ingredient in the OTC oral health

care drug products rulemaking, the proposed dosage range serves only as

a guide to anyone interested in testing eucalyptol for upgrading to

Category I. However, data on any concentration of eucalyptol may be

submitted.

References

(1) OTC Vol. 130053.

(2) OTC Vol. 130042.

K. Comments on Labeling for Oral Antiseptic Ingredients

20. Three comments objected to the Oral Cavity Panel's

recommendation that the term ``antiseptic'' and any reference to the

pharmacologic effects of antimicrobial agents not be included in its

recommended monograph. One comment stated that the Panel's position is

contrary to the act, which requires a statement of pharmacologic effect

or class of drug in OTC labeling. Another comment contended that the

term ``antiseptic'' should be preserved in the statement of identity

because, by traditional definition, an antiseptic is a substance that

kills or inhibits the growth of microorganisms. Stating that antiseptic

activity is synonymous with antimicrobial activity, the comment

requested the approval of the following terms as statements of identity

for OTC oral antimicrobials: (1) Oral antimicrobial, (2) oral

antiseptic, and (3) oral antibacterial. The other comment added that

the terms ``antiseptic'' and ``kills germs'' should be placed in

Category I in the tentative final monograph.

In discussing the use of the terms ``antiseptic,''

``disinfectant,'' and ``antimicrobial agent,'' the Oral Cavity Panel

stated that the term ``antimicrobial agent'' describes an ingredient in

OTC oral health care drug products that kills or interferes with the

proliferation and activity of microorganisms, both pathogenic or

nonpathogenic, and that a therapeutic benefit may or may not be derived

from its use (47 FR 22760 at 22833). The Panel defined the term

``antiseptic'' as an antimicrobial agent that, when used on living

tissue, produces some therapeutic benefit and acts to counteract an

infection. A ``disinfectant'' was defined as an antimicrobial agent

used on inanimate objects. Thus, the Panel considered the term

``antimicrobial agent'' to be a general term that encompasses both

antiseptics and disinfectants, disregarding how the ingredient is used.

The Panel included the following statement of identity in

Sec. 356.51(a) of its recommended monograph (47 FR 22760 at 22928):

``oral health care antimicrobial.''

The agency disagrees with the Panel's recommendation that the term

``antiseptic'' not be used as part of the statement of identity for

antimicrobial agents contained in OTC oral health care drug products

(47 FR 22760 at 22833). The agency believes that the Panel was opposed

to the term ``antiseptic'' because, according to the Panel's

definition, this term implies therapeutic benefit and the Panel was not

convinced of the effectiveness of OTC antiseptics in providing a

therapeutic benefit, i.e., relief of sore mouth and sore throat

symptoms. However, the agency believes that the term ``oral

antiseptic'' is appropriate for use in the statement of identity for

the active ingredients included in this segment of the oral health care

drug products rulemaking. Those found effective could provide a

therapeutic benefit. An antiseptic is a substance that can kill or

inhibit the growth of microorganisms when applied to living tissues

without significant harm to the tissues (Ref. 1). This definition is in

keeping with the definition of an antiseptic in section 201(o) of the

act (21 U.S.C. 321(o)). If safety and effectiveness data support the

inclusion in Category I of any antiseptic active ingredient(s) for OTC

use in oral health care drug products, the agency believes that the

term ``antiseptic'' is well recognized by consumers and can

appropriately be used in the labeling for such products.

The agency believes that the term ``health care,'' while

appropriate for classification purposes and used to identify this

rulemaking, is cumbersome and unnecessary in consumer labeling as a

statement of identity for an OTC oral antiseptic. Therefore, in this

tentative final monograph, the agency is proposing to revise the

statement of identity in Sec. 356.51(a) of the Panel's recommended

monograph (47 FR 22928) to include the term ``antiseptic'' instead of

the term ``health care antimicrobial.'' The agency is also revising the

statement of identity to include dosage forms (see section I.K.,

comment 21), and is renumbering the statement of identity section as

Sec. 356.64(a).

Because the term ``antiseptic'' is well recognized by consumers and

because the agency wishes to minimize consumer confusion about the

labeling of similar marketed products, the terms ``oral antimicrobial''

and ``oral antibacterial'' are not being included as alternate

statements of identity for this class of drug products. However, the

agency has no objection to such terms appearing in the labeling as

other information provided it does not appear in any portion of the

labeling required by the monograph and does not detract from such

required information.

The agency is not including in this tentative final monograph the

Panel's definition for an antimicrobial agent in Sec. 356.3(c) of its

recommended monograph (47 FR 22760 at 22927). Instead, the agency is

proposing definitions for the terms ``antiseptic drug'' and ``oral

antiseptic'' in Sec. 356.3 as follows:

Antiseptic drug. In accordance with section 201(o) of the

Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321(o)), ``The

representation of a drug, in its labeling, as an antiseptic shall be

considered to be a representation that it is a germicide, except in

the case of a drug purporting to be, or represented as, an

antiseptic for inhibitory use as a wet dressing, ointment, dusting

powder, or such other use as involves prolonged contact with the

body.''

Oral antiseptic. An antiseptic-containing drug product applied

topically to the oral cavity to help prevent infection in wounds

caused by minor oral irritations, cuts, scrapes, or injury following

minor dental procedures.

The agency believes that claims such as ``kills germs'' could be

potentially misleading to the average consumer if directly associated

with the term ``infection'' that is included in the indication. The

term ``kill germs'' may be interpreted to imply elimination of all

bacteria in the mouth when, in fact, oral antiseptics used in the mouth

only decrease the number of certain bacteria. However, the agency

believes this term is familiar to the average consumer and may be

useful in describing a product's action or intended effect. Although

this term is not included in the monograph, it may be included in

labeling of oral antiseptic drug products provided it is not

intermingled with labeling established by the monograph and is not used

in a false or misleading manner.

Reference

(1) Berkow, R., editor, ``The Merck Manual of Diagnosis and

Therapy,'' 14th ed., Merck and Co., Inc., Rahway, NJ, p. 2300, 1982.

21. One comment requested that the agency approve the following

statements of identity, and any reasonably synonymous statements, for

the combination of 0.045 percent cetylpyridinium chloride and 0.005

percent domiphen bromide: ``(1) oral antiseptic, (2) oral

antimicrobial, (3) mouthwash, (4) gargle, and (5) mouthwash and

gargle.''

The statement of identity for oral health care antiseptics is

discussed in section I.K., comments 20 and 22. As explained there, the

agency believes that the term ``oral antiseptic'' is appropriate as the

statement of identity for these products. Because the term

``antiseptic'' is well re

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