[Federal Register Volume 59, Number 27 (Wednesday, February 9, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-2262]


[[Page Unknown]]

[Federal Register: February 9, 1994]


_______________________________________________________________________

Part II





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



_______________________________________________________________________



21 CFR Part 356




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

Food and Drug Administration

21 CFR Part 356

[Docket No. 81N-033A]
RIN 0905-AA06

 
Oral Health Care Drug Products for Over-the-Counter Human Use; 
Tentative Final Monograph for Oral Antiseptic Drug Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of proposed rulemaking.

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

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 recognized by consumers, and in order to avoid 
confusion in the marketplace, the term ``oral antimicrobial'' is not 
being included in the monograph as an alternate statement of identity. 
However, the agency has no objection to the term ``oral antimicrobial'' 
appearing in the labeling as other information provided it is not 
intermingled with labeling established by the monograph, and it is not 
used in a false or misleading manner.
    In accord with 21 CFR 201.61, wherever possible, the agency prefers 
to use the general pharmacological category as the statement of 
identity for OTC drug products; where this is not appropriate, the 
principal intended action is used. The terms ``mouthwash,'' ``gargle,'' 
or ``mouthwash and gargle'' by themselves do not inform consumers of 
the pharmacological category or the principal intended action of a drug 
product. The agency recognizes that oral products have been marketed 
for years as ``mouthwashes,'' ``gargles,'' and ``mouthwashes and 
gargles.'' However, many of these products have been marketed for daily 
long-term use as cosmetics, and the agency believes that consumers 
associate the term mouthwash with such unlimited cosmetic use. In this 
document, the agency is proposing to limit the use of oral antiseptic 
drug products to 7 days or less. The agency believes that use of the 
term ``mouthwash'' on such products could be confusing to consumers, 
who might be led to assume that the product could be used for an 
unlimited period of time. However, the agency believes that use of the 
term ``rinse'' in the statement of identity would be acceptable because 
the term ``rinse'' implies a therapeutic use (e.g., fluoride rinse). 
Also, the agency does not oppose the inclusion of the term ``gargle'' 
in the statement of identity, when included in addition to the required 
pharmacological category. Therefore, in this tentative final monograph, 
the agency is proposing an alternate statement of identity for oral 
antiseptics to include a choice of terms describing the appropriate 
dosage form of the product, i.e., ``rinse,'' ``gargle,'' or ``rinse and 
gargle,'' as follows: The labeling of the product contains the 
established name of the drug, if any, and identifies the product as an 
``oral antiseptic,'' or an ``antiseptic'' (select one of the following: 
``rinse,'' ``gargle,'' or ``rinse and gargle''). (See section I.K., 
comment 20.)
    In this tentative final monograph, the agency is classifying 
cetylpyridinium chloride, domiphen bromide, and a combination of 
cetylpyridinium chloride and domiphen bromide in Category III for 
effectiveness as oral health care antiseptics. (See section I.E., 
comment 9; section I.G., comment 13; and section I.L., comments 30 and 
31.) If cetylpyridinium chloride, domiphen bromide, or a combination of 
these ingredients are upgraded to Category I for OTC oral antiseptic 
use, the product may be labeled with either statement of identity 
proposed in Sec. 356.64(a) of this tentative final monograph.
    22. Four comments objected to the Oral Cavity Panel's position that 
antimicrobial agents should not be used for therapeutic purposes in OTC 
oral health care products. Three of the comments disagreed with the 
Panel's statement that antiseptics are used in an attempt to sterilize 
intact cutaneous and mucous surfaces, contaminated or infected wounds, 
mucosal ulcerations, or other lesions caused by pathogenic microbial 
activity (47 FR 22760 at 22831). The comments pointed out that topical 
antimicrobials are used to decrease the number of bacteria present and 
to help prevent the chance of infection after minor injury to the mouth 
or gums; they are not used as sterilizing agents. The comments 
presented excerpts from the advance notice of proposed rulemaking on 
alcohol drug products for topical antimicrobial OTC human use published 
in the Federal Register of May 21, 1982 (47 FR 22324) and the tentative 
final monograph on OTC topical antibiotic drug products published in 
the Federal Register of July 9, 1982 (47 FR 29986) which, they stated, 
show that the Miscellaneous External Panel and the agency, 
respectively, favor the use of antimicrobial agents to reduce the 
number of bacteria on the skin and thus help prevent infection. One of 
the comments also pointed out that the Oral Cavity Panel's position is 
directly contrary to that of the Dental Panel which found that the use 
of an oral antimicrobial is rational therapy (47 FR 22712 at 22720).
    One comment noted that the Oral Cavity Panel identified and 
evaluated two categories of products containing antimicrobial active 
ingredients: (1) Those used on a short-term basis to relieve symptoms 
of sore mouth or sore throat, or both, due to microbial infections, and 
(2) those used on a long-term, often day-to-day, basis. The comment 
contended that the category of products used on a short-term basis 
should be further divided into two groups: (1) Products used on a 
short-term basis that are applied locally (i.e., to the affected site 
of infection to reduce the number of bacteria), and (2) products used 
on a short-term basis that are applied to the total oral cavity.
    Stating that presentations had been made to the Oral Cavity Panel 
concerning the existence of a target population for locally applied 
topical antiseptics, the comment felt that the data supplied on the 
historical use of topical antiseptics to assist in preventing infection 
were adequate to establish an oral first aid antiseptic category (Ref. 
1). The comment stated that the only indication provided by the Panel 
for any OTC oral antimicrobial ingredient does not address the issue of 
reducing organisms at the lesion or site of infection to help prevent 
oral infection, i.e., the ``first aid'' category. The comment requested 
that the following indication and other allowable indications be 
included as Category I labeling:
    Indication: First aid and/or antiseptic to help prevent 
infection in wounds caused by minor oral irritation; cuts, scrapes 
or injury such as following minor dental procedures or from dentures 
and orthodontic appliances.
    Other Allowable Indications: (i) ``Decreases'' or ``Helps'' 
reduce the number of bacteria on the treated area.
    (ii) Helps ``prevent,'' ``guard against,'' or ``protect 
against'' oral infections.
    (iii) Helps reduce the ``risk'' or ``chance'' of oral infection.
    (iv) Helps prevent bacterial contamination in minor injuries or 
lesions of the mouth.
    The comment also requested that, based upon available data, 
carbamide peroxide in anhydrous glycerin, sodium phenolate and phenol, 
and povidone-iodine be classified in Category I as topical antiseptics 
for local application.
    Regarding the Oral Cavity Panel's statement that antiseptics are 
used in an attempt to sterilize surfaces, wounds, and lesions caused by 
pathogenic microbial activity (47 FR 22760 at 22831), the agency agrees 
with the comments that most of the antiseptic agents used in OTC health 
care drug products are not effective as sterilizing agents. For an 
antiseptic agent to be an effective sterilizing agent, the ingredient 
must be sporicidal, i.e., must kill bacterial spores. The majority of 
the antiseptics used in OTC oral health care products will not destroy 
bacterial spores. However, as the Panel stated, ``Topical antimicrobial 
ingredients are applied to the mucous membranes of the mouth and throat 
to kill, inhibit the proliferation of, or alter the metabolic activity 
of all types of microorganisms, both pathogenic and nonpathogenic,'' 
(47 FR 22760 at 22831). The antiseptics are used in an ``attempt to 
sterilize'' intact surfaces with complete sterilization of the wound 
site viewed as the ultimate achievement by the drug. In an ideal sense, 
a drug that could sterilize a wound site would be very beneficial in 
the treatment of cuts and scratches. The agency believes that is the 
point the Panel was trying to relate in its description of the effects 
of these drugs.
    The agency notes that the Panel listed nine reasons why it believed 
that antiseptic ingredients should not be used in OTC oral health care 
drug products (47 FR 22760 at 22834). Most of the reasons were based on 
the Panel's belief that: (1) Antiseptics are nonspecific ingredients 
that would not be effective in treating wounds in the oral cavity and 
could possibly be harmful, (2) these ingredients do not penetrate 
deeply into tissue, and (3) the ingredients would be significantly 
diluted and removed from the wound site by the action of saliva. 
Therefore, the Panel did not recommend any Category I indications for 
antiseptics, but instead included a Category III indication, ``For the 
temporary relief of minor sore mouth and sore throat by decreasing the 
germs in the mouth.'' However, the agency disagrees with the Panel's 
position that antiseptic ingredients should not be used for other 
therapeutic purposes in OTC oral health care drug products. The agency 
believes that antiseptics may be useful in helping to reduce the chance 
of infection in minor sore mouth conditions by decreasing the number of 
bacteria on the mucous membranes of the mouth.
    Two of the studies submitted by one comment provide support that 
there is a target population that would benefit from the availability 
of an OTC antiseptic drug product to help prevent or reduce the 
incidence of certain oral conditions (Ref. 1). Addy et al. (Ref. 2) 
reported that an antibacterial mouthwash (0.2 percent chlorhexidine 
gluconate) reduced the incidence, duration, and severity of aphthous 
ulcers (canker sores) as compared to a control and an astringent 
mouthwash when evaluated subjectively. The mouthwash was used for 1 
minute three times daily for a period of 5 weeks. The authors 
speculated that, in such conditions, oral hygiene is frequently 
neglected due to oral discomfort that further increases the possibility 
of infection from bacterial plaque deposits. Thus, attempts to reduce 
secondary infection of the aphthous ulcers may be of value for the 
patient. Olsen (Ref. 3) evaluated patients with denture stomatitis. The 
treatment consisted of each patient sucking placebo, amphotericin B, or 
chlorhexidine chloride lozenges combined with denture soaking in a 0.2-
percent aqueous solution of chlorhexidine digluconate. Olsen concluded 
that denture disinfection was an essential part in the management of 
denture stomatitis, finding that denture immersion in 0.2 percent 
chlorhexidine solution significantly reduced the number of organisms 
both on the mucous membranes and on the denture. The combination of 
amphotericin B lozenges and chlorhexidine denture disinfection was the 
most effective regimen. Although chlorhexidine, a drug available by 
prescription for oral use, was used in the studies, the agency believes 
that these studies do support the existence of a target population that 
would benefit from the use of antiseptic ingredients in helping to 
alleviate some oral conditions. However, additional data are needed to 
support the above indications for OTC oral antiseptics.
    The Panel identified two categories of products containing 
antiseptics for oral use: (1) Those used on a short-term basis to 
relieve symptoms of sore mouth and sore throat, or both, due to 
microbial infections, and (2) those used on a long-term, often day-to-
day, basis for cleansing the mouth, suppressing mouth odors, and other 
related purposes in which no symptoms of an infectious process are 
evident but for which antiseptic claims are made (47 FR 22760 at 
22890).
    The agency does not see a need at this time to follow one comment's 
request to subdivide the category of OTC oral antiseptic products used 
on a short-term basis into two groups: (1) Those applied locally, and 
(2) those applied to the total oral cavity. The agency believes that on 
a short-term basis antiseptic ingredients can be used for local 
application or for application to the total oral cavity to help prevent 
infection in minor sore mouth conditions. Other monographs, e.g., the 
tentative final monograph for OTC first aid antiseptic drug products 
(56 FR 33644 at 33677) and the amendment to the tentative final 
monograph for OTC oral health care drug products (56 FR 48302 at 48343 
to 48346), identify situations where short-term use of a product for 
minor sore mouth conditions is appropriate for consumer selfmedication 
(e.g., use in minor oral wounds, accidental injury or irritation of the 
mouth or gums, or minor wounds resulting from orthodontic appliances or 
dentures). Accordingly, the agency is proposing the following 
indication for these products in this tentative final monograph:
    ``First aid to help'' (select one of the following: ``prevent,'' 
(``decrease'' (``the risk of'' or ``the chance of'')), (``reduce'' 
(``the risk of'' or ``the chance of'')), ``guard against,'' or 
``protect against'') (select one of the following: ``infection'' or 
``bacterial contamination'') ``in'' (select any of the following: 
``minor cuts,'' ``minor scrapes,'' or ``minor oral irritation'') (which 
may be followed by) ``caused by'' (select any of the following: 
``dental procedures,'' ``dentures,'' ``orthodontic appliances,'' or 
``accidental injury'').
    The Panel's Category III indication for oral antiseptics also 
included use of these ingredients for sore throat by decreasing the 
number of germs in the mouth. The agency has determined that this part 
of the indication should remain in Category III because inadequate data 
have been submitted to support a ``relief of sore throat'' indication.
    The agency notes that the Panel discussed long-term uses of oral 
antiseptics to cleanse the mouth and suppress mouth odors. The agency 
considers such uses to be cosmetic in nature. Cosmetic claims are not 
subject to this rulemaking. (See section I.A., comment 3.) However, 
antiseptic mouthwashes used on a long-term basis for plaque reduction 
are considered drugs. The agency will address the long-term use of 
antiseptic mouthwash products for plaque reduction in a subsequent 
segment of the OTC oral health care drug product rulemaking. (See 
section I.A., comment 1 and section I.M., comment 32.)
    In conclusion, the agency agrees with the comment that a first aid 
claim is appropriate for OTC oral antiseptics and is proposing such a 
claim in this tentative final monograph. Claims related to ``sore 
throat,'' ``canker sores,'' and ``denture stomatitis'' are Category III 
because additional data are needed to support these claims for OTC oral 
antiseptics. The agency's evaluations of the ingredients phenol and 
povidone-iodine, requested by the comment for Category I 
classification, are discussed in section I.H., comment 14 and section 
I.I., comment 16. No additional data were submitted to support the 
efficacy of carbamide peroxide; thus, this ingredient remains in 
Category III in this tentative final monograph. The agency invites the 
submission of data to support reclassification of any oral antiseptic 
ingredient(s) from Category III to Category I.

References

    (1) Comment No. LET004 and OTC Vols. 130132 and 130163, Docket 
No. 81N-0033, Dockets Management Branch.
    (2) Addy, M. et al., ``Trial of Astringent and Antibacterial 
Mouthwashes in the Management of Recurrent Aphthous Ulceration,'' 
British Dental Journal, 136:452-455, 1974.
    (3) Olsen, I., ``Denture Stomatitis--Effects of Chlorhexidine 
and Amphotericin B on the Mycotic Flora,'' Acta Odontologica 
Scandinavica, 33:41-46, 1974.
    23. One comment requested that the agency amend the Oral Cavity 
Panel's Category III indication for oral health care antimicrobials 
that states ``For the temporary relief of minor sore mouth and sore 
throat by decreasing the germs in the mouth'' (47 FR 22760 at 22889). 
The comment claimed that a portion of the statement, ``by decreasing 
the germs in the mouth,'' is not an indication for use, but is a 
statement of mechanism of action and should be deleted from the 
proposed indication. The comment stated that including a mechanism of 
action in the indication is not consistent with the labeling of other 
OTC oral health care products such as anesthetic/analgesic agents, 
astringents, debriding agents, or demulcents. Another comment requested 
that the agency place the following labeling claim in Category I for 
the combination of 0.045 percent cetylpyridinium chloride and 0.005 
percent domiphen bromide: ``Temporarily reduces bacteria in the mouth 
and throat.''
    The agency acknowledges that the Oral Cavity Panel's recommended 
Category III indication for oral antiseptics contains a phrase denoting 
a mechanism of action as does the agency's proposed Category I 
indication (see section I.K., comment 22). However, this type of 
labeling is not inconsistent with some of the labeling indications 
proposed by the agency for other oral health care drug products. For 
example, the agency's proposed indication for debriding agents, which 
states ``aids in the removal of phlegm, mucus * * * associated with 
occasional sore mouth'' (56 FR 48302 at 48345), and the proposed 
indication for demulcent drugs, which states ``* * * protection of 
irritated areas in sore mouth and sore throat'' (56 FR 48346), contain 
wording denoting a mechanism of action. Thus, although monograph 
indications do not always include a mechanism of action, at times such 
labeling is included in a monograph.
    The agency does not believe that the labeling claim requested by 
one comment, ``Temporarily reduces bacteria in the mouth and throat,'' 
is an appropriate indication for OTC oral health care drug products. 
The indication does not inform consumers of what benefit might be 
expected to result from reducing the bacteria in the mouth and throat. 
Furthermore, the agency is not aware of any data demonstrating that 
reducing the bacteria in the throat has a therapeutic benefit. However, 
the agency has no objection to labeling referring to reduction of 
bacteria in the mouth (e.g., temporarily reduces the number of bacteria 
in the mouth) appearing in the labeling of OTC oral antiseptic drug 
products as other information, provided it is not intermixed with 
labeling established by the monograph and it is not used in a false or 
misleading manner.
    24. One comment objected to the Oral Cavity Panel's Category II 
classification of the indication that states ``Helps provide soothing 
temporary relief of dryness and minor irritations of the mouth,'' (47 
FR 22760 at 22858) for mouthwash products containing povidone-iodine. 
The comment mentioned that the Panel concluded that this statement 
indicates that the product is used for cosmetic purposes but implies 
that the product exerts a therapeutic effect (47 FR 22857 to 22858). 
The comment felt that dryness and irritation of the mouth and throat 
are recognized by the consumer as an abnormal condition and are thought 
to be synonymous with such statements as ``minor irritation, pain, sore 
mouth, and sore throat,'' ``discomfort,'' and ``irritated areas in sore 
mouth and sore throat.'' The comment claimed that these statements 
should be permitted as an alternate or adjunct to Category I labeling 
for antimicrobial products, where the effects are documented with 
substantial evidence.
    The comment added that substantial evidence was submitted to show 
that a povidone-iodine mouthwash provides relief of dryness and minor 
irritations of the mouth and throat. The comment referred to evidence 
supporting this indication, approved under NDA 10-290, but the comment 
did not include any additional data concerning this claim. The comment 
requested that the following indications be allowed under Sec. 356.51 
for antimicrobial drug products containing povidone-iodine: (1) ``To 
help (or Helps) provide soothing temporary relief of dryness and minor 
irritations of the mouth and throat,'' and (2) ``Aids in the temporary 
relief of occasional minor irritation, pain, sore mouth, and sore 
throat.'' The comment noted that this second indication was recommended 
by the Oral Cavity Panel for astringent drug products.
    A second comment stated that the indications ``An aid to daily oral 
care,'' and ``Provides soothing temporary relief of dryness and minor 
irritations of the mouth and throat,'' and any reasonably synonymous 
statements, should be approved for the combination of cetylpyridinium 
chloride 0.045 percent and domiphen bromide 0.005 percent. A third 
comment requested that the following claim be approved for use on 
products containing cetylpyridinium chloride: ``For daily use as an 
adjunct to good oral hygiene.''
    In the Federal Register of December 2, 1971 (36 FR 23000), as part 
of the agency's DESI program, the agency stated that 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 was deferred pending evaluation of the data and information 
concerning such products under the OTC drug review. However, in the 
meantime, the agency found the following labeling claims acceptable for 
mouthwash products, on an interim basis: ``To help provide soothing 
temporary relief of dryness and minor irritations of the mouth and 
throat,'' ``an aromatic mouth freshener,'' ``an aid to daily care of 
the mouth,'' and ``for causing the mouth to feel clean.'' Thus, the 
comments' requested indication, ``To help provide soothing temporary 
relief of dryness and minor irritations of the mouth and throat,'' was 
allowed as a result of that DESI notice. In this tentative final 
monograph, the agency is further addressing the claims permitted by 
that DESI notice and requested by the comments.
    The agency believes that the Panel was correct in placing the 
statement ``Helps provide soothing temporary relief of dryness and 
minor irritations of the mouth'' and similar statements in Category II 
as an indication for the use of drug products containing antiseptic 
ingredients. However, the agency believes that the Panel erred when it 
included this statement under the heading of ``Statements or phrases 
that indicate a product is used for cosmetic purposes but imply that 
the product exerts a therapeutic effect'' (47 FR 22760 at 22857 and 
22858). Statements containing phrases such as ``relief of dryness'' and 
``irritation of the mouth and throat'' are more appropriate as 
indications for drug products containing astringents (47 FR 22904) and 
demulcents (47 FR 22919). Astringents alleviate irritation of the mouth 
and throat and demulcents exert therapeutic actions that will alleviate 
the conditions of ``dryness'' and ``irritation.'' On the other hand, 
the agency does not have adequate evidence showing that antiseptic 
ingredients are effective in alleviating dryness or irritation of the 
mouth. These ingredients act by destroying microorganisms that may be 
present, and there is no proof that the destruction of microorganisms 
alleviates dryness or irritation.
    Regarding the substantial evidence supporting the claim of ``relief 
of dryness and minor irritations of the mouth and throat'' mentioned by 
the first comment, the agency notes that no data were submitted to show 
that consumers associate the therapeutic activity of an antiseptic 
agent with the relief of dryness and minor irritations, nor were 
adequately controlled studies substantiating the claim included in NDA 
10-290. Therefore, the agency is not proposing such claims for any 
antiseptic products.
    The agency has already proposed a ``relief of dryness'' claim for 
demulcent ingredients as part of this rulemaking in Sec. 356.58 of the 
amendment to the tentative final monograph for OTC oral health care 
drug products (56 FR 48302 at 48346). That claim states: ``For 
temporary relief of minor discomfort and protection of irritated areas 
in sore mouth and sore throat.'' As mentioned by one comment, the 
proposed indications for oral health care astringent ingredients 
presently include a claim for ``relief of minor irritation.'' (See 
proposed Sec. 356.54 in the amendment to the tentative final monograph 
for OTC oral health care drug products (56 FR 48345).)
    With regard to the other labeling claims permitted in the December 
2, 1971 DESI notice and the labeling claims suggested by the second and 
third comments, i.e., ``An aid to daily oral care'' and ``For daily use 
as an adjunct to good oral hygiene,'' the agency now considers these 
types of claims to be cosmetic claims that are not subject to this 
rulemaking. (See section I.A., comment 3.)
    25. One comment stated that the 2-day duration of treatment 
recommended by the Oral Cavity Panel for antimicrobial drug products 
(47 FR 22760 at 22928) is insufficient ``to address normal healing 
time.'' Stating that the Topical Antimicrobial Drug Products Panel 
provided a 7-day use limit, the comment recommended that a 7-day 
duration of use be adopted for this monograph.
    The Oral Cavity Panel recommended the 2-day use limit for all OTC 
oral health care drug products because of the risk of serious illness 
if appropriate treatment of a sore throat is delayed. However, although 
a sore mouth may denote the presence of a condition that requires 
diagnosis and treatment by a physician, in most cases it is caused by 
minor ulcerations and other benign conditions that are self-limited, 
last only short periods of time, and generally heal spontaneously in 7 
to 10 days (47 FR 22760 at 22774 to 22776). As stated in the first 
segment of the oral health care drug products tentative final monograph 
(53 FR 2436 at 2448), the agency believes that because symptoms 
associated with a sore mouth are unlikely to be indicative of a serious 
health threat, a 7-day use limitation of an OTC oral health care drug 
product is appropriate for the relief of symptoms of a sore mouth, 
e.g., pain and minor irritation. Because a sore throat can be the 
symptom of a serious disease and may require more immediate attention, 
the agency believes that it is necessary to place a 2-day limit on the 
use of an OTC oral health care drug product that is used to relieve 
symptoms of a sore throat.
    For these reasons, in an amendment to the first segment of the OTC 
oral health care drug products tentative final rulemaking (56 FR 48302 
at 48343 and 48346), the agency subsequently proposed the following 
warning for OTC oral health care drug products that are indicated for 
the relief of sore mouth and sore throat symptoms: ``If sore throat is 
severe, persists for more than 2 days, is accompanied or followed by 
fever, headache, rash, swelling, nausea, or vomiting, consult a doctor 
promptly. If sore mouth symptoms do not improve in 7 days, or if 
irritation, pain, or redness persists or worsens, see your dentist or 
doctor promptly.'' For products labeled for the relief of sore mouth 
only, the proposed warning reads: ``Do not use this product for more 
than 7 days unless directed by a dentist or doctor. If sore mouth 
symptoms do not improve in 7 days, if irritation, pain, or redness 
persists or worsens, or if swelling, rash, or fever develops, see your 
dentist or doctor promptly.'' (See 56 FR 48302 at 48343, 48345, and 
48346.)
    Likewise, the agency believes that part of this proposed warning 
may be applicable to OTC oral health care antiseptic drug products. At 
this time, sore throat claims are Category III for oral antiseptic 
ingredients. Therefore, in this document, the agency is not proposing 
the first portion of the above warning for oral health care drug 
products that are indicated for the relief of sore throat. If sore 
throat claims for oral antiseptic ingredients are upgraded to Category 
I, the agency will include the first portion of the above warning in 
the final monograph for oral antiseptic drug products. The agency is 
proposing in this amendment to the OTC oral health care tentative final 
monograph that the second portion of the above warning replace the 
warnings recommended by the Panel in Sec. 356.51(c)(1)(i) and 
(c)(1)(ii). The agency believes that this warning fully conveys the 
intent of the Panel's recommended warnings. This warning is included in 
Sec. 356.64(c) of this tentative final monograph in case any oral 
antiseptic ingredients are classified in Category I to help in reducing 
the chance of infection in minor oral irritations.
    26. One comment requested that the agency approve the following 
wording, as well as reasonable variations thereof, for directions for 
use for OTC oral antimicrobials/antiseptics: ``Rinse or gargle for 20 
seconds with one ounce first thing in the morning, after meals, and 
before social engagements.''
    In this tentative final monograph, the agency is addressing only 
the drug use of antiseptic ingredients in oral rinses and gargles. The 
agency believes that the comment's suggested directions for use apply 
to the cosmetic use of oral antiseptic products for the suppression of 
oral malodor (e.g., ``first thing in the morning,'' and ``before social 
engagements'') and for oral cleansing (e.g., ``after meals''). Such 
directions are not appropriate for the drug use of these products and 
therefore are not being included in this tentative final monograph. 
However, antiseptic products intended for use only as cosmetics are not 
subject to this rulemaking and may bear appropriate directions and 
other labeling for cosmetic uses. (See section I.A., comment 3.)
    27. One comment requested that the following professional labeling 
for povidone-iodine be included in the oral health care drug products 
monograph: ``Professional labeling--for local degerming prior to dental 
prophylaxis and gingivectomy.'' Noting that the Antimicrobial I Panel 
recommended labeling limited to professional use, the comment stated 
that professional labeling should likewise be allowed for oral health 
care drug products. The comment explained that the value of local 
degerming using povidone-iodine mouthwash in dental prophylaxis and 
gingivectomy procedures was shown in studies presented to the Panel 
(Ref. 1). The comment added that the studies demonstrated substantial 
evidence of the effectiveness of povidone-iodine mouthwash/gargle in 
significantly reducing gingival surface bacteria prior to dental 
prophylaxis and procedures, thereby reducing the risk of systemic 
infection.
    In the tentative final monograph for OTC health care antiseptic 
drug products that will be published in a future issue of the Federal 
Register, the agency intends to propose povidone-iodine in Category I 
for use as a patient preoperative skin preparation, a surgical hand 
scrub, and a health care personnel handwash. The agency has reevaluated 
the data submitted to the Oral Cavity Panel (Ref. 1) and believes that 
some of the submitted data (Refs. 2 and 3) support the requested 
professional labeling for povidone-iodine in aqueous solution.
    The Oral Cavity Panel stated that povidone-iodine's ``application 
on the injection site of the oral mucosa prior to administering local 
anesthesia virtually eliminates all readily cultivable organisms'' (47 
FR 22760 at 22884). The Panel cited three studies (Refs. 2, 4, and 5) 
that indicate that irrigation of the gingival sulcus and rinsing the 
mouth with povidone-iodine immediately before tooth extraction or 
gingivectomy markedly reduces the incidence of associated bacteremia 
(i.e., the presence of bacteria in the blood). However, because two of 
the cited studies (Refs. 4 and 5) were published only in abstract form, 
the Panel considered the data insufficient in detail to be properly 
evaluated (47 FR 22884).
    One study cited by the Panel (Ref. 2) is supportive of professional 
labeling for povidone-iodine solution for use in local degerming prior 
to dental prophylaxis and gingivectomy. In this study, 52 patients 
scheduled for gingivectomy were randomly divided into two equal groups. 
Test patients were administered a 0.5-percent povidone-iodine solution, 
whereas control patients were administered a placebo solution that was 
identical in appearance to the povidone-iodine solution but contained 
no povidone-iodine. Immediately prior to gingivectomy, each patient 
rinsed for 30 seconds with about 20 mL of the assigned preparations. 
The solution was then expectorated and, after a 2-minute interval, the 
rinsing was repeated. The sulci of the teeth in the quadrant scheduled 
for gingivectomy and the surrounding mucosa were then irrigated for 
about 1 minute using 20 mL of the assigned liquid delivered by a 
standard syringe with a blunt, angulated needle. Gingival surface 
samples were obtained by swabbing the gingiva just prior to rinsing and 
immediately after irrigation with the assigned preparation. These 
gingival swabs provided the inoculum for blood agar plates that were 
incubated aerobically and anaerobically at 36  deg.C for 48 hours. 
After incubation, the colonies on the plates were counted. The grading 
system for estimating the number of bacterial colonies per plate ranged 
from 1+ (i.e., few) to 4+ (i.e., too-numerous-to-count), and the major 
genera and/or species were enumerated. About 15 mL of blood were drawn 
from each patient before rinsing with the assigned preparation and 
within 3 minutes after the gingivectomy. The samples were cultured 
aerobically and anaerobically, and subsequent isolates were identified 
by standard bacteriological procedures.
    The use of the povidone-iodine solution significantly reduced the 
incidence of post-gingivectomy bacteremia (p < 0.5). Fifteen control 
patients developed positive blood cultures, but only six patients in 
the test group developed positive blood cultures. Virtually all 
prerinse bacterial cultures resulted in colony count scores of 4+. Use 
of the test preparation produced an average decrease of 33 to 42 
percent in colony count scores (for example, a decrease from a average 
score of 4+ to a average score of 2.7). Comparable degerming occurred 
for both aerobic and anaerobic bacteria.
    In a double-blind clinical study (Ref. 3), Scopp and Orvieto 
randomly assigned 64 patients requiring dental extraction into two 
groups. One group of 32 patients was prepared preoperatively by 
gingival sulcal irrigation and rinsing with a 0.5-percent povidone-
iodine oral rinse; the other 32 patients were prepared preoperatively 
in the same manner except that a placebo solution (colored, flavored, 
and packaged to match the active drug) was used for irrigation and 
rinsing. All patients were instructed to rinse for 30 seconds with 10 
to 20 mL of the assigned oral rinse, then wait 2 minutes and repeat the 
rinse. The gingival sulcus of each tooth to be extracted and the 
surrounding gingival mucosa were then irrigated for approximately 1 
minute with 10 to 20 mL of the assigned solution using a standard 
syringe and blunt, angulated needle. Prior to rinsing and immediately 
after irrigation, cultures of the gingival sulcus were obtained. Dental 
extraction was performed without further antisepsis. Blood samples were 
obtained for culture before rinsing and within 3 minutes after the 
dental extraction.
    Bacteremia (i.e., positive blood cultures) occurred in 28 percent 
of the patients using the povidone-iodine oral rinse and in 56 percent 
of the patients using the placebo solution. The difference between the 
two groups is statistically significant in favor of povidone-iodine (p 
< 0.05). The gingival sulcus cultures taken immediately after rinsing 
and irrigation with the povidone-iodine oral rinse showed reduction or 
elimination of bacteria in 14 patients, no change in 17 patients, and 
increased growth in 1 patient. For the placebo group, the gingival 
sulcus cultures showed no growth and reduced growth in 1 patient each, 
no change in 28 patients, and increased growth in 2 patients. The 
difference in bacterial reduction of the gingival sac in the two groups 
is also statistically significant (p < 0.01).
    The agency believes that these studies demonstrate the 
effectiveness of a 0.5-percent povidone-iodine aqueous solution for the 
preparation of the oral mucosa prior to injection, dental surgery, or 
tooth extraction when used by a health care professional according to 
the directions proposed in Sec. 356.80(c)(3) of this tentative final 
monograph. However, these studies do not demonstrate the effectiveness 
of povidone-iodine when used by consumers as an oral antiseptic. In 
order for an ingredient to be classified in Category I as an oral 
antiseptic, the agency believes that, among other things, the 
ingredient should demonstrate the ability to decrease the number of 
bacteria in the oral cavity over an extended period of time (e.g., up 
to 4 hours). In addition, the ingredient should provide clinically 
significant benefits under OTC conditions of use (e.g., helping to 
prevent infection in minor wounds in the mouth, or relieving the 
symptoms of sore throat). (See section I.M., comment 33 for further 
discussion of testing procedures.) These data demonstrate that applying 
povidone-iodine according to the directions proposed in 
Sec. 356.80(c)(3) of this tentative final monograph results in an 
immediate decrease of bacteria around the operation or extraction site 
and a decrease of bacteremia after oral surgery or tooth extraction. 
Although the studies sampled the gingival mucosa surrounding the 
operation sites prior to and immediately after surgery or tooth 
extraction, they did not demonstrate a decrease in the number of oral 
bacteria over an extended period of time. In addition, the organisms 
affected by the povidone-iodine treatment were not completely 
identified. Furthermore, these data do not demonstrate a therapeutic 
benefit from the OTC use of povidone-iodine. Therefore, the agency is 
classifying povidone-iodine in Category III for effectiveness as an OTC 
oral antiseptic in this tentative final monograph. (See section I.I., 
comment 16.) The agency is placing povidone-iodine in Category I for 
use as a dental preoperative by health care professionals and is 
proposing labeling for such products in Sec. 356.80.

References

    (1) OTC Vol. 130176.
    (2) Brenman, H. S., and E. Randall, ``Local Degerming with 
Povidone-Iodine II. Prior to Gingivectomy,'' Journal of 
Periodontology, 45:870-872, 1974.
    (3) Scopp, I. W., and L. D. Orvieto, ``Gingival Degerming by 
Povidone-Iodine Irrigation: Bacteremia Reduction in Extraction 
Procedures,'' Journal of the American Dental Association, 83:1294-
1296, 1971.
    (4) Brenman, H. S., and E. Randall,``Reduction of Gingival 
Bacteria and Gingivectomy-Related Bacteremia by Povidone-Iodine,'' 
International Association of Dental Research, (Abstract #211), 1972.
    (5) Randall, E., and H. S. Brenman, ``Antimicrobial Action of 
Povidone-Iodine Mouthwash Before and During Dental Prophylaxis,'' 
Journal of Dental Research, 51:101, 1972.

L. Comments on Combination Oral Antiseptic Drug Products

    28. One comment noted that the Dental Panel recognized that the 
combination of an oral antiseptic (i.e., antimicrobial agent) and an 
oral wound cleanser (i.e., debriding agent) was rational and should 
provide additional protection for an oral wound (44 FR 63270 at 63276). 
The Oral Cavity Panel, however, placed the same combination in Category 
II because it believed that the antimicrobial agent would be diluted 
and washed away from the diseased surface (47 FR 22760 at 22792). The 
comment stated that manufacturer's directions state that these products 
should remain in contact with the wound site for at least 1 minute. The 
comment added that there are active ingredients that function as 
antimicrobial agents as well as debriding agents and that ingredients 
with both properties are effective when applied locally. The comment 
explained that because the purpose of an antiseptic is to decrease the 
number of bacteria and reduce the chance of infection after minor 
injuries to oral cavity tissues, the combination of a debriding agent 
and an antiseptic provides logical therapy to reduce chances of 
infection, while cleansing the wound site.
    In the first segment of the tentative final monograph for OTC oral 
health care drug products (53 FR 2436), the agency incorporated 
portions of the OTC oral mucosal injury rulemaking, which includes oral 
wound cleansers and oral wound healing agents, into the oral health 
care rulemaking and proposed that debriding agents and oral wound 
cleansers be treated as a single therapeutic class of ingredients. The 
agency addressed OTC oral wound healing agents separately in a final 
rule (51 FR 26112) and deferred consideration of the combination of an 
oral wound cleanser and an oral antiseptic (as recommended in 
Sec. 353.20(b) by the Dental Panel) to this antiseptic segment of the 
rulemaking for OTC oral health care drug products.
    Although the Dental Panel recommended that the combination of an 
oral wound cleanser and an oral antiseptic be classified as Category I, 
it stated in a parenthetical note that ``the advisability of adding an 
antiseptic for the stated purpose is under review by the OTC Advisory 
Review Panel on Oral Cavity Drug Products'' (44 FR 63270 at 63276). 
After reviewing both Panels' recommendations, the agency agrees with 
the Oral Cavity Panel's Category II classification of one or more 
antiseptic ingredients combined with any debriding agent. The agency is 
concerned that combining an antiseptic ingredient with a debriding 
agent/oral wound cleanser would decrease the effectiveness of the 
antiseptic ingredient. Because debriding agent/oral wound cleansers 
loosen and remove tissue, debris, mucus, etc., from mucosal surfaces by 
their chemical and mechanical action (e.g., foaming, lowering surface 
tension, and reducing viscosity of mucus), the antiseptic ingredient 
might not be in direct contact with the oral mucosa for a long enough 
period of time to exert a significant antiseptic effect, even though 
the manufacturer's directions state that these products should remain 
in contact with the wound site for at least 1 minute before spitting 
out. The agency believes that a reasonable time to apply a Category I 
antiseptic to an oral mucosal wound site or to the site of an oral 
inflammation is after that site has been cleansed with a debriding 
agent/oral wound cleanser. Additionally, the agency has surveyed the 
marketplace and is not aware of any currently available OTC drug 
product containing a combination of an oral health care antiseptic 
ingredient and an oral wound cleanser or debriding agent, nor were data 
on any such products submitted to either the Dental Panel or the Oral 
Cavity Panel.
    The comment mentioned that some debriding agents also function 
effectively as antiseptic agents. However, there are no Category I 
debriding agent/oral wound cleansers that are also Category I 
antiseptic agents in this tentative final monograph.
    In conclusion, for the reasons stated above, the agency is 
classifying the combination of an antiseptic agent and a debriding 
agent/oral wound cleanser in Category II in this tentative final 
monograph. Data are needed to show that the two ingredients are 
effective when used in combination.
    29. Several comments pointed out that the Dental Panel had placed 
the following combinations in Category I in Sec. 354.20(b), (c), and 
(d), respectively, of its recommended monograph: (1) An oral mucosal 
protectant and an oral antiseptic, (2) an oral mucosal analgesic and an 
oral antiseptic, and (3) an oral mucosal protectant, an oral mucosal 
analgesic, and an oral antiseptic. The comments noted that the Dental 
Panel had deferred review of the antiseptic ingredients to the Oral 
Cavity Panel, but that Panel failed to address locally applied 
antiseptics in the combinations placed in Category I by the Dental 
Panel. The comments maintained that these combinations are rational 
because the antiseptic ingredient will help to prevent or reduce 
possible infection while the oral mucosal analgesic will relieve the 
pain due to minor irritations or injury to the oral mucosa, and the 
addition of an oral mucosal protectant provides a coating over the 
wound for protection and holds the analgesic and antiseptic ingredients 
in place where they can act most effectively. The comments urged FDA to 
accept the recommendations of the Dental Panel and permit these 
combinations in the tentative final monograph for OTC oral health care 
drug products.
    One of the comments added that the labeling in the tentative final 
monograph for OTC topical antimicrobial drug products (47 FR 22986 at 
29989) is consistent with the rationale expressed by the Dental Panel 
for its recommendation to place the combination of an oral mucosal 
analgesic and an oral antiseptic in Category I. The comment contended 
that the following claims could be used for topically applied oral 
antiseptics in such combination products:
    (1) (Select one of the following: ``Decreases'' or ``Helps 
reduce'') ``the number of bacteria on the treated area.''
    (2) ``Helps'' (select one of the following: ``prevent,'' ``guard 
against,'' or ``protect against'') ``* * * infection.''
    (3) ``Helps reduce the'' (select one of the following ``risk'' 
or ``chance'') ''of * * * infection.''
    (4) ``Helps prevent bacterial contamination in minor cuts, 
scrapes, and burns.''
    The agency has reviewed the Dental Panel's discussion regarding 
combinations (47 FR 22712 at 22720) and, in general, agrees with that 
Panel that the following combinations are rational: (1) Oral antiseptic 
and oral anesthetic/analgesic; (2) oral antiseptic and oral mucosal 
protectant; (3) and oral antiseptic, oral anesthetic/analgesic, and 
oral mucosal protectant. In addition, the agency has reviewed the Oral 
Cavity Panel's evaluation of combinations containing oral antiseptic 
active ingredients (47 FR 22760 at 22790 to 22793) and agrees that the 
following combinations are reasonable: (1) Oral antiseptic and oral 
astringent; (2) oral antiseptic and oral demulcent; (3) oral 
antiseptic, oral anesthetic/analgesic, and oral astringent; and (4) 
oral antiseptic, oral anesthetic/analgesic, and oral demulcent. 
Accordingly, the agency is proposing these seven combinations in 
Sec. 356.26 of this tentative final monograph.
    However, this tentative final monograph does not include any 
Category I oral antiseptic ingredients. Therefore, these combinations 
will not be included in the final monograph unless at least one oral 
antiseptic active ingredient achieves monograph status. Further, the 
agency notes that the seven proposed Category I combinations may not be 
appropriate for all Category III oral antiseptic ingredients. For 
example, if hydrogen peroxide were upgraded to Category I as an oral 
antiseptic, it might not be appropriate to combine hydrogen peroxide 
with an oral mucosal protectant or an oral demulcent. As each oral 
antiseptic ingredient achieves monograph status, the agency will 
evaluate that ingredient specifically as to which combinations are 
suitable.
    In this tentative final monograph, the indication being proposed 
for oral health care antiseptic drug products is similar in content to 
those recommended by one of the comments. (See section I.K., comment 
22.) Indications for oral anesthetic/analgesic, oral astringent, oral 
demulcent, and oral mucosal protectant drug products were proposed in 
Secs. 356.52(b), 356.54(b), 356.58(b), and 356.60(b) of the amendment 
to the tentative final monograph for OTC oral health care drug products 
(56 FR 48302 at 48343 to 48346).
    The agency considers that the indication proposed for oral 
anesthetic/analgesic ingredients in Sec. 356.52(b)(1) (``For the 
temporary relief of occasional minor irritation, pain, sore mouth, and 
sore throat,'') as not appropriate for a combination product containing 
an oral antiseptic because ``temporary relief of sore throat'' is a 
Category III indication for OTC oral antiseptics. (See section I.K., 
comment 22.) In addition, the agency considers the indication proposed 
for oral anesthetic/analgesic ingredients in Sec. 356.52(b)(2) (``For 
the temporary relief of pain associated with canker sores'') as not 
suitable for a combination product containing an OTC oral antiseptic 
ingredient because claims related to canker sores are Category III for 
OTC oral antiseptics. Likewise, the agency does not consider the 
indication proposed for oral anesthetic/analgesic ingredients in 
Sec. 356.52(b)(7) for denture adhesive products containing an oral 
anesthetic/analgesic (``For the temporary relief of pain or discomfort 
of the mouth and gums due to dentures'') as appropriate for products 
containing an oral antiseptic ingredient because there is no Category I 
combination that includes an oral antiseptic and a denture adhesive. 
Therefore, when an oral antiseptic is present in certain combination 
products (i.e., with: (1) An oral anesthetic/analgesic, (2) an oral 
anesthetic/analgesic and an oral mucosal protectant, (3) an oral 
anesthetic/analgesic and an oral astringent, or (4) an oral anesthetic/
analgesic and an oral demulcent), the labeling of the product may not 
contain the indications proposed for oral anesthetic/analgesic 
ingredients in Sec. 356.52(b)(1), (b)(2), and (b)(7).
    Additionally, the Oral Cavity Panel recommended that oral 
antiseptics should not be used in children under 3 years of age (47 FR 
22760 at 22928). In Sec. 356.50(d), Sec. 356.54(d), Sec. 356.56(d), and 
Sec. 356.58(d) of the tentative final monograph for OTC oral health 
care drug products, the agency proposed that the lower age limit for 
OTC oral health care ingredients be 2 years, except for sodium 
perborate monohydrate (6-year lower age limit), phenol preparations 
that are intended for ingestion or that could be inadvertently ingested 
(6-year lower age limit), tooth desensitizers (12-year lower age 
limit), butacaine sulfate (12-year lower age limit), and teething 
preparations (4-month lower age limit) (56 FR 48302 at 48343 to 48346). 
The agency does not believe that oral antiseptics should be used in 
children under 2 years of age unless done so under a doctor's 
supervision. Therefore, the agency is not proposing the indication for 
oral anesthetic/analgesic ingredients in Sec. 356.52(b)(6) for 
benzocaine or phenol used in products for teething pain (``For the 
temporary relief of sore gums due to teething in infants and children 4 
months of age and older'') for a combination product containing an oral 
antiseptic and an oral anesthetic/analgesic or an oral antiseptic, an 
oral anesthetic/analgesic, and an oral mucosal protectant.
    The agency does not consider the indication proposed for oral 
astringents in Sec. 356.54 (``For the temporary relief of occasional 
minor irritation, pain, sore mouth, and sore throat'') as appropriate 
for a combination product containing an oral antiseptic and an oral 
astringent because oral antiseptics are not indicated for use in 
relieving the discomfort of sore throat. Therefore, when an oral 
antiseptic is combined with an oral astringent or an oral anesthetic/
analgesic and an astringent, the indication proposed for oral 
astringent drug products in Sec. 356.54 is not appropriate. Instead, 
the agency is proposing the following indication for a combination 
product containing an oral antiseptic and an oral astringent: ``For 
temporary relief of occasional minor irritation, pain, and sore 
mouth.'' The agency is also proposing that a combination product 
containing an oral antiseptic, an oral astringent, and an oral 
anesthetic/analgesic be labeled with any of the applicable indications 
proposed in Sec. 356.52(b)(3), (b)(4), or (b)(5) or with the indication 
proposed above for a combination drug product containing an oral 
antiseptic and an oral astringent.
    The agency does not consider the indication proposed for oral 
demulcents in Sec. 356.58 (``For temporary relief of minor discomfort 
and protection of irritated areas in sore mouth and sore throat'') as 
appropriate for a combination product containing an oral antiseptic and 
an oral demulcent because oral antiseptics are not indicated for use in 
relieving the discomfort of sore throat. Therefore, when an oral 
antiseptic is combined with an oral demulcent or an oral anesthetic/
analgesic and an oral demulcent, the indication proposed for oral 
demulcent drug products in Sec. 356.58 is not appropriate. Instead, the 
agency is proposing the following indication for a combination product 
containing an oral antiseptic and an oral demulcent: ``For temporary 
relief of minor discomfort and protection of irritated areas in sore 
mouth.'' The agency is also proposing that a combination product 
containing an oral antiseptic, an oral demulcent, and an oral 
anesthetic/analgesic be labeled with any of the applicable indications 
proposed in Sec. 356.52(b)(3), (b)(4), or (b)(5) or with the indication 
proposed above for a combination product containing an oral antiseptic 
and an oral demulcent.
    The agency has determined that the indication proposed for oral 
mucosal protectant active ingredients in Sec. 356.60(b)(4) (``For 
protecting recurring canker sores'') should not be used for a 
combination product containing an oral antiseptic and an oral mucosal 
protectant because claims related to canker sores are Category III for 
oral antiseptics. (See section I.K., comment 22.) Therefore, when an 
oral antiseptic is combined with an oral mucosal protectant, the 
indication proposed for oral mucosal protectants in Sec. 356.60(b)(4) 
is not appropriate.
    The agency also notes that certain warnings proposed for oral 
anesthetic/analgesic ingredients in Sec. 356.52(c)(1), (c)(5), and 
(c)(6), for oral astringents in Sec. 356.54(c), and for oral demulcents 
in Sec. 356.58(c)(1) would not be applicable to certain combination 
products containing an oral antiseptic. The warnings in 
Sec. 356.52(c)(1), Sec. 356.54(c), and Sec. 356.58(c)(1) are partially 
sore throat warnings that limit use of a product to 2 days if the sore 
throat is severe or is accompanied by or followed by fever, headache, 
rash, swelling, nausea, or vomiting. These warnings are not applicable 
to a combination product containing an antiseptic because an oral 
antiseptic is not indicated for use to relieve the symptoms of sore 
throat. In addition, because oral antiseptics may not be used in 
teething products or denture adhesives, the warnings related to such 
products in Sec. 356.52(c)(5) and (c)(6) are not applicable to 
combination drug products containing an oral antiseptic and an oral 
anesthetic/analgesic or an oral antiseptic, an oral anesthetic/
analgesic, and any other oral health care ingredient.
    Because this tentative final monograph does not include any 
Category I antiseptic ingredients, the agency is not proposing any 
directions for oral antiseptic ingredients. The agency is reserving 
Sec. 356.64(d) for directions should any oral antiseptic ingredients be 
included in the final monograph. Likewise, for the same reason, the 
agency is not proposing any directions for oral health care combination 
drug products containing antiseptic ingredients.
    Based on the above discussion, the agency is proposing to include 
specific indications and warnings in Sec. 356.66(b) and (c) for the 
labeling of combination drug products that include an oral antiseptic. 
This labeling will appear in the final monograph only if at least one 
oral antiseptic active ingredient achieves monograph status.
    30. One comment requested that the agency approve the combination 
of 0.045 percent cetylpyridinium chloride and 0.005 percent domiphen 
bromide as a Category I oral antiseptic. The comment contended that the 
addition of small amounts of domiphen bromide to a formulation 
containing cetylpyridinium chloride enhances the in vitro activity of 
the formulation against gram-positive and gram-negative standard 
bacterial cultures. The comment contended that this performance 
improvement satisfies even the Oral Cavity Panel's criteria for the 
combination of two active ingredients from the same therapeutic 
category having the same pharmacological mechanism of action (47 FR 
22760 at 22792). The comment added that in calling for ``improvement of 
safety or enhanced effectiveness or both,'' the Panel went well beyond 
the existing regulatory guidelines for OTC combinations in 
Sec. 330.10(a)(4)(iv), which requires only that each ingredient in the 
combination make a contribution to the claimed effect.
    The comment submitted the results of two in vitro studies designed 
to justify the combination of 0.045 percent cetylpyridinium chloride 
and 0.005 percent domiphen bromide (Ref. 1). It also submitted a 
published article suggesting that this combination was more effective 
in a clinical study than a formulation containing cetylpyridinium as 
the sole oral antiseptic ingredient (Ref. 2).
    The agency discussed the Oral Cavity Panel's recommendations 
regarding combination products in the first segment of the tentative 
final monograph for OTC oral health care drug products (53 FR 2436 at 
2450). The Panel recommended that any Category I oral health care 
ingredient could be combined with one or more ingredients from the same 
therapeutic category if each ingredient is present in its full 
therapeutic dose, or subtherapeutic dose where appropriate, only when 
there is a clear demonstration that there is an improvement of safety 
or enhanced effectiveness or both (47 FR 22760 at 22927). However, the 
agency currently uses the combination policy in Sec. 330.10(a)(4)(iv) 
and its guidelines for OTC drug combination products (Ref. 3) as the 
criteria for evaluating all OTC combination drug products.
    The combination policy in Sec. 330.10(a)(4)(iv) states that an OTC 
drug may combine two or more safe and effective (Category I) 
ingredients when each ingredient makes a contribution to the claimed 
effect(s); when combining the ingredients does not decrease the safety 
or effectiveness of any of the individual ingredients; and when the 
combination, used under adequate directions for use and warnings 
against unsafe use, provides rational therapy for a significant 
proportion of the target populations. Paragraph 3 of the agency's 
guidelines (Ref. 3) requires that, for combinations of ingredients from 
the same therapeutic category with the same mechanism of action, such 
combinations should not ordinarily be combined unless there is some 
advantage over the single ingredients in terms of enhanced 
effectiveness, safety, patient acceptance, or quality of formulation. 
The ingredients may be combined in selected circumstances to treat the 
same symptoms or conditions if the combination meets the OTC 
combination policy in all respects, the combination offers some 
advantage over the active ingredients used alone, and the combination 
is, on a benefit-risk basis, equal to or better than each of the active 
ingredients used alone at its therapeutic dose.
    Although the agency believes that the ingredients cetylpyridium 
chloride and domiphen bromide in the concentrations mentioned by the 
comment are safe for OTC use as oral antiseptics, neither ingredient 
has been demonstrated to be an effective oral antiseptic. (See section 
I.E., comment 9 and section I.G., comment 13.) The data submitted by 
the comment are not adequate to demonstrate the effectiveness of either 
ingredient or a combination of the two ingredients. The two in vitro 
studies tested the ingredients against only two organisms, 
Staphylococcus aureus and Salmonella typhosa (Ref. 1). The agency does 
not believe that demonstrating antiseptic effectiveness against these 
two microorganisms is relevant to the use of an antiseptic in the oral 
cavity. The published article reported the results from a study of the 
effects of two mouthwashes on bacterial plaque (Ref. 2). As stated in 
section I.M., comment 32, the agency agrees with the Panel that 
reduction of plaque accumulation is not an appropriate criterion for 
establishing oral antiseptic effectiveness. (See section I.M., comment 
33 for a discussion of appropriate testing procedures.)

References

    (1) Attachment D, C00013, Docket No. 81N-0033, Dockets 
Management Branch.
    (2) Barnes, G. P. et al., ``Effects of Two Cetylpyridinium 
Chloride-Containing Mouthwashes on Bacterial Plaque,'' C00013, 
Docket No. 81N-0033, Dockets Management Branch.
    (3) FDA, ``General Guidelines for OTC Drug Combination 
Products,'' September 1978, Docket No. 78D-0322, Dockets Management 
Branch.
    31. One comment stated that cetylpyridinium chloride and domiphen 
bromide are effective OTC oral antiseptics and that an application (NDA 
14-598) for a product containing these ingredients had been approved 
for 18 years, i.e., up to November 17, 1982, the date of the comment. 
The comment stated that NDA 14-598 established the safety and 
effectiveness of the active ingredients, cetylpyridinium chloride 0.045 
percent and domiphen bromide 0.005 percent, and their combination; and 
that the same combination is used today. The comment maintained that 
supplementation of the application and periodic reporting have 
supported and even strengthened the proof of safety and effectiveness. 
In addition, the comment stated that extensive tests demonstrating the 
ability of a product containing cetylpyridinium chloride and domiphen 
bromide to kill bacteria and viruses in vitro were reported to the 
Panel (Ref. 1) and are included in NDA 14-598. The comment also stated 
that NDA 14-598 contains the results of numerous tests showing 
reduction of bacterial counts after rinsing with the product and that 
the application contains data showing effectiveness of the product in 
temporarily relieving minor sore throat. The comment stated that 
although the bulk of the material in NDA 14-598 is not publicly 
available, it is in the agency's files and may be used by the agency to 
support these comments. Moreover, the comment contended that it regards 
the continuing validity of the application as conclusive evidence of 
the product's safety and effectiveness for use as an OTC oral 
antiseptic (Ref. 2).
    The agency notes that data contained in an application are 
confidential information covered by 21 CFR 20.61 and are not publicly 
available. The sponsor of the application would have to affirmatively 
submit these data as part of the public administrative record for the 
agency to consider them in this rulemaking proceeding. As the agency 
has indicated elsewhere under similar conditions concerning an 
antitussive drug product containing diphenhydramine hydrochloride (48 
FR 48576 at 48582), determination by FDA that a new drug is safe and 
effective and the approval of an application for the drug are not 
synonymous with a determination that a drug is generally recognized as 
safe and effective in the OTC drug review. See Weinberger v. Bentex 
Pharmaceuticals, Inc., 412 U.S. 645, 651 (1973). In addition, the 
agency is aware that the commentor requested that approval of NDA 14-
598 be withdrawn because the product was no longer being marketed as a 
drug (Ref. 4).
    General recognition of the effectiveness of a drug in the OTC drug 
review must be based on adequate published or publicly available 
medical and scientific data. (United States v. 41 Cases * * * Naremco, 
420 F.2d 1126 (C.A. 5, 1970); United States v. An Article of Drug * * * 
Mykocert, 345 F. Supp. 571 (D.C. 1972); United States v. An Article of 
Drug * * * Asper Sleep, CCH F.D. and Cosm. L. Rep. 40,821 Civil No. 70-
C-196 (N.D. Ill. 1971); United States v. An Article of Drug * * * 
(Furestorol Vaginal Suppositories 294 F. Supp 1307 (N.D. Ga. 1968).) 
There is not adequate information publicly available at this time to 
demonstrate that cetylpyridinium chloride, domiphen bromide, or the 
combination of the two ingredients are generally recognized as 
effective for the Category I indication proposed in this document. 
Therefore, the agency is unable to conclude at this time that these 
ingredients or a combination of these ingredients are generally 
recognized as effective oral antiseptic agents, and is proposing that 
they be Category III for effectiveness. (See section I.E., comment 9; 
section I.G., comment 13; and section I.L., comment 30.)

References

    (1) OTC Vols. 130078, 130118, 130134, 130160, and 130187.
    (2) Attachment F, Comment No. C00013, Docket No. 81N-0033, 
Dockets Management Branch.
    (3) Attachment G, Comment No. C00013, Docket No. 81N-0033, 
Dockets Management Branch.
    (4) Letter from W. E. Cooley, The Procter & Gamble Co., to the 
Division of Radiopharmaceutical, Surgical, and Dental Drug Products, 
FDA, NDA 14-598, dated January 5, 1990, OTC Vol. 130CTFM.

M. Comments on Testing

    32. Addressing the Oral Cavity Panel's consideration of protocols 
for testing antiseptic mouthwashes, two comments stated that the 
measurement of plaque reduction is a valid technique to assess the 
antimicrobial activity of oral antiseptics. Noting that dental plaque 
is largely composed of living bacteria within a polysaccharide matrix, 
one comment contended that experts recognize that ``antiseptic activity 
may be measured in the mouth by taking counts of unattached organisms 
before and after treatment, or by measuring plaque differences among 
subjects receiving either the test substance or a control.'' The 
comment mentioned that the Panel's minority report outlines a scheme of 
reasonable in vitro and in vivo tests that are well accepted and have 
been shown to be satisfactory in demonstrating the antiseptic activity 
of mouthwashes (47 FR 22760 at 22893 to 22901). The comment added that, 
in 1978, the Oral Cavity Panel voted approval of the clinical protocols 
needed to support Category I status for oral antimicrobials for use in 
mouthwashes, and that a professional association of manufacturers 
concurred with that recommendation. The comment urged that these 
protocols be reinstated as the proof required to obtain Category I 
status for antimicrobial mouthwashes.
    Also citing the Panel's minority report, the second comment stated 
that the majority of the Panel, at its next-to-last meeting, voted to 
reject the testing guidelines for demonstrating antiseptic activity 
that the Panel had recommended to industry over the course of several 
years and that the firm submitting the comment had relied upon to 
confirm its product's antiseptic properties. Although pointing out that 
the majority of the Panel evidently desired an objective test to 
justify plaque reduction as a criterion for establishing antimicrobial 
activity (47 FR 22760 at 22841), the comment contended that such an 
objective test was originally prescribed by the Panel and successfully 
conducted for the firm's mouthwash product containing a combination of 
volatile oils. The comment stated that reductions in dental plaque 
biomass have been shown to correlate with reductions in dental plaque 
bacteria by objective weight measurement (47 FR 22894 to 22895) and 
that other equally valid plaque reduction measurements, such as area 
measurement, were also successfully conducted for the firm's product. 
The comment concluded that these ``state of the art'' plaque reduction 
measurements should be accepted as indices of antiseptic action.
    The agency is aware that the majority of the Panel stated 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. Plaque 
reduction, therefore, is not accepted by this Panel as a criterion for 
determining effectiveness of antimicrobial agents for oral health care 
products intended to treat sore mouth or sore throat,'' (47 FR 22840). 
The agency agrees with the Panel and believes that plaque reduction has 
not been established as a valid technique for determining the 
antiseptic effectiveness of ingredients used for the types of 
indications being considered in this segment of the tentative final 
monograph: (1) First aid to help prevent infection in the mouth, or (2) 
for the temporary relief of minor sore throat symptoms.
    The agency believes that the types of tests suggested in the 
Panel's testing guidelines at 47 FR 22760 at 22890 to 22893 are better 
suited to demonstrate the effectiveness of antiseptic ingredients in 
reducing the risk of infection in the oral cavity or in relieving sore 
mouth and sore throat symptoms. These testing guidelines are further 
discussed in section I.M., comment 33. However, as discussed in the 
previous segments of this tentative final monograph (see 53 FR 2436 and 
56 FR 48302), in developing this monograph the agency is not addressing 
specific testing guidelines for upgrading ingredients to Category I. In 
revising the OTC drug review procedures relating to Category III, 
published in the Federal Register of September 29, 1981 (46 FR 47730), 
the agency advised that tentative final and final monographs will not 
include recommended testing guidelines for conditions that industry 
wishes to upgrade to monograph status. Instead, the agency will meet 
with industry representatives at their request to discuss testing 
protocols. The revised procedures also state the time in which test 
data must be submitted for consideration in developing the final 
monograph. (See also part II. paragraph A.2.--Testing of Category II 
and Category III conditions.)
    The agency wishes to point out that, as discussed in the call-for-
data for antiplaque ingredients and claims (55 FR 38560), the Dental 
Products Panel will evaluate data regarding the safety and 
effectiveness of active ingredients contained in products displaying 
antiplaque and antiplaque-related claims. A subsequent segment of the 
rulemaking for OTC oral health care drug products will cover that 
Panel's recommendations to the agency regarding drug ingredients used 
for the reduction of plaque and plaque-related claims. Methods 
discussed by the comments and by the minority of the Oral Cavity Panel 
may be appropriate to demonstrate antiseptic activity of ingredients 
intended to reduce or prevent plaque.
    33. Two comments stated that presentations had been made to the 
Oral Cavity Panel concerning guidelines for in vitro and in vivo 
testing of topical antiseptics (Refs. 1, 2, and 3) and that these data 
were not considered or included in that Panel's discussion. The 
comments contended that the guidelines were adequate to test 
ingredients for effectiveness and to establish a first aid antiseptic 
category for oral health care drug products that meet these guidelines. 
The comments stated that the guidelines provide for a statistically 
significant reduction in vivo combined with a 95-percent reduction in 
vitro of the organisms tested and, thus, provide proof of clinically 
useful antiseptic activity.
    One comment paraphrased an agency statement that was published in 
the tentative final monograph for OTC topical antimicrobial drug 
products (i.e., first aid antibiotic drug products) (47 FR 29986 at 
29991 to 29992) as follows:
    The agency agrees with the comments that minor skin injuries, 
such as cuts and scrapes, are self-healing and that the body's 
healing mechanisms can handle some infections that might develop in 
these injuries. However, as the reply comment pointed out, some 
minor skin injuries do not heal without treatment and it is 
impossible to make that distinction at the time of injury. It is 
well documented that applying topical antibiotics to skin wound 
lesions reduces the number of bacteria at the site of application 
and serves as an adjunct to cleansing wounds.
The comment argued that, in view of the agency's medical assessments of 
topical antibiotics as stated above, clinical testing of each 
ingredient or product is unnecessary. The comment felt that in vitro 
data demonstrating that a product's active ingredient is effective 
against the organism(s) likely to be found at the site should be 
sufficient to allow classification in Category I. The comment added 
that such a decision would be consistent with the agency's acceptance 
of all Category I topical antibiotics for the first aid indication to 
help prevent infection in minor cuts, scrapes, and burns (47 FR 29986 
at 29999).
    The Oral Cavity Panel considered the presentations concerning 
guidelines for in vitro and in vivo testing (Refs. 1, 2, and 3) and 
made suggestions concerning requirements for conducting such studies 
designed to obtain data for reclassifying Category III ingredients to 
Category I for safety and effectiveness or both (47 FR 22760 at 22890 
to 22893). The Panel suggested that preliminary, well-designed in vitro 
studies be required to demonstrate antiseptic effectiveness and that 
the data obtained from in vitro studies be verified and supported by in 
vivo animal and human studies. The Panel stated that human model 
studies should be followed by appropriate clinical trials. The Panel 
included recommendations for in vitro and in vivo testing procedures to 
indicate the types of data necessary to upgrade ingredients from 
Category III to Category I and provided suggestions for obtaining such 
data.

Clinical Testing of OTC Oral Antiseptics
    The agency believes that data from in vitro testing alone are 
insufficient to establish that an oral antiseptic is generally 
recognized as effective in: (1) Decreasing the number of microorganisms 
in the oral cavity and thus helping to prevent or reduce the chance of 
infection or bacterial contamination in minor oral wounds, or (2) 
temporarily relieving the symptoms of minor sore throat or mouth. The 
agency's assessment of the effectiveness of topical antibiotics in 
helping to prevent infection in minor skin cuts, scrapes, and burns (47 
FR 29986 at 29991 to 29992) is not relevant in evaluating the 
effectiveness of oral antiseptic ingredients in helping to prevent 
infection in minor wounds in the mouth. Although demonstrated in vitro 
antiseptic bactericidal or bacteriostatic action is of predictive value 
in projecting clinical efficacy for antiseptics used on the skin (39 FR 
33103 at 33110 and 56 FR 33644 at 33671), the agency believes that such 
activity alone is not sufficient to allow classification of an 
ingredient in Category I.
    The environment of the oral cavity is very different from that of 
the skin. The oral cavity supports one of the most concentrated and 
varied microbial population of the body. The total microscopic count of 
saliva has been given as anything from 43 million to 5.5 billion per mL 
with an average of about 750 million. The microbial concentration of 
the gingival sulcus and in plaque is at least 100 fold greater, or 
approximately 200 billion cells per gram of sample (Ref. 4). 
Conversely, the skin, for the most part, is an inhospitable place for 
most microorganisms because the secretions of the skin are acidic and 
most of the skin contains little moisture (Ref. 5). The agency believes 
that, on the fairly dry surface of the skin, a reduction in 
microorganisms caused by the application of a topical antiseptic will 
persist for some time and, thus, may help to prevent minor skin 
infections. However, even if one could demonstrate a reduction of 
microorganisms on a site in the oral cavity, it is unlikely that this 
reduction would result in a therapeutic benefit because the action of 
saliva would reinoculate the site almost immediately. As the Oral 
Cavity Panel stated, approximately 0.25 to 1 mL of saliva is excreted 
per minute in the oral cavity (47 FR 22766). Therefore, oral surfaces 
are constantly bathed with saliva, and organisms are readily 
transported from one area of the mouth to another. This may be 
particularly true of minor oral irritations, cuts, and scraps where 
there is an almost irresistible urge to probe the site with the tongue. 
This continuous reinoculation of the site with large numbers of 
microorganisms is likely to counteract any therapeutic benefit that 
might result from topical antiseptic action in the oral cavity. 
Therefore, the agency tentatively concludes that clinical testing is 
necessary to demonstrate that an antiseptic ingredient truly has a 
therapeutic effect in the oral cavity.
    Clinical trials to demonstrate the effectiveness of an OTC oral 
antiseptic ingredient should be well-designed and well-controlled. Such 
trials should be structured to closely approximate the clinical 
situations for which a product is intended to be used and to 
substantiate proposed claims. These studies should demonstrate that the 
topically-applied antiseptic ingredient helps to prevent infection in 
minor wounds in the mouth better than the vehicle alone.

In Vivo Testing Procedures
    Three in vivo studies submitted to the Panel (Ref. 2), and 
mentioned by the comments, were designed to answer specific questions 
raised by the Panel during its evaluation of in vivo testing guidelines 
for oral antiseptics (Ref. 1). The basic method used in the three 
studies (Ref. 2) involved the use of 10 normal subjects with no medical 
problems. The subjects were treated with cetylpyridinium chloride (0.1 
or 1 percent) and a placebo (distilled or deionized water). In some of 
the studies, a template was used to define the cheek treatment area, 
and in other studies, no template was used. Each subject served as his 
or her own control. The technique consisted of using a swab to sample 
the cheek before treatment, treating the cheek with the designated 
agent (i.e., active ingredient or placebo), and sampling again 1 minute 
later. Samples were mixed, serially diluted, plated, incubated, and 
visible bacterial colonies counted. A variety of mixing, plating 
methods, and environmental conditions were used (e.g., drop plate 
counting method, standard plating procedures, sonication, and 
incubation under carbon dioxide, aerobic, and anaerobic conditions.) 
The results of all three studies indicated that cetylpyridinium 
chloride decreased the number of bacteria within 1 minute after 
application on the cheek. Individual studies included the following 
results: (1) Subjects differ from each other by 10 to 100 fold in their 
normal bacterial counts, but vary little from 1 day to another in their 
own bacterial counts; (2) a swab sampling procedure and a drop-plate 
counting method are sensitive, adequate methods to detect small 
decreases in bacterial counts in a 10-subject panel, and decreases 
smaller than 2 logs or 100 fold are significant; (3) a template is not 
necessary to limit the treatment area; (4) successive samples taken 
before treatment invariably decrease, as do samples taken after 
treatment with water while samples taken after treatment with 
cetylpyridinium chloride level off or increase in successive samples, 
indicating that the antiseptic killed bacteria in the top layer of the 
oral mucosa but not in the lower layers; (5) sonication of swab samples 
increases the sensitivity of the method, but does not affect the 
estimate of antiseptic effectiveness; thus, this method may be used 
optionally; (6) conventional plating methods and other well-tested 
plating methods are highly reproducible; and (7) although results for 
all three incubation environments were essentially the same, the effect 
of some oral antiseptics could have differing effects against types of 
bacteria requiring specific gaseous environments; thus, three 
environments should be used in future studies.
    The agency concludes that the techniques of the in vivo testing 
guidelines presented to the Panel for demonstrating the effectiveness 
of a locally applied antiseptic ingredient (Refs. 1 and 2) represent a 
partial guide for helping to assess an ingredient's effectiveness as an 
OTC oral health care antiseptic, but are not totally adequate for that 
purpose. The agency believes that in vivo testing methods used to help 
demonstrate the effectiveness of oral health care antiseptic 
ingredients should stipulate the specific organisms to be tested, the 
acceptable decrease in bacterial numbers, and the period of time for 
which the antiseptic activity should persist. The Panel's discussion of 
in vivo testing did not include such information (47 FR 22760 at 
22891). Such testing methods should also take into account the 
following: (1) The normal flora of the site to be used in the study, 
(2) the complexity of the oral flora, (3) the site-to-site variation of 
the oral flora within the mouth, (4) when tissue is abraded, burned, or 
punctured, sites may be exposed that allow the binding of oral 
microorganisms that would not otherwise reside in that particular 
ecological niche, and (5) what shifts in the balance of the flora and/
or colonization by other species are to be expected if the site is 
abraded or otherwise damaged. A spectrum of activity against a 
representative battery of organisms should be developed (i.e., Candida 
albicans, representative actinomyces and streptococcal species, and 
other flora frequently isolated from the site). A thorough review of 
the literature should identify the appropriate microorganisms.
    In addition, the in vivo testing guidelines presented to the Panel 
(Ref. 1) did not include adequate sampling intervals after treatment 
with the oral antiseptic. Using the guidelines, a statistically 
significant difference was obtained between treatment of the cheek with 
the placebo and treatment with cetylpyridinium chloride; however, the 
length of time that the antiseptic effect persists past the 1-minute 
time interval used in the studies was not explored. The transient 
decrease in the number of bacteria at the 1-minute interval after 
cetylpyridinium chloride application, as noted in the comment's studies 
(Ref. 2), is not unexpected. The ability to maintain such a decrease 
over a reasonable interval of time is more significant and important, 
especially when one considers the effect of the oral environment. The 
agency believes that, for demonstrating antiseptic activity in the oral 
cavity, more appropriate time intervals might be 1 minute, 10 minutes, 
30 minutes, 1 hour, 2 hours, and 4 hours.
    The agency also believes that it might be useful to use more than 
one incubation environment because some microniches in the oral cavity 
(e.g., the gingival crevice) support anaerobic growth, and organisms 
commonly isolated from the oral cavity include facultative anaerobes as 
well as strict anaerobes. One approach would be to use a nonselective 
medium under anaerobic and carbon dioxide conditions and several 
selective media under appropriate conditions depending upon the 
microorganism of interest.

In Vitro Testing Procedures
    The agency believes that the Panel's proposed in vitro testing 
guidelines represent a good starting point for the design of in vitro 
studies to help upgrade a Category II or Category III oral antiseptic 
ingredient to Category I (47 FR 22760 at 22890 to 22891. However, all 
such testing should be designed using the most current technology 
available.
    Although the agency offers the above comments on clinical, in vivo, 
and in vitro testing as guidance, specific testing guidelines for 
upgrading ingredients to Category I are not included in this monograph. 
(See part II. paragraph A.2.--Testing of Category II and Category III 
conditions.) Instead, 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. (See also section I.M., 
comments 32 and 35.)
    The above discussion applies only to the testing required to 
upgrade OTC oral antiseptic ingredients from Categories II or III to 
Category I. In addition, the agency has tentatively concluded that 
final formulation testing of OTC oral antiseptic drug products is 
necessary. For a further discussion of such testing, see part II. 
paragraph B.10--Summary of the Agency's Changes.

References

    (1) OTC Vol. 130117, Docket No. 81N-0033, Dockets Management 
Branch.
    (2) OTC Vol. 130132, Docket No. 81N-0033, Dockets Management 
Branch.
    (3) OTC Vol. 130163, Docket No. 81N-0033, Dockets Management 
Branch.
    (4) Burnett, G. W., H. W. Scherp, and G. S. Schuster, ``Oral 
Microbiology and Infectious Disease,'' The Williams and Wilkins Co., 
Baltimore, 1976, p. 219.
    (5) Tortora, G. J., B. R. Funke, and C. L. Case, ``Microbiology, 
An Introduction,'' The Benjamin Cummings Publishing Co., Inc., 
Redwood City, CA, 1989, p. 502.
    34. Three comments disagreed with the Oral Cavity Panel's 
discussion concerning chlorhexidene as a standard for testing the 
effectiveness of oral antimicrobials. One comment stated that the use 
of chlorhexidene is inappropriate and unnecessary for this class of 
products and that the proposed guidelines for topically applied 
antiseptics for use on the skin do not include chlorhexidene as a 
standard. The second comment stated that the use of chlorhexidene as a 
standard is unreasonable because its usefulness is currently at issue, 
and the drug is not yet accepted as a safe and effective oral 
antiseptic. The third comment stated that chlorhexidine is unproven as 
a standard reference for pathogens responsible for the production of 
sore throat and sore mouth.
    The agency acknowledges that neither the tentative final monograph 
for OTC antimicrobial drug products (43 FR 1210) nor the amended 
tentative final monograph (now called OTC first aid antiseptic drug 
products) (56 FR 33644) includes chlorhexidene as a standard for 
topical antiseptics. However, since the comment was submitted, a 
chlorhexidene antiseptic mouthwash has been approved for oral use in 
the U.S. (Ref. 1).
    The Oral Cavity Panel's minority report recommended an in vitro 
test utilizing chlorhexidene as a standard and recommended that all 
antimicrobial oral products be compared to the standard (47 FR 22760 at 
22897). However, as discussed in section I.M., comment 32, the testing 
procedures recommended by the minority of the Panel are not being 
accepted by the agency for testing the active ingredients that are 
included in this segment of the oral health care drug products 
rulemaking.
    In its in vitro testing procedure for determining the effectiveness 
of oral antimicrobials, the majority of the Panel recommended the use 
of a positive standard control to validate the test procedure by 
assuring the consistent susceptibility of the test organisms. The 
Panel's majority report stated that ``chlorhexidene digluconate, 0.2 
percent in sterile water, is acceptable for this purpose,'' (47 FR 
22891). The agency does not agree with the Panel that chlorhexidine is 
an appropriate positive control for this purpose. Determining whether 
or not an organism is susceptible to chlorhexidine does not correlate 
to whether or not the organism is susceptible to the test ingredient. 
Furthermore, as discussed in prt II. paragraph B.10--Summary of the 
Agency's Changes, the agency is suggesting that the active ingredient, 
in a suitable inactive medium, be used as a positive control.

Reference

    (1) ``Physician's Desk Reference,'' 47th ed., Medical Economics 
Data, Montvale, NJ, 1993, pp. 1867-1868.
    35. Two comments stated that the Oral Cavity Panel's guidelines for 
testing topically applied antimicrobials (47 FR 22760 at 22890 to 
22893) should permit variations in the methods used. One comment 
mentioned that variations should be allowed depending on the ingredient 
being tested. As an example of an appropriate variation, the other 
comment suggested that a method that had been submitted to the Panel 
would provide adequate status of in vivo antimicrobial activity (Ref. 
1). The comment described that method as ``swabbing of the active 
ingredient three times using a template and comparing this to a 
control.''
    The agency is not including specific guidelines for upgrading 
active ingredients to Category I in this document. Instead, the agency 
will meet with industry representatives at their request to discuss 
testing protocols and, therefore, revisions may be made from time-to-
time. (See section I.E., comment 8; section I.G., comment 12; and 
section I.M., comment 33 for a discussion of appropriate testing 
procedures.)
    The agency notes that the procedure referred to by one comment 
calls for volunteer subjects with no symptoms of an oral disease state. 
The agency does not believe this procedure by itself will provide 
adequate proof of the in vivo effectiveness of an oral antiseptic.

Reference

    (1) OTC Vol. 130153.
    36. Referring to the Oral Cavity Panel's discussion of in vivo 
testing, two comments disagreed with the suggested protocol for the 
determination of an antimicrobial ingredient's adverse effect on wound 
healing (47 FR 22760 at 22892). The comment felt that the procedure 
described by the Panel would be impossible to control if there were 
only one wound in the mouth. Expressing the opinion that, in order to 
compare the rate of healing, a controlled study would require multiple 
wounds, of comparable size and depth, in comparable locations in the 
mouth, and at a comparable stage in the healing process, both comments 
considered it virtually impossible to find such a situation occurring 
naturally in human subjects. The comments agreed with the Panel that 
such a study could be done in animals, but felt that animal studies 
would be of little value because animals have different microbial 
populations than humans. One of the comments added that if a product 
does not have an excessively high degree of substantivity, the risks of 
retarding wound healing are limited and such tests are unwarranted.
    The agency agrees with the comments that it would be almost 
impossible to find a representative population of human subjects with 
multiple mouth wounds so that one wound could serve as a test site and 
another as a control site in the same subject. However, the agency 
believes that the Panel was referring to a ``controlled study'' as one 
in which a population of subjects with comparable wounds is divided 
into a group that is treated with the test ingredient and a group that 
receives a control, such as the vehicle lacking the test ingredient. In 
the Panel's discussion of general considerations applying to the 
testing for recategorization of Category III oral health care 
ingredients (47 FR 22760 at 22782 to 22783), the design for a 
controlled study is described as one in which subjects who have similar 
conditions are divided into a treated group and a placebo group. In the 
discussion cited by the comments (47 FR 22891), the Panel stated that 
control groups should receive treatment with inert vehicles that are 
identical in appearance, color, and consistency to the test materials. 
The agency believes that the general principles stated above can be 
coordinated so that well-controlled studies to investigate the adverse 
effects of oral health care antimicrobial ingredients on wound healing 
could be designed according to the Panel's recommendations.
    The agency disagrees with the comments' belief that animal studies 
are of little value and concurs with the Panel's position on animal 
studies. Although believing that the final appraisal of an oral 
antiseptic must be done by clinical trials, the Panel recommended that 
in vivo testing, including animal and human models, should be performed 
prior to clinical studies (47 FR 22891). The agency agrees that an 
initial assessment of safety and effectiveness of a drug should be made 
using animal models before the test formulation is given to humans in a 
controlled clinical study.
    However, the agency does not believe that further wound healing 
studies are necessary for OTC oral antiseptic ingredients. As part of 
the rulemaking for OTC topical antiseptic drug products, the agency has 
reviewed many studies designed to show the effect of antiseptic 
ingredients on wound healing. The agency's conclusions on these data 
are stated in the tentative final monograph for OTC first aid 
antiseptic drug products (56 FR 33644 at 33658, 33660, and 33662). 
Several of the first aid antiseptic ingredients for which wound healing 
studies were submitted are also classified as Category III oral 
antiseptic ingredients, i.e., benzalkonium chloride, iodine, and 
povidone-iodine. The submitted studies show that these antiseptic 
ingredients do not delay wound healing when used for a short period of 
time, i.e., 7 days, on limited areas of the body. The agency believes 
that these wound healing data are also relevant to oral antiseptic 
ingredients that are limited to a maximum of 7 days of use on the 
affected area of the mouth and throat. The Panel was concerned about 
the lack of data on possible adverse effects on the oral mucosa 
resulting from the use of oral antiseptic drug products on a daily 
basis for months at a time (47 FR 22760 at 22834). However, the agency 
is proposing labeling limiting self-medication with these products to a 
7-day period for relief of the symptoms of sore mouth. (See section 
I.K., comment 25.) In addition, the oral antiseptic ingredients are 
used in lower concentrations than the first aid antiseptic ingredients 
and are in contact with the affected area for a shorter time period 
following application. This occurs because the oral antiseptic 
ingredients are mixed with the saliva of the mouth and then 
expectorated. Therefore, oral antiseptic ingredients would not be 
expected to delay wound healing. For the above reasons, the agency 
concludes that additional studies to demonstrate that oral antiseptic 
ingredients do not delay wound healing are unnecessary. Further, 
according to 21 CFR 310.534(b), any OTC drug product that is labeled, 
represented, or promoted for use as an oral wound healing agent (e.g., 
``promotes wound healing'') is regarded as a new drug, and an approved 
application is required before marketing.
    37. One comment stated that the Oral Cavity Panel's recommended 
studies to prove that antiseptic mouthwashes aid in the treatment of 
sore mouth and sore throat are not feasible for the following reasons: 
(1) It is not feasible to attempt to collect enough data in any 
reasonable period of time from volunteers who have symptoms of a sore 
throat or sore mouth due to the unique infection with a single pathogen 
in order to prove specific activity of an antibacterial agent (47 FR 
22760 at 22779); (2) Koch's Postulates would be virtually impossible to 
fulfill because proof of the presence of the offending etiologic agent 
specifically responsible for the sore mouth/sore throat, in addition to 
correlation of relief of symptoms of sore mouth/sore throat with a 
decrease or elimination of the etiologic agent, could of itself be 
impossible to achieve; (3) complementary animal studies simulating 
these symptoms would be difficult to perform without the introduction 
of a systemic pathogen and, under these circumstances, the natural 
conditions specified as a prerequisite for proof of efficacy could not 
be approximated (47 FR 22890); (4) the test organisms originally 
approved by the Panel to demonstrate antimicrobial activity (the Bahn 
test), Streptococcus mutans, Actinomyces viscosus, C. albicans and 
optionally, Pseudomonas aeruginosa, have no precedent for use as test 
organisms for antibacterial activity relating to production of symptoms 
of sore mouth or sore throat; and (5) such studies must by necessity 
avoid the use of any systemic antimicrobial agent and would obviously 
create a situation which is not only medically unsound but also 
unethical.
    In its discussion of the data required for the evaluation of oral 
antiseptic ingredients (47 FR 22760 at 22890 to 22893), the Oral Cavity 
Panel recommended general principles applicable to the design of 
experimental protocols for demonstrating the safety and efficacy of 
these ingredients. The Panel did not consider its recommendations for 
testing the effectiveness of these ingredients to be mandatory 
requirements, but presented its recommendations merely to indicate the 
types of data it considered necessary and to provide suggestions for 
obtaining such data. The agency is adopting this approach and treating 
the Panel's recommendations as guidelines for obtaining data to upgrade 
Category II or Category III ingredients to Category I. However, in this 
tentative final monograph, the agency is proposing testing procedures 
for final formulations containing Category I oral antiseptics. (See 
section I.M., comments 32 and 35.)
    The Panel recognized that it would be impossible to propose a 
single general protocol because of the diverse etiology of oral 
inflammation. The Panel recommended that the data obtained in support 
of Category I status for oral antiseptic ingredients show that 
preparations applied to the mucous membranes of the mouth and throat 
act topically and relieve symptoms caused by an infection by reducing 
pathogenic microbial populations (47 FR 22760 at 22890), but it also 
recognized that appropriate individual tests must be devised to 
demonstrate this for a particular ingredient and that the 
responsibility of selecting or devising reliable methods for procuring 
acceptable evidence of the effectiveness of an ingredient rests with 
the manufacturer sponsoring the product.
    The agency is, however, proposing testing procedures for OTC oral 
antiseptic final formulations in Sec. 356.90 of this tentative final 
monograph. In those testing procedures, the agency is accepting the 
Panel's recommendations regarding the use of S. mutans, A. viscosus, 
and C. albicans as test organisms. (See Part II. paragraph B.10--
Summary of the Agency's Changes.) These organisms are representative of 
organisms commonly found in the oral cavity. The agency believes that a 
decrease in the number of these organisms in the proposed in vitro 
testing procedures indicates that the final formulation of a product 
has not decreased the effectiveness of a Category I oral antiseptic.

II. The Agency's Tentative Conclusions and Adoption of the Panel's 
Report

A. Summary of Ingredient Categories and Testing of Category II and 
Category III Conditions

1. Summary of Ingredient Categories.
    The agency has reviewed all claimed active ingredients submitted to 
the Oral Cavity Panel, as well as other data and information available 
at this time, and has made one change in the categorization of oral 
antiseptic ingredients recommended by the Panel. As a convenience to 
the reader, the following list is included as a summary of the 
categorization of oral antiseptic ingredients recommended by the Panel 
and the proposed categorization by the agency.

------------------------------------------------------------------------
   Antiseptic Active                                                    
      Ingredients                 Panel                   Agency        
------------------------------------------------------------------------
Alcohol                  III....................  III                   
Benzalkonium chloride    III....................  III                   
Benzethonium chloride    III....................  III                   
Benzoic acid             III....................  III                   
Boric acid               II.....................  II                    
Boroglycerin             II.....................  II                    
Camphor                  II.....................  II                    
Carbamide peroxide in    III....................  III                   
 anhydrous glycerin                                                     
Cetalkonium chloride     III....................  III                   
Cetylpyridinium          III....................  III                   
 chloride                                                               
Chlorophyllin copper     III....................  III                   
 complex                                                                
Cresol                   II.....................  II                    
Dequalinium chloride     III....................  III                   
Domiphen bromide         III....................  III                   
Eucalyptol               III....................  III                   
Ferric chloride          II.....................  II                    
Gentian violet           III....................  II                    
Hydrogen peroxide        III....................  III                   
Iodine                   III....................  III                   
Menthol                  III....................  III                   
Meralein sodium          II.....................  II                    
Methyl salicylate        III....................  III                   
Nitromerso               lII....................  II                    
Oxyquinoline             III....................  III                   
Phenol preparations      III....................  III                   
 (phenol and/or                                                         
 phenolate sodium)                                                      
Potassium chlorate       II.....................  II                    
Povidone-iodine          III....................  III                   
Secondary                III....................  III                   
 amyltricresols                                                         
Sodium caprylate         III....................  III                   
Sodium dichromate        II.....................  II                    
Thymol preparations      III....................  III                   
 (thymol and thymol                                                     
 iodide)                                                                
Tincture of myrrh        II.....................  II                    
Tolu balsam              III....................  III                   
------------------------------------------------------------------------

2. Testing of Category II and Category III Conditions.
    The Oral Cavity Panel recommended testing guidelines for OTC oral 
health care antimicrobial drug products (47 FR 22760 at 22890 to 
22893). The agency's position regarding these testing guidelines is 
discussed in Part I, paragraph E of this document. Interested persons 
may communicate with the agency about the submission of data and 
information to demonstrate the safety or effectiveness of any OTC oral 
antiseptic active ingredient or condition included in the review by 
following the procedures outlined in the agency's policy statement 
published in the Federal Register of September 29, 1981 (46 FR 47740) 
and clarified April 1, 1983 (48 FR 14050). That policy statement 
includes procedures for the submission and review of proposed 
protocols, agency meetings with industry or other interested persons, 
and agency communications on submitted test data and other information.

B. Summary of the Agency's Changes

    FDA has considered the comments and other relevant information and 
concludes that it will tentatively adopt the antiseptic section of the 
Oral Cavity Panel's report and recommended monograph with the changes 
described in FDA's responses to the comments above and with other 
changes described in the summary below. A summary of the changes made 
by the agency follows.
    1. In order to be consistent with terminology used in the 
rulemaking for OTC topical antiseptic drug products, the agency is 
proposing to replace the Panel's term ``antimicrobial'' with the term 
``antiseptic'' in this tentative final monograph. (See section I.A., 
comment 1.)
    2. 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 to add definitions for the terms ``antiseptic drug'' and 
``oral antiseptic'' to Sec. 356.3 of this tentative final monograph. 
(See section I.K., comment 20.)
    3. The Oral Cavity Panel concluded that gentian violet was safe for 
use in the oral cavity, but that there were insufficient data available 
to permit final classification of its effectiveness as an oral 
antiseptic (47 FR 22760 at 22873 to 22875). The Panel based its safety 
determination on several factors: (1) the oral LD50 of gentian 
violet in mice and rats is 1.2 to 10 g/kg; (2) it is nontoxic when 
applied to the mucous membrane and skin; and (3) gentian violet has 
been used orally in both children and adults as an anthelmintic. 
However, the Panel noted that when gentian violet is ingested, it may 
cause nausea, vomiting, diarrhea, and lassitude, and that intravenous 
injection of impure preparations may produce a severe shock-like 
reaction.
    Regarding the use of gentian violet as an anthelmintic, in its 
report on OTC anthelmintic drug products published in the Federal 
Register of September 9, 1980 (45 FR 59540), the Miscellaneous Internal 
Panel reviewed the information available to it regarding the safety of 
gentian violet and acknowledged both a scarcity of acute toxicity data 
and ``a high incidence of undesirable side effects associated with its 
clinical use in children.'' That Panel also reviewed reports regarding 
the potential carcinogenicity of gentian violet and recommended ``that 
further testing be performed to resolve the carcinogenic concerns.'' 
According to the Miscellaneous Internal Panel, these concerns were not 
convincing when weighed against the lack of adverse effects reported 
during the long marketing history of gentian violet. Thus, that Panel 
concluded that gentian violet was safe when used as directed. FDA, 
however, reviewed the available data relevant to the genetic toxicity 
of gentian violet and stated in its preamble to the Panel's report on 
OTC anthelmintic drug products that a definitive conclusion regarding 
the carcinogenic activity of gentian violet could not be reached at 
that time. On the basis of the available evidence, the agency nominated 
gentian violet for study in the NTP. The agency concluded that the 
potential risk of using gentian violet as an oral anthelmintic 
outweighed the benefits and announced its intent to classify gentian 
violet in Category II in the tentative final monograph for OTC 
anthelmintic drug products (45 FR 49540).
    In that tentative final monograph published in the Federal Register 
of August 24, 1982 (47 FR 37062 at 37063), the agency further discussed 
the genetic toxicity of gentian violet, and reaffirmed its earlier 
conclusions regarding the safety of gentian violet. In that proposal, 
gentian violet was classified in Category II as an oral anthelmintic. 
In the final rule published in the Federal Register of August 1, 1986 
(51 FR 27756 at 27758), the agency determined that gentian violet is a 
nonmonograph drug for OTC anthelmintic use.
    In a proposed rule published in the Federal Register of February 
13, 1990 (55 FR 5194) regarding the safety of gentian violet in animal 
feed, FDA discussed the National Center for Toxicology Research's 
(NCTR) series of studies that provide additional new information on the 
toxicity and carcinogenicity of gentian violet. One lifetime study 
(chronic study) showed gentian violet to be a carcinogen in mice. 
Another lifetime study in rats also resulted in a carcinogenic 
response. A residue study showed that residues of gentian violet 
occurred in the edible tissues of chickens after they were administered 
gentian violet. Reproductive-teratology studies were negative or 
inconclusive. A multigeneration study in rats showed a lower body 
weight, a dose-related necrosis in the thymus, and a dose-related 
effect on the kidneys in females. However, a pairwise statistical 
evaluation of these parameters was not performed. Metabolism studies in 
rats and mice showed that orally administered gentian violet is 
absorbed, with the highest residue levels of the compound and its 
metabolites occurring in fat and liver. The proposal also discussed the 
results of an extensive search of the published literature relevant to 
the safety of gentian violet (55 FR 5194 at 5200).
    The agency concluded that even if the chronic studies that had been 
performed by NCTR did not establish that gentian violet is an animal 
carcinogen, they did not establish that gentian violet is safe. There 
is a paucity in the scientific literature of the kind of studies that 
are needed to support an expert opinion that gentian violet is 
generally recognized as safe. In fact, FDA's literature survey 
generally found that gentian violet tends to have mutagenic, genotoxic, 
and other toxic properties. FDA believes where such incriminating 
studies exist, experts generally agree that chronic studies must 
affirmatively show that the substance does not cause cancer before it 
can be recognized as safe (55 FR 5194 at 5201). The agency concluded 
that gentian violet is not generally recognized as safe for use in 
animal feed or as a food additive. The agency also concluded that 
gentian violet for veterinary drug use in food animals is not generally 
recognized as safe and effective and is a new animal drug (55 FR 5201).
    In the Federal Register of August 15, 1991 (56 FR 40502), the 
agency issued a final rule amending its regulations (21 CFR 500.29) to 
declare that gentian violet is neither generally recognized as safe nor 
prior sanctioned and is a food additive when added to animal feed for 
any nondrug use. The agency also amended its regulations (21 CFR 
500.30) to reflect its determination that gentian violet is not 
generally recognized as safe, not generally recognized as effective, or 
not ``grandfathered'' under the Drug Amendments of 1962 (Pub. L. 87-
781). Therefore, gentian violet is a new animal drug when used for any 
veterinary drug purpose in food animals.
    Based on the above, the agency concludes that gentian violet is not 
safe for use as an oral antiseptic. Therefore, in this tentative final 
monograph, the agency is reclassifying gentian violet from Category III 
to Category II.
    4. The agency believes that the safety data evaluated by the Panel 
are sufficient to conclude that cetylpyridinium chloride, domiphen 
bromide, and povidone-iodine are safe for use as OTC oral antiseptics 
when labeled for short-term use (not to exceed 7 days). However, there 
are insufficient data to demonstrate the effectiveness of these 
ingredients, and they are classified in Category III. (See section 
I.E., comments 8 and 9; section I.G., comments 12 and 13; and section 
I.I., comments 15 and 16.)
    5. The agency is proposing the following combinations in 
Sec. 356.26 (and labeling for these combinations in Sec. 356.66): (1) 
oral antiseptic and oral anesthetic/analgesic; (2) oral antiseptic and 
oral astringent; (3) oral antiseptic and oral demulcent; (4) oral 
antiseptic and oral mucosal protectant; (5) oral antiseptic, oral 
anesthetic/analgesic, and oral astringent; (6) oral antiseptic, oral 
anesthetic/analgesic, and oral demulcent; and (7) oral antiseptic, oral 
anesthetic/analgesic, and oral mucosal protectant. (See section I.L., 
comment 29.)
    6. The agency is proposing to revise the statement of identity in 
Sec. 356.51(a) of the Panel's recommended monograph (and including the 
revised statement in Sec. 356.64(a) of this tentative final monograph) 
as follows: ``The labeling of the product contains the established name 
of the drug, if any, and identifies the product as an `oral 
antiseptic,' or an `antiseptic' (select one of the following: `rinse,' 
`gargle,' or `rinse and gargle').'' (See section I.K., comments 20 and 
21.)
    7. The agency is proposing the following indication in 
Sec. 356.64(b) of this tentative final monograph: ``First aid to help'' 
(select one of the following: ``prevent,'' (``decrease'' (``the risk 
of'' or ``the chance of'')), (``reduce'' (``the risk of'' or ``the 
chance of'')), ``guard against,'' or ``protect against'') (select one 
of the following: ``infection'' or ``bacterial contamination'') ``in'' 
(select any of the following: ``minor cuts,'' ``minor scrapes,'' or 
``minor oral irritation'') (which may be followed by) ``caused by'' 
(select any of the following: ``dental procedures,'' ``dentures,'' 
``orthodontic appliances,'' or ``accidental injury''). (See section 
I.K., comment 22.)
    8. The agency is proposing to replace the Panel's recommended 
warnings in Sec. 356.51(c)(1)(i) and (c)(1)(ii) with the following 
warning found in Sec. 356.64(c) of this document: ``Do not use this 
product for more than 7 days unless directed by a dentist or doctor. If 
sore mouth symptoms do not improve in 7 days, if irritation, pain, or 
redness persists or worsens, or if swelling, rash, or fever develops, 
see your dentist or doctor promptly.'' (See section I.K., comment 25.)
    9. The agency is proposing professional labeling in Sec. 356.80 for 
the use of povidone-iodine as a dental preoperative preparation by 
health care professionals. (See section I.K., comment 27.)
    10. The agency has determined that, because the final formulation 
of an oral antiseptic drug product can affect the effectiveness of the 
active ingredient, final formulation testing of oral health care 
antiseptic drug products is necessary. Therefore, the agency is 
proposing final formulation testing procedures be included in this 
tentative final monograph. These testing procedures are being put forth 
for comment in this document.
    The Panel recommended that evidence be submitted to verify that 
each antiseptic ingredient is released from its vehicle when applied to 
mucous membranes, but it did not include final formulation testing 
procedures for OTC oral antiseptics in its recommended monograph (47 FR 
22760 at 22890). The agency, however, is aware that the final 
formulation of an oral health care drug product can affect the activity 
of an antiseptic ingredient included in that product. Therefore, in 
keeping with the final formulation testing procedures proposed for 
first aid antiseptic drug products (i.e., those applied to the skin) 
(56 FR 33644 at 33673) and those that will be proposed for health care 
antiseptic drug products (e.g., surgical scrubs) in a future issue of 
the Federal Register, the agency is proposing procedures for testing 
the final formulations of oral health care antiseptic drug products in 
this tentative final monograph. These testing procedures are based upon 
the in vitro effectiveness testing procedures recommended by the Oral 
Cavity Panel (47 FR 22760 at 22890 to 22893) and the first aid 
antiseptic testing procedures proposed by the agency in Sec. 333.70 of 
the tentative final monograph for OTC first aid antiseptic drug 
products (56 FR 33644 at 33673). In general, the proposed testing 
procedures for first aid antiseptic drug products have been modified to 
account for the different test organisms required for testing the 
effectiveness of oral antiseptics. The agency has also taken into 
account all comments pertaining to the Oral Cavity Panel's recommended 
in vitro testing guidelines. (See section I.M., comments 34 and 35.)
    In the testing procedures included in the tentative final monograph 
for OTC first aid antiseptic drug products, the agency proposed in 
Sec. 333.70(b)(2)(i) and (b)(2)(ii) a ``neutralizer inactivation of 
antiseptic test'' and a ``neutralizer effect on bacterial viability 
test'' (56 FR 33644 at 33678 and 33679). Differences in microbial plate 
counts greater than 20 percent between test and control cultures 
require that the overall test results be discarded. Based upon new 
information, the agency is concerned that a 20-percent difference in 
microbial plate counts might be too restrictive. There is a relatively 
large inherent variation in microbial plate counts. In addition, 
because the criterion for fulfilling the requirements of the overall 
testing procedures is a 3-log10 reduction in viable organisms 
(i.e., 99.9 percent), the agency now questions whether a 1-log10 
(i.e., 90 percent) difference might not be a more reasonable criterion 
for the differences in microbial plate counts for the neutralizer 
tests. Although the agency is proposing the 20-percent criterion in 
this tentative final monograph for consistency with the OTC first aid 
antiseptic tentative final monograph, the agency requests comment on 
this matter.
    In addition, in Sec. 333.70(c)(5) of the OTC first aid antiseptic 
tentative final monograph, the agency proposed a ``test organism 
antiseptic resistance test'' in which the test organisms' resistance to 
phenol is determined in order to ensure that the resistance of each 
organism to antiseptics has not changed (56 FR 33679). The Oral Cavity 
Panel recommended that a 0.2-percent chlorhexidine gluconate solution 
be used as a positive control to assure the consistent susceptibility 
of the test organisms (47 FR 22760 at 22891). However, the agency 
believes that determining an organism's resistance or lack of 
resistance to phenol or chlorhexidine gluconate has no bearing upon 
whether or not that organism's susceptibility to a particular test 
ingredient has changed. The mechanism of action of the test antiseptic 
may be quite different than that of phenol or chlorhexidine gluconate. 
Because the ``test organism antiseptic resistance test'' is designed to 
demonstrate that the active ingredient is still active in the specific 
formulation under test, and the active ingredient has presumably 
already been shown to have in vitro and in vivo antiseptic activity by 
itself, the proper control is the active ingredient alone. Therefore, 
the agency is suggesting that the active ingredient, in a suitable 
inactive medium, be used as a positive control.
    The complete testing procedures are included in Sec. 356.90 of this 
tentative final monograph. The agency invites specific comment at this 
time on the final formulation testing procedures proposed in this 
document. After reviewing any submitted comments or data, the agency 
may revise the testing procedures prior to establishing a final 
monograph. The agency also recognizes that the testing procedures may 
need to be revised periodically as newer techniques are developed and 
proven adequate.
    11. For an active ingredient to be included in an OTC drug final 
monograph, in addition to information demonstrating safety and 
effectiveness, it is necessary to have publicly available sufficient 
chemical information that can be used by all manufacturers to determine 
that the ingredient is appropriate for use in their products. Only some 
of the oral antiseptic active ingredients that the Panel evaluated are 
standardized and characterized for quality and purity and are included 
in official compendia. Alcohol, benzalkonium chloride, benzethonium 
chloride, benzoic acid, boric acid, camphor, carbamide peroxide, 
cetylpyridinium chloride, cresol, gentian violet, hydrogen peroxide, 
iodine, menthol, methyl salicylate, nitromersol, oxyquinoline sulfate, 
phenol, povidone-iodine, tolu balsam, and thymol are currently included 
as articles in the U.S.P. (Ref. 1). The remaining oral antiseptic 
active ingredients are not adequately characterized and would need to 
be if data are submitted to upgrade them to monograph status.
    The agency believes that it would be appropriate for parties 
interested in upgrading nonmonograph ingredients to monograph status to 
develop with the United States Pharmacopoeial Convention appropriate 
standards for the quality and purity of any of these ingredients that 
are not already included in official compendia. Should appropriate 
standards fail to be established, ingredients otherwise eligible for 
monograph status will not be included in the final monograph.

Reference

    (1) ``United States Pharmacopeia XXII--National Formulary 
XVII,'' United States Pharmacopeial Convention, Inc., Rockville, MD, 
pp. 34, 146, 149, 219-220, 223, 268, 605, 663, 703-703, 821-822, 
954, 1061, 1119, 1390, 1904-1905, 1906, 1921-1922, 1947-1948, 1955, 
1991, 1989.
    The agency has examined the economic consequences of this proposed 
rulemaking and has determined that it does not require either a 
regulatory impact analysis, as specified in Executive Order 12866, or a 
regulatory flexibility analysis, as defined in the Regulatory 
Flexibility Act (Pub. L. 96-354). This rulemaking for OTC oral 
antiseptic drug products is not expected to have an impact on small 
businesses.
    This proposed rule does not include any Category I ingredients. 
Some ingredients are in Category II (not generally recognized as safe 
and effective), but most are in Category III (more data needed to 
establish safety and effectiveness). If data are not submitted to 
upgrade these ingredients to monograph status, OTC products containing 
oral antiseptics will not bepermitted to display antiseptic drug claims 
in labeling. However, most of these products could remain in the 
marketplace. After relabeling, many products could be marketed as 
cosmetics; others could be marketed as OTC oral wound cleansing drug 
products. After reformulation and relabeling, a few products could be 
sold as OTC oral anesthetic/analgesics. Many OTC products containing 
oral antiseptics are labeled for use to reduce or prevent the 
accumulation of dental plague. Unless a safety concern arises, such 
products may remain on the market until the agency's evaluation of 
antiplaque and antiplaque-related products is completed.
    The impact of the proposed rule, if implemented, appears to be 
minimal. Therefore, the agency concludes that the proposed rule is not 
a major rule as defined in Executive Order 12866. Further, the agency 
certifies that this proposed rule, if implemented, will not have a 
significant economic impact on a substantial number of small entities 
as defined in the Regulatory Flexibility Act.
    The agency invited public comment in the advance notice of proposed 
rulemaking regarding any impact that this rulemaking would have on OTC 
oral antiseptic drug products. No comments on economic impacts were 
received.
    The agency invites public comment regarding any substantial or 
significant economic impact that this rulemaking would have on OTC oral 
antiseptic drug products. Comments regarding the impact of this 
rulemaking should be accompanied by appropriate documentation. The 
agency will evaluate any comments and supporting data that are received 
and will reassess the economic impact of this rulemaking in the 
preamble to the final rule.

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

    Interested persons may, on or before August 8, 1994, submit to the 
Dockets Management Branch (address above) written comments, objections, 
or requests for oral hearing before the Commissioner on the proposed 
regulation. A request for an oral hearing must specify points to be 
covered and time requested. Written comments on the agency's economic 
impact determination may be submitted on or before August 8, 1994. 
Three copies of all comments, objections, and requests are to be 
submitted, except that individuals may submit one copy. Comments, 
objections, and requests are to be identified with the docket number 
found in brackets in the heading of this document and may be 
accompanied by a supporting memorandum or brief. Comments, objections, 
and requests may be seen in the office above between 9 a.m. and 4 p.m., 
Monday through Friday. Any scheduled oral hearing will be announced in 
the Federal Register.

    Interested persons, on or before February 9, 1995, may also submit 
in writing new data demonstrating the safety and effectiveness of those 
conditions not classified in Category I. Written comments on the new 
data may be submitted on or before April 10, 1995. These dates are 
consistent with the time periods specified in the agency's final rule 
revising the procedural regulations for reviewing and classifying OTC 
drugs, published in the Federal Register of September 29, 1981 (46 FR 
47730). Three copies of all data and comments on the data are to be 
submitted, except that individuals may submit one copy, and all data 
and comments are to be identified with the docket number found in 
brackets in the heading of this document. Data and comments should be 
addressed to the Dockets Management Branch. Received data and comments 
may also be seen in the office above between 9 a.m. and 4 p.m., Monday 
through Friday.

    In establishing a final monograph, the agency will ordinarily 
consider only data submitted prior to the closing of the administrative 
record on (insert date 14 months after date of publication in the 
Federal Register). Data submitted after the closing of the 
administrative record will be reviewed by the agency only after a final 
monograph is published in the Federal Register, unless the Commissioner 
finds good cause has been shown that warrants earlier consideration.

List of Subjects in 21 CFR Part 356

    Labeling, Over-the-counter drugs.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 356 (as proposed in the Federal Register of 
May 25, 1982 (47 FR 22760), the Federal Register of January 27, 1988 
(53 FR 2436), and the Federal Register of September 24, 1991 (56 FR 
48302)) be amended as follows:

PART 356--ORAL HEALTH CARE DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN 
USE

    1. The authority citation for 21 CFR part 356 continues to read as 
follows:

    Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 
355, 360, 371).

    2. Section 356.3 is amended by adding new paragraphs (m) and (n) to 
read as follows:

Sec. 356.3  Definitions.

* * * * *

    (m) 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.''

    (n) 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.

    3. New Sec. 356.11 is added to subpart B to read as follows:

 Sec. 356.11  Antiseptics.

    Povidone-iodine provided to health professionals (but not to the 
general public).
    4. Section 356.26 is amended by adding new paragraphs (i), (j), 
(k), (l), (m), (n), and (o) to read as follows:

 Sec. 356.26  Permitted combinations of active ingredients.

* * * * *
    (i) Any single oral antiseptic active ingredient identified in 
Sec. 356.11 may be combined with any single oral anesthetic/analgesic 
active ingredient identified in Sec. 356.12.
    (j) Any single oral antiseptic active ingredient identified in 
Sec. 356.11 may be combined with any single oral astringent active 
ingredient identified in Sec. 356.14.
    (k) Any single oral antiseptic active ingredient identified in 
Sec. 356.11 may be combined with any single oral demulcent active 
ingredient identified in Sec. 356.18.
    (l) Any single oral antiseptic active ingredient identified in 
Sec. 356.11 may be combined with any single oral mucosal protectant 
active ingredient identified in Sec. 356.20.
    (m) Any single oral antiseptic active ingredient identified in 
Sec. 356.11 may be combined with any single oral anesthetic/analgesic 
active ingredient identified in Sec. 356.12 and any single oral 
astringent active ingredient identified in Sec. 356.14.
    (n) Any single oral antiseptic active ingredient identified in 
Sec. 356.11 may be combined with any single oral anesthetic/analgesic 
active ingredient identified in Sec. 356.12 and any single oral 
demulcent active ingredient identified in Sec. 356.18.
    (o) Any single oral antiseptic active ingredient identified in 
Sec. 356.11 may be combined with any single oral anesthetic/analgesic 
active ingredient identified in Sec. 356.12 and any single oral mucosal 
protectant active ingredient identified in Sec. 356.20.

    5. New Sec. 356.64 is added to subpart C to read as follows:

 Sec. 356.64  Labeling of oral antiseptic drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as an 
``oral antiseptic,'' or an ``antiseptic'' (select one of the following: 
``rinse,'' ``gargle,'' or ``rinse and gargle'').
    (b) Indications. The labeling of the product states, under the 
heading ``Indications,'' the following: ``First aid to help'' (select 
one of the following: ``prevent,'' (``decrease'' (``the risk of'' or 
``the chance of'')), (``reduce'' (``the risk of'' or ``the chance 
of'')), ``guard against,'' or ``protect against'') (select one of the 
following: ``infection'' or ``bacterial contamination'') ``in'' (select 
any of the following: ``minor cuts,'' ``minor scrapes,'' or ``minor 
oral irritation'') (which may be followed by) ``caused by'' (select any 
of the following: ``dental procedures,'' ``dentures,'' ``orthodontic 
appliances,'' or ``accidental injury'').
    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings'': ``Do not use this product for 
more than 7 days unless directed by a dentist or doctor. If sore mouth 
symptoms do not improve in 7 days, if irritation, pain, or redness 
persists or worsens, or if swelling, rash, or fever develops, see your 
dentist or doctor promptly.''
    (d) Directions. [Reserved]

    6. Section 356.66 is amended by adding new paragraphs (b)(3), 
(b)(4), (b)(5), (b)(6), (b)(7), (b)(8), (b)(9), (c)(1), (c)(2), (c)(3), 
and (c)(4) to read as follows:

 Sec. 356.66  Labeling of combination drug products.

* * * * *
    (b) * * *
    (3) For permitted combinations identified in Sec. 356.26(i). In 
addition to any or all of the indications in Sec. 356.64(b), any or all 
of the indications in Sec. 356.52(b)(3), (b)(4), and (b)(5) should be 
used.
    (4) For permitted combinations identified in Sec. 356.26(j). In 
addition to any or all of the indications in Sec. 356.64(b), the 
following indication for oral astringent active ingredients should be 
used: ``For temporary relief of occasional minor irritation, pain, and 
sore mouth.''
    (5) For permitted combinations identified in Sec. 356.26(k). In 
addition to any or all of the indications in Sec. 356.64(b), the 
following indication for oral demulcent active ingredients should be 
used: ``For temporary relief of minor discomfort and protection of 
irritated areas in sore mouth.''
    (6) For permitted combinations identified in Sec. 356.26(l). In 
addition to any or all of the indications in Sec. 356.64(b), any or all 
of the indications in Sec. 356.60(b)(1), (b)(2), and (b)(3) should be 
used.
    (7) For permitted combinations identified in Sec. 356.26(m). In 
addition to any or all of the indications in Sec. 356.64(b), any or all 
of the indications in Sec. 356.52(b)(3), (b)(4), and (b)(5) should be 
used. The following indication for oral astringent active ingredients 
should be used: ``For temporary relief of occasional minor irritation, 
pain, and sore mouth.''
    (8) For permitted combinations identified in Sec. 356.26(n). In 
addition to any or all of the indications in Sec. 356.64(b), any or all 
of the indications in Sec. 356.52(b)(3), (b)(4), and (b)(5) should be 
used. The following indication for oral demulcent active ingredients 
should be used: ``For temporary relief of minor discomfort and 
protection of irritated areas in sore mouth.''
    (9) For permitted combinations identified in Sec. 356.26(o). In 
addition to any or all of the indications in Sec. 356.64(b), any or all 
of the indications in Sec. 356.52(b)(3), (b)(4), and (b)(5) and in 
Sec. 356.60(b)(1), (b)(2), and (b)(3) should be used.
    (c) * * *
    (1) For permitted combinations identified in Sec. 356.26(i). In 
addition to the warnings in Sec. 356.64(c), the warnings in 
Sec. 356.52(c)(2), (c)(3), and (c)(4), if applicable, should be used.
    (2) For permitted combinations identified in Sec. 356.26(j). The 
warnings in Sec. 356.64(c) should be used.
    (3) For permitted combinations identified in Sec. 356.26(k). The 
warnings in Sec. 356.64(c) should be used.
    (4) For permitted combinations identified in Sec. 356.26(k). In 
addition to the warnings in Sec. 356.64(c), the warnings in 
Sec. 356.52(c)(2), (c)(3), and (c)(4), if applicable, should be used.

    7. Section 356.80 is amended by adding new paragraph (d) to read as 
follows:

 Sec. 356.80  Professional labeling.

* * * * *
    (d) The labeling of aqueous products containing povidone-iodine 
identified in Sec. 356.11 provided to health professionals (but not to 
the general public) may contain the following:
    (1) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as an 
``oral antiseptic,'' or an ``antiseptic'' (select one of the following: 
``rinse,'' ``gargle,'' or ``rinse and gargle'').
    (2) Indications. The labeling of the product states under the 
heading ``Indications,'' the following: ``For preparation of the oral 
mucosa prior to injection, dental surgery, or tooth extraction.''
    (3) Directions. The labeling of the product contains the following 
information under the heading ``Directions:'' For products containing 
povidone-iodine identified in Sec. 356.11, the final product to be 
applied is a 0.5 percent aqueous solution. Manufacturers may also 
market a more concentrated solution provided that it contains adequate 
directions to dilute the product to a 0.5 percent aqueous solution. 
``Apply 10 to 20 milliliters of solution to the operative site. 
Instruct the patient to rinse for 30 seconds and then spit out. Wait 2 
minutes, and apply another 10 to 20 milliliters of solution to the 
operative site. Instruct the patient to rinse again for 30 seconds and 
then spit out. With a standard syringe and a blunt, angulated needle, 
irrigate the operative site and the surrounding gingival mucosa for 1 
minute with 10 to 20 milliliters of the solution. Instruct the patient 
to spit out the solution after the irrigation procedure.''
    8. New subpart D consisting of Sec. 356.90 is added to read as 
follows:

Subpart D--Final Formulation Testing Procedures


 Sec. 356.90  Testing of oral antiseptic drug products.

    An oral antiseptic drug product in a form suitable for topical 
application will be recognized as effective if it contains an active 
ingredient included in Sec. 356.11 and if, at its lowest recommended 
use concentration, it decreases the number of bacteria per milliliter 
in Streptococcus mutans (ATCC No. 25175), Actinomyces viscosus (ATCC 
No. 19246), and Candida albicans (ATCC No. 18804) cultures (available 
from American Type Culture Collection (ATCC), 12301 Parklawn Dr., 
Rockville, MD 20852) by 3 log10  within 10 minutes at 37  deg.C in 
the presence of 10 percent serum in vitro. Oral antiseptic drug 
products must meet the specified requirements when tested in accordance 
with the following procedures unless a modification is approved as 
specified in paragraph (e) of this section.
    (a) Laboratory facilities, equipment, and serum reagent--(1) 
Laboratory facilities. To prevent the contamination of test 
microorganism cultures with extraneous microorganisms, perform the test 
using aseptic techniques in an area as free from contamination as 
possible. Because test cultures of microorganisms may be adversely 
affected by exposure to ultraviolet light or chemicals in aerosols, do 
not test under direct exposure to ultraviolet light or in areas under 
aerosol treatment. Do environmental tests to assess the suitability of 
the testing environment frequently enough to assure the validity of 
test results.
    (2) Equipment. Use laboratory equipment that is adequate for its 
intended use. Thoroughly cleanse the equipment after each use to remove 
any antiseptic residues. Keep the equipment covered when not in use. 
Sterilize clean glassware intended for holding and transferring the 
test organisms in a hot air oven at 200 to 220  deg.C for 2 hours. Use 
volumetric flasks, pipets, or accurately calibrated diluting devices 
when diluting standard and sample solutions. Use plastic or glass Petri 
dishes having dimensions of 20 X 100 millimeters. Use covers of 
suitable material.
    (3) Serum Reagent--Use inactivated fetal bovine serum without added 
preservatives and/or antiinfective products.
    (b) Culture media and diluting fluids--(1) Culture media. Use Brain 
Heart Infusion Medium for culture media and diluting fluids. Prepare 
the medium as follows:


------------------------------------------------------------------------
                                             Brain Heart Infusion Medium
------------------------------------------------------------------------
Calf Brain, Infusion from                                      200 grams
Beef Heart, Infusion from                                      250 grams
Peptone                                                         10 grams
Sodium chloride                                                  5 grams
Disodium phosphate                                             2.5 grams
Dextrose                                                         2 grams
Water, distilled                               q.s. to 1,000 milliliters
------------------------------------------------------------------------

Mix thoroughly. Heat with frequent agitation and boil for 1 minute. 
Sterilize by autoclaving at 121  deg.C for 15 minutes. In lieu of 
preparing the media from the individual ingredients, the media may be 
made from dehydrated mixtures which, when reconstituted with distilled 
water, have the same or equivalent composition as media prepared from 
individual ingredients. Media prepared from dehydrated mixtures is to 
have growth-promoting, buffering, and oxygen tension-controlling 
properties equal to or better than media prepared from individual 
ingredients. Adjust the pH of each medium with 1 Normal hydrochloric 
acid or sodium hydroxide before sterilization, if necessary, so that 
the medium will have a final pH of 7.4 after sterilization.
    (i) Medium A (without neutralizers). Use Brain Heart Infusion 
medium corresponding to that described in paragraph (b)(1) of this 
section.
    (ii) Medium B. Brain Heart Infusion agar medium. Same as Medium A, 
except for the addition of 15 grams of agar per liter.
    (iii) Medium C. Same as diluting fluid 1, except for the addition 
of 15 grams of agar per liter.
    (iv) Medium D. Same as diluting fluid 2, except for the addition of 
15 grams of agar per liter.
    (2) Diluting fluids--(i) Diluting fluid 1. Diluting medium for 
neutralizing quaternary ammonium and phenolic antiseptic ingredients. 
Same as Medium A, except for the addition of 5 grams of lecithin and 40 
milliliters of polysorbate 20 per liter.
    (ii) Diluting fluid 2. Diluting medium for neutralizing iodophor 
antiseptic ingredients. Same as Medium A, except for the addition of 5 
grams of sodium thiosulfate per liter.
    (3) Neutralizers. When neutralizers are added to culture media and 
diluting fluid, perform the following tests.
    (i) Neutralizer inactivation of antiseptic test. Assay the 
neutralizer efficacy for the test antiseptic as follows: Prewarm the 
test antiseptic, culture medium, test culture, and serum to 37  deg.C 
by incubating appropriate volumes of all solutions in a water bath at 
37  deg.C for 5 minutes. Mix 0.8 milliliter of antiseptic (for controls 
use 0.8 milliliter of sterile water) with 9.0 milliliters of culture 
medium containing an appropriate antiseptic neutralizer followed by the 
addition of 0.2 milliliter of the test culture in 50 percent serum. 
Incubate the mixture of cells, serum, antiseptic, and neutralizer at 37 
 deg.C for 10 minutes. Remove aliquots, dilute, and assay for surviving 
bacteria by the plate-count assay method using diluting and plating 
media containing appropriate neutralizers, if required. Results 
obtained showing differences greater than 20 percent between test and 
control cultures indicate that the neutralizer used to inactivate the 
test antiseptic is ineffective. Reject results obtained from tests 
employing ineffective neutralization procedures.
    (ii) Neutralizer effect on bacteria viability test. Test the effect 
of neutralizers used to inactivate antiseptic active ingredients on 
cell viability by diluting aliquots of each test organism culture in 
Medium A (without neutralizer), specified in paragraph (b)(1)(i) of 
this section, and in the appropriate diluting fluid (neutralizing 
medium), specified in paragraph (b)(2) of this section. Determine the 
number of bacteria in aliquots of appropriate dilutions by the plate-
count assay method utilizing growth agar medium containing the same 
neutralizer concentration as the diluting medium. Determine neutralizer 
effects on cell viability by comparing the relative number of 
microorganisms growing on Medium B, specified in paragraph (b)(1)(ii) 
of this section, with and without added neutralizers. Results obtained 
showing differences greater than 20 percent between cultures diluted in 
medium with and without neutralizers indicate that, at the 
concentration utilized, the antiseptic neutralizer alters the 
determination of viable cells in the test cultures. Reject results 
obtained from tests in which the neutralizer employed alters the 
determination of viable cell numbers.
    (c) Test organisms--(1) Use cultures of the following 
microorganisms:
    (i) Streptococcus mutans (ATCC No. 25175).
    (ii) Actinomyces viscosus (ATCC No. 19246).
    (iii) Candida albicans (ATCC No. 18804).
    (2) Preparation of suspension. Maintain stock cultures on Medium B 
agar slants by monthly transfers. Alternatively, cultures may be 
lyophilized and stored at -70  deg.C. Incubate new stock transfers 2 
days at 37  deg.C; then store at 2 to 5  deg.C. Incubate Streptococcus 
mutans and Actinomyces viscosus anaerobically. Incubate Candida 
albicans aerobically. From stock culture, inoculate tubes of Medium A 
and make at least 4 but less than 30 consecutive daily transfers in 
Medium A, incubating at 37  deg.C, before using the culture for 
testing. Use a 16- to 18-hour culture of Streptococcus mutans and 
Candida albicans and a 32- to 36-hour culture of Actinomyces viscosus 
grown in Medium A at 37  deg.C for the test.
    (3) Determination of cell number in broth cultures. Prepare serial 
1:10 dilutions of each culture in Medium A and determine the number of 
cells per milliliter of culture by the plate-count assay method. Do not 
use cultures stored at 4  deg.C for more than 48 hours for assay. Do 
not use cultures containing less than 109 cells per milliliter.
    (4) Plate-count assay. For each culture to be assayed, pipet 1.0 
milliliter of each prepared dilution into each of two sterile Petri 
plates. To each plate, add 20 milliliters of sterile Medium B that has 
been melted and cooled to 45  deg.C (if neutralizers are required, use 
the corresponding agar growth medium with the appropriate neutralizer). 
Mix the sample with the agar by tilting and rotating the plate and 
allow the contents to solidify at room temperature. Invert the Petri 
plates and incubate at 37  deg.C for 48 hours. Following incubation, 
count the number of developing colonies. Use Petri plates containing 
between 30 and 300 colonies in calculating the number of bacteria per 
milliliter of original culture.
    (5) Test organism antiseptic resistance test. To ensure that 
antiseptic resistance properties of each organism have not changed 
substantially, determine the susceptibility of each organism to the 
active ingredient(s) being tested, in a suitable inactive medium, using 
the testing procedures in this section. The organisms are satisfactory 
if the number of organisms per milliliter are reduced by 3 log10 
within 10 minutes at 37  deg.C in the presence of 10 percent serum.
    (d) Test procedures--(1) Method 1--(i) Method validation. This test 
is valid only for those antiseptics that are water soluble and/or 
miscible and that can be neutralized by one of the subculture media 
specified in paragraphs (b)(2)(i) and (b)(2)(ii) of this section or 
that can be overcome by dilution.
    (ii) Bactericidal assay procedure. Prewarm all test solutions by 
incubating appropriate volumes at 37  deg.C in a water bath for 5 
minutes. Pipet 1.0 milliliter of serum, 1.0 milliliter of appropriate 
bacterial test culture, and 8.0 milliliters of the test antiseptic 
product at its recommended use concentration into a medication tube and 
mix well. Incubate at 37  deg.C for 10 minutes. Remove triplicate 1-
milliliter sample aliquots and dilute in Medium A containing 
appropriate neutralizers. Determine the number of surviving organisms 
per milliliter of test culture by the plate-count method using plating 
media containing appropriate neutralizers, if required.
    (iii) Bacteriostatic assay procedure. Prewarm all test solutions by 
incubating appropriate volumes at 37  deg.C in a water bath for 5 
minutes. Pipet 1.0 milliliter of serum, 1.0 milliliter of appropriate 
bacterial test culture, and 8.0 milliliters of the test antiseptic 
product at its recommended use concentration into a medication tube and 
mix well. Pipet 1.0 milliliter aliquots of this test mixture into 
triplicate medication tubes containing 100 milliliters of Medium A 
without neutralizers and mix well. Incubate at 37  deg.C for 48 hours 
and determine the number of organisms per milliliter of culture by the 
plate-count method.
    (2) [Reserved]
    (e) Test modifications. The formulation or mode of administration 
of certain products may require modification of the testing procedures 
in this section. In addition, alternative assay methods (including 
automated procedures) employing the same basic chemistry or 
microbiology as the methods described in this section may be used. Any 
proposed modification or alternative assay method shall be submitted as 
a petition under the rules established in Sec. 10.30 of this chapter. 
The petition should contain data to support the modification or data 
demonstrating that an alternative assay method provides results of 
equivalent accuracy. All information submitted will be subject to the 
disclosure rules in part 20 of this chapter.

    Dated: December 10, 1993.
Michael R. Taylor,
Deputy Commissioner for Policy.
[FR Doc. 94-2262 Filed 2-8-94; 8:45 am]
BILLING CODE 4160-01-F