# 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

> Briefs, arguments, decisions, and more.

URL: https://www.frixlaw.com/law-library/documents/fr%3A94-2262

## Record

- **Collection:** Federal Register
- **Document type:** Uncategorized Document
- **Published:** February 9, 1994

## Text

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 (vagin

[Text truncated at 120,000 characters. The full text is on the page linked above.]

---

Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/fr%3A94-2262. Public record. Not legal advice.