[Federal Register Volume 60, Number 194 (Friday, October 6, 1995)]
[Rules and Regulations]
[Pages 52474-52510]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-24693]




[[Page 52473]]

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Part II





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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21 CFR Part 310 et al.



Anticaries Drug Products for Over-the-Counter Human Use; Final 
Monograph; Final Rule

  Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules 
and Regulations  
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[[Page 52474]]


DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310, 355, and 369

[Docket No. 80N-0042]
RIN 0910-AA01


Anticaries Drug Products for Over-the-Counter Human Use; Final 
Monograph

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule 
in the form of a final monograph establishing conditions under which 
over-the-counter (OTC) anticaries drug products (products that aid in 
the prevention of dental cavities) are generally recognized as safe and 
effective and not misbranded. FDA is issuing this final rule after 
considering public comments on the agency's proposed regulation, which 
was issued in the form of a tentative final monograph, and all new data 
and information on OTC anticaries drug products that have come to the 
agency's attention. This final monograph is part of the ongoing review 
of OTC drug products conducted by FDA.

EFFECTIVE DATE: October 7, 1996.

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 March 28, 1980 
(45 FR 20666), 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 anticaries drug products, together with the 
recommendations of the Advisory Review Panel on OTC Dentifrice and 
Dental Care Drug Products (the 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 June 
26, 1980. Reply comments in response to comments filed in the initial 
comment period could be submitted by July 28, 1980.
    In accordance with Sec. 330.10(a)(10), the data and information 
considered by the Panel, after deletion of a small amount of trade 
secret information, were placed on display in the Dockets Management 
Branch (HFA-305), Food and Drug Administration, rm. 1-23, 12420 
Parklawn Dr., Rockville, MD 20857.
    The agency's proposed regulation, in the form of a tentative final 
monograph, for OTC anticaries drug products was published in two 
segments. The first segment was published in the Federal Register of 
September 30, 1985 (50 FR 39854). It addressed general issues on OTC 
anticaries drug products, the switch of prescription anticaries drug 
products to OTC status, specific anticaries active ingredients, dosages 
for anticaries active ingredients, and labeling of anticaries drug 
products. Interested persons were invited to file by November 29, 1985, 
written comments, objections, or requests for oral hearing on the 
proposed regulation before the Commissioner of Food and Drugs (the 
Commissioner). Interested persons were invited to file comments on the 
agency's economic impact determination by January 28, 1986. New data 
could have been submitted until September 30, 1986, and comments on the 
new data until December 1, 1986.
    The agency stated in the advance notice of proposed rulemaking that 
the Panel's recommended Laboratory Testing Profiles (LTP's) represented 
a new concept with many technical issues yet to be resolved. Thus, the 
LTP's were not included in the first segment of the tentative final 
monograph. The agency mentioned in the tentative final monograph (50 FR 
39854) that an open public meeting was held on September 26 and 27, 
1983, to discuss unresolved technical issues concerning the LTP's. The 
LTP's were subsequently discussed in the second segment of the 
tentative final monograph, published in the Federal Register of June 
15, 1988 (53 FR 22430). This amendment of the tentative final monograph 
addressed final formulation testing for monograph active ingredients in 
dentifrice formulations and issues relating to this testing. Interested 
persons were invited to file by October 13, 1988, written comments, 
objections, or requests for oral hearing on the proposed regulation 
before the Commissioner. Interested persons were invited to file 
comments on the agency's economic impact determination by October 13, 
1988. New data could have been submitted until June 15, 1989, and 
comments on the new data until August 15, 1989.
    In a notice published in the Federal Register of May 8, 1992 (57 FR 
19823), the agency reopened the administrative record to include data 
and information in support of a request to increase the package size 
limitation for fluoride dentifrice drug products from not more than 260 
milligrams (mg) of total fluorine per package to not more than 350 mg. 
Interested persons were invited to submit written comments by July 7, 
1992.
    In the Federal Register of November 24, 1992 (57 FR 55199), the 
agency also reopened the administrative record to obtain public comment 
on whether the labeling of OTC fluoride-containing drug products should 
include the quantity of fluoride, i.e., the specific amount of fluoride 
present in the product. Interested persons were invited to submit 
written comments by January 25, 1993. In the Federal Register of 
January 26, 1993 (58 FR 6102), the agency extended the comment period 
to March 26, 1993.
    This final rule encompasses all of the above segments. Final agency 
action on all OTC anticaries drug products occurs with the publication 
of this final rule establishing a monograph for OTC anticaries drug 
products.
    The OTC drug procedural regulations (Sec. 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 is no longer using 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 Category II or III, 
the term ``nonmonograph conditions'' is used.
    As discussed in the proposed regulation for OTC anticaries drug 
products (50 FR 39854), the agency advised that the conditions under 
which the drug products that are subject to this monograph will be 
generally recognized as safe and effective and not misbranded 
(monograph conditions) will be effective 12 months after the date of 
publication in the Federal Register. Therefore, on or after October 7, 
1996, 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 or abbreviated application (hereinafter called 
application). Further, any OTC drug product subject to this monograph 

[[Page 52475]]
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 response to the proposed rule, the amended proposed rule, and 
the two reopenings of the administrative record for OTC anticaries drug 
products, 19 drug manufacturers, 2 drug manufacturers associations, 2 
health care professionals, 1 health care professional society, and 3 
academic institutions submitted comments. Copies of the comments are on 
public display in the Dockets Management Branch (address above.) 
Additional information that has come to the agency's attention since 
the publication of the proposed rule, amended proposed rule, and 
notices to reopen the administrative record is also on display in the 
Dockets Management Branch.
    All ``OTC Volumes'' cited throughout this document refer to the 
submissions made by interested persons pursuant to the call-for-data 
notice published in the Federal Register of August 9, 1972 (37 FR 
16029) 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.

I. The Agency's Conclusions on the Comments-

A. General Comments on Anticaries Drug Products

    1. One comment noted its continuing position that FDA could not 
legally and should not, as a matter of policy, prescribe exclusive 
lists of terms from which indications for use for OTC drug products 
must be drawn.-The comment stated that FDA could not legally prohibit 
alternative OTC indications for use in terminology that is otherwise 
truthful and not misleading. The comment added that its views on this 
subject were presented in oral and written testimony submitted to FDA 
in connection with the September 29, 1982, FDA hearing on the 
exclusivity policy. The comment noted that a proposed revision to the 
exclusivity policy had been published on April 22, 1985 (50 FR 15810). 
The comment mentioned that it had submitted its views in response to 
that proposal and was incorporating those views into the rulemaking for 
OTC anticaries drug products. A second comment strongly supported the 
proposed revision of the exclusivity policy and discussed a number of 
constitutional and policy concerns about the agency's labeling policies 
for OTC drug products.
    The agency notes that the comments in the current rulemaking were 
submitted before the agency published a final rule changing its 
labeling policy for stating the indications for use of OTC drug 
products in the Federal Register of May 1, 1986 (51 FR 16258). The 
comments' concerns were addressed by the agency's change in its 
labeling policy for stating indications for use. Under the new policy 
in Sec. 330.1(c)(2) (21 CFR 330.1(c)(2)), the label and labeling of OTC 
drug products are required to contain in a prominent and conspicuous 
location, either: (1) The specific wording on indications for use 
established under an OTC drug monograph, which may appear within a 
boxed area designated ``APPROVED USES''; (2) other wording describing 
such indications for use that meets the statutory prohibitions against 
false or misleading labeling, which shall neither appear within a boxed 
area nor be designated ``APPROVED USES''; or (3) the approved monograph 
language on indications, which may appear within a boxed area 
designated ``APPROVED USES''; plus alternative language describing 
indications for use that is not false or misleading, which shall appear 
elsewhere in the labeling.
    2. One comment contended that OTC drug monographs are interpretive, 
as opposed to substantive, regulations. The comment referred to 
statements on this issue submitted earlier to other OTC drug rulemaking 
proceedings.
    The agency addressed this issue in paragraphs 85 through 91 of the 
preamble to the procedures for classification of OTC drug products, 
published in the Federal Register of May 11, 1972 (37 FR 9464 at 9467 
to 9472); in paragraph 3 of the preamble to the tentative final 
monograph for OTC antacid drug products, published in the Federal 
Register of November 12, 1973 (38 FR 31260); and in paragraph 1 of the 
preamble to the tentative final monograph in the present proceeding (50 
FR 39854 at 39855). FDA reaffirms the conclusions stated in those 
documents. Court decisions have confirmed the agency's authority to 
issue substantive regulations by informal rulemaking. (See, e.g., 
National Nutritional Foods Association v. Weinberger, 512 F.2d 688, 
696-698 (2d Cir. 1975) and National Association of Pharmaceutical 
Manufacturers v. FDA, 487 F. Supp. 412 (S.D.N.Y. 1980), aff'd, 637 F.2d 
887 (2d Cir. 1981).)
    3. One comment noted that interested persons must file new data 
within 1 year after publication of a tentative final monograph per 21 
CFR 330.10(a)(7)(iii). For this reason, the comment contended that it 
is important that persons submitting comments or objections to the 
tentative final monograph be provided with early feedback from FDA so 
that sufficient time will remain to allow any necessary additional 
testing or market research. The comment requested that the agency 
provide feedback on requests no later than 6 months following the 
submission of comments or objections to the proposed rule. The comment 
also asked that the agency's regulations for the OTC drug review be 
amended to contain this provision.
    The agency is unable to make a specific commitment to provide 
feedback on all comments and objections received in this and other OTC 
drug rulemakings within a specific time frame, as requested by the 
comment. Competing priorities and the constraints of limited resources 
make this impossible to do. However, the agency does review all 
comments and objections and tries to provide timely feedback as the 
situation requires and as workloads permit.
    4. The Public Health Service Ad Hoc Subcommittee on Fluoride of the 
Committee to Coordinate Environmental Health and Related Programs (the 
Subcommittee) discussed dental fluorosis resulting from fluoride intake 
in its report entitled ``Review of Fluoride: Benefits and Risks'' (Ref. 
1). The Subcommittee stated that dental fluorosis only occurs during 
tooth formation and becomes apparent upon eruption of the teeth. Dental 
fluorosis ranges from very mild (symmetrical whitish areas on teeth) to 
severe (pitting of the enamel, frequently associated with brownish 
discoloration). The Subcommittee recommended that manufacturers of 
dental products explore whether the levels of fluoride in their 
products can be reduced while preserving clinical effectiveness. 
(However, the Subcommittee did not suggest an acceptable fluoride 
exposure level.) In response to the Subcommittee's recommendation, the 
agency asked a professional dental association and two manufacturers 
associations (Refs. 2, 3, and 4) for information on dentifrices 
containing low levels of fluoride, particularly for use by children 2 
to under 6 years of age.
    The dental association stated that it is not currently considering 
a low fluoride toothpaste, but would evaluate such a product if one 
were to be submitted. 

[[Page 52476]]
The association indicated that such a product would be accepted if 
clinical data demonstrating effectiveness were available.
    The two manufacturers associations provided a joint response, in 
which they reviewed the report and relevant clinical and 
epidemiological literature, with the following conclusions: (1) There 
is a lack of scientific support for a cause and effect relationship 
between the ingestion of fluoride from dentifrice products and the 
subsequent development of enamel fluorosis; (2) the reported increase 
in enamel fluorosis, which ranges from very mild to mild, appears to be 
a result of factors other than dentifrice use, while, importantly, 
dentifrice use has been the principal contributor to the caries decline 
over the past 20 years; and (3) manufacturing changes to reduce the 
fluoride content of baby formulas, as well as cautionary advice to 
physicians about the administration of fluoride supplements to young 
children, are steps that have already been initiated and may well 
counteract the increase of the very mild to mild forms of enamel 
fluorosis that have been reported, as new epidemiologic data become 
available in the future.
    The manufacturers associations recommended that there be no 
reduction in the 850- to 1,150-parts per million (ppm) theoretical 
total fluorine levels proposed in the tentative final monograph for OTC 
anticaries drug products, contending that any reduction in this range 
could have serious public health consequences in terms of reducing the 
current level of anticaries protection in young children. The 
associations noted that data from studies evaluating low-potency (250 
to 550 ppm) fluoride dentifrices were contradictory and very sparse in 
children 2 to 6 years of age.
    The agency agrees that there is not enough evidence available at 
this time to support the safety and effectiveness of a low-fluoride 
dentifrice for children 2 to under 6 years of age, or to determine an 
appropriate fluoride concentration for a low-level dentifrice. As noted 
by the Subcommittee, dental fluorosis does not compromise oral health 
or tooth function as do dental caries. Therefore, the risk of dental 
caries from inadequate fluoride protection is a greater health hazard 
than the cosmetic detriment of fluorosis. Until adequate data become 
available, the agency is not able to generally recognize a low-fluoride 
dentifrice as safe and effective. If data become available, the agency 
will consider them.

References

    (1) Department of Health and Human Services, ``Review of 
Fluoride Benefits and Risks: Report of the Ad Hoc Subcommittee on 
Fluoride, of the Committee to Coordinate Environmental Health and 
Related Programs,'' February, 1991, in OTC Vol. No. 08AFM, Docket 
No. 80N-0042, Dockets Management Branch.
    (2) Comment No. LET15, Docket No. 80N-0042, Dockets Management 
Branch.
    (3) Comment No. LET16, Docket No. 80N-0042, Dockets Management 
Branch.
    (4) Comment No. LET17, Docket No. 80N-0042, Dockets Management 
Branch.
    5. One comment stated that the proposed definitions for dentifrice, 
treatment gel, and treatment rinse in Sec. 355.3(d), (g), and (h), 
respectively, should be revised to exclude discussion of the ``cosmetic 
function or nonfunction'' of these treatment categories. The comment 
noted, for example, that the first sentence in the definition for 
dentifrice, ``A substance used with a toothbrush to clean the 
accessible surfaces of the teeth,'' refers to a cosmetic function and 
should be deleted. The comment proposed modifying the definitions for 
dentifrice and treatment gel to be consistent with the definition for a 
treatment rinse as follows: A dentifrice is an abrasive-containing 
dosage form for delivering an anticaries drug to the teeth, a treatment 
gel is a gel dosage form for delivering an anticaries drug to the 
teeth, and a treatment rinse is a liquid dosage form for delivering an 
anticaries drug to the teeth. The comment suggested the following 
alternative definition for the entire category of anticaries drug 
products rather than defining individual dosage forms: ``an anticaries 
drug product is one which aids in the prevention or treatment of dental 
caries. It may be formulated as an abrasive-containing paste or powder, 
nonabrasive-containing gel, liquid rinse, or other appropriate product 
types.'' The comment concluded that this alternative definition more 
clearly emphasizes the intended use of these products rather than 
emphasizing the dosage form.
    Another comment requested that some proposed definitions of OTC 
anticaries dosage forms be revised to delete those terms that refer to 
both therapeutic and cosmetic functions. The comment specifically 
referred to the definitions in Sec. 355.3(a) (abrasive), (d) 
(dentifrice), (g) (treatment gel), (h) (treatment rinse), (i) 
(treatment rinse concentrated solution), (j) (treatment rinse 
effervescent tablets), and (k) (treatment rinse powder). The comment 
contended that the combination of therapeutic and cosmetic functions in 
these definitions would be confusing and inappropriate. The comment 
recommended that this section be revised to more clearly emphasize the 
intended therapeutic function of these dosage forms. For example, ``an 
anticaries drug product is one which aids in the prevention or 
treatment of dental caries (decay, cavities) and may be formulated as 
an abrasive-containing dentifrice, paste, or powder, nonabrasive gel, 
liquid rinse, or effervescent powder or tablets.''
    The agency has reviewed the Panel's evaluation of the definition of 
different fluoride dosage forms and concludes that there is a 
significant difference between dentifrices and nonabrasive dental gels 
and rinses. A dentifrice formulation contains an abrasive that is 
included in the formulation to clean the teeth (45 FR 20666 at 20671), 
while nonabrasive dental gels and rinses do not (45 FR 20666 at 20671).
    The agency agrees with the comments that OTC drug monographs should 
not regulate cosmetic claims and are limited to only drug claims. The 
monograph definitions are intended to refer to the therapeutic uses of 
the dosage forms defined. Accordingly, the agency is deleting any 
references to a ``cosmetic function'' (e.g., cleaning) from the 
proposed definitions. In the definition for dentifrice, the first 
sentence (``A substance used with a toothbrush to clean the accessible 
surfaces of the teeth.'') is deleted. The second sentence is revised to 
read ``An abrasive-containing dosage form for delivering an anticaries 
drug to the teeth.'' In the definition for treatment gels, the words 
``and are not intended for use in cleaning the teeth'' are deleted. 
Other definitions mentioned by the comment (treatment rinse, treatment 
rinse concentrated solution, treatment rinse effervescent tablets, and 
treatment rinse powder) do not need to be revised because they do not 
contain any ``cosmetic functions'' language.
    6. One comment recommended that the definition of an ``anticaries 
drug,'' proposed in Sec. 355.3(b) as ``a drug that aids in the 
prevention of dental cavities (decay, caries),'' be revised to include 
``treatment'' in addition to ``prevention'' of dental cavities. The 
comment also requested that the definition of ``anticaries drug'' 
reflect the various product dosage forms by adding the following 
sentence to the definition: ``It may be formulated as an abrasive-
containing paste or powder, nonabrasive-containing gel, liquid rinse, 
or other appropriate product type.'' The comment indicated that the 
expanded definition more clearly defines an anticaries drug and 
encompasses the various product dosage forms.

[[Page 52477]]

    The agency does not agree that the term ``treatment'' alone should 
be added to the definition of an anticaries drug. In the context of 
this definition, the word ``treatment'' alone implies that anticaries 
drug products could treat an existing caries lesion rather than being 
useful as a preventive treatment. The Panel recommended and the agency 
previously proposed conditions under which OTC anticaries drug products 
that aid in the prevention of dental cavities would be generally 
recognized as safe and effective, and not misbranded (45 FR 20666 at 
20690 and 50 FR 39854 at 39871). Treatment of dental cavities is 
generally understood to be a process by which medical or dental 
intervention in the management of cavities results in either repair or 
stabilization of tooth decay. Neither the Panel nor the agency received 
data indicating that fluoridated compounds included in the monograph 
are effective in treating or stabilizing tooth decay. The fluoride 
drugs included in the monograph are intended as preventive measures 
against tooth decay and not as treatment modalities for the management 
of existing dental cavities. However, if the term ``treatment'' is 
expanded to read ``prophylactic treatment,'' the preventive nature of 
such ``treatments'' would not necessarily imply treatment of an 
existing caries lesion. Prophylactic treatment is generally described 
as the act or manner of protection for or prevention of disease. Thus, 
the agency is adding the term ``prophylactic treatment'' in the 
definition for ``anticaries drug'' in Sec. 355.3(c) of this final 
monograph.
    The agency does not agree with the comment that the definition of 
``anticaries drug'' should specify various dosage forms. The definition 
is only included in the monograph to reflect the intended use of these 
drug products.
    The agency agrees with the comment that an ``anticaries drug'' can 
be formulated in various dosage forms and has defined numerous dosage 
forms in the final monograph (see Sec. 355.3(e) and (h) through (m)). 
These dosage forms include those requested by the comment.
    7. Two comments objected to the second sentence of the definition 
for ``treatment gel'' in proposed Sec. 355.3(g), which reads: 
``Treatment gels are formulated in an anhydrous glycerin base with 
suitable thickening agents included to adjust viscosity.'' The comments 
indicated that treatment gels, including 0.4-percent stannous fluoride 
treatment gel, may be formulated in bases that do not contain any 
anhydrous glycerin compound without compromising the safety or 
effectiveness of the anticaries drug product. Therefore, the comments 
recommended that the agency delete the second sentence of the 
definition.
    The agency does not agree that the second sentence of the 
definition of a ``treatment gel'' should be deleted. The definition in 
proposed Sec. 355.3(g) was based on the only formulation for this 
dosage form that was submitted to the Panel for review. The Panel 
stated that stannous fluoride is stable in anhydrous glycerin (45 FR 
20666 at 20688) and defined ``dental gels'' as being ``formulated in an 
anhydrous glycerin base with suitable thickening agents included to 
adjust viscosity'' (45 FR 20690). The Panel (45 FR 20688) and the 
agency have used this definition based on the results of laboratory and 
clinical studies that supported the safety and effectiveness of a 
specific formulation. For greater clarity, the agency is changing the 
term ``treatment gel'' in Sec. 355.3(i) to ``preventive treatment gel'' 
to make it clear that the product's intended purpose is prevention of 
dental cavities. Preventive treatment gels formulated in bases other 
than anhydrous glycerin could be considered for inclusion in the 
monograph provided that stability of the fluoride compound is 
demonstrated and the available fluoride ion is not adversely affected 
by the base used in the formulation. If such a formulation were found 
acceptable, the definition of a preventive treatment gel could be 
revised as necessary to describe such a formulation. However, the 
agency currently has no data to support such formulations. Accordingly, 
the agency is not revising the definition at this time.
    8. One comment disagreed with the agency's suggestion in the 
tentative final monograph (53 FR 22430 at 22432) that interested 
persons may petition the agency to amend the anticaries monograph to 
include specific organic fluorides as active ingredients for use in 
dental formulations rather than file to obtain an approved new drug 
application (NDA). The comment stated that allowing submission of a 
petition to include organic fluorides in the monograph presupposes that 
these active ingredients can be shown to be generally recognized as 
safe and effective, and have been used for a material time and to a 
material extent. The comment noted that although organic fluoride 
formulations have been used outside the United States, they do not meet 
the conditions for inclusion in the OTC drug review because they have 
never been sold in this country. The comment therefore suggested that 
the agency not allow the alternative of petitioning to amend the 
monograph to include organic fluoride formulations, but instead require 
filing an NDA.
    The agency agrees with the comment that organic fluoride 
formulations do not have a marketing history in the United States. 
However, the agency is currently reevaluating whether foreign marketing 
can satisfy the material time and extent criteria for inclusion of an 
ingredient in the OTC drug review. The agency intends to address this 
issue in a future issue of the Federal Register. In the meantime, it 
would not be in the public interest to unduly delay publication of the 
final monograph for OTC anticaries drug products while this matter is 
being resolved.
    Interested persons may submit a petition requesting amendment of 
the final anticaries monograph to include an organic fluoride 
formulation. Such a petition would be considered in the context of the 
agency's reevaluation of the marketing history threshold criteria for 
the OTC drug review. Alternatively, an NDA may be filed under part 314 
(21 CFR part 314). With either procedure, the manufacturer must submit 
adequate data showing the organic fluoride to be safe and effective for 
its intended use.

B. Comments on Specific Anticaries Active Ingredients and Dosage Forms

    9. One comment requested that the agency consider the anticaries 
activities of both the stannous and the fluoride ions in 0.4 percent 
stannous fluoride, as well as the combined anticaries effect of the 
total compound, instead of considering the fluoride ions alone. The 
comment contended that the stannous ions in 0.4 percent stannous 
fluoride have significant anticaries properties, by reducing enamel 
solubility and through antibacterial activity. However, the comment did 
not submit any data to support its position.
    The Panel reviewed extensive data on stannous fluoride dentifrices, 
rinses, and gels (45 FR 20666 at 20684 to 20685 and 20687 to 20688) and 
attributed effectiveness to the fluoride ion present in the product. 
The agency is not aware of any data supporting anticaries activity of 
stannous ions in stannous fluoride. Without data demonstrating this 
activity, the agency has no basis to consider the stannous ions as 
contributing to the anticaries effects of these drug products.
    10. Several comments requested that the allowable upper limit of 
fluoride concentration in a dentifrice marketed under the final 
monograph be increased from 1,150 ppm theoretical total fluorine to 
1,500 ppm. The comments stated that 850 to 1,150 ppm levels of fluoride 
in dentifrice products were 

[[Page 52478]]
established nearly 25 years ago. One comment mentioned that, at that 
time, concentrations of fluoride were set arbitrarily low because of 
concerns about fluoride toxicity. The comments indicated that there is 
sufficient evidence that much higher fluoride concentrations are safe 
and effective, based on widespread use of such concentrations in the 
United States and Europe. With more toxicological data now available, 
the comments suggested a higher dosage of fluorides in dentifrices 
should be available for persons who reside in nonfluoridated areas or 
who have a greater propensity to develop caries. The comments contended 
that such a need has been acknowledged by the agency's approval of an 
NDA for an ``extra-strength'' (1,500 ppm) fluoride dentifrice. One 
comment indicated that it manufactures and distributes ``extra-
strength'' fluoride dentifrices in other countries and has received no 
reports of ill effects from use of these products.
    The comments submitted several clinical studies (Refs. 1, 2, and 3) 
demonstrating that a dentifrice containing 1,500 ppm theoretical total 
fluorine can provide greater anticaries protection than 850- to 1,150-
ppm levels. The first study (Ref. 1) was a 3-year, double-blind 
clinical comparison of the anticaries effectiveness of a test 
dentifrice containing 1.14 percent sodium monofluorophosphate (1,500 
ppm theoretical total fluorine) with a control dentifrice containing 
0.76 percent sodium monofluorophosphate (1,000 ppm theoretical total 
fluorine). This study involved 2,415 children, primarily 8 to 11 years 
of age, who resided in a nonfluoridated community. The children were 
randomly assigned to one of the two groups. The children brushed 
normally at home and participated in a daily supervised toothbrushing 
exercise at school. Results of this study indicated that 48 percent of 
the subjects who used the 1,000-ppm fluoride dentifrice remained caries 
free and 57 percent of those who used the 1,500-ppm dentifrice remained 
caries free. The study also suggested that the participants using the 
1,000-ppm dentifrice would have projected a savings of 639 additional 
surfaces and 344 teeth if they had received the 1,500-ppm dentifrice 
during the 3-year trial.
    The second study (Ref. 2) was also a 3-year, double-blind clinical 
comparison of two sodium monofluorophosphate dentifrices, one 
containing 1,500 ppm and the other containing 1,000 ppm theoretical 
total fluorine. The study involved 1,913 children between 6 and 11 
years of age. The subjects were randomly assigned to one of the two 
groups. The children brushed in the same manner as in the first study. 
Results of this study demonstrated that, even in an area with optimal 
water fluoridation, a 1,500-ppm concentration provides greater 
anticaries protection than a 1,000-ppm theoretical total fluorine 
concentration.
    The third clinical study (Ref. 3) compared the anticaries effect of 
three dentifrices containing the following concentrations of 
theoretical total fluorine: (1) 1,100 ppm (as sodium fluoride), (2) 
2,800 ppm (as sodium fluoride ), and (3) 2,800 ppm (as sodium 
monofluorophosphate). Approximately 4,500 school children between 7 and 
15 years of age, whose community water supply contained less than 0.3 
ppm fluoride, were assigned at random to brush unsupervised with one of 
the three dentifrices. Results of the 3-year clinical study showed no 
significant difference between the 2,800-ppm sodium monofluorophosphate 
and the positive control (1,100 ppm as sodium fluoride). However, the 
study demonstrated that the group assigned to brush with sodium 
fluoride containing 2,800 ppm theoretical total fluoride received an 
estimated 15 percent fewer cavities than those subjects who brushed 
with the sodium fluoride dentifrice containing 1,100 ppm theoretical 
total fluoride.
    One comment noted that two of these clinical studies (Refs. 1 and 
2) formed the basis for FDA approval of the 1,500-ppm ``extra-
strength'' dentifrice under an NDA. Based on these data, the comment 
requested that the 1,500-ppm dentifrice be included in the monograph.
    One comment requested that the agency specifically include higher 
strength sodium fluoride dentifrice products (1,500 ppm) in the final 
monograph. The comment stated its belief that consumers should be 
permitted the widest possible choice of safe and effective OTC drugs 
and that the monograph should be flexible to permit the use of 
equivalent fluoride species.
    Several other comments argued that increasing the fluoride 
concentration to a level as high as 1,500 to 1,650 ppm would be unwise 
without adequate scientific support to justify the increased risk of 
developing fluorosis. One comment indicated that clinical trials using 
higher strength fluoride-containing dentifrices have demonstrated no 
adverse experiences or changes of any consequence with respect to soft 
tissue aberrations in children 8 to 12 years of age. However, the 
comment added that there has not been sufficient attention paid to the 
potential risk of enamel fluorosis in children under 6 years of age 
using such higher strength fluoride dentifrices, particularly if the 
children live in an optimally-fluoridated community. Another comment 
cited two reports (Refs. 4 and 5) indicating that the prevalence of 
dental fluorosis in children residing in nonfluoridated areas has 
increased appreciably during the past decade with more than 20 percent 
of the children having mild fluorosis. The comment also cited another 
study (Ref. 6) suggesting that the use of fluoride dentifrices prior to 
2 years of age is a major risk factor for dental fluorosis. The comment 
pointed out that modifying the monograph to permit the use of elevated 
fluoride concentrations in dentifrices (i.e., 1,500 to 1,650 ppm) would 
clearly increase the risk of children developing dental fluorosis. The 
comment further stated that the modest increase in anticaries 
effectiveness attributable to elevated fluoride levels in dentifrices 
may not be adequate to justify the increased risk of developing 
fluorosis. The comment concluded that the proposed increase of fluoride 
in dentifrices to 1,500 ppm would affect the risk/benefit ratio 
unfavorably. Accordingly, the comment urged the agency to reject the 
proposed increase in the fluoride level in dentifrices to 1,500 to 
1,650 ppm.
    Another comment expressed similar concern for the potential risk of 
enamel fluorosis in children under 6 years of age who may use 
dentifrices containing the proposed higher levels of fluoride during 
toothbrushing. The comment indicated that there exists ample 
documentation that young children swallow a significant amount of 
dentifrice. The comment submitted two published clinical studies (Refs. 
7 and 8) evaluating the significance of fluoride dentifrices as a risk 
factor in dental fluorosis. One study (Ref. 7) indicated that a portion 
of the dentifrice introduced to the mouth and not expectorated, but 
swallowed and absorbed, ranged from 0 to 100 percent. The study 
suggested that inadequate control of the swallowing reflex by younger 
children accounts for the excessive ingestion of fluorides, 
particularly from dentifrices and mouthrinses. The other study (Ref. 8) 
indicated that, on average, children used 0.662 gram (g) of dentifrice 
and ingested 0.299 g per brushing. Results from this study indicated: 
(1) The younger the children, the more likely they are to swallow a 
greater proportion of dentifrice; and (2) young children who rinse 
their mouths and expectorate properly after brushing ingest less 

[[Page 52479]]
dentifrice. The comment predicted that if manufacturers are allowed to 
market an increased level of fluoride without requiring an agency-
approved application, routine use of these extra strength dentifrices 
would increase the potential risk of enamel fluorosis in younger 
children. However, the comment did not indicate how or why the routine 
use of NDA-approved extra strength dentifrice products would prevent an 
increased risk of enamel fluorosis in younger children.
    In the tentative final monograph for OTC anticaries drug products 
(53 FR 22430 at 22432), the agency stated that a 1,500-ppm theoretical 
total fluoride level is safe, but indicated that general recognition of 
the effectiveness of this strength fluoride dentifrice must be based on 
adequate published or publicly available medical and scientific data. 
Two clinical studies (Refs. 1 and 2) that formed the basis of an agency 
NDA approval of this strength sodium monofluorophosphate dentifrice 
have now been included in the public record for this rulemaking by the 
NDA holder. Results of these studies indicate an enhanced anticaries 
benefit derived over a 3-year period from the use of the higher 
fluoride sodium monofluorophosphate dentifrice (1,500 ppm) when 
compared to the positive control fluoride dentifrice (1,000 ppm). The 
studies also indicated that children who are at increased risk to 
develop caries and those with erupting premolars and second molars may 
derive more benefit from a 1,500-ppm dentifrice than a 1,000-ppm 
dentifrice.
    The agency has not received any clinical or available fluoride ion 
data on any 1,500-ppm sodium fluoride dentifrice comparable to the 
information for 1,500-ppm sodium monofluorophosphate dentifrice. 
Therefore, the agency is not including higher strength (1,500 ppm) 
sodium fluoride dentifrice drug products in this final monograph at 
this time.
    As noted above, comments expressed concern that an increase of 
theoretical total fluorine to 1,500 ppm could increase the incidence of 
dental fluorosis in children. The agency agrees that for children under 
6 years of age a risk/benefit analysis indicates that levels of 
fluoride in dentifrices should not exceed the currently accepted OTC 
level of 1,150 ppm (see discussion of fluorosis in comment 23). 
Although an NDA was approved in 1986 for an extra-strength fluoride 
dentifrice (1,500 ppm) whose labeling allowed for use in children above 
2 years of age, the agency recognizes that more recent data (Refs. 4 
and 8) suggest that the incidence of fluorosis in children under 6 
years of age is increasing in the United States. The agency does not 
believe that the increased risk of fluorosis outweighs the benefit of 
using an extra-strength fluoride dentifrice in children under 6 years 
of age. The agency has determined from the results of the submitted 
clinical studies that the enhanced benefit of using an extra-strength 
dentifrice product does not present additional risk to children above 6 
years of age and to adults, particularly for those with a greater 
propensity to develop cavities or for those who live in communities 
with nonfluoridated water. As discussed in the tentative final 
monograph (50 FR 39854 at 39864), developing teeth of children under 6 
years of age may show objectionable dental fluorosis from repeated 
ingestion of excessive amounts of fluoride. However, epidemiological 
and clinical findings indicate that the formative state of the teeth of 
children 6 years of age and older (excepting third molars) is too 
advanced to be affected by the amount and frequency of use of fluoride 
dentifrices.
    The agency is including sodium monofluorophosphate dentifrices that 
contain 1,500 ppm theoretical total fluorine in this final monograph. 
Because of concerns about dental fluorosis, the agency is requiring 
that dentifrice products with these fluorine concentrations be clearly 
labeled for use only by children above 6 years of age. Accordingly, the 
agency is including the following directions in Sec. 355.50(d)(1)(ii):
    Paste dosage form with a theoretical total fluorine 
concentration of 1,500 ppm identified in Sec. 355.10(b)(2). Adults 
and children 6 years of age and older: brush teeth thoroughly, 
preferably after each meal or at least twice a day, or as directed 
by a dentist or doctor. Instruct children under 12 years of age in 
good brushing and rinsing habits (to minimize swallowing). Supervise 
children as necessary until capable of using without supervision. 
Children under 6 years of age: Do not use unless directed by a 
dentist or doctor.
    The agency believes that extra-strength fluoride dentifrice 
products may be beneficial to consumers who have a greater propensity 
to develop cavities, and that manufacturers may wish to promote these 
products for this purpose. Therefore, the agency is expanding 
Sec. 355.50(f)(2) to include an optional additional labeling statement 
for these products as follows:
    For dentifrice products containing 1,500 ppm theoretical total 
fluorine. Adults and children over 6 years of age may wish to use 
this extra-strength fluoride dentifrice if they reside in a 
nonfluoridated area or if they have a greater tendency to develop 
cavities.
    Finally, the agency does not find that sufficient data exist to 
support the safety and effectiveness of a theoretical total fluorine 
level above 1,500 ppm. Accordingly, the agency is not including 
dentifrices with such theoretical total fluorine levels in the 
monograph.

References-

    (1) Conti, J. A. et al., ``A 3-year Clinical Trial to Compare 
Efficacy of Dentifrices Containing 1.14 Percent and 0.76 Percent 
Sodium Monofluorophosphate,'' Community Dental Oral Epidemiology, 
16:135-138, 1988.--
    (2) Fogels, H. R. et al., ``A Clinical Investigation of a High-
Level Fluoride Dentifrice,'' Journal of Dentistry for Children, 
55(3):210-215, 1988.---
    (3) Lu, K. H. et al., ``A Three-year Clinical Comparison of a 
Sodium Monofluorophosphate Dentifrice with Sodium Fluoride 
Dentifrices on Dental Caries in Children,'' Journal of Dentistry for 
Children, 54(4):241-244, 1987.
    (4) Woolfolk, M. W. et al., ``Relation of Sources of Systemic 
Fluoride to Prevalence of Dental Fluorosis,'' Journal of Public 
Health Dentistry, 49:78-82, 1989.
    (5) Leverett, D. H., ``Fluorides and the Changing Prevalence of 
Dental Caries,'' Science, 217:26-30, 1982.
    (6) Osuji, O. O. et al., ``Risk Factors for Dental Fluorosis in 
a Fluoridated Community,'' Journal of Dental Research, 67(12):1488-
1492, 1988.
    (7) Whitford., G. M., D. W. Allmann, and A. R. Shahed, ``Topical 
Fluorides: Effects on Physiologic and Biochemical Processes,'' 
Journal of Dental Research, 66(5):1072-1078, 1987.
    (8) Simard, P. L. et al., ``The Ingestion of Fluoride Dentifrice 
by Young Children,'' Journal of Dentistry for Children, 56:177-181, 
1989.
    11. One comment (from the holder of the only approved NDA for a 
1,500-ppm fluoride dentifrice) provided data indicating that the lowest 
available fluoride ion concentration measured during the 3-year 
clinical trial of its 1,500-ppm sodium monofluorophosphate dentifrice 
product was 1,295 ppm, with an analytical variability of  
20 ppm (Refs. 1 and 2).
    Based on the available fluoride ion data for this product, the 
agency has determined at this time that all 1,500-ppm sodium 
monofluorophosphate dentifrices must provide an available fluoride ion 
concentration equal to or greater than 1,275 ppm. Accordingly, the 
agency is including higher strength (1,500 ppm) sodium 
monofluorophosphate dentifrice products in Sec. 355.10(b)(2) of this 
final monograph as follows:
    Dentifrices containing 1,500 ppm theoretical total fluorine in a 
paste dosage form. Sodium monofluorophosphate 1.153 percent with an 
available fluoride ion concentration (consisting of PO3F= 
and F- combined) gr-thn-eq 1,275 ppm. 

[[Page 52480]]


References

    (1) Comment LET18, Docket No. 80N-0042, Dockets Management 
Branch.
    (2) Comment LET20, Docket No. 80N-0042, Dockets Management 
Branch.
    12. One comment requested that the active ingredient listings for 
sodium fluoride treatment rinses in proposed Sec. 355.10(b)(3), (b)(4), 
and (b)(5) be combined as follows: ``Sodium fluoride 0.02 to 0.05 
percent in a final solution with a pH of approximately 7.'' The comment 
stated that this would provide a range of allowable concentrations for 
these rinses without affecting the technical accuracy of the monograph.
    The agency disagrees with the comment. The active ingredient 
listings in Sec. 355.10(b)(3), (b)(4), and (b)(5) specify particular 
concentrations for sodium fluoride in a rinse dosage form. The 
monograph is not intended to provide a range of concentrations for 
these products. The 0.02- and 0.05-percent sodium fluoride 
concentrations were included in the monograph based on separate, 
independent clinical studies, as discussed for the 0.05-percent 
concentration in the Panel's report (45 FR 20666 at 20686) and for the 
0.02-percent concentration in the agency's tentative final monograph 
(50 FR 39854 at 39863). More importantly, the directions for 0.02 
percent sodium fluoride in a neutral dental rinse (pH of approximately 
7) are for use twice daily and for 0.05 percent sodium fluoride rinse 
are for use only once a day. These dosage regimens are each supported 
by separate, independent clinical data. There are no data to support 
directions for other concentrations. Accordingly, there is no basis to 
combine the active ingredient listings for the sodium fluoride 
treatment rinses included in this final monograph.
    13. One comment requested that sodium fluoride/sodium bicarbonate 
powdered dentifrices be included in the final monograph for OTC 
anticaries drug products. In response to the agency's concerns 
discussed in the tentative final monograph (53 FR 22430 at 22443) about 
the safety and effectiveness of powdered fluoride dentifrices, the 
comment submitted several analytical and biological studies (Ref. 1). 
The comment contended that these studies demonstrate the effectiveness 
and comparable bioavailability of a powdered fluoride dentifrice with a 
toothpaste containing a similar abrasive system and an equivalent 
concentration of theoretical total fluorine.
    The comment submitted several animal studies (Refs. 2, 3, and 4) 
that determined the anticaries effect of a sodium fluoride/sodium 
bicarbonate powdered dentifrice in rats that were infected with highly 
virulent strains of cariogenic bacteria. In one study (Ref. 2), a group 
of rats infected with Streptococcus sobrinus that was treated topically 
with sodium fluoride/sodium bicarbonate powdered dentifrice experienced 
42 percent fewer caries lesions than a control group treated only with 
distilled water. Rats exposed to either the tooth powder or 10 ppm 
fluoridated drinking water produced similar reduction in caries (42 and 
47 percent, respectively).
    In another study (Ref. 3), rats infected with S. mutans were 
treated with a 1:2 part slurry of sodium bicarbonate-based powdered 
dentifrice containing 0.22 percent sodium fluoride (1,000 ppm) in water 
for 1 minute daily for 3 weeks. Results indicated a 51-percent caries 
reduction in infected rats treated with the tooth powder as compared to 
the group of rats treated with distilled water. Rats treated with an 
equal concentration of sodium fluoride aqueous solution without other 
inactive ingredients developed a 36-percent reduction in cavities as 
compared to the control group. The data also indicated that no 
significant difference in the incidence of cavities was observed in the 
group of rats treated topically with sodium fluoride/sodium bicarbonate 
powdered dentifrice and the group of rats receiving no other treatment 
except 10 ppm fluoride in their drinking water (51 percent versus 54 
percent).
    In another animal study (Ref. 4), rats infected with S. sobrinus 
were treated with an undiluted sodium bicarbonate-base powdered 
dentifrice containing 0.22 percent sodium fluoride. Results of this 
study indicated a 47-percent reduction in cavities as compared to the 
control group. This reduction in cavities was not statistically 
different from the 43-percent reduction in total cavities obtained by 
topical treatment with an undiluted sodium bicarbonate-based toothpaste 
containing the same level of sodium fluoride.
    The comment also submitted several clinical studies that evaluated 
the anticaries effectiveness of fluoridated and nonfluoridated powdered 
dentifrices. However, the studies involving nonfluoridated powdered 
dentifrices were not related to and do not support the effectiveness of 
the comment's dentifrice product that contains sodium fluoride as the 
active ingredient.
    The comment submitted a 1-year clinical study (Ref. 5) that 
demonstrated the anticaries effectiveness of tooth powders containing 
fluorapatite (essentially calcium fluoride). Although the powdered 
dentifrice used in this study contained an active ingredient 
(fluorapatite) different than the active ingredient found in the 
comment's sodium fluoride dentifrice product, the study supported the 
anticaries effectiveness of a powdered dentifrice dosage form. In this 
study, 150 medical students brushed daily with one of three dentifrices 
containing: (1) 71.4 percent fluorapatite, (2) an ion-free ``synthetic 
apatite'' consisting of hydroxyapatite with a surface layer of 
fluorapatite (total fluorine content, 0.25 percent), or (3) a control 
powdered dentifrice not containing fluoride. Results of this study 
indicated that the group that brushed with the fluorapatite powder and 
the group that bushed with the ``synthetic apatite'' paste developed an 
average of 38 and 67 percent fewer cavities, respectively, than those 
students who brushed with the nonfluoride tooth powder.
    Another study (Ref. 6) compared human enamel uptake of fluoride 
from a sodium fluoride/sodium bicarbonate dentifrice in a powdered and 
a paste dosage form. In this study, human enamel was ground and 
polished flat to provide a uniform surface and then demineralized to 
create a simulated white-spot caries lesion. Several enamel slabs were 
exposed continuously for 30 minutes at body temperature to a tooth 
powder (with a poured-bulk density of 1.0 to 1.2 g/milliliter (mL) and 
available fluoride ion concentration equal to or greater than 850 ppm) 
and a toothpaste containing sodium fluoride/sodium bicarbonate with an 
available fluoride ion concentration equal to or greater than 650 ppm. 
Results of this study indicated that both the powder and paste dosage 
forms demonstrated comparable enamel uptake of fluoride ions.
    The comment concluded by stating that the data demonstrate the 
safety and effectiveness of a powdered dentifrice containing sodium 
fluoride and show that such a product can provide effectiveness 
equivalent to a toothpaste containing a similar abrasive system. The 
comment urged the agency to include sodium fluoride/sodium bicarbonate 
powdered dentifrices in the final monograph for OTC anticaries drug 
products.
    The agency has reviewed the data provided by the comment and 
determined that sufficient data have been provided to generally 
recognize as safe and effective powdered dentifrices containing sodium 
fluoride with a sodium bicarbonate abrasive. However, the agency points 
out that several of the studies submitted measured the anticaries 
effectiveness of dentifrices containing active agents (fluorapatite, 
carbamide-urease, and fluoridated table 

[[Page 52481]]
salt) different than the active ingredient contained in the comment's 
tooth powder (sodium fluoride). Although the data from one study 
provide some indication of cariostatic effectiveness of a fluorapatite 
dentifrice, the agency does not find these studies pertinent to the 
determination of the safety and effectiveness of the comment's sodium 
fluoride/sodium bicarbonate powdered dentifrice.
    The agency considers the biological studies submitted by the 
comment as demonstrating that the bioequivalence and bioavailability of 
fluoride ions are comparable for sodium fluoride/sodium bicarbonate 
powdered and paste dentifrices containing the same concentration of 
theoretical total fluorine. Results of several well-designed animal 
caries studies (Refs. 2, 3, and 4) demonstrate that rats inoculated 
with cariogenic bacteria and fed a caries promoting diet developed 42 
to 51 percent fewer cavities when treated with a topical application of 
sodium fluoride/sodium bicarbonate powdered dentifrice than rats in a 
control group. In addition, the agency concludes that the results of 
the submitted human enamel uptake study (Ref. 6) indicate that the 
measured human enamel uptake of fluoride from a powder containing 
sodium fluoride/sodium bicarbonate with a fluoride ion concentration of 
1,000 ppm was better than the fluoride uptake of a similar dentifrice 
paste formulation. Although the agency does not believe that this 
system is comparable to real-life development of early dental caries or 
that a one-time exposure of enamel slabs continually for 30 minutes at 
37  deg.C simulates real-life conditions of short, intermittent 
exposures during a month's usage, the agency does believe that fluoride 
uptake is a marker of potential anticaries effectiveness and considers 
the two fluoride dosage forms at least equivalent.
    Accordingly, the agency is including sodium fluoride/sodium 
bicarbonate powdered dentifrices in Sec. 355.10(a)(2) of this final 
monograph as follows:
    Dentifrices containing 850 to 1,150 ppm theoretical total 
fluorine in a powdered dosage form: Sodium fluoride 0.188 to 0.254 
percent with an available fluoride ion concentration of 
gr-thn-eq 850 ppm for products containing the abrasive sodium 
bicarbonate and a poured-bulk density of 1.0 to 1.2 grams per 
milliliter.

References-

    (1) Comment No. C00066, Docket No. 80N-0042, Dockets Management 
Branch.
    (2) Tanzer, J. M. et al., ``Effects of Bicarbonate-based Dental 
Powder, Fluoride, and Saccharin on Dental Caries and on 
Streptococcus  sobrinus Recoveries in Rats,'' Journal of Dental 
Research, 66(3):791-794, March, 1987.
    (3) Tanzer, J. M. et al., ``Bicarbonate-based Dental Powder, 
Fluoride, and Saccharin Inhibition of Dental Caries Associated with 
Streptococcus mutans Infection of Rats,'' Journal of Dental 
Research, 67(6):969-972, June, 1988.---
    (4) McMahon, T. et al., ``Caries Inhibition by Bicarbonate-based 
Dental Powder in S. mutans 10449S-infected Rats,'' Journal of Dental 
Research, 67:343, 1988.
    (5) McClendon, J. F., and W. C. Foster, ``Prevention of Dental 
Caries by Brushing The Teeth With Powders Containing Fluorapatite,'' 
Journal of Dental Research, 26:233-239, 1947.--
    (6) Letter from J. J. Hefferren, J. J. Hefferren Resources, 
Inc., to T. Winston, Church & Dwight Co., Comment No. C00066 
(Attachment 1), Docket No. 80N-0042, Dockets Management Branch.
    14. One comment responded to the agency's concern expressed in the 
tentative final monograph (53 FR 22430 at 22444) that several possible 
methods of applying a powdered dosage form to a toothbrush may lead to 
significant variations of fluoride ion delivered to the teeth. The 
comment agreed that directions for using powdered products have been 
varied. However, the comment indicated that this is not a reason to 
determine that a sodium fluoride powdered dentifrice would not be safe 
and effective. The comment added that after several years of marketing 
a powdered dentifrice, it has found that pouring a powdered dentifrice 
from a container with a flip-top spout provides a cleaner and simpler 
application of the product with a uniform dosage of fluoride.
    The comment claimed that the available fluoride ion obtained from 
two applications of a tooth powder containing a minimum of 850 ppm 
soluble (available) fluoride ion will be equal to or greater than the 
Panel's recommended 650 ppm available fluoride ion for sodium fluoride 
dentifrices. The comment based the need for two applications of tooth 
powder on its recommendation that sodium fluoride/sodium bicarbonate 
powdered dentifrices have a poured-bulk density of 1.0 to 1.2 g/mL and 
an available fluoride ion concentration equal to or greater than 850 
ppm. The comment responded to several concerns raised by the agency in 
the tentative final monograph (53 FR 22430 at 22443). These concerns 
involved previous recommendations that two poured-bulk density ranges 
(0.5 to 0.99 g/mL and 1.0 to 1.7 g/mL) were necessary for powdered 
fluoride dentifrices and that two applications per brushing with a 
powdered dentifrice in the lower poured-bulk density range would 
provide an appropriate dose of fluoride. The comment stated that the 
two poured-bulk density ranges were based on the assumption that equal 
volumes of tooth powder and toothpaste are applied in a single 
application to the brush; however, that assumption may no longer be 
correct because of the difference in consistency of the two dosage 
forms. The comment mentioned that more toothpaste than tooth powder can 
be applied to a brush without falling off; thus, the level of fluoride 
delivered to the teeth in one application is greater with a toothpaste 
than with a tooth powder, assuming comparable theoretical total 
fluorine.
    The comment submitted a study (Ref. 1) that measured the weight of 
tooth powder and toothpaste applied in a single application to a tooth 
brush. Subjects were instructed to generously pour tooth powder onto a 
wet toothbrush so that the bristles were completely covered. The 
subjects were also instructed to apply to a similar size brush an 
amount of toothpaste they would normally use during brushing. The 
weight of dental powder in a single application was determined by 
weighing the toothbrush (plus a piece of paper used to catch spillage) 
before and after application; whereas the weight of the toothpaste was 
determined by weighing the package before and after applying a single 
dose to a toothbrush. The results of this study indicated that 
consumers applied an average of 0.8 g of powdered dentifrice and 1.46 g 
of paste to the same type of toothbrush. Results of this study 
indicated that two applications of a powdered dentifrice product of 
poured-bulk density 1.1 g/mL provides a level of fluoride comparable to 
a single application of a fluoridated toothpaste containing the same 
fluoride concentration.
    The data were further analyzed (Ref. 2) to determine what dosage of 
fluoride would be provided if two applications of tooth powder with an 
available fluoride concentration of 850 to 1,100 ppm were placed on a 
toothbrush. The comment stated that, assuming two applications of tooth 
powder and one of toothpaste, the extrapolated amount of available 
fluoride ion delivered to the teeth by the tooth powder is comparable 
to the amount of soluble fluoride ion provided by a toothpaste. Based 
on these data, the comment recommended that the directions specify two 
applications of fluoride powder dentifrices containing 850 to 1,100 ppm 
theoretical total fluorine and a poured-bulk density range of between 
1.0 and 1.2 g/mL.
    One comment discussed directions for use of powdered fluoride 
dentifrices by children under 12 years of age. In the 

[[Page 52482]]
tentative final monograph (53 FR 22430 at 22444), the agency had stated 
that children under 12 years of age may require greater manual 
dexterity to properly use a powdered dentifrice than is needed to 
correctly use a toothpaste. The agency expressed concern about the 
potential for young children to accidentally consume a toxic amount of 
fluoride when using a tooth powder compared to a toothpaste. The 
comment contended that powdered dentifrices do not pose any greater 
risk over pastes for accidental overdoses by children. The comment 
added that, while it believes that children between 6 and 12 years of 
age can use a powdered dentifrice properly, it has no objection to the 
monograph providing that powdered dentifrices not be labeled for use by 
children under 6 years of age and requiring labeling that states use by 
children 6 to under 12 years of age should be only with adult 
supervision. However, the comment expressed concern that such labeling 
might give the false impression that there is an inherent unsafe 
quality with the product, rather than merely a difficulty for children 
to use the product properly. The comment suggested the monograph 
include the following directions and labeling for powdered fluoride 
dentifrices to prevent any such false impressions: ``Since a powdered 
fluoride dentifrice may be difficult for children to use, this product 
is not recommended for children under 6. Children between the ages of 6 
and 12 should use this product under adult supervision.''
    The agency has reviewed the data (Refs. 1 and 2) and determined 
that the directions for use of fluoride powdered dentifrices with a 
poured-bulk density of 1.0 to 1.2 g/mL and an available fluoride ion 
concentration equal to or greater than 850 ppm must specify two 
applications to deliver a comparable amount of fluoride as a fluoride 
toothpaste of the same strength. One study (Ref. 1) showed that in a 
single application 45 percent less tooth powder than toothpaste was 
applied to a similar size brush. Because spillage that occurred during 
the weighing procedure was included in the final applied weight of 
powder, even less tooth powder than toothpaste was actually placed on 
the brush. Thus, the agency agrees with the comment that consumers who 
use two applications of a fluoride tooth powder with a poured-bulk 
density of 1.0 to 1.2 g/mL containing 850 to 1,100 ppm available 
fluoride ion receive an amount of fluoride ion comparable to using a 
single application of a sodium fluoride toothpaste with an available 
fluoride ion concentration equal to or greater than 650 ppm. 
Accordingly, the agency is including directions in this final monograph 
that provide for two applications of fluoride powdered dentifrices. The 
agency is also including in the LTP tables a poured-bulk density range 
of 1.0 to 1.2 g/mL for powdered dentifrices (see section I.F., comment 
37 of this document).
    Regarding the use of powdered fluoride dentifrices by children, the 
agency does not believe that powdered fluoride dentifrices pose a 
greater threat for accidental ingestion than fluoride toothpaste. Also, 
the agency does not believe that children 6 years of age and older are 
likely to consume a toxic amount of fluoride from a dentifrice powder. 
In most instances, such products will be used under adult supervision. 
Further, existing regulations (Sec. 310.201(a)(10)(iv)) establish 
package size limitations for sodium fluoride preparations.
    The agency agrees with the comment that these products should not 
be labeled for use by children under 6 years of age, and should be 
labeled for use with adult supervision by children 6 to under 12 years 
of age. Accordingly, the agency is adding the following directions for 
powdered dentifrices in Sec. 355.50(d)(1)(iii):
    Powdered dosage form with a theoretical total fluorine 
concentration of 850 to 1,150 ppm identified in Sec. 355.10(b)(2). 
Adults and children 6 years of age and older: Apply powder to a wet 
toothbrush; completely cover all bristles. Brush for at least 30 
seconds. Reapply powder as before and brush again. Rinse and spit 
out thoroughly. Brush teeth, preferably after each meal or at least 
twice a day, or as directed by a dentist or doctor. Instruct 
children under 12 years of age in good brushing and rinsing habits 
(to minimize swallowing). Supervise children as necessary until 
capable of using without supervision. Children under 6 years of age: 
Do not use unless directed by a dentist or doctor.
    The agency believes that these directions will not give consumers a 
false impression that there is any inherent unsafe quality with these 
products.

References-

    (1) J. Ross Associates, ``A Dentifrice Use Test,'' draft of 
unpublished study, Comment No. C00066 (Attachment I, Exhibit 5), 
Docket No. 80N-0042, Dockets Management Branch.
    (2) J. Ross Associates, ``A Dentifrice Use Test,'' draft of 
unpublished study, Comment No. C00066 (Attachment I, Exhibit 7), 
Docket No. 80N-0042, Dockets Management Branch.
    15. One comment agreed with the agency's concern expressed in the 
tentative final monograph (53 FR 22430 at 22444) that proper packaging 
is important to prevent moisture contamination of a powdered 
dentifrice, particularly in areas where the humidity is high due to 
showering and bathing. The comment indicated that its powdered 
dentifrice product is sold in a plastic bottle with a flip top cap and, 
therefore, quite effectively prevents moisture contamination.
    As discussed in the tentative final monograph (53 FR 22444), the 
agency agrees with the comment that powdered fluoride dentifrices would 
probably remain more stable for a longer period of time than the paste 
form because there would be less interaction between dry ingredients 
during storage of the dentifrice. However, the agency recognizes that 
the storage conditions of a powdered fluoride dentifrice would have a 
significant impact on whether the product would remain stable longer 
than the paste form. Storage of the powdered product in areas where the 
humidity is high due to showering and bathing would require that the 
container be resistant to moisture contamination.
    A ``tight container,'' as defined in the United States Pharmacopeia 
(U.S.P.), would meet this criterion. The U.S.P. defines a ``tight 
container'' (Ref. 1) as a container that ``protects the contents from 
contamination by extraneous liquids, solids, or vapors, from loss of 
the article, and from efflorescence, deliquescence, or evaporation 
under the ordinary or customary conditions of handling, shipment, 
storage, and distribution, and is capable of tight re-closure.''
    In addition, Sec. 211.94 (21 CFR 211.94) of the FDA current good 
manufacturing practice (GMP) regulations addresses drug product 
containers and closures. Section 211.194(a) states: ``Drug product 
containers and closures shall not be reactive, additive, or absorptive 
so as to alter the safety, identity, strength, quality, or purity of 
the drug beyond the official or established requirements.'' Section 
211.194(b) states: ``Container closure systems shall provide adequate 
protection against foreseeable external factors in storage and use that 
can cause deterioration or contamination of the drug product.''
    Therefore, based on Sec. 211.94 of the FDA GMP regulations and the 
U.S.P. standard for a ``tight container,'' the agency is adding a new 
paragraph in Sec. 355.20(b) that reads: ``Tight container packaging. To 
minimize moisture contamination, all fluoride powdered dentifrices 
shall be packaged in a tight container, which is defined as a container 
that protects the contents from contamination by extraneous liquids, 
solids, or vapors, from loss of the article, and from efflorescence, 
deliquescence, 

[[Page 52483]]
or evaporation under the ordinary or customary conditions of handling, 
shipment, storage, and distribution, and is capable of tight 
reclosure.''

Reference-

    (1) The United States Pharmacopeia 23--The National Formulary 
18, United States Pharmacopeial Convention, Inc., Rockville, MD, p. 
10, 1994.

C. Comments on Labeling of OTC Anticaries Drug Products

    16. One comment responded to the agency's question whether 
consumers would benefit in having OTC fluoride-containing drug products 
labeled to state their fluoride levels. The comment objected to 
fluoride level labeling for OTC anticaries drug products and provided 
the results of a consumer survey as support (Ref. 1). The survey was 
conducted in shopping malls in eight different geographic areas and 
included a sample of 200 women between the ages of 18 and 49. The women 
routinely purchased dentifrice products for their households. In 
addition, 150 women with children between 1 and 5 years of age were 
interviewed to determine the habits and practices of women with 
children regarding the use of fluoride dentifrices. The comment stated 
that the results of the survey indicate that: (1) Consumers believe 
that fluoride in dentifrice products is important in preventing 
cavities, (2) regardless of the unit of measurement, e.g., ppm, 
percent, or milligrams per inch (mg/in), used to label the fluoride 
concentration, consumers believe ``more is better'' when choosing a 
dentifrice because they consistently selected dentifrices labeled with 
the higher net fluoride, indicating that consumers believe that there 
are differences in the effectiveness of fluoride dentifrice products, 
(3) most consumers know how to use fluoride dentifrices, (4) most 
consumers are aware of the fluoride ingredient in the toothpaste, and 
(5) most parents take an interest in and supervise their children's 
brushing habits. Based on these results, the comment concluded that 
labeling fluoride-containing products to state their fluoride levels is 
not useful to consumers and could be misleading. The comment 
recommended that such labeling not be required for OTC fluoride drug 
products.
    The agency has evaluated the consumer survey and determined that it 
has some methodology deficiencies. The major deficiency is an 
inadequate respondent sample size. In order to generalize the findings 
of this study to the general population, it would be necessary to have 
a larger number of respondents. Further, the survey involved only women 
between the ages of 18 and 49 years of age. There were no men in the 
survey nor women above 49 years of age; these people might also have 
reasons for wanting to know the fluoride content. In addition, the 
survey did not attempt to assess the relative understanding by the 
respondents of the various methods of expressing quantities of 
fluoride. Contextual material could have been used to clarify the 
meaning of the measures used, making it more likely that consumers 
could make use of the information provided, regardless of the type of 
measurements used.
    Nonetheless, the survey provides some useful information. It 
demonstrates that more consumers chose a dentifrice labeled with the 
higher net fluoride content, based on the concept that ``more fluoride 
is better.'' Rather than emphasizing fluoride concentration numbers, 
the agency believes that labeling would be more beneficial if it 
informs consumers who have a greater propensity to develop cavities of 
the need to use a higher strength fluoride dentifrice. Therefore, in 
this final rule, the agency is including in Sec. 355.50(f)(2) the 
following optional additional labeling statement for dentifrice 
products containing 1,500 ppm theoretical total fluorine: ``Adults and 
children over 6 years of age may wish to use this extra-strength 
fluoride dentifrice if they reside in a nonfluoridated area or if they 
have a greater tendency to develop cavities.'' Because of concerns 
about dental fluorosis occurring in children under 6 years of age, the 
agency is requiring extra-strength fluoride dentifrice products to 
state in their labeling that the product should not be used by children 
under 6 years of age unless directed by a doctor or dentist. (See 
section I.B., comment 10 of this document.)
    In conclusion, no comments, data, or information were submitted in 
support of fluoride level labeling. Accordingly, this final monograph 
does not contain a requirement that fluoride-containing dentifrice 
products label the quantity of fluoride. However, it does provide an 
optional additional labeling statement that manufacturers may use for 
these products.

Reference-

    (1) Comment No. C0097, Docket No. 80N-0042, Dockets Management 
Branch.
    17. One comment objected to the inclusion of the term ``treatment'' 
as the single recommended term in the proposed statement of identity in 
Sec. 355.50(a). The comment stated that the terms ``treatment'' and 
``dental'' are both appropriate statements of identity for various 
anticavity product dosage forms and that other equally truthful and 
nonmisleading identifiers are also appropriate. The comment made two 
recommendations: (1) The term ``treatment'' be retained as an optional 
statement of identify for gels, rinses, concentrated rinses, rinse 
powders, or rinse effervescent tablets, and (2) the term ``dental'' 
also be listed as optional, such as in connection with a professionally 
promoted ``dental treatment gel.'' The comment concluded that its 
suggested revisions to Sec. 355.50(a) would provide for truthful and 
accurate statements of identity.
    Another comment suggested that the agency delete the term 
``treatment'' from the statement of identity and permit ``anticavity 
dental rinse'' or ``fluoride dental rinse'' as a statement of identity, 
because the term ``treatment'' does not appropriately describe the 
activity of these products. The comment stated that these rinse 
products provide their anticaries benefits primarily through a 
prophylactic mode of action and are perceived by consumers as 
preventive prophylactic measures rather than therapeutic treatments. 
The mechanism of fluoride action is well recognized in the scientific 
community and was addressed in the Panel's report (45 FR 20666 at 
20672). According to the comment, the Panel noted that fluoride 
increases enamel resistance to acid solubility, making the teeth less 
susceptible to plaque acid attack, thereby producing its cariostatic 
effect. The comment concluded this is primarily a preventive mode of 
action as contrasted to a therapeutic action. The comment thus proposed 
that the agency delete the term ``treatment'' from the statement of 
identity and permit ``anticavity dental rinse'' or ``fluoride dental 
rinse'' as a statement of identity. The comment concluded that these 
statements of identity are more descriptive and meaningful to consumers 
and more accurately define the therapeutic benefit of an anticaries 
drug product.
    The agency discussed the use of the term ``treatment'' as part of 
the statement of identity for nonabrasive gels and rinses in the 
tentative final monograph (50 FR 39854 at 39866) in response to a 
comment that pointed out that some current dentifrice (abrasive-
containing) products are transparent or translucent and are called gels 
by manufacturers and consumers. Two other comments also expressed 
concern that the use of the term ``gel'' alone for a nonabrasive 0.4-
percent stannous fluoride product could be confusing to 

[[Page 52484]]
the consumer in distinguishing between abrasive and nonabrasive 
fluoride gels; these comments suggested the term ``nonabrasive dental 
gel.'' The agency agreed with the comments that it is important to 
provide labeling that would allow consumers to easily distinguish 
between a nonabrasive and an abrasive-containing fluoride gel, but 
stated that the term ``nonabrasive'' may not be meaningful for 
consumers. The agency also stated that because nonabrasive fluoride 
gels had not been widely marketed, consumers were not familiar with the 
use of the term ``dental gel'' to identify such products, particularly 
in the context of widely marketed abrasive-containing fluoride 
dentifrices labeled as gels. Thus, the agency proposed that the term 
``treatment'' be included in the statement of identity for all 
nonabrasive OTC fluoride products to clearly distinguish between a 
dentifrice and a nonabrasive fluoride product.
    The agency agrees with the comment that the term ``treatment'' can 
be optional for fluoride dental rinses, but disagrees with making this 
term optional for nonabrasive fluoride gels. As discussed in section 
I.A., comment 7 of this document, the agency has added the word 
``preventive'' to the definition of a ``treatment gel.'' The comments 
did not discuss the possibility that consumers could be confused in 
distinguishing a nonabrasive fluoride treatment gel from an abrasive-
containing dentifrice gel. The comment also did not explain how such 
labeling would distinguish a nonabrasive fluoride gel from an abrasive 
fluoride dentifrice. In order for consumers to be better able to make 
this distinction, the agency is requiring that the term ``preventive 
treatment'' be included in the statement of identity for nonabrasive 
fluoride gels. Because a distinction is not needed for fluoride dental 
rinses, the agency is providing that the phrase ``preventive 
treatment'' be optional in the statement of identity for these 
products. The statement of identity for OTC anticaries drug products in 
Sec. 355.50(a) of this final monograph reads as follows:
    The labeling of the product contains the established name of the 
drug, if any, and identifies the product as the following: 
``anticavity fluoride'' (select one of the following as appropriate: 
``dentifrice,'' ``toothpaste,'' ``tooth polish,'' ``tooth powder;'' 
(optional: ``dental'') ``preventive treatment gel;'' or (optional: 
``preventive treatment'' or ``dental'')) (select one of the 
following: ``rinse,'' ``concentrated solution,'' ``rinse powder,'' 
or ``rinse effervescent tablets''). The word ``mouthwash'' may be 
substituted for the word ``rinse'' in this statement of identity if 
the product also has a cosmetic use, as defined in section 201(i) of 
the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 
321(i)).
    18. One comment requested revisions in the proposed statement of 
identity for fluoride-containing products in Sec. 355.50(a). The 
comment contended that a fluoride-containing liquid product labeled 
both to prevent cavities and to freshen the breath should be identified 
as an ``anticavity or fluoride mouthwash,'' whereas a fluoride rinse 
that makes no cosmetic claims should properly be identified as an 
``anticavity or fluoride rinse.''
    Several other comments requested that the statement of identity for 
anticaries drug products include the terms ``tooth powder'' and ``tooth 
polish.'' The comments stated that these terms are commonly recognized 
and have been used in dentifrice product labeling for many years.-
    The agency agrees that a fluoride-containing liquid product 
represented both to prevent cavities and to freshen the breath can 
properly be identified as an ``anticavity or fluoride mouthwash.'' 
Further, the agency agrees that a fluoride rinse with no cosmetic 
claims in its labeling is appropriately identified as a ``rinse.'' The 
agency also agrees that the terms ``tooth polish'' and ``tooth powder'' 
are suitable for use as part of the statement of identity for 
anticaries drug products. The word ``tooth'' indicates the site of 
usage; ``powder'' is a dosage form; and ``polish'' has been used in 
labeling of these products for many years without consumer confusion. 
The word ``polish'' indicates a cosmetic usage. As discussed in comment 
19, the agency's OTC drug regulations do not prohibit placing a 
cosmetic statement of identity of a drug/cosmetic product on the 
principal display panel. Accordingly, the agency is including the terms 
``mouthwash'' (if the product also has a cosmetic use), ``tooth 
polish,'' and ``tooth powder'' in Sec. 355.50(a) in this final rule. 
(For further discussion of the statement of identity, see section I.C., 
comments 17 and 19 of this document.)
    19. Two comments noted that many anticaries drug products also 
properly contain cosmetic ingredients and include cosmetic labeling. 
The comments contended that manufacturers must be permitted to label 
such products with statements of identity that include truthful drug/
cosmetic terminology. For example, the comments stated that the same 
product may be used both as an anticaries dentifrice and as a cleaning 
and breath freshening toothpaste. The comment maintained that such a 
product should be able to truthfully declare in its statement of 
identity what it is and what it does.
    One comment maintained that the agency's labeling policy set forth 
in a proposal to amend the statement of identity requirements for OTC 
drugs published in the Federal Register of April 17, 1986 (51 FR 
13023), along with the agency's exclusivity and label separation 
policies, make it impossible for a manufacturer to comply with both the 
drug and cosmetic labeling requirements set forth in the statute and 
regulations. The comment pointed out that existing FDA regulations 
require that the statement of identity for both drug and cosmetic 
products appear on the principal display panel of the product. The 
comment contended that the effect of the agency's drug-cosmetic label 
separation policy is that the cosmetic statement of identity may not be 
placed on the principal display panel.
    The comment argued that cosmetic terminology should be allowed 
anywhere in the labeling of an anticaries dentifrice that is also a 
cosmetic product so long as it does not render the product's labeling 
false or misleading. The comment argued that consumers would not be 
misled by the inclusion of both kinds of labeling on an anticaries drug 
product. On the contrary, the comment stated that consumers would more 
likely be misled if the drug and cosmetic statements of identity and 
other claims were to appear on entirely different portions of the 
label. The comment concluded that there is no legal or policy 
justification for this label separation policy.
    If a product covered by this rulemaking is marketed for both drug 
and cosmetic use, it must conform to the requirements of the final OTC 
drug monograph and bear appropriate labeling for cosmetic uses in 
accord with section 602 of the act (21 U.S.C. 362) and the provisions 
of 21 CFR parts 701 and 740.
    Sections 201.61 and 701.11 of the CFR require that the statement of 
identity for OTC drug and cosmetic products each appear on the 
principal display panel of the product. The agency's OTC drug 
regulations do not prohibit placing the cosmetic statement of identity 
of a drug/cosmetic product on the principal display panel. However, in 
accordance with the revised labeling requirements for OTC drug 
products, cosmetic claims may not appear within the boxed area 
designated ``APPROVED USES.'' (See section I.A., comment 1 of this 
document.) As discussed in the final rule on the agency's ``exclusivity 
policy'' (51 FR 16258 at 16264 (paragraph 14)), cosmetic terminology is 


[[Page 52485]]
not reviewed and approved by FDA in the OTC drug monographs and 
therefore can not be placed in the boxed portion of the label. Cosmetic 
terminology can, however, be placed outside the box and on the 
product's principal display panel. In addition, 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 other than 
in the product's indications section, such claims should be 
appropriately described so that consumers will be readily 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 sections 502(a) and 602(a) of the act (21 U.S.C. 352(a) and 
362(a)).
    20. One comment objected to the first portion of the agency's 
proposed additional labeling statement for fluoride dental rinses in 
Sec. 355.50(e)(2), which states: ``This is a(n)'' (select one or both 
of the following: ``anticavity'' or ``fluoride'') ``treatment rinse, 
not a mouthwash. Read directions carefully before using.'' The comment 
contended that a properly formulated and labeled product could be 
legally and accurately promoted as both an anticavity dental rinse and 
a cosmetic mouthwash. The comment added that requiring the ``not a 
mouthwash'' statement on fluoride dental rinses is not consistent with 
the agency's well-established policy regarding OTC drugs that claim 
both therapeutic and cosmetic benefits. The comment stated that dual 
drug/cosmetic labeling is permitted in other product categories (e.g., 
antiperspirants, dentifrices, and antidandruff shampoos), and that the 
agency does not require similar labeling statements for such products. 
The comment contended that requiring an anticavity dental rinse/
mouthwash product to display the ``not a mouthwash'' labeling statement 
is inconsistent with agency policy for these other OTC products and 
could be confusing to consumers who have been receiving both benefits 
from previous use of these products.
    The comment argued that the agency's proposal would adversely 
affect the truthful promotion of OTC anticavity dental rinses, and that 
consumers desiring both anticavity and breath freshening activity would 
have to purchase two separate products (i.e., an anticavity dental 
rinse and a cosmetic mouthwash) instead of purchasing one product that 
would provide both benefits. The comment requested the agency to delete 
the statement in proposed Sec. 355.50(e)(2) that says ``This is a(n)'' 
(select one or both of the following: ``anticavity'' or ``fluoride'') 
``treatment rinse, not a mouthwash.''
    In the tentative final monograph for OTC anticaries drug products, 
the agency expressed concern that, because fluoride dental rinses and 
cosmetic mouthwashes are similar in appearance, consumers might confuse 
such products (50 FR 39854 at 39869). The agency stated that proper 
labeling is an important aid to preventing consumer confusion as to the 
use of these products. Therefore, the agency proposed labeling, 
including the labeling statement ``* * * not a mouthwash * * *'' in 
Sec. 355.50(e)(2), to minimize confusion and to help consumers 
distinguish between dental rinses and cosmetic mouthwashes.
    The agency sees no reason why an appropriately labeled OTC fluoride 
rinse cannot also be used for freshening the breath. Such a product can 
properly be identified as an anticavity or fluoride rinse or mouthwash 
(see section I.C., comment 18 of this document). However, the agency 
believes that proper labeling of OTC fluoride rinses is an important 
factor in helping to ensure the safe and effective use of these 
products.
    The agency is concerned that, based upon familiarity with cosmetic 
mouthwash use, a consumer might overuse and/or misuse an OTC fluoride 
rinse. For example, directions for use of fluoride rinses are notably 
different from directions for use of cosmetic mouthwashes. Cosmetic 
mouthwashes are often labeled for multiple use during the day (e.g., 
``first thing in the morning, after meals, and before social 
engagements'') (Ref. 1). Fluoride rinses are labeled for use once or 
twice a day (Sec. 355.50(d)(2)). Cosmetic mouthwash labeling directs 
consumers to ``rinse or gargle 30 seconds'' (Ref. 1). The directions 
for use of fluoride rinses state that consumers should ``* * * swish * 
* * between your teeth for 1 minute * * * Do not eat or drink for 30 
minutes after rinsing'' (Sec. 355.50(d)(2)).
    Based on the above discussion, the agency has determined that the 
``not a mouthwash'' statement need not be required labeling for OTC 
fluoride rinses. Accordingly, the agency is not including proposed 
Sec. 355.50(e)(2) in this final monograph. However, in order to 
maximize the safe and effective use of OTC fluoride rinses, the agency 
concludes that these products must contain labeling that clearly 
instructs consumers to read the directions. The agency also believes 
that this information should be displayed on the principal display 
panel. Therefore, the agency is including in this final monograph new 
Sec. 355.55 as follows: ``Principal display panel of all fluoride rinse 
drug products. In addition to the statement of identity required in 
Sec. 355.50, the following statement shall be prominently placed on the 
principal display panel: `IMPORTANT: Read directions for proper use'.''

Reference-

    (1) Labeling for Scope, OTC Vol. 08AFM, Docket No. 
80N-0042, Dockets Management Branch.
    21. One comment disagreed that the heading ``Indication'' proposed 
in Sec. 355.50(b) was needed in the labeling of OTC fluoride dentifrice 
products. The comment contended that the function of a fluoride 
toothpaste is generally known, and consumers have safely and correctly 
used these products for years without the heading ``Indication'' in the 
labeling of these products. The comment added that the consuming public 
probably does not consider fluoride toothpaste to be a drug in the same 
sense as other common OTC drug products; thus, consumers could be 
confused by this new labeling requirement. The comment suggested that 
Sec. 355.50(b) be revised to make use of the heading ``Indication'' 
optional.
    The agency does not agree that the heading ``Indication(s)'' should 
be optional. All OTC drug monographs in parts 331 through 358 (21 CFR 
331 through 358) have been promulgated with a standard ``Indications'' 
paragraph requiring that the labeling of the product state its FDA 
approved use(s) under the heading ``Indication(s).'' However, two 
general OTC drug product labeling provisions, which were promulgated 
after the comment was submitted, provide alternatives. Section 
330.1(c)(2)(i) provides that, at the option of the manufacturer, the 
``Indications'' may be designated ``APPROVED USES'' or given a similar 
designation as permitted in that paragraph of the regulations. Section 
330.1(i)(8) provides that ``indications'' or ``uses'' may be used 
interchangeably.
    Although the comment claims that consumers may not be accustomed to 
reading such information on dentifrice product labels, the agency 
believes that consumers should be aware that these products are drugs. 
This same principle would apply to other OTC products that consumers 
might not consider to be drugs because they have not contained such 
labeling in the past, e.g., antiperspirants and sunscreens. The comment 
did not provide any evidence that consumers would be confused by 

[[Page 52486]]
reading this type of labeling, which has appeared for years on many 
widely used OTC drug products. The agency finds that informative 
headings such as ``Indications'' or ``Uses'' (as well as ``Warnings'' 
and ``Directions'') are useful to consumers and provide uniformity to 
OTC drug product labeling. Therefore, the agency is not making use of 
the heading ``Indication(s)'' optional.
    22. One comment noted that Sec. 330.1(g) (21 CFR 330.1(g)) requires 
that all drugs, unless exempted, be labeled with the warning ``Keep 
this and all drugs out of the reach of children.'' The comment stated 
that OTC anticaries dentifrices and rinses obviously should not be 
subject to the general warning because they bear directions for use by 
children. The comment requested that OTC anticaries drug products be 
exempted from the requirement to bear this warning.
    The agency agrees, in part, with the comment. The agency recognizes 
that fluoride dentifrices are generally kept within the reach of 
children to encourage use on a regular basis. The agency is concerned 
that the general warning ``Keep this and all drugs out of the reach of 
children'' could discourage or inhibit parents from keeping fluoride 
dentifrices within easy reach of children 6 years of age and older who 
are able to use dentifrice products safely and effectively. However, 
these products should not be within easy reach of children under 6 
years of age, who should be supervised and instructed in the proper use 
of these products and who are vulnerable to dental fluorosis. Thus, in 
Sec. 355.50(c) of this final monograph, the agency is modifying the 
Sec. 330.1(g) warning to read as follows for fluoride dentifrice 
products: ``Keep out of the reach of children under 6 years of age.''
    The agency disagrees with the comment with respect to fluoride 
rinses and gels. The agency believes that these dosage forms should not 
be within easy reach of any children. These products are not indicated 
for use in children under 6 years of age on an OTC basis. For children 
6 to under 12 years of age, the products must be labeled for use under 
the supervision of an adult. These fluoride dosage forms are 
potentially more toxic than fluoride dentifrice products because they 
do not contain an abrasive that can bind some the fluoride ion and 
because a child under 6 is more likely to drink a flavored liquid than 
eat large amounts of toothpaste, which may contain up to 40 percent by 
weight of inert abrasive ingredients.
    The agency has reviewed its adverse reaction data base covering the 
period from 1985 to 1992 for reports related to fluoride rinses, gels, 
and dentifrices (Ref. 1). In the 0- to 9-year age group, there were 22 
reports for fluoride rinses and gels, but no reports for fluoride 
dentifrice products. In addition, the agency has reviewed available 
data concerning exposures to fluoride toothpastes and fluoride rinses 
(mouthwash) in annual reports of the American Association of Poison 
Control Centers for the years 1989 to 1991 (Refs. 2, 3, and 4). For 
children under 6 years of age, the number of accidental exposures 
averaged approximately 1,200 per year for fluoride toothpastes and 
almost 1,000 per year for fluoride rinses. However, fluoride toothpaste 
usage is estimated to be 300 times that of fluoride rinses. Thus, the 
accidental ingestion rate for fluoride toothpaste is much lower than 
for fluoride liquid products. Therefore, the available data strongly 
support a requirement that fluoride rinses and gels be labeled in 
accord with the general warning in Sec. 330.1(g), without any 
modifications. This requirement appears in Sec. 355.50(c)(2) of this 
final monograph.

References-

    (1) Food and Drug Administration, Center for Drug Evaluation and 
Research, Adverse Reaction Summary Listing for Fluoride Rinses, 
Gels, and Dentifrices for years 1985 to 1992, OTC Vol. O8AFM, Docket 
No. 80N-0042, Dockets Management Branch.
    (2) Litovitz, T. L. et al., ``1989 Annual Report of the American 
Association of Poison Control Centers National Data Collection 
System,'' The American Journal of Emergency Medicine, 8:421, 1990.
    (3) Litovitz, T. L. et al., ``1990 Annual Report of the American 
Association of Poison Control Centers National Data Collection 
System,'' The American Journal of Emergency Medicine, 9:488, 1991.
    (4) Litovitz, T. L. et al., ``1991 Annual Report of the American 
Association of Poison Control Centers National Data Collection 
System,'' The American Journal of Emergency Medicine, 10:480, 1992.
    23. Two comments disagreed with the directions proposed in 
Sec. 355.50(d)(1) for anticaries dentifrices, which state: ``Adults and 
children 2 years of age and older: brush teeth thoroughly at least once 
daily or as directed by a dentist or doctor. Children under 6 years of 
age should be supervised in the use of this product.'' The comments 
disagreed in two major areas: (1) The agency's reference to brushing at 
least once daily may be misinterpreted by the public as being adequate 
and, therefore, may lead to less brushing and poor oral health care. 
The comments indicated that there is no clear consensus within the 
dental profession as to the number of times teeth should be brushed 
each day. Many dentists recommend brushing after each meal, and, for 
reasons of practicality, brushing at least twice a day--after breakfast 
and in the evening. The comments indicated that they are unaware of any 
data that suggest brushing once a day is adequate, and therefore urged 
the agency not to refer to any minimum number of times for brushing. 
(2) The contraindication for the use of fluoride dentifrices by 
children under 2 years of age is unwarranted because children that age 
have many teeth requiring anticaries protection. The comments stated 
that early instruction of children regarding dental care minimizes the 
risk of fluorosis due to ingestion of fluoride dentifrice and 
encourages good oral health care habits.
    The Panel reviewed several clinical studies that showed fluoride-
containing dentifrices effectively increase resistance to enamel 
solubility and therefore reduce dental decay when applied to the teeth 
at least once a day (Refs. 1, 2, and 3). Radike (Ref. 3) describes 
three 1-year clinical studies with a similar design conducted to 
determine whether the frequency of application affects the 
anticariogenic effect of a stannous fluoride dentifrice. Each study 
used similar stannous fluoride dentifrices, but the subjects (school 
children) were assigned one of three different brushing procedures: (1) 
Unsupervised brushing, (2) supervised brushing once-a-day after the 
noon meal, and (3) supervised brushing three times a day (after 
breakfast and dinner and before retiring). Each brushing regimen was 
assigned approximately the same number of control subjects as test 
subjects. Subjects in a control group assigned to a specific brushing 
procedure brushed with a nonfluoride-containing dentifrice. In the 
study in which no toothbrushing instructions were given and the 
subjects were allowed to follow their usual brushing habits, the 
fluoride dentifrice subjects developed 23 percent fewer new caries than 
those in the control group. In the study with one supervised brushing 
in the school room after the noon meal, the fluoride dentifrice 
subjects developed 34 percent fewer caries than those in the control 
group. In the third study with supervised brushing three times a day 
(after breakfast and dinner and before retiring), the fluoride 
dentifrice subjects developed 57 percent fewer new caries than those in 
the control group. The results from these studies clearly suggest that 
simply cleansing the teeth with an abrasive containing nonfluoridated 
dentifrice is not as effective in reducing the incidence of caries as 
brushing with a fluoride-

[[Page 52487]]
containing dentifrice. The data also show that more frequent topical 
applications of fluoride significantly enhance anticaries protection. 
Supervised brushing with a fluoride dentifrice once-a-day after the 
noon meal resulted in 33 percent fewer cavities than unsupervised 
brushing. Further, subjects who brushed three times a day with a 
fluoride dentifrice experienced: (1) 40 percent fewer new cavities than 
those who brushed with a fluoride dentifrice only once-a-day, even 
under supervision, and (2) 60 percent fewer cavities than those whose 
brushing was unsupervised. The results of these three studies indicate 
that fewer caries occur as frequency of supervised brushing and 
brushing after meals is increased.
    Several additional studies (Refs. 4 through 7) also indicate that 
brushing immediately after meals is the most favorable time to reduce 
the number of cariogenic bacteria from all tooth surfaces. Two review 
studies (Refs. 4 and 6) discussed the role nutrition plays in the 
etiology of dental disease. Both studies concluded that one 
preventative measure to effectively reduce the number of cariogenic 
bacteria present in the mouth is to brush thoroughly after each meal 
with a fluoride-containing dentifrice. Forty years ago, another study 
(Ref. 7) indicated that many dentists and health workers strongly 
recommend that toothbrushing be performed immediately after the 
ingestion of sugar-containing food if brushing is to be effective in 
reducing dental cavities. The study also included a clinical 
investigation evaluating the effectiveness of reducing dental cavities 
by brushing the teeth with one of three types of nonfluoridated 
dentifrices immediately after the ingestion of food. This report (Ref. 
7) dealt with only one of the dentifrices, the neutral paste. Subjects 
in the experimental group were instructed individually to brush their 
teeth thoroughly within 10 minutes after each ingestion of food or 
sweets and, when brushing was not possible, to rinse the mouth 
thoroughly with water. Toothbrushes and dentifrice were supplied to all 
experimental subjects. Subjects in the control group were not supplied 
with dentifrices or brushes, but were instructed to continue their 
customary oral hygiene habits of brushing only on arising and before 
retiring, rather than after the ingestion of food. When this study was 
conducted in 1950, fluoridated toothpastes were not available in the 
marketplace; thus, the control subjects would not have used a 
fluoridated dentifrice as a part of their customary oral hygiene 
habits. Clinical results after 1 year indicated that brushing 
thoroughly immediately after the ingestion of food resulted in a 63-
percent reduction in caries activity in the experimental group when 
compared to the control group.
    A more recent 1982 study (Ref. 8) reviewed the prevention control 
of oral diseases and recommended at least two daily brushings with a 
fluoride dentifrice as effective in reducing the incidence of dental 
cavities. The study further stated that because toothbrushing is 
intended to remove food debris and dental plaque from the teeth, 
brushing after meals and sweet snacks is commonly recommended in dental 
health messages to the public.
    The agency agrees with the comments and with many dentists that 
brushing properly and thoroughly more often than once daily will 
promote better oral health care. Reducing cariogenic activity by 
brushing more often than once a day, particularly after meals, can be 
explained by the synergistic effect of the antienzymatic properties of 
fluoride (45 FR 20666 at 20672) along with the mechanical removal of 
food debris. The Panel recognized that three factors are necessary for 
caries to occur (45 FR 20666 at 20672): (1) The teeth must be 
susceptible to caries, (2) acid-producing bacteria of the mouth must 
colonize on the teeth, and (3) a substrate must be present for bacteria 
to proliferate and to produce acid for demineralization of the teeth. 
Effective anticaries protection is achieved by exposing the tooth 
enamel to fluoride ions and by the mechanical removal of dental plaque 
and food debris from tooth surfaces and gingival tissue areas. Both 
objectives are better accomplished by toothbrushing more often than 
once daily, preferably after meals. The mechanical removal of food 
debris from teeth and gingival areas decreases the availability of 
metabolized carbohydrate sources, which are required for caries 
development.
    The agency agrees with the Panel that brushing with a fluoride-
containing dentifrice at least once daily effectively renders the teeth 
less susceptible to dental cavities. The agency also recognizes, 
however, that anticaries protection could be enhanced by brushing more 
than once a day, preferably after each meal to remove the food 
particles that provide the substrate necessary for bacteria to 
proliferate and produce acid in the development of dental caries (Ref. 
3). Therefore, the agency is revising part of the directions for all 
OTC fluoride dentifrices to read: ``* * * brush teeth thoroughly, 
preferably after each meal or at least twice a day, or as directed by a 
dentist or doctor.''
    The agency disagrees with the comments suggesting that the 
contraindication for children under 2 years of age is unwarranted. Very 
young children cannot be expected to rationally interpret and 
consistently follow the instructions involving proper toothbrushing; 
nor do they have the manual dexterity to use the fluoride dentifrice 
product properly. Children under 2 years of age do not have control of 
their swallowing reflex and do not have the skills to expectorate the 
toothpaste properly (50 FR 39854 at 39867). Although the prevalence of 
dental caries is decreasing, some reports suggest the incidence of mild 
fluorosis (a permanent, mottled discoloration of the teeth) in young 
children is increasing in the United States due to the increase of 
fluoride in our food chain (Ref. 9). Excessive ingestion of fluoride by 
young children increases the risk of fluorosis during the critical time 
of anterior teeth development and can interfere with the successful 
development of other emerging teeth (Ref. 10). Toothbrushing for 
children under 2 years of age when teeth are first emerging may also 
cause minor injury to the soft tissue in the mouth. The agency 
recognizes that young children are most susceptible to mild fluorosis 
as a result of improper use and swallowing of a fluoride dentifrice 
product. Based on the above, the agency concludes that it is 
appropriate to include in the labeling of fluoride dentifrice drug 
products containing 1,000 ppm theoretical total fluorine the following 
sentence: ``Children under 2 years of age: Consult a dentist or 
doctor.'' The agency is including this sentence in the directions in 
Sec. 355.50(d)(1)(i) of this final monograph. The agency is also 
including a similar statement in the directions for dentifrices 
containing 1,500 ppm theoretical total fluorine for children under 6 
years of age (see section I.B., comment 10 of this document).

References-

    (1) Council on Dental Therapeutics, Accepted Dental 
Therapeutics, 37th ed., American Dental Association, Chicago, p. 
303, 1977.
    (2) Council on Dental Therapeutics, ``Evaluation of Super Stripe 
Toothpaste,'' Journal of the American Dental Association, 71:930-
931, 1966.
    (3) Radike, A. W., ``Current Status of Research on the Use of a 
Stannous Fluoride Dentifrice,'' in OTC Vol. 080099.
    (4) Massler, M., ``Nutrition and Dental Decay,'' Food and 
Nutrition News, 39:1-4, 1968.
    (5) Nikiforuk, G., and J. B. MacDonald, ``An Evaluation of 
Dentifrices in the Prevention of Dental Caries and Gingivitis,'' 
Journal of the 

[[Page 52488]]
Canadian Dental Association, 21:557-565, 1955, Abstracted in Dental 
Abstracts, 1(4):227, 1956. -
    (6) Finn, S. B., and R. B. Glass, ``Sugar and Dental Decay,'' 
World Review of Nutrition and Dietetics, 22:318-320, 1975.
    (7) Fosdick, L. S., ``The Reduction of the Incidence of Dental 
Caries. 1. Immediate Tooth-Brushing with a Neutral Dentifrice,'' The 
Journal of the American Dental Association, 40(2):133-143, 1950.
    (8) Council on Dental Therapeutics, Accepted Dental 
Therapeutics, 39th ed., American Dental Association, Chicago, pp. 
335-337, 1982.--
    (9) Leverett, D. H., ``Fluorides and the Changing Prevalence of 
Dental Caries,'' Science, 217:26-30, 1982.--
    (10) Simard, P. L. et al., ``The Ingestion of Fluoride by Young 
Children,'' Journal of Dentistry for Children, 56:177-181, 1989.
    24. Three comments objected to the directions proposed in 
Sec. 355.50(d)(1) for anticaries products marketed in a dentifrice 
dosage form (containing 1,000 ppm theoretical total fluorine), which 
states: ``Children under 6 years of age should be supervised in the use 
of this product.'' The comments contended that this is the type of 
language that is customarily used for products or activities that are 
dangerous, thus the language is needlessly alarmist. The comments 
explained that ``supervision'' in this usage connotes watchfulness to 
prevent any action by the child that could lead to harm. The comments 
claimed that a parent reading this direction for use might infer that 
toothpaste has some dangerous hidden toxicity. The comments emphasized 
that the important point is that children should be trained how to 
brush their teeth so that they will obtain the desired benefit of 
toothbrushing without swallowing excessive amounts of toothpaste, which 
would increase their risk of fluorosis. One comment stated that the 
proposed labeling implies that even after good brushing habits are 
acquired, every toothbrushing event until age 6 should be supervised by 
a parent. The comments requested that the directions be revised to 
read: ``Instruct children under 6 years of age in good brushing and 
rinsing habits as recommended by your dentist.'' The comments argued 
that implicit in the concept of instruction is supervision until the 
parent is satisfied that the child can follow the instruction 
correctly. The comments concluded that the term ``instruction'' rather 
than ``supervision'' provides the correct emphasis, provides useful 
guidance adequate to deal with the concern about fluorosis, and does so 
without stimulating unwarranted parental concern.
    Another comment did not object to the term ``supervised'' in the 
direction for dentifrices containing 1,000 ppm theoretical total 
fluorine, but requested the agency to expand Sec. 355.50(d)(1) to read: 
``To prevent swallowing, children under 6 years of age should be 
supervised in the use of toothpaste (mouthrinse).'' The comment stated 
that young children should be educated in the proper manner of 
toothbrushing so as to help enhance proper brushing technique as well 
as appropriate product use (i.e., using small portions and spitting the 
dentifrice out after use, rather than ingestion). The comment stated 
that the Council on Dental Therapeutics of the American Dental 
Association (ADA) has recently adopted this statement and directed its 
use on all labeling for Council-accepted fluoride-containing 
dentifrices and mouthwashes.
    The agency agrees with the comments. The Panel recommended that 
fluoride dentifrices be labeled to indicate that children under 6 years 
of age should be supervised in the use of these products. In the 
tentative final monograph for OTC anticaries drug products (50 FR 39854 
at 39867), the agency interpreted the Panel's statement to mean that 
all children under 6 years of age should be properly instructed and 
supervised in the use of a dentifrice, but the amount of supervision 
may vary depending on a child's skills. If a child has fairly good 
toothbrushing skills, parents may allow unsupervised brushing, but may 
wish to check the child's toothbrushing techniques periodically. The 
agency did not intend that every toothbrushing event until age 6 should 
be supervised. As the comments suggested, the important point is for 
parents to assure themselves that their children are learning the 
proper use of dentifrices, and once they are assured of this, 
supervision is no longer required. The agency agrees that the labeling 
should make this point without being unnecessarily overcautious or 
alarmist.
    Regarding the request to expand Sec. 355.50(d)(1) to include the 
language ``To prevent swallowing * * * ,'' the agency agrees that the 
objective of instruction and supervision is to avoid excessive 
ingestion of the dentifrice. However, the agency believes that the word 
``prevent'' may be too strong a term and that prevention of some 
swallowing of dentifrices is unachievable in young children. The amount 
of dentifrice ingested varies with the age and skill of the child. The 
Panel reviewed a study (Ref. 1) involving children 2 to 6 years of age 
that showed large individual variations in expectorated volumes after 
mouthrinsing with water. Only a few of the children between 2 and 3 
years of age could perform mouthrinsing without swallowing the fluid. 
The 3- and 4-year-old children could, as a rule, keep the fluid in 
their mouths for 30 seconds. The 5- and 6-year-old children could all 
perform the rinse for 1 minute; these children had considerably less 
individual variation in expectorated volumes. Based on these data, the 
agency finds that suggesting to parents that swallowing can be 
prevented may cause unnecessary alarm when they observe a young child 
swallow small amounts of dentifrice during the learning process. 
Accordingly, the agency is using the word ``minimize'' instead of 
``prevent'' in this final monograph. The revised direction statement in 
Sec. 355.50(d)(1)(i) reads: ``Instruct children under 6 years of age in 
good brushing and rinsing habits (to minimize swallowing). Supervise 
children as necessary until capable of using without supervision.''

Reference-

    (1) Ericsson, Y., and B. Forsman, ``Fluoride Retained from 
Mouthrinses and Dentifrices in Preschool Children,'' Caries 
Research, 3:290-299, 1969.
    25. One comment objected to the part of the proposed directions in 
Sec. 355.50(d)(2)(i) for anticaries products marketed for use as 
treatment rinses, which states: ``Children under 12 years of age should 
be supervised in the use of this product.'' The comment stated that the 
Panel recommended that children under 6 years of age be supervised in 
the use of fluoride dentifrices (45 FR 20666 at 20673), but did not 
mention children above 6 years of age. The comment suggested that the 
Panel's recommendation was made in order to limit daily fluoride 
ingestion and thereby avoid possible dental fluorosis. The comment 
cited the Panel's discussion of epidemiological and clinical findings 
that indicated that teeth of children 6 years of age and older are 
``(excepting third molars) * * * too advanced to be affected by 
excessive daily fluoride ingestion.'' The comment mentioned the Panel's 
discussion (45 FR 20666 at 20673) that children 6 years of age and 
older have developed control of their swallowing reflexes and are able 
to rinse for 1 minute and expectorate properly. The comment stated that 
if the agency is concerned that children between 6 and 12 years of age 
using the product for the first time may not be able to follow label 
directions without instruction from a parent or other adult, then 
limited directions about supervision might be useful. However, the 
comment expressed concern that continuing 

[[Page 52489]]
supervision each time the product is used did not appear warranted and 
that this unnecessarily overcautious labeling could discourage use of 
these products.
    The agency agrees. As discussed in comment 24, the agency 
interpreted the Panel's statement to mean that children under 6 years 
of age should be properly instructed and supervised in the use of a 
dentifrice, not because of any particular hazard, but to ensure that 
the child is developing adequate toothbrushing skills and is using the 
product correctly. Instruction and supervision serve the same purpose 
for fluoride rinses (i.e., to assure proper use of these products) and 
are not intended to discourage use of fluoride rinses by children. Once 
the parent is certain that the child is using the product correctly, 
unsupervised use may be allowed. Therefore, the agency is revising part 
of the directions statement to read: ``Instruct children under 12 years 
of age in good rinsing habits (to minimize swallowing). Supervise 
children as necessary until capable of using without supervision.''
    26. One comment disagreed with the agency's proposal to include the 
following statement in Sec. 355.50(c) as a warning for concentrated 
treatment rinse solutions, powders, and effervescent tablets: ``Do not 
use before mixing with water. Read the directions carefully.'' The 
comment stated that neither the Panel in the advance notice of proposed 
rulemaking (45 FR 20666) nor the agency in the tentative final 
monograph for OTC anticaries drug products identified a compelling 
safety hazard that warrants including the information in the warnings 
section rather than in the directions for use. The comment contended 
that the safe use of these concentrated products is amply ensured by 
including the quoted language in the directions for use. The comment 
requested that this information be included in the directions section 
only, because it concerns proper use of a product rather than 
cautioning to prevent possible dangers of misuse.
    In the tentative final monograph, the agency stated that, in order 
to alert consumers that dental rinse products in concentrated form 
(solutions, powders, and effervescent tablets) must be diluted or 
dissolved in water before using, the agency is proposing the warning 
stated above for these dosage forms. The agency agrees with the comment 
that consumers could equally be alerted if this information appeared in 
the directions for use section. Accordingly, in this final monograph, 
the agency is moving the statement ``Do not use before mixing with 
water.'' from the warnings to the directions for use section. This 
statement is to appear as the first statement under the directions for 
use for concentrated treatment rinse solutions, powders, and 
effervescent tablets. It should then be followed by the proper 
directions for preparing the diluted rinse product. The part of the 
proposed warning that stated ``Read the directions carefully.'' is not 
needed when this revised labeling format is used.
    27. Several comments objected to the agency's proposed labeling 
statement in Sec. 355.50(e)(3) for OTC stannous fluoride-containing 
dentifrices, treatment gels, and treatment rinses, which states: ``This 
product may produce surface staining of the teeth. Adequate 
toothbrushing may prevent these stains which are not harmful or 
permanent and may be removed by your dentist.'' In support of their 
objections to this statement, one comment cited five published studies 
(Refs. 1 through 5) and another comment submitted an unpublished study 
of the incidence of stained teeth in school children who used a 
stannous fluoride dentifrice (Ref. 6). Stating that the evidence 
regarding the propensity of stannous fluoride products to stain teeth 
is equivocal, another comment argued that the labeling statement should 
be required only on those stannous fluoride products that have been 
scientifically proven to cause substantial and discernible staining on 
the teeth of users. The comment urged the agency to abandon or strictly 
limit its proposal to require a teeth staining labeling statement on 
OTC stannous fluoride dentifrice products.
    Three comments noted that the Panel specifically stated in its 
discussion of stannous fluoride dentifrice drug products (45 FR 20666 
at 20685) that ``* * * the frequency and intensity of staining with the 
level of tin present in these formulations does not appear to present 
any significant problem; therefore, no labeling statement on staining 
shall be required for stannous fluoride dentifrice formulations * * 
*.'' Two of the comments stated that the agency failed to offer any new 
evidence that would make the findings of the expert panel 
inappropriate. One of the comments asserted that all the studies cited 
by the agency in support of the proposed labeling statement for 
stannous fluoride dentifrice products (50 FR 39854 at 39865 and 39866) 
were cited previously by the Panel as support for its conclusion that 
no labeling statement about tooth staining was necessary (45 FR 20666 
at 20685). Another comment mentioned extensive experience with the 
first stannous fluoride dentifrice formulation marketed in the United 
States. This comment stated that no incidence of surface staining was 
found that would justify such a labeling statement.
    One comment suggested that the tendency of stannous fluoride 
products to cause staining of the teeth is directly related to a number 
of factors. It may be highly dependent on the formulation of the 
product and/or the brushing habits of the user. The comment stated that 
the stability of the fluoride and the stannous ions in a product have 
an effect on whether or not the product causes tooth staining. For 
example, a product that contains a high level of stannous ions may be 
more likely to stain teeth than a product that is stabilized and, 
therefore, does not contain many stannous ions. The comment asserted 
that stable stannous fluoride products (e.g., dental gels) are not 
likely to cause discernible staining. The comment concluded that the 
labeling statement about tooth staining should not be imposed 
indiscriminately on all stannous fluoride products without regard to 
the stability of the product.
    One comment contended that requiring the labeling statement about 
tooth staining on stannous fluoride dentifrice products would cause 
undue concern among consumers. The comment was concerned that the 
proposed warning would cause users to avoid safe and effective stannous 
fluoride products in favor of other products that do not bear such a 
warning. Another comment stated that requiring such a labeling 
statement without reliable scientific support is damaging to consumers 
who may place undue emphasis on the possibility of some transient 
staining. The first comment added that requiring the labeling statement 
regardless of whether or not a product caused staining of the teeth 
would handicap stannous fluoride products that could be shown not to 
cause a greater amount of staining than any other fluoride product.
    Another comment contended that the data used by the agency to 
support the tooth staining labeling statement (50 FR 39854 at 39865 and 
39866) are flawed and do not support the agency's decision to require 
this statement on stannous fluoride products. Stating that none of the 
studies attempted to relate the incidence of staining to any element of 
the dentifrice other than stannous fluoride, the comment asserted that 
interaction between the polishing agent (abrasive) and the fluoride 
moiety may be responsible for any staining observed. The comment noted 
that the polishing agent in the stannous fluoride dentifrices in some 
studies was sodium 

[[Page 52490]]
metaphosphate. The comment maintained that it is impossible to know 
whether similar results would have occurred if a different polishing 
agent had been used. The comment concluded that these data show that 
stannous fluoride contained in a dentifrice base of sodium 
metaphosphate can cause mild staining in some subjects when analyzed by 
investigators in blind, controlled settings.
    The comment added that the studies used by the agency to support 
the proposed staining statement (50 FR 39854 at 39865 and 39866) did 
not compare the reported incidence of tooth staining with consumer 
perception of such staining. The comment maintained that these studies 
demonstrate that tooth staining caused by stannous fluoride products is 
barely perceptible by consumers and is of little importance to the vast 
majority of people under normal conditions of daily use. The comment 
and another comment mentioned a study by Ness, Rosekrans, and Welford 
(Ref. 5) that also demonstrates that staining is barely perceptible and 
not important to consumers.
    One comment agreed with the Panel that a labeling statement about 
tooth staining is unnecessary for stannous fluoride dentifrices. 
However, the comment asserted that, if the agency determines that such 
a labeling statement is necessary, the data support only a limited 
labeling statement for stannous fluoride dentifrice products in which 
sodium metaphosphate is the polishing agent. In addition, the comment 
requested that this labeling statement be modified to reflect the 
underlying data as follows: ``This product may occasionally produce 
minor temporary surface staining of teeth. Adequate toothbrushing will 
prevent these stains and they may be easily removed by your dentist.''
    The agency does not believe that the studies submitted by the 
comments support eliminating the labeling statement regarding tooth 
staining from stannous fluoride dentifrice products. Although two of 
the six studies submitted do not show significant staining caused by 
stannous fluoride dentifrice products (Refs. 5 and 6), four of the six 
studies (Refs. 1 through 4) demonstrate that test groups using stannous 
fluoride dentifrice products had significantly more tooth staining than 
groups using dentifrice products without fluoride. Three of these 
studies (Refs. 1, 2, and 4) used a dentifrice with calcium 
pyrophosphate as the abrasive agent. Sodium metaphosphate was the 
abrasive agent used in the other study (Ref. 3). These studies do not 
indicate that tooth staining is related to any individual polishing 
agent. However, based on the information available from the studies, 
the agency is unable to determine if staining is a formulation specific 
problem. The agency believes that the information submitted clearly 
demonstrates that stannous fluoride dental products (i.e., dentifrices, 
nses, and gels) have the potential to produce surface staining of the 
teeth. The agency is not aware that such staining results from the use 
of any other commonly utilized fluoride ingredients.
    The agency reaffirms its conclusion that a labeling statement 
regarding tooth staining should be required on all stannous fluoride 
products. The agency believes that: (1) Consumers should be advised 
that staining of the teeth may be caused by stannous fluoride products, 
including dentifrices, and (2) that adequate brushing or dental 
prophylaxis may prevent the stains. The agency does not believe that 
one comment's suggested labeling statement about tooth staining has any 
advantage over the statement proposed by the agency in the tentative 
final monograph. The comment's suggested statement uses words like 
``occasionally'' and ``minor'' and is more ambiguous than the agency's 
proposed statement. The agency's statement conveys a more meaningful 
message using the phrase ``may produce surface staining.'' In addition, 
the agency's statement advises the consumer that the staining is not 
harmful or permanent. The agency considers its proposed statement to be 
more informative than the comment's suggested statement and more 
helpful to consumers. Therefore, the agency is including its proposed 
labeling statement in Sec. 355.50(e)(2) of this final monograph.

References--

    (1) Jackson, D., and P. Sutcliffe, ``Clinical Testing of a 
Stannous Fluoride-Calcium Pyrophosphate Dentifrice in Yorkshire 
School Children,'' British Dental Journal, 123:40-48, 1967.
    (2) James, P. M. C., and R. J. Anderson, ``Clinical Testing of a 
Stannous Fluoride-Calcium Pyrophosphate Dentifrice in 
Buckinghamshire School Children,'' British Dental Journal, 123:33-
39, 1967.
    (3) Naylor, M. N., and R. D. Emslie, ``Clinical Testing of 
Stannous Fluoride and Sodium Monofluorophosphate Dentifrices in 
London School Children,'' British Dental Journal, 123:17-23, 1967.
    (4) Slack, G. L. et al., ``Clinical Testing of a Stannous 
Fluoride-Calcium Pyrophosphate Dentifrice in Essex School Girls,'' 
British Dental Journal, 123:26-33, 1967.
    (5) Ness, L., D. L. Rosekrans, and J. F. Welford, ``An 
Epidemiological Study of Factors Affecting Extrinsic Staining of 
Teeth in an English Population,'' Community Dentistry and Oral 
Epidemiology, 5:55-60, 1977.
    (6) Katayama, T., ``Incidence of Stained Teeth on School 
Children Who Have Used Stabilized SnF2 Toothpaste for Three 
Years,'' unpublished study in Comment No. C63, Docket No. 80N-0042, 
Dockets Management Branch.
    28. One comment requested that the professional labeling in 
Sec. 355.60 be modified to require that only dental rinse formulations 
composed of ingredients suitable for swallowing be used as fluoride 
supplements intended for ingestion in areas where the water supply is 
nonfluoridated. The comment stated that this section, as proposed, does 
not mention that fluoride rinses promoted to health professionals and 
not offered to the general public are specially formulated with 
ingredients suitable for ingestion. These products are intended to be 
swallowed. The comment mentioned that dental rinse products not 
intended to be swallowed are formulated differently and contain other 
ingredients.
    The agency agrees that further explanation of the term 
``supplement'' would help to reduce possible confusion. Therefore, the 
agency is modifying the introductory language in the professional 
labeling in Sec. 355.60 as follows: ``The labeling for anticaries 
fluoride treatment rinses identified in Sec. 55.10 that are specially 
formulated so they may be swallowed (fluoride supplements) and are 
provided to health professionals (but not to the general public) may 
contain the following additional dosage information: * * *.'' Also, the 
agency is including a definition of fluoride supplement in Sec. 355.3 
as follows: ``Fluoride supplement. A special treatment rinse dosage 
form that is intended to be swallowed, and is promoted to health 
professionals for use in areas where the water supply contains 0 to 0.7 
parts per million fluoride ion.''

D. Comments on the Switch of Prescription Anticaries Drug Products to 
OTC Status

    29. One comment objected to the proposed prescription-to-OTC switch 
of 0.4 percent stannous fluoride gel products for economic and labeling 
reasons. The comment indicated that currently only small manufacturers 
make and market these products on a prescription basis. The comment 
asserted that OTC status would disadvantage these small companies by 
forcing them into the OTC marketplace with obvious competitive and 
marketing expenses. According to the comment, promoting its products 
through health-care professionals is less costly than promoting the 
products to the general 

[[Page 52491]]
public on an OTC basis. The comment contended that OTC status creates a 
labeling problem that does not exist when these products are marketed 
as prescription drugs. The comment identified this problem as 
a``negative statement'' required in the product's labeling, i.e., ``not 
a toothpaste.'' The comment concluded by suggesting that the interests 
of the consuming public and ``small'' entities are best served by not 
including 0.4 percent stannous fluoride gel in the OTC drug monograph 
and by continuing its prescription status.
    The agency does not agree with the comment. The Panel recommended 
that certain fluoride dental rinses and gels, which had previously been 
restricted to prescription use, be made available OTC provided that 
they conform to package size limitations and proper labeling to avoid 
misuse (45 FR 20666 at 20666, 20674, and 20691). (Package size 
limitations are discussed in section I.G., comment 46.) The Panel 
reviewed four published studies on stannous fluoride dental gels 
containing 0.4 percent stannous fluoride in an anhydrous glycerin gel 
(45 FR 20682) and concluded that these studies provide sufficient 
documentation of the safety and effectiveness of this dental gel dosage 
form for OTC use. In the tentative final monograph (50 FR 39854 at 
39858), the agency concurred with the Panel's recommendation that 0.4 
percent stannous fluoride in an anhydrous glycerin gel be switched to 
OTC status and labeled with proper directions for use (45 FR 20688).
    The agency is aware that the change of 0.4 percent stannous 
fluoride dental gels from prescription-to-OTC status will lead to 
different marketing strategies and promotional activities. However, the 
agency has determined that such a product can be generally recognized 
as safe and effective and marketed as an OTC product. This OTC status 
does not prevent a manufacturer from continuing to promote the use of 
such products through health-care professionals, who then would 
instruct their patients to purchase and use the products.
    In response to the comment's objection to the proposed labeling of 
its product with the statement ``This is not a toothpaste,'' the agency 
indicated in the tentative final monograph (50 FR 39869) that a 
nonabrasive dental gel packaged in a conventional tube can be confused 
with a conventional abrasive-containing dentifrice. There is also a 
safety concern because dentifrices contain an abrasive, while these 
dental gels do not. This safety concern is discussed in section I.G., 
comment 46 of this document. The agency considers the statement for 
dental gel products to be important to their safe OTC use.
    The agency concludes that the OTC availability of 0.4 percent 
stannous fluoride dental gel products provides benefit to consumers and 
poses very little risk of misuse when the products are packaged and 
labeled properly. Therefore, the agency is including 0.4 percent 
stannous fluoride dental gel products in this final monograph.
    30. One comment objected to the 120-mg package size limitation for 
fluoride treatment gels proposed in Sec. 55.20. The comment requested 
that a 7-ounce (oz) package size for 0.4 percent stannous fluoride 
preventive treatment gels (containing 192 mg total fluorine) remain in 
the marketplace, at least as a prescription drug product for use under 
the supervision and direction of the dental profession. The comment 
noted that its decision to market a 7-oz package size of 0.4 percent 
stannous fluoride treatment gel was partially based on the 7-oz package 
size of 0.4 percent stannous fluoride dentifrice products marketed at 
the time its product was introduced into the marketplace. The comment 
noted that, in the tentative final monograph (50 FR 39854 at 39857), 
the agency cited the position and experience since 1958 of the ADA 
concerning package size limitations for OTC rinses and gels in support 
of the proposal in Sec. 355.20 to limit package sizes for dental rinses 
and gels.
    The comment mentioned over 10 years of safe prescription marketing 
of its 7-oz product with a child-proof safety closure. The comment 
contended that consumer use is different with regard to the safe 
handling of prescription drug products, as compared to OTC drug 
products. The comment noted that the agency concluded in the tentative 
final monograph that a toxic dose of fluorine via a dentifrice drug 
product could not be ingested without vomiting, although the agency did 
not address the effect of glycerin (which is used in the treatment gel) 
with regard to vomiting. The comment stated that the 7-oz package size 
of this product represents over 50 percent of its dollar volume and its 
discontinuance would represent a hardship. The comment requested 
reconsideration of the OTC status of the 7-oz package size for its 0.4-
percent stannous fluoride treatment gel. The comment stated that, at a 
minimum, allowing this product to remain in the marketplace on a 
prescription basis would best serve the interests of the dental 
profession and small businesses in the stannous fluoride industry 
without endangering public safety.
    In the tentative final monograph (50 FR 39854 at 39857), the agency 
concurred with the Panel's recommendation that the package size of OTC 
preventive treatment gel products be limited to 120 mg total fluorine 
because of possible safety concerns. The Panel was concerned about the 
significant differences in the amount of fluorine available for 
pharmacological or toxicological action between dentifrices (abrasive-
containing) and nonabrasive treatment gels and rinses. Available 
fluoride in a dentifrice is dependent upon the chemical reactivity of 
the fluoride ion with the abrasive (45 FR 20675 to 20677), while all of 
the fluoride ion in the nonabrasive preventive treatment gel is 
available. There are potential safety concerns (i.e., ingestion of an 
entire package that could cause serious effects, particularly for a 
small child) when the 120-mg total fluorine package size limitation for 
a preventive treatment gel is exceeded. This package size limitation 
appears in Sec. 355.20 of this final monograph. Although the package 
size will vary depending on the concentration of the fluoride 
ingredient in the product, the maximum OTC package size of a 0.4-
percent stannous fluoride preventive treatment gel product is 4.375 oz. 
The agency has no objection to larger size packages being available as 
prescription drug products. However, if a manufacturer wishes to market 
a 0.4-percent stannous fluoride preventive treatment gel product in a 
larger package size on a prescription basis, the manufacturer must 
obtain an approved NDA under section 505 of the act (21 U.S.C. 355) and 
part 314 of the regulations.
    The comment provided no data or information in support of its 
contention that the general public handles prescription drugs 
differently than OTC drugs. The agency believes that more potent 
prescription drug products generally are handled differently than most 
OTC drugs. However, the agency is unaware of any data that suggest that 
consumers handle prescription anticaries gels and treatment rinses 
differently than OTC anticaries fluoride mouthwashes and rinses.
    The agency indicated in the tentative final monograph (50 FR 39857) 
that the safety of dentifrice pastes containing up to 260 mg fluoride 
can be attributed to: (1) The decreased amount of fluoride actually 
available for absorption because of the reactivity of fluoride with the 
abrasive in dentifrice pastes; and (2) the likelihood that the amount 
of dentifrice that contains a toxic dose of fluoride 

[[Page 52492]]
could not be ingested without vomiting. The comment provided no 
information or data on the effect of glycerin in a dental gel with 
regard to vomiting in support of its contention that larger package 
sizes be allowed for the gel dosage form. Without data, the agency 
cannot determine glycerin's role on vomiting if large amounts of a 
dental gel were to be ingested. In conclusion, the agency does not 
consider the comment's arguments supportive of its requests that 0.4 
percent stannous fluoride gels remain prescription drugs or that the 
120-mg package size be increased for such products marketed on an OTC 
basis.

E. Comments on Combination Anticaries Drug Products

    31. One comment submitted new data and information to support the 
safety and effectiveness of a combination drug product containing 0.05 
percent sodium fluoride and 1.5 percent hydrogen peroxide. The comment 
stated that this combination drug product, which was not considered in 
the tentative final monograph for OTC anticaries drug products, is 
targeted for once-daily use in an orthodontic population. The comment 
contended that this combination of ingredients provides rational, 
concurrent therapy as an oral cleanser and anticaries agent for 
orthodontic patients for two reasons: (1) Orthodontic appliances 
occasionally cause minor irritation or injury to the oral mucosa and 
the product cleanses these irritations or injuries, and (2) the 
configuration of the orthodontic appliance and its duration of use may 
cause decalcification of teeth in orthodontic patients and the product 
reduces tooth decalcification.
    The comment stated that the safety of the 0.05-percent sodium 
fluoride component of the product was recognized by FDA in the 
tentative final monograph for OTC anticaries drug products (50 FR 39854 
at 39872). The comment submitted data (Ref. 1) from an enamel 
solubility reduction test and an enamel fluoride uptake test to support 
the effectiveness of the sodium fluoride in the combination product. 
The comment also submitted a clinical study of the combination product 
to support the safety of daily exposure of the oral mucosa to 1.5 
percent hydrogen peroxide for an 18-month period (Ref. 1). The comment 
added that the effectiveness of up to 3 percent hydrogen peroxide as an 
oral cleanser was established in the tentative final monograph for OTC 
oral health care drug products published in the Federal Register of 
January 27, 1988 (53 FR 2436). Based on these data, the comment 
requested that the agency include this combination product in the final 
monograph for OTC anticaries drug products.
    The agency agrees that 0.05 percent sodium fluoride and 1.5 percent 
hydrogen peroxide may be a rational combination for concurrent therapy 
in orthodontic patients. However, as the agency discussed in the 
tentative final monograph for OTC oral health care drug products, the 
Advisory Review Panel on OTC Oral Health Care Drug Products (Oral 
Cavity Panel) was concerned about the chronic use of hydrogen peroxide 
in products such as antimicrobial mouthwashes (53 FR 2436 at 2446 and 
2447). The agency further stated in this discussion that the effects of 
long-term OTC use of hydrogen peroxide would be considered as part of 
the antiseptic segment of the oral health care drug products 
rulemaking.
    After that tentative final monograph was published, the agency 
published a call-for-data for OTC antiplaque drug products in the 
Federal Register of September 19, 1990 (55 FR 38560). The data 
submitted to the agency as a result of this call-for-data will be 
evaluated by the Dental Products Panel. That Panel will consider, among 
other things, the safety of the long-term oral use of hydrogen peroxide 
solutions. The agency believes that the Dental Products Panel is the 
appropriate forum to consider whether a combination product containing 
0.05 percent sodium fluoride and 1.5 percent hydrogen peroxide can be 
generally recognized as safe and effective for long-term OTC use in the 
oral cavity. The agency has informed the manufacturer that it considers 
the combination product to be a new drug that may not be introduced or 
delivered for introduction into interstate commerce without an approved 
NDA (Ref. 2). The agency has deferred this product to the Dental 
Products Panel and will address the submitted data as part of the OTC 
oral health care rulemaking applicable to antiplaque drug products.

References

    (1) Comment No. C80, Docket No. 80N-0042, Dockets Management 
Branch.
    (2) Letter from R. J. Chastonay, FDA, to R. Finn, Chesebrough-
Pond's USA Co., in OTC Vol. 08AFM, Docket No. 80N-0042, Dockets 
Management Branch.
    32. Two comments requested the agency to include the combination of 
sodium fluoride with sodium monofluorophosphate in a dentifrice in the 
final monograph. The comments contended that the combination of two 
Category I fluoride ingredients, particularly sodium fluoride and 
sodium monofluorophosphate, provides a rational combination that has an 
enhanced therapeutic effect and satisfies the agency's combination 
policy in Sec. 30.10(a)(4)(iv) (21 CFR 330.10(a)(4)(iv)).
    One comment submitted two clinical studies (Refs. 1 and 2) to 
support the combination of two fluoride ingredients in a dentifrice. 
The first study (Ref. 1) was a 3-year double-blind, randomized clinical 
study involving 799 children 14 to 15 years old. Two combination 
dentifrices, each containing 0.76 percent sodium monofluorophosphate 
(1,000 ppm theoretical total fluorine) and 0.10 percent sodium fluoride 
(455 ppm theoretical total fluorine) (to provide a theoretical total 
fluorine level of 1,455 ppm) were compared with a fluoride-free control 
dentifrice and with a positive control 0.76 percent sodium 
monofluorophosphate dentifrice (1,000 ppm theoretical total fluorine). 
One of the two experimental combination fluoride dentifrices had an 
alumina abrasive system. The other had a dicalcium phosphate abrasive 
system. The combination dentifrices reduced the incidence of dental 
caries by approximately 26 percent compared with the fluoride-free 
placebo dentifrice, and by approximately 15 percent compared with the 
positive control 0.76 percent sodium monofluorophosphate dentifrice 
with an alumina abrasive system.
    The second study (Ref. 2) was a 3-year clinical trial that involved 
school children who resided in an area with nonfluoridated water. Two 
combination dentifrices containing sodium monofluorophosphate and 
sodium fluoride, either 1,450 or 2,000 ppm theoretical total fluorine, 
were compared to a sodium monofluorophosphate dentifrice containing 
1,000 ppm theoretical total fluorine. Results indicated that after 3 
years of unsupervised brushing, the children who used either the 1,450- 
or 2,000-ppm fluoride dentifrice combinations developed fewer cavities 
than those who brushed with the 1,000-ppm sodium monofluorophosphate 
dentifrice. No significant difference in caries reduction between the 
1,450-ppm and 2,000-ppm fluoride dentifrices was reported.
    Another comment submitted laboratory and clinical data (Ref. 3) to 
support the safety and effectiveness of a dentifrice containing sodium 
fluoride (1,000 ppm) and sodium monofluorophosphate (420 ppm). In one 
study, enamel specimens exposed for 24 hours to a suspension of sodium 
monofluorophosphate alone or in combination with sodium fluoride had 

[[Page 52493]]
greater fluoride uptake with the combination fluorides than with sodium 
monofluorophosphate alone. In another study, a nearly three-fold 
reduction in enamel solubility was shown with the combination of sodium 
fluoride and sodium monofluorophosphate compared to sodium 
monofluorophosphate alone. The comment also provided a graph of enamel 
solubility reduction data from dentifrices containing sodium fluoride 
or sodium monofluorophosphate alone or various combinations of sodium 
monofluorophosphate and sodium fluoride. The comment noted that a 
combination containing 75 percent sodium fluoride and 25 percent sodium 
monofluorophosphate would be optimal. The comment contended that this 
combination produces twice as much reduction in enamel solubility as 
either of the ingredients alone at comparable fluoride concentrations.
    The comment included an animal study in which male rat pups were 
inoculated with streptococci (strain not provided) and placed on a 
standard cariogenic diet for 3 weeks. During this period, the teeth 
were brushed with a sodium monofluorophosphate/sodium fluoride 
dentifrice combination or a control fluoride dentifrice (active 
ingredient and strength not specified). The results of this study 
indicated that the combination of sodium fluoride and sodium 
monofluorophosphate was significantly more ``cariostatic'' than the 
single fluoride dentifrice.
    The comment also mentioned a 3-year clinical study involving 573 
school children. This study was designed to determine the anticaries 
effect of a dentifrice containing a sodium monofluorophosphate/sodium 
fluoride combination (1,420 ppm) with a comparable control toothpaste 
containing only sodium monofluorophosphate (1,315 ppm). After 2 and 3 
years of unsupervised brushing, the number of new decayed, missing, or 
filled (DMF) surfaces was 12 to 50 percent lower in the combination 
fluoride group than in the sodium monofluorophosphate control group. 
Based on the results of this study, the comment concluded that the 
combination of sodium fluoride and sodium monofluorophosphate is 
significantly more effective than sodium monofluorophosphate alone in 
reducing the incidence of dental cavities.
    The comment acknowledged that combinations of fluoride active 
ingredients have not been marketed in the United States. The comment 
stated, however, that the combination of sodium fluoride and sodium 
monofluorophosphate has been widely available in the United States for 
many years. The comment stated that this combination occurs as a result 
of the hydrolysis of sodium monofluorophosphate during contact with the 
tooth surface and during the aging process of the fluoride dentifrice 
formulation itself. The comment indicated that as the dentifrice ages, 
sodium monofluorophosphate undergoes hydrolysis resulting in a 
significant increase of sodium fluoride within the sodium 
monofluorophosphate formulation. The comment added that in the oral 
environment sodium fluoride may represent more than 50 percent of the 
hydrolyzed fluoride species in contact with the tooth surface as a 
result of the hydrolysis of sodium monofluorophosphate alone. The 
comment included several studies showing that sodium 
monofluorophosphate undergoes rapid hydrolysis in saliva and even more 
rapid hydrolysis in the presence of plaque microorganisms. In one study 
(Ref. 3), during a short period of toothbrushing, the levels of 
fluoride ions in saliva were initially much lower with the sodium 
monofluorophosphate dentifrice than with the comparable sodium fluoride 
preparation. However, after 10 minutes in saliva, both dentifrice 
formulations provided almost similar levels of fluoride ions. The 
comment stated that the uncontrolled hydrolysis of the two fluoride 
agents results in an important, but suboptimal, increase in the 
bioavailability of fluoride ions. The comment indicated that a 
combination of fluoride ingredients may provide greater product 
stability if the agency allows manufacturers the opportunity to control 
the ratio of these two fluoride ingredients in the dentifrice 
formulation. According to the comment, this would be better than 
relying on the unpredictable chemical process of hydrolysis to create a 
fluoride combination product. The comment asserted that its dentifrice 
product controls the process of hydrolysis by providing a combination 
fluoride dentifrice with a fluoride ingredient ratio of 3 to 1 (sodium 
fluoride to sodium monofluorophosphate), thereby enhancing the 
therapeutic effect of the anticaries product. However, the comment did 
not indicate how it proposed to control the hydrolysis of the one-
quarter proportion of sodium monofluorophosphate in its product. This 
information is particularly significant if the hydrolysis of sodium 
monofluorophosphate occurs as rapidly in the mouth as the comment 
indicated.
    The comment maintained that the fluoride ion is the effective 
anticaries moiety, and it is irrelevant whether the fluoride ion comes 
from one fluoride salt or a combination of two fluoride salts, as long 
as the fluoride ion is present in safe and effective quantities. The 
comment concluded that these data demonstrate the safety and 
effectiveness of the combination of sodium fluoride and sodium 
monofluorophosphate in a dentifrice product. The comment urged the 
agency to include the combination of sodium fluoride with sodium 
monofluorophosphate in a 3 to 1 ratio as a dentifrice in the final 
monograph.
    The agency has reviewed the available data and concludes that they 
do not support the comments' claims. The data do not demonstrate the 
cariostatic superiority of combination dentifrices containing sodium 
fluoride and sodium monofluorophosphate compared to conventionally 
formulated 0.76 percent sodium monofluorophosphate dentifrices. The 
data do not show that the effect of the sodium fluoride/sodium 
monofluorophosphate combination is greater than the effect achieved by 
the individual active ingredients alone at comparable fluoride ion 
concentrations.
    A combination drug product containing Category I active ingredients 
from the same therapeutic category must satisfy the criteria in 
Sec. 330.10(a)(4)(iv). The ``General Guidelines for OTC Drug 
Combination Products, September 1978'' give clarifying examples 
regarding the combination policy (Ref. 4). Paragraph 3 of these 
guidelines states:
    Category I active ingredients from the same therapeutic category 
that have the same mechanism of action should not ordinarily be 
combined unless there is some advantage over the single ingredients 
in terms of enhanced effectiveness, safety, patient acceptance, or 
quality of formulation. They may be combined in selected 
circumstances to treat the same symptoms or conditions if the 
combination meets the OTC combination policy in all respects, the 
combination offers some advantage over the active ingredients used 
alone, and the combination is, on a benefit-risk basis, equal to or 
better than each of the active ingredients used alone at its 
therapeutic dose.
The agency has not received sufficient data to conclude that the use of 
a combination fluoride product has an advantage over or is more 
effective in controlling the incidence of dental caries than a product 
containing a single fluoride active ingredient at comparable fluoride 
ion concentrations.
    In the clinical studies submitted by the comment, there was no 
comparison of a combination and single ingredient product at comparable 
fluoride concentrations. The agency notes that 

[[Page 52494]]
the higher levels of fluoride concentration in the combination 
dentifrices, 1,455 ppm (Ref. 1) and 1,450 or 2,000 ppm (Ref. 2), as 
compared to the fluoride levels in the positive control single fluoride 
ingredient dentifrice (1,000 ppm), most likely account for the enhanced 
effectiveness of the combination products. Because of these higher 
concentrations, the presence of two sources of fluoride ions may be 
unrelated to the observed increase in effectiveness.
    The agency has also evaluated two other clinical studies (Refs. 6 
and 7) that compared comparable fluoride concentrations (1,000 ppm) for 
a single-ingredient sodium monofluorophosphate dentifrice and a 
combination containing sodium fluoride and sodium monofluorophosphate. 
In these studies, the two dentifrices were comparably effective. One 
study (Ref. 6) was a 31-month, double-blind clinical study involving 
1,027 school-aged children. The anticaries effectiveness of a single 
fluoride ingredient dentifrice containing sodium monofluorophosphate 
(1,000 ppm theoretical total fluorine) was compared with a combination 
fluoride dentifrice containing sodium fluoride and sodium 
monofluorophosphate (1,000 ppm theoretical total fluorine, with 500 ppm 
contributed by each fluoride ingredient). During this study, the 
children brushed daily in school under supervision and were clinically 
and radiologically examined annually. After 31 months of use, no 
statistically significant difference in the incidence of dental caries 
was observed between children in the two dentifrice groups.
    In the second study (Ref. 7), the effectiveness of three 
dentifrices was compared over a 2-year period. The study involved 2,769 
children; a nearly equal number did unsupervised brushing at home with 
one of the following dentifrices: (1) Sodium monofluorophosphate (1,000 
ppm), (2) a combination of sodium fluoride and sodium 
monofluorophosphate containing equimolar amounts of each active 
ingredient (theoretical total fluorine of 1,000 ppm), or (3) a 
combination of sodium fluoride and sodium monofluorophosphate 
containing equimolar amounts of each active ingredient (theoretical 
total fluorine of 2,500 ppm). The results of this study indicated no 
significant differences in caries inhibition among the dentifrices 
tested.
    In most of the in vitro studies submitted (Ref. 3), exposure times 
of the tooth enamel surface to suspensions of dentifrice were for 
lengthy periods of time ranging from 30 minutes to 24 hours. The agency 
questions the relevancy of a 24-hour exposure time when the exposure 
time to a dentifrice formulation in the mouth during actual 
toothbrushing is a few minutes only. In the animal study measuring the 
effect of three dentifrices on the incidence of caries in rats, no 
details were given regarding the active ingredients or the fluoride 
concentrations in the dentifrices tested. Regarding hydrolysis during 
the aging process of sodium monofluorophosphate products, the Panel 
stated that sodium monofluorophosphate exists in water in dynamic 
equilibrium with sodium fluoride, and with the various ions produced by 
the hydrolysis of the compound (45 FR 20666 at 20674). The agency does 
not consider this reaction as producing a combination drug product. The 
agency considers the sodium monofluorophosphate compound as a single 
active ingredient, even though it is aware that the compound always 
contains some amounts of sodium fluoride.
    In conclusion, the agency has determined that the submitted 
information and data do not demonstrate the cariostatic superiority of 
combination dentifrices containing sodium fluoride and sodium 
monofluorophosphate relative to single-ingredient fluoride dentifrices 
with a comparable fluoride ion concentration. Accordingly, these 
fluoride combinations are not included in this final monograph.

References

     (1) Hodge, H. C. et al., ``Caries Prevention by Dentifrices 
Containing a Combination of Sodium Monofluorophosphate and Sodium 
Fluoride,'' British Dental Journal, 149:201-204, 1980.
    (2) Diodati, R. R. et al., ``Clinical Anticaries Effect of 
Various Fluoride Dentifrices,'' Abstract No. 258, Journal of Dental 
Research, 65:198, 1986.
    (3) Comment No. C00059, Docket No.80N-0042, Dockets Management 
Branch.
    (4) Food and Drug Administration ``General Guidelines for OTC 
Drug Combination Products, September 1978,'' Docket No. 78D-0322, 
Dockets Management Branch.
    (5) Conti, A. J. et al., ``A 3-Year Clinical Trial to Compare 
Efficacy of Dentifrices Containing 1.14 Percent and 0.76 Percent 
Sodium Monofluorophosphate,'' Community Dental Oral Epidemiology, 
16:135-138, 1988.
    (6) Juliano, G. F. et al., ``Clinical Study Comparing the 
Anticaries Effect of Two Fluoride Dentifrices,'' Abstract No. 131, 
Journal of Dental Research, 64:189, 1985.-
    (7) Ripa, L. W. et al., ``Clinical Comparison of the Caries 
Inhibition of Two Mixed NaF-Na2PO3F Dentifrices Containing 
1,000 and 2,500 ppm F Compared to a Conventional Na2PO3F 
Dentifrice Containing 1,000 ppm F: Results after Two Years,'' Caries 
Research, 21:149-157, 1987.

F. Comments on Testing Guidelines

    33. One comment agreed with the agency's conclusion that laboratory 
test data are not adequate to establish comparative claims of 
effectiveness for anticaries active ingredients (53 FR 22430 at 22446). 
However, the comment contended that the agency should recognize the 
possibility that, in certain cases, claims of superior performance in a 
laboratory test may be desirable. As a hypothetical example, the 
comment stated that it may be important to a dental professional that 
(1) one active ingredient provides more rapid fluoride uptake than 
another and (2) this performance could promote hardening of enamel in 
certain instances. The comment suggested that such claims could be made 
in professional labeling without needing clinical studies for support.
    The agency reiterates its conclusion that the extension of 
laboratory test data to a comparative evaluation of effectiveness 
between different fluoride products or fluoride active ingredients is 
inappropriate (53 FR 22446). In general, the agency does not believe 
that claims of superior performance in a laboratory test are 
appropriate for use in either the consumer or professional labeling of 
OTC anticaries drug products unless that superior performance has been 
shown to have clinical significance. However, the agency will evaluate 
any such laboratory test data submitted on a case-by-case basis.
    34. One comment (from an agency dental reviewing officer) objected 
to the use of Laboratory Testing Profiles (LTP's) for final formulation 
testing for Category I active ingredients in fluoride dentifrice 
formulations. The comment expressed unawareness of any data submitted 
to the agency demonstrating that the results from the biological test 
requirements in the LTP's were correlated with adequate and well-
controlled anticaries clinical studies. The comment did not submit any 
data demonstrating that the LTP's do not correlate with clinical 
studies.
    Two comments (from manufacturers) concurred with the agency's 
proposal that the LTP's be used to ensure the effectiveness of 
abrasive-containing fluoride drug products. One of the comments 
contended that, based on the current state of dental research, it is 
not necessary to do clinical studies to verify anticaries performance 
except in certain situations, such as the introduction of a new 
anticaries active ingredient.
    Regarding the comment questioning whether the LTP's were correlated 
with 

[[Page 52495]]
adequate and well-controlled clinical testing, the agency notes that 
the Panel based its recommendations on the results of actual biological 
tests performed on fluoride dentifrices that had been shown to be 
clinically effective in preventing caries (45 FR 20666 at 20677). Thus, 
the Panel's recommendations were based on the correlation of laboratory 
testing results with clinical results.
    The agency considers the LTP final formulation test requirements in 
this final monograph to be adequate to ensure the safety and 
effectiveness of dentifrices containing fluoride active ingredients 
included in the monograph. In the tentative final monograph (53 FR 
22430 at 22433), the agency stated reasons why it concurred with the 
Panel's recommended laboratory testing requirements, as set forth in 
the Panel's LTP tables (45 FR 20666 at 20679 to 20681) for Category I 
fluoride ingredient/abrasive combinations. Thus, the agency concludes 
that lengthy clinical trials are not necessary to ensure the safety and 
effectiveness of dentifrices containing monograph fluoride ingredients.
    35. One company asked whether the monograph would preclude FDA's 
accepting valid clinical trials in lieu of LTP's. The comment noted the 
agency's statement in the tentative final monograph that the use of 
LTP's to establish efficacy should not in any way preclude the option 
of clinical testing as a final demonstration of efficacy for those 
companies that prefer to use this method (53 FR 22430 at 22434).
    The monograph does not preclude manufacturers from performing 
clinical testing to ensure the effectiveness of a fluoride dentifrice. 
However, the regulatory requirement for all fluoride dentifrice drug 
products marketed pursuant to the monograph is that the product must 
meet the final formulation test requirements (LTP's) included in 
Sec. 355.70.
    36. One comment stated that all toothpaste advertised as containing 
fluoride should be tested for stannous fluoride concentration, per unit 
volume or weight. The comment contended that this is necessary to 
ensure that the concentration of stannous fluoride is not being 
reduced.
    There are a number of requirements applicable to fluoride 
dentifrices that will ensure the fluoride concentration of the product. 
While toothpastes can contain one of several different fluoride 
ingredients, the LTP's included in the final monograph are intended to 
ensure available fluoride ion in the final products. The aged minimal 
fluoride ion values in the LTP tables are used to determine the 
product's expiration date. This date provides consumers relevant 
information regarding use of the product. In addition, Sec. 211.166 of 
the agency's current good manufacturing practice regulations (21 CFR 
211.166) contains stability testing requirements for drug products, 
including toothpastes. Accordingly, these requirements address the 
comment's concern.
    37. Two comments requested that the agency revise LTP Table 3 to 
include corrected test values submitted by the industry for stannous 
fluoride dentifrices (45 FR 20666 at 20681). One comment noted that the 
agency's revisions in the LTP tables discussed in the tentative final 
monograph (53 FR 22430 at 22435 and 22436) omitted a correction 
mentioned in an earlier comment concerning stannous fluoride that was 
made to this rulemaking. The comment requested that the agency revise 
Table 3 under ``II. Soluble Stannous Ion,'' by inserting a statement 
indicating that the test dilution for the silica abrasive should remain 
1:10 as stated in the tentative final monograph (45 FR 20666 at 20681). 
The second comment indicated that the appropriate values for soluble 
fluoride should discriminate between dentifrices using insoluble sodium 
metaphosphate and silica abrasives. The comment indicated that in Table 
3 for stannous fluoride dentifrices (45 FR 20681) under ``I. Soluble 
Fluoride Ion,'' the test values for fluoride ion listed for the silica 
abrasive formulation should be 600 ppm for the fresh value and 500 ppm 
for the aged minimal value with a test dilution of 1:10, rather than 
700 ppm for the fresh value and 650 ppm for the aged minimal value. The 
comment stated that this revision would discriminate between 
dentifrices using insoluble sodium metaphosphate and those using silica 
abrasives.
    The agency recognizes that the data the Panel used to establish the 
LTP tables were developed by industry and submitted to the Panel to 
provide a basis for the LTP tables. The agency has reviewed the 
industry's corrections of the LTP tables as noted above and agrees that 
these corrections should be made. However, the agency does not find it 
necessary to insert an additional clarification statement in the 
corrected LTP tables as requested by one comment. Instead, the agency 
has revised the LTP tables to reflect the changes made to the tables in 
the tentative final monograph (53 FR 22435 and 22436) and in this final 
monograph (see section I.B., comments 10, 13, 14, and 15 of this 
document, and section I.F., comments 38, 39, and 42 of this document) 
as follows:

              TABLE 1.--Acceptable Test Values for 1,000 PPM Theoretical Total Fluorine Sodium Fluoride Dentifrices in a Paste Dosage Form              
                                                              I. Soluble Fluoride Ion (F-)                                                              
--------------------------------------------------------------------------------------------------------------------------------------------------------
              Abrasive                           Fresh F- value1                   Aged minimal F- value 1,2                 Test dilution (w/w)        
--------------------------------------------------------------------------------------------------------------------------------------------------------
High-beta-phase calcium                                                                                                                                 
 pyrophosphate                                               648 ppm                                403 ppm                                   1:3       
--------------------------------------------------------------------------------------------------------------------------------------------------------


                                                                                                                                                                                   II. Hydrogen Ion Concentration (pH)                                                                                                                                                                                  
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                    Abrasive                                                                                                      Test value                                                                                                                                                              Test dilution (w/w)                                                                           
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
High-beta-phase calcium pyrophosphate                                                                                                                                                                            6.5 to 8.0                                                                                                                                                                         1:3 
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Values listed are parts of the measured substance per million parts of the whole dentifrice.                                                                                                                                                                                                                                                                                                        
\2\ Values listed are intended for use in determining expiration dating for fluoride dentifrices covered by the final monograph. These values are not intended to be used to determine if a dentifrice meets monograph requirements, i.e., is safe and effective.                                                                                                                                       


                                                                                                                                                                                                                                                                                                                                                                                                        

[[Page 52496]]
TABLE 2.--Acceptable Test Values for 1,000 PPM Theoretical Total Fluorine Sodium Monofluorophosphate Dentifrices
                                             in a Paste Dosage Form                                             
                                    I.-Soluble Fluoride Ions (PO3F= and F-)1                                  
----------------------------------------------------------------------------------------------------------------
                                                                           Aged                                 
          Abrasive               Ion              Fresh value2           minimal        Test dilution (w/w)     
                                                                         value2,3                               
----------------------------------------------------------------------------------------------------------------
Applicable to all abrasives  PO3F=                           650 ppm4   Half                               1:10 
                                                                         total                                  
                                                                         (PO3F=                                 
                                                                         and F-)                                
                                                                         value                                  
                             F-                         10 to 150 ppm   10 ppm to                          1:10 
                                                                         PO3F=                                  
                                                                         value                                  
                             Total                            800 ppm   600 ppm                            1:10 
                              (PO3F=                                                                            
                              and F-)                                                                           
----------------------------------------------------------------------------------------------------------------



                                                                                                                                                                                   II.-Hydrogen Ion Concentration (pH)                                                                                                                                                                                  
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                     Abrasive                                                                                                      Test value                                                                                                                                                             Test dilution (w/w)                                                                           
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Alumina                                                                                                                                                                                                           6.4 to 9.0                                                                                                                                                                       1:10 
Calcium carbonate                                                                                                                                                                                                7.0 to 10.0                                                                                                                                                                       1:10 
Calcium pyrophosphate                                                                                                                                                                                             5.0 to 5.4                                                                                                                                                                       1:10 
Dicalcium phosphate                                                                                                                                                                                               6.3 to 7.6                                                                                                                                                                       1:10 
Insoluble sodium metaphosphate                                                                                                                                                                                    5.6 to 6.9                                                                                                                                                                       1:10 
Silica                                                                                                                                                                                                            5.5 to 7.4                                                                                                                                                                       1:10 
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ For the compound sodium monofluorophosphate in a dentifrice formulation, fluoride ion exists as a combination of the ions PO3F= and F-. Values are given for each of these ions as well as the ``Total'': combination of PO3F= plus F-.                                                                                                                                                             
\2\ Values listed are parts of the measured substance per million parts of the whole dentifrice.                                                                                                                                                                                                                                                                                                        
\3\ Values listed are intended for use in determining expiration dating for fluoride dentifrices covered by the final monograph. These values are not intended to be used to determine if a dentifrice meets monograph requirements, i.e., is safe and effective.                                                                                                                                       
\4\ Soluble PO3 is derived either by direct analytical measurement or by subtracting soluble fluoride ion (F-) from total soluble available fluoride (PO3F= plus F-).                                                                                                                                                                                                                                   


             TABLE 3.--Acceptable Test Values for 1,000 PPM Theoretical Total Fluorine Stannous Fluoride Dentifrices in a Paste Dosage Form             
                                                              I. Soluble Fluoride Ion (F-)                                                              
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                 Abrasive                                        Fresh F- value1      Aged minimal F- value1,2    Test dilution (w/w)  
--------------------------------------------------------------------------------------------------------------------------------------------------------
Insoluble sodium metaphosphate                                                              700 ppm                   650 ppm                       1:3 
Silica                                                                                      600 ppm                   500 ppm                      1:10 
Calcium pyrophosphate                                                                       288 ppm                  108 ppm3                       1:3 
--------------------------------------------------------------------------------------------------------------------------------------------------------


                                         II. Soluble Stannous Ion (Sn++)                                        
----------------------------------------------------------------------------------------------------------------
                                                         Aged minimal Sn++                                      
    Abrasive               Fresh Sn++ value1                 value1,2                Test dilution (w/w)        
----------------------------------------------------------------------------------------------------------------
Insoluble sodium                           2,000 ppm   Qualitatively                                       1:10 
 metaphosphate                                          detectable                                              
Silica                      Qualitatively detectable   Qualitatively                                       1:10 
                                                        detectable                                              
Calcium                                      900 ppm   Qualitatively                                        1:3 
 pyrophosphate                                          detectable                                              
----------------------------------------------------------------------------------------------------------------


                                                                                                                                                                                  III. Hydrogen Ion Concentration (pH)                                                                                                                                                                                  
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                Abrasive                                                                                                   Test value                                                                                                                                                                  Test dilution (w/w)                                                                              
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Insoluble sodium metaphosphate                                                                                                                                                                            4.2 to 5.4                                                                                                                                                                               1:4  
Silica                                                                                                                                                                                                    4.6 to 5.1                                                                                                                                                                               1:4  
Calcium pyrophosphate                                                                                                                                                                                     4.4 to 5.1                                                                                                                                                                               1:3  
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Values listed are parts of the measured substance per million parts of the whole dentifrice.                                                                                                                                                                                                                                                                                                        
\2\ Values listed are intended for use in determining expiration dating for fluoride dentifrices covered by the final monograph. These values are not intended to be used to determine if a dentifrice meets monograph requirements, i.e., is safe and effective.                                                                                                                                       
\3\ Value corresponds to that of aged product found clinically effective.                                                                                                                                                                                                                                                                                                                               


            TABLE 4.--Acceptable Test Values for all OTC Fluoride Dentifrices in a Paste Dosage Form            
                                                                                                                
                                                                                                                
                                                                                                                 
I.- Theoretical Total Fluorine1                                                                                 

[[Page 52497]]
                                                                                                                
  A. 850 to 1,150 ppm for all active ingredients                                                                
  B. 1,500 ppm for sodium monofluorophosphate                                                                   
                                                                                                                



                                                                                                                
----------------------------------------------------------------------------------------------------------------
     II. Available Fluoride Ion Concentration1                                                                  
  Active Ingredient                                 Minimum Available Fluoride Ion1                             
A. For 850 to 1,150 ppm Dentifrices:                                                                            
  Sodium fluoride                                    650 ppm                                         
  Sodium monofluorophosphate                         800 ppm (consisting of PO3F= and F- combined)   
  Stannous fluoride/calcium pyrophosphate            290 ppm                                         
  Stannous fluoride/with abrasive other than         700 ppm                                         
   calcium pyrophosphate                                                                                        
B. For 1,500 ppm Dentifrices:                                                                                   
  Sodium Monofluorophosphate                         1,275 ppm (consisting of PO3F= and F- combined) 


                                                                                                                
----------------------------------------------------------------------------------------------------------------
                           III. Total Fluorine in Milligram Per Milliliter Dentifrice                           
A. For 850 to 1,150 ppm Dentifrices:                                                                            
  0.935 to 1.955                                                                                                
B. For 1,500 ppm Sodium Monofluorophosphate Dentifrices:                                                        
  1.650 to 2.550                                                                                                
----------------------------------------------------------------------------------------------------------------
\1\ Values listed are parts of the measured substance per million parts of the whole dentifrice.                


  TABLE 5.--Acceptable Test Values for Sodium Fluoride/Sodium Bicarbonate Powdered Dentifrices Containing 1,000 
                                         PPM Theoretical Total Fluorine                                         
                                                                                                                
                                                                                                                
                                                                                                                 
I. Theoretical Total Fluorine1                                                                                  
  850 to 1,150 ppm                                                                                              
II. Minimum Available Fluoride Ion1                                                                             
  850 ppm                                                                                                       
III. Poured-bulk Density Range in Gram Per Milliliter Dentifrice                                                
  1.0 to 1.2                                                                                                    
                                                                                                                
\1\ Values listed are parts of the measured substance per million parts of the whole dentifrice.                


          TABLE 6--Biological Testing Requirements for all Dentifrices in Paste and Powder Dosage Forms         
                                                                                                                
                                                                                                                
                                                                                                                 
I. Animal Caries Reduction                                                                                      
      and,                                                                                                      
II. One of the Following Tests:                                                                                 
  A. Enamel Solubility Reduction                                                                                
  B. Fluoride Enamel Uptake                                                                                     
                                                                                                                

    38. One comment concurred with the agency's statement (53 FR 22430 
at 22435) that measurements such as specific gravity, pH, stannous ion 
content, maximum test dilution, and lower limit of available fluoride 
at the expiration date should not be included in the final monograph. 
The comment agreed that these measurements are adequately addressed in 
the current good manufacturing practices (CGMP) regulations. The 
comment stated that the CGMP regulations in part 211 (21 CFR part 211) 
provide for acceptable outcomes of the performing, validating, 
recording, and reporting of procedures in drug manufacturing, but the 
CGMP regulations do not provide test methods or acceptable values of 
measurement.
    The comment provided the following example: If control of pH is 
important in manufacturing a dentifrice, the CGMP regulations provide 
that it is necessary to institute and document procedures for ensuring 
accurate recording, control of pH during the process, and acceptable 
checking of equipment. However, the comment stated that the regulations 
do not specify equipment, measurements, or the proper pH range. The 
comment contended that one could reasonably conclude that omission of 
pH, specific gravity, stannous ion concentration, or maximum test 
dilutions from the provisions of the monograph means that manufacturers 
may set these specifications as they see fit.
    However, the comment added that there are other statements in the 
agency's discussion of LTP's that cast doubt on the above 
interpretation. As an example, the comment cited the phrase ``the 
allowable range for specific gravity (1.1 to 1.7) and theoretical total 
fluoride (850 to 1,150 ppm) * * *'' (53 FR 22430 at 22437). The comment 
noted that, even though these ranges are given 

[[Page 52498]]
equal force in this discussion, theoretical total fluoride is specified 
in proposed Sec. 355, while specific gravity is not. The comment also 
mentioned the Panel's recommendations regarding specific pH guidelines 
(53 FR 22443) and the agency's statement that ``* * * manufacturers 
should use the aged minimal fluoride ion limits provided in the LTP 
Tables * * * to determine the expiration dates for fluoride dentifrices 
* * *'' (53 FR 22445). The comment added that the third agency change 
in the Panel's recommendations states that the agency is proposing the 
LTP values of pH and specific gravity (but not stannous ion levels, 
maximum test dilutions, or aged minimal fluoride levels) as guidelines 
of appropriate testing limits. The comment requested that the agency 
clarify its position on these matters.
    The agency's proposal (53 FR 22430 at 22434 and 22435) states that 
fluoride dentifrices shall: (1) Meet or exceed the soluble fluoride ion 
level specified for each particular fluoride ingredient listed in the 
monograph, and (2) meet the requirements for biological testing. The 
agency included these criteria in the proposed monograph. Furthermore, 
the agency is including requirements pertaining to available fluoride 
content and biological testing in this final monograph. (See section 
I.F., comment 40 of this document.) These requirements must be 
satisfied for an anticaries dentifrice to be considered generally 
recognized as safe and effective.
    The agency stated in the tentative final monograph (53 FR 22430 at 
22435) that certain recommended requirements in the LTP tables are 
adequately addressed in the CGMP regulations (21 CFR part 211) and need 
not be specifically addressed in the monograph. These included 
parameters such as specific gravity and pH, which relate to inactive 
ingredients and appropriate manufacturing procedures. The CGMP 
regulations require establishing and following test methods and 
specifications that are appropriate and scientifically sound. These 
required methods and specifications may be found in a variety of 
sources (e.g., the United States Pharmacopeia/National Formulary or 
codified monographs).
    The discussion about testing parameters not specifically included 
in the monograph (such as pH, specific gravity (w/v), stannous ion 
concentration, aged minimal fluoride ion values, and test dilution) was 
intended as guidance only. While these parameters are important to the 
manufacturer's product, only those requirements specifically set out in 
the final monograph are considered essential by the agency and must be 
met. In the preamble to the tentative final monograph (53 FR 22435 and 
22436), the agency revised the Panel's recommended testing guidelines 
for a number of testing parameters. The agency intended that these 
testing values be used solely as guidance for fulfilling CGMP 
requirements.
    In this document, the agency has further revised the proposed 
testing guidelines for parameters other than available fluoride ion and 
biological test requirements (see section I.F., comments 35 and 39 of 
this document). These revised parameters are also intended only as 
guidance, e.g., for use in determining expiration dating. The agency is 
including a revised LTP chart in the preamble of this document for 
informational purposes (see section I.F., comment 37 of this document).
    39. One comment stated its approval of the agency's proposed 
modification of the Panel's recommended ranges for theoretical total 
fluorine. The proposal set out a range of 0.935 to 1.955 mg theoretical 
total fluorine per mL for dentifrices with a specific gravity lower 
than 1.1 or higher than 1.7 (53 FR 22430 at 22438). The comment 
indicated that the proposed modification reflects the dynamic nature of 
dental research and provides innovation without compromising the 
required amount of fluoride ion available to the teeth with each 
brushing. The comment added that this single required range of 
theoretical total fluorine values more accurately defines the amount of 
fluoride ions available to the teeth during each brushing. For that 
reason, the proposed range is more descriptive of products that have 
been proven clinically effective. The comment suggested that a single 
theoretical total fluorine range would be better than the two previous 
proposed ranges of specific gravity and theoretical total fluorine. The 
comment contended that a single range would ensure consumers that the 
active ingredient in dentifrice products delivers the required 
concentration of fluoride ion, thus providing the desired anticaries 
effect.
    In the tentative final monograph for OTC anticaries drug products 
(53 FR 22430 at 22437), the agency proposed a range of 850 to 1,150 ppm 
for theoretical total fluorine and a specific gravity range of 1.1 to 
1.7. This range of values was intended to accommodate the newer, less 
dense abrasive systems without compromising the effectiveness of 
fluoride dentifrices. The agency indicated that these ranges are 
intended for formulation purposes and not as a variation for quality 
control purposes. The agency also acknowledges that changes in specific 
gravity result in a corresponding change in the amount of fluoride 
contained in a given volume of dentifrice if the concentration of the 
fluoride is expressed as a weight-to-weight measurement, such as ppm.
    The agency also indicated that a fluoride range of 0.935 to 1.955 
mg per mL of dentifrice might be appropriate. These weight-to-volume 
measurements correspond directly to allowable ranges for specific 
gravity (1.1 to 1.7) and theoretical total fluorine (850 to 1,150 ppm). 
The agency presented the following guidelines for dentifrices: The 
lower limits of 850 ppm theoretical total fluorine and a specific 
gravity of 1.1 convert to a lower limit of 0.935 mg fluorine per mL 
toothpaste. The upper limits of 1,150 ppm theoretical total fluorine 
and a specific gravity of 1.7 convert to an upper limit of 1.955 mg 
fluorine per mL toothpaste. This provides a range of 0.935 to 1.955 mg 
fluorine per mL toothpaste. This range ensures that fluoride 
dentifrices with different specific gravities, due to changes in the 
abrasive system, will contain the same range of total fluoride per 
volume of dentifrice as specified in the LTP tables. This fluoride 
range also will provide flexibility to accommodate the development of 
new abrasive systems.
    The agency indicated in an earlier comment (see section I.B., 
comment 10 of this document) that it is including extra-strength sodium 
monofluorophosphate dentifrices (1,500 ppm) in this final monograph as 
generally recognized as safe and effective dentifrice products. 
Therefore, the agency is also providing a range of 1.65 to 2.55 mg per 
mL of dentifrice for higher strength dentifrices (1,500 ppm). This 
range corresponds directly to the allowable ranges for specific gravity 
(1.1 to 1.7).
    The agency concludes that fluoride ranges of 0.935 to 1.955 mg (for 
all 850 to 1,150 ppm dentifrices) and 1.6 to 2.55 mg (for 1,500 ppm 
sodium monofluorophosphate dentifrices) theoretical total fluorine per 
mL toothpaste are appropriate for these Category I fluoride dentifrice 
formulations, irrespective of their specific gravity. The agency is 
including these ranges in the revised LTP tables. (See also section 
I.F., comment 37 of this document.)
    40. Several comments addressed the use of LTP's, rather than 
clinical trials, to predict the anticaries effectiveness of monograph 
fluoride dentifrices formulated with ``new'' abrasive systems or with 
anticalculus agents. One comment (from a professional 

[[Page 52499]]
dental association) objected to the agency's proposal in the tentative 
final monograph (53 FR 22430 at 22442) to allow LTP's for this testing. 
The comment contended that all fluoride-containing dentifrice products 
should either be clinically tested or should be equivalent to 
clinically tested products. The comment stated that the agency's 
proposed LTP's would permit marketing of any dentifrice product 
containing an established fluoride agent regardless of whether or not 
the abrasive system had been clinically tested. The comment argued 
that, because of the very limited nature of the monograph LTP's, there 
is no assurance of the availability of fluoride ions during the time of 
brushing. The comment added that abrasives can play a very critical 
role in the rate of release/availability of the active ingredient. 
Furthermore, the comment stated that the LTP's proposed in the 
tentative final monograph assess the steady state level of release of 
the active species. This value, according to the comment, has no 
meaning in examining the potential efficacy of fluoride dentifrice 
products. The comment maintained that only clinically tested fluoride/
abrasive systems should be eligible for review under the OTC drug 
monograph system. The comment added that any fluoride dentifrice with 
an untested abrasive system should be required to supply clinical data 
demonstrating effectiveness. The comment stated that its association 
had established testing guidelines designed to demonstrate equivalency 
of fluoride agents provided that the formulations have a fluoride/
abrasive system similar to a clinically effective product.
    The comment also contended that fluoride dentifrices containing 
agents that inhibit calculus formation, thus influencing the 
calcification/decalcification process associated with caries, should be 
required to submit a more extensive LTP than the agency had proposed in 
the tentative final monograph (53 FR 22430 to 22448). The comment 
recommended that either animal caries or remineralization studies be 
required for these products. The comment stated that such studies would 
evaluate the potential inactivation of the fluoride agent by a 
secondary nontherapeutic additive.
    A comment from a manufacturers' association objected to the first 
comment's position, contending that no data or other information were 
submitted to rebut the agency's LTP proposal. The comment also 
disagreed with the dental association's contention that calculus 
inhibiting agents can influence the calcification/decalcification 
process associated with caries. The comment submitted three clinical 
studies (Refs. 1, 2, and 3) to demonstrate that the inclusion of 
anticalculus agents in fluoride-containing dentifrices does not 
interfere with the anticaries effectiveness of these products. The 
comment noted that three clinically proven anticalculus agents 
(pyrophosphate salts, zinc chloride, and zinc citrate) are currently 
marketed in dentifrices in the United States. According to the comment, 
these agents have been shown not to adversely affect fluoride activity 
in three biological tests that were included in the tentative final 
monograph (53 FR 22430 at 22447). The comment objected to the dental 
association's position concerning the validity of using LTP's to 
predict the anticaries effectiveness of fluoride dentifrices with an 
anticalculus agent, contending that the dental association's concern is 
not warranted by existing scientific data. The comment indicated that 
it would be a waste of scarce resources and funds to require further 
clinical testing when laboratory tests can accurately determine whether 
or not anticalculus agents interfere with fluoride efficacy. The 
comment requested that the agency continue to require only LTP's as set 
forth in the tentative final monograph (53 FR 22430 at 22434).
    The agency recognizes that inactive ingredients, such as abrasives 
and anticalculus agents, can play an important role in the rate of 
release/availability of fluoride from a fluoride compound during the 
time period of toothbrushing. Although the analytical tests do not 
directly measure the availability of fluoride ions during the time of 
toothbrushing, the biological tests indicate that the fluoride ion is 
active in preventing dental caries. In addition, one of the biological 
tests, the animal caries reduction, directly measures the anticaries 
effectiveness of a fluoride dentifrice product in an animal model in 
vivo after a limited brushing time. The severity of caries in each 
group is computed, and a favorable result for the test sample indicates 
that the fluoride ion has activity. The test sample is compared with a 
U.S.P. fluoride dentifrice reference standard that has been proven 
effective in clinical studies.
    In the tentative final monograph (53 FR 22430 at 22433 and 22440, 
comments 4 and 11), the agency discussed why lengthy clinical trials 
are no longer warranted. The comments did not provide any new data or 
information to alter that conclusion. The agency determined that 
appropriate laboratory testing, including biological testing, is 
adequate to ensure the effectiveness of dentifrices containing 
monograph fluoride ingredients. The agency indicated that the Panel 
based its development of LTP's on laboratory testing results from 
studies on fluoride dentifrice formulations that had actually been 
clinically tested and found effective. The agency agreed with the 
Panel's view that a monograph fluoride ingredient/abrasive system in a 
dentifrice formulation not specifically reviewed by the Panel, must 
contain an amount of available fluoride ion equal to or greater than 
the highest available fluoride ion value recommended for the specific 
fluoride ingredient. This requirement applies to fluoride dentifrices 
that contain a monograph fluoride ingredient and either (1) a new 
abrasive ingredient (not previously included in marketed dentifrices) 
or (2) an abrasive ingredient included in previously marketed 
dentifrices in a combination not specifically reviewed by the Panel (53 
FR 22430 at 22441). The agency proposed that fluoride dentifrices must 
meet or exceed the soluble fluoride ion level specified for each 
particular fluoride ingredient listed in the monograph and meet the 
test requirements of any two of the following biological tests: (1) 
Enamel solubility reduction (ESR), (2) fluoride uptake by enamel, and/
or (3) animal caries reduction (53 FR 22430 at 22434).
    The agency does not agree that one of the clinical studies (Ref. 1) 
submitted by one comment adequately demonstrates whether or not an 
anticalculus additive affects the anticaries effectiveness of a 
dentifrice. The study did not include a positive control (Category I) 
fluoride toothpaste in the experimental design. Instead, a fluoride/
anticalculus dentifrice was compared to a negative control toothpaste 
(not containing either fluoride or anticalculus agent). However, the 
two other studies (Refs. 2 and 3) submitted by the comment clearly 
indicate that the anticaries effectiveness of the dentifrice 
formulations tested was not adversely affected by the anticalculus 
agents used in the studies. In one study (Ref. 2), three dentifrices 
containing 1,000, 1,500, or 2,500 ppm fluoride (as sodium 
monofluorophosphate) and an anticalculus agent (0.5 percent zinc 
citrate trihydrate) were compared with dentifrices that contained the 
same fluoride concentrations but no anticalculus agent. At the 
conclusion of the 3-year study, no clinically significant difference 
was observed between the fluoride dentifrices with or without the 
anticalculus agent. However, a dose-response effect was 

[[Page 52500]]
observed at varying fluoride concentrations. In the other clinical 
study (Ref. 3), three dentifrices containing 1,000 or 1,100 ppm of 
fluoride (as sodium fluoride and sodium monofluorophosphate) and 
different anticalculus ingredients (3.3 percent soluble pyrophosphate, 
2 percent zinc chloride, and 1.25 percent unspecified zinc compound) 
were evaluated. The three dentifrices produced anticaries protection 
similar to a control sodium monofluorophosphate toothpaste containing 
1,000 ppm fluoride, but without an anticalculus ingredient. These two 
clinical studies corroborate that these anticalculus agents do not 
interfere with the anticaries effectiveness of the fluoride active 
ingredients sodium fluoride and sodium monofluorophosphate.
    The agency is concerned that newer abrasives and anticalculus 
agents may reduce the availability of fluoride ions, and that this 
reduction may not be detected by the chemical tests suggested in the 
LTP's. These chemical tests may not always reflect the true anticaries 
effectiveness of fluoride dentifrices with or without additives in situ 
when diluted in the mouth by saliva or exposed to the subtle reactions 
between dentifrice ingredients and salivary components. Although these 
in vitro tests may show positive results that are predictive of 
anticaries activity, during actual use in the mouth the product may not 
provide the same expected level of anticaries effectiveness. The 
limitations of in vitro tests are particularly significant in 
evaluating fluoride toothpastes that contain additives that may affect 
fluoride ion availability under in situ conditions. For that reason, 
the agency considers them to be only markers of potential 
effectiveness, not actual proof.
    During one study (Ref. 4), several laboratory tests (including ESR, 
enamel uptake of fluoride, and animal caries reduction tests) were 
investigated as indicators of the compatibility of an abrasive system 
and a fluoride source. Dentifrices containing 1,000 ppm of fluoride (as 
sodium fluoride, stannous fluoride, or sodium monofluorophosphate) were 
formulated with abrasives known either to interact or not interact with 
particular fluorides. The in vitro tests measured fluoride uptake for a 
considerably longer time period than would be experienced during actual 
intermittent use. The authors claimed that the in vitro tests provide 
valuable information. They also stated that the results of the ESR test 
did not correlate well with the animal caries assay results. 
Furthermore, the authors noted that the sodium monofluorophosphate 
dentifrices provided high levels of available active fluoride ions but 
produced only small reductions in enamel solubility. Thus, this study 
indicated that the animal caries reduction studies gave the most 
complete assessment of effectiveness of the dentifrices tested compared 
with the test results from the two in vitro tests (ESR and enamel 
uptake of fluoride). Therefore, the agency concludes that both animal 
and human studies provide a more complete assessments of anticaries 
effectiveness.
    The agency has thoroughly reviewed the comments, the clinical 
studies involving anticalculus agents added to dentifrice products 
containing monograph fluoride ingredients, and data comparing the 
results of in vitro biological tests with in vivo animal caries tests. 
Based on this evaluation, the agency concludes that biological testing 
is necessary for all clinically untested dentifrice products to ensure 
fluoride ion availability. Therefore, the agency is revising the 
biological testing requirements in this final monograph to require that 
all OTC anticaries dentifrice drug product formulations not 
specifically reviewed by the Panel be tested in an animal caries 
reduction test. This type of biological test will be required rather 
than optional, as proposed in the tentative final monograph (53 FR 
22430 at 22434). Based upon a review of all the available data, the 
agency still concludes that long-term clinical trials are not needed 
for different or new dentifrice products containing a monograph 
fluoride ingredient/abrasive system, including untested abrasive 
systems or new additives. The agency considers fluoride availability as 
well as ESR and fluoride uptake studies to be good predictors of 
potential effectiveness of a fluoride toothpaste. However, the in vivo 
animal caries reduction test provides further assurance that the 
dentifrice is active against dental caries. The biological portion of 
the recommended testing provides an important assurance that, in 
addition to being chemically available as demonstrated by the 
analytical portion of the testing recommendations, the fluoride is also 
bioavailable in that it will alter tooth structure in the biological 
tests to make the tooth resistant to caries.
    Accordingly, the agency is revising the first sentence in 
Sec. 355.70 of the testing procedures for fluoride dentifrice drug 
products to read: ``A fluoride dentifrice drug product shall meet the 
biological test requirements for animal caries reduction and one of the 
following tests: Enamel solubility reduction or fluoride enamel 
uptake.''
    Although the agency encourages the development of additional 
testing procedures, such as remineralization tests, the agency 
considers the three biological tests recommended by the Panel as 
sufficient at this time to demonstrate anticaries effectiveness. 
Demineralization/remineralization studies in humans may also be 
predictive of anticaries effectiveness. However, the agency has not 
received sufficient data to correlate specifically the results of 
remineralization tests with clinical studies that demonstrate 
anticaries effectiveness of fluoride dentifrices. The agency would 
consider such tests as an option to animal caries reduction tests if 
adequate data were submitted to the agency in the form of a petition to 
amend the monograph.

References-

    (1) Lu, K. H. et al., ``The Effect of a Fluoride Dentifrice 
Containing an Anticalculus Agent on Dental Caries in Children,'' 
Journal Of Dentistry For Children, 52(6):449-451, 1985. -
    (2) Stephen, K. W. et al., ``A 3-Year Oral Health Dose-Response 
Study of Sodium Monofluorophosphate Dentifrices with and without 
Zinc Citrate: Anti-Caries Results,'' Community Dentistry and Oral 
Epidemiology, 16:321-325, 1988.
    (3) Triol, C. W. et al., ``A Clinical Study of the Anticaries 
Efficacy of Three Fluoride Dentifrices Containing Anticalculus 
Ingredients: One and Two Year Results,'' The Journal of Clinical 
Dentistry, 1(2):48-50, 1988.
    (4) Pader, M. et al., ``The Evaluation of Fluoride 
Dentifrices,'' Journal of the Society of Cosmetic Chemistry, 28:681-
694, 1977.
    41. One comment stated that it is unclear what the reference 
standards will be for the required analytical and biological testing of 
fluoride dentifrices. The comment contended that it is difficult to 
comment on the whole program without knowing what the standards are. 
The comment suggested that an additional period of time be permitted to 
allow interested groups to comment on the acceptability of the actual 
United States Pharmacopeia (U.S.P.) reference standards when they are 
established.
    In the tentative final monograph, the agency stated that it was 
coordinating establishment of the fluoride dentifrice reference 
standard formulations with the United States Pharmacopeial Convention 
(U.S.P.C.) (53 FR 22430 at 22439). Since then, industry has worked with 
the U.S.P.C. to establish reference standards, through the joint 
Nonprescription Drug Manufacturers Association and Cosmetic, Toiletry 
and Fragrance Association task force. Information about the reference 
standards was made public in U.S.P.'s Pharmacopeial Forum in 1990 (Ref. 
1), 

[[Page 52501]]
and interested parties had an opportunity to comment at that time. 
Reference standards have been available from U.S.P.C. since 1990.
    Based on the public availability and use of these U.S.P. fluoride 
dentifrice reference standards by the industry since 1990, the agency 
concludes that it is not necessary to provide an additional comment 
period.

Reference-

    (1) The United States Pharmacopeial Convention, Inc., 
``Headquarters Column,'' Pharmacopeial Forum, 16:3-4, 1990.
    42. Two comments requested that the agency refrain from mandating 
specific biological test procedures in the final monograph for OTC 
anticaries drug products. Instead, the two comments requested that the 
biological test procedures proposed in Sec. 355.70 be considered as 
guidelines only. The comments agreed with the agency that the 
substitution of a new test, such as remineralization, for one of the 
three qualifying biological tests should require a petition for FDA 
approval. However, the comments strongly disagreed with the need for a 
petition for minor modifications in the biological testing protocols 
when the results are at least as valid, reliable, and accurate as the 
current test procedures. One comment added that, without this 
flexibility, the acceptance by the agency of even minor changes may 
take an inordinate period of time without helping to protect the 
dentifrice user from an ineffective product. The comment suggested that 
if the agency continues to maintain control over changes in test 
procedures, approval of the changes should be timely and a list of 
criteria should be provided so that manufacturers can be assured that 
changes will be accepted by the agency.
    The second comment indicated that mandating specific test protocols 
tends to discourage scientific experimentation and the application of 
advanced technology in method development. The comment noted that 
advances in technology alone will result in changes in test protocols 
and the precision, sensitivity, and accuracy of various measurements. 
Therefore, the comment requested that the agency designate the 
biological testing procedures as guidelines only and explicitly 
indicate that other valid, reproducible methods are acceptable. The 
comment indicated that requiring a petition to modify and improve a 
procedure would not only be time consuming, but also would be expensive 
and thus not in the interest of consumers. The comment concluded that 
companies should have the opportunity to make minor modification to 
test methods as long as the changes are scientifically validated and 
produce accurate and reliable results.
    The agency does not agree that the specific biological testing 
procedures for fluoride dentifrices should be considered as test 
guidelines only. The agency indicated in the tentative final monograph 
(53 FR 22430 at 22443) that the availability of the fluoride ion in a 
dentifrice formulation and meeting the biological testing requirements 
are the most important testing criteria for predicting the 
effectiveness of a fluoride dentifrice product. The agency considers 
demonstration of the bioavailability of the fluoride ion in the 
biological tests listed in Sec. 355.70 as necessary to ensure the 
anticaries effectiveness of fluoride dentifrices. The agency points out 
that the required biological tests are based on the results of actual 
biological testing procedures performed on fluoride dentifrices that 
had been shown to be clinically effective in preventing caries. These 
testing procedures are a regulatory standard that supports general 
recognition of the safety and effectiveness of fluoride dentifrices.
    The agency has had a similar petition procedure for many years for 
modifications to the in vitro test for OTC antacid drug products (see 
21 CFR 331.29). The agency has processed these petitions in a timely 
manner. Accordingly, the agency is including the biological testing 
procedures in Sec. 355.70 as required tests for any fluoride dentifrice 
drug product marketed pursuant to this monograph.
    The agency finds no basis to agree with the comment's suggestion 
that requiring these specific biological testing procedures interferes 
with the advancement of science and technology. The agency does not 
intend for the testing procedures to preclude the application of new, 
advanced technology in testing fluoride dentifrices. The agency agrees 
with the two comments that as technology continues to evolve, 
modifications to the existing testing procedures may result in more 
sensitive, reliable, and accurate measurements. However, there should 
be a consensus in the scientific community that these new procedures 
are generally accepted. The agency encourages the development of new 
testing technology and methods for fluoride dentifrices and has 
provided in the monograph the opportunity for interested persons to 
propose modifications or alternative testing procedures through the 
petition process in 21 CFR 10.30. Any petition should contain 
sufficient data to support the modification and to demonstrate that the 
alternative testing procedure provides results that are equivalent to 
the currently required biological test methods.
    43. Two comments objected to fluoride dentifrice reference 
standards being provided through the U.S.P.C. The comments suggested 
that exact specifications for these reference standards (including 
levels of ingredients, source of raw materials, product specifications, 
and detailed production directions) be provided as part of the U.S.P. 
monograph system so that manufacturers could prepare their own fresh 
reference standards when needed. One comment contended that, given 
sufficient detailed specifications, manufacturers would certainly be as 
qualified to produce properly prepared standards as the U.S.P.C.
    Following publication of the tentative final monograph, FDA and 
industry developed procedures for introduction of new or modified 
commercial dentifrice formulations without full clinical testing, 
provided that bioavailability/bioequivalence of the formulation was 
demonstrated against an appropriate reference standard (Ref. 1). Six 
U.S.P. fluoride dentifrice reference standards were initially 
established for use in the biological testing of fluoride dentifrices: 
(1) Sodium fluoride-calcium pyrophosphate (high beta-phase), (2) sodium 
fluoride-silica, (3) sodium monofluorophosphate-calcium carbonate, (4) 
sodium monofluorophosphate-dicalcium phosphate, (5) sodium 
monofluorophosphate-silica, (6) stannous fluoride-silica (Ref. 2). 
These reference standards are prepared by manufacturers of dentifrice 
drug products and provided to the U.S.P.C. for distribution. Thus, the 
agency agrees with one comment that manufacturers are qualified to 
produce these reference standards. Based on the development of these 
reference standards by manufacturers of OTC dentifrice drug products, 
neither the agency nor the U.S.P.C. sees a need to include exact 
specifications for these reference standards in the U.S.P. monograph 
system. Furthermore, the U.S.P. monograph system does not include exact 
specifications for other reference standards the U.S.P.C. provides.
    The agency had a meeting with U.S.P.C. and industry representatives 
on May 20, 1993 (Ref. 3), to discuss the existing U.S.P. program for 
dentifrice reference standards and to determine if any changes were 
needed once the final monograph for OTC anticaries drug products is 
issued. Additional procedures to assure continued 

[[Page 52502]]
availability of these dentifrice reference standards from the U.S.P.C. 
were developed. The U.S.P.C.'s current supply of dentifrice reference 
standards were subsequently tested to monitor stability (Refs. 4 
through 7). Manufacturers of each reference standard have committed to 
retest stability every 18 months and to make every effort to resupply 
the U.S.P.C. with additional reference standards when supplies are 
depleted (Ref. 3). This should occur within 1 to 2 months after the 
U.S.P.C. makes a request. The U.S.P.C. will provide information 
concerning the reference standards' stability profile (including total 
fluoride, available fluoride ions, pH, and specific gravity) that is 
provided by each manufacturer to any purchaser upon written request. 
The agency believes that the availability of this information 
adequately addresses the comments' concerns about specifications for 
these dentifrice reference standards. Other information of concern, 
such as source of raw materials and detailed production directions, are 
considered confidential commercial information or trade secret 
information. The agency concludes that distribution of dentifrice 
reference standards by the U.S.P.C. is appropriate.

References-

    (1) The United States Pharmacopeial Convention, Inc., 
``Headquarters Column,'' Pharmacopeial Forum, 16:3-4, 1990.
    (2) The United States Pharmacopeial Convention, Inc., 
``Reference Standards Catalog,'' Pharmacopeial Forum, 17:2458, 1991.
    (3) Minutes of meeting between FDA, U.S.P.C., and industry 
representatives, May 20, 1993, identified as MM6, Docket No. 80N-
0042, Dockets Management Branch.
    (4) Comment No. RPT4, Docket No. 80N-0042, Dockets Management 
Branch.
    (5) Comment No. RPT5, Docket No. 80N-0042, Dockets Management 
Branch.
    (6) Comment No. RPT6, Docket No. 80N-0042, Dockets Management 
Branch.
    (7) Comment No. RPT7, Docket No. 80N-0042, Dockets Management 
Branch.
    44. Two comments suggested that several U.S.P. reference standards 
for dentifrices should be provided for each Category I fluoride 
ingredient and abrasive combination for which clinical proof of 
effectiveness has been submitted. The comments stated that the types 
and sources of abrasives and other ingredients present in dentifrice 
reference standards could have a significant effect on the results of 
bioavailability tests. As an example, the comments suggested that 
U.S.P. dentifrice reference standards for sodium fluoride products 
should include sodium fluoride/calcium pyrophosphate, sodium fluoride/
silica, and sodium fluoride/sodium bicarbonate combinations, all of 
which have been proven effective in clinical trials. According to one 
comment, providing all of these standards would ensure the exclusion of 
ineffective combinations without unfairly excluding dentifrices that 
are effective but fail to meet the performance of an inappropriate 
standard.
    The agency agrees with the comments that the availability of 
appropriate U.S.P. reference standards is essential to conduct the 
biological testing included in this final monograph for OTC anticaries 
drug products. In the tentative final monograph (53 FR 22430 at 22439), 
the agency stated that it was coordinating with U.S.P.C. to establish 
fluoride dentifrice reference standards that would be made available to 
manufacturers interested in manufacturing fluoride dentifrices. 
Subsequently, U.S.P. fluoride dentifrice reference standards have been 
established for Category I fluoride ingredient/abrasive combinations 
that had been reviewed by the Panel and determined by clinical trials 
to be effective anticaries drug products. These reference standards 
include the fluoride dentifrice combinations suggested by the comments, 
i.e., sodium fluoride/calcium pyrophosphate and sodium fluoride/silica, 
as well as sodium monofluorophosphate/calcium carbonate, sodium 
monofluorophosphate/dicalcium phosphate, sodium monofluorophosphate/
silica, and stannous fluoride/silica (see section I.F., comment 43 of 
this document). A list of U.S.P. reference standards available as of 
the date of this final rule is on file in the Dockets Management Branch 
(Ref. 1).
    The U.S.P. reference standards that have been established include 
only those dentifrice formulations that have been demonstrated to be 
clinically effective and that were reviewed by the Panel. At the time 
of the Panel's deliberation, no clinical data supporting the 
effectiveness of a sodium fluoride/sodium bicarbonate dentifrice were 
submitted for review. Consequently, a U.S.P. reference standard for 
this dentifrice formulation has not been established.
    The agency indicated in the tentative final monograph (53 FR 22430 
at 22443) that any Category I fluoride compound formulated with an 
appropriate abrasive can be marketed provided the dentifrice meets the 
biological testing requirements in Sec. 355.70 and contains the amount 
of available fluoride ion stated in Sec. 355.10. The particular 
fluoride ingredient contained in the chosen reference standard must be 
the same as the fluoride ingredient in the dentifrice formulation being 
tested; however, it is not necessary that the abrasive be the same as 
the abrasive contained in the reference standard. The agency is aware 
that several manufacturers use the U.S.P. reference standards, sodium 
fluoride/calcium pyrophosphate or sodium fluoride/silica, in the 
biological testing of their sodium fluoride/sodium bicarbonate 
dentifrice products (Ref. 2). A manufacturers' association has recently 
informed the agency that a new supply of one of the U.S.P. reference 
standards, sodium fluoride/calcium pyrophosphate (high-beta phase), 
will not be manufactured when the current supply at U.S.P.C. is 
exhausted (Ref. 3). When this sodium fluoride/calcium pyrophosphate 
dentifrice reference standard is no longer available, manufacturers 
should use the sodium fluoride/silica dentifrice reference standard in 
its place to conduct the biological tests. Thus, in response to the 
comment's suggestion that a reference standard be established for a 
sodium fluoride/sodium bicarbonate dentifrice, it is sufficient that 
the formulation meet the biological testing requirements using a 
reference standard containing sodium fluoride, and the available 
fluoride ion concentration of the dentifrice be equal to or greater 
than 650 ppm.

References-

    (1) OTC Vol. 08BTPRS, Docket No. 80N-0042, Dockets Management 
Branch.
    (2) Memoranda of telephone conversations between C. Martin, FDA, 
and W. Cooley, Procter & Gamble Co., dated February 8, 1993; P. 
Okarma, Colgate-Palmolive Co., dated February 9, 1993; and D. 
Worrell, Church & Dwight Co., dated February 17, 1993, OTC Vol. 
08AFM, Docket No. 80N-0042, Dockets Management Branch.
    (3) Comment No. RPT4, Docket No. 80N-0042, Dockets Management 
Branch.

G. Comments on Package Size Limitation

    45. One comment requested that the agency increase the fluoride 
dentifrice package size limitation from 260 mg of total fluorine per 
package to 350 mg to accommodate the increased amount of fluoride 
contained in dentifrices containing 1,500 ppm. The comment noted that 
dentifrice products marketed pursuant to the proposed OTC drug 
monograph contain less than 1,150 ppm fluoride and are marketed in 9-oz 
package sizes to adhere to the 260-mg total fluorine package size 
limitation. The comment indicated that FDA had obviously reconsidered 
the 260-mg dentifrice package size limitation in approving an NDA for 
an OTC dentifrice 

[[Page 52503]]
product containing 1,500 ppm fluoride. According to the comment, the 
NDA fluoride dentifrice is marketed in 8.2 and 6.4 oz package sizes 
that contain 350 and 272 mg theoretical total fluorine, respectively. 
The comment added that these package sizes do not have any special 
cautionary labeling concerning the additional fluoride and do not have 
child-resistant closures. The comment contended that consumers would 
not be able to differentiate the amount of fluoride contained in 
packages of the 1,150-ppm and the 1,500-ppm products, and thus would 
not treat or use the products differently. The comment remarked that 
there appears to have been no concern at all that ingestion of the 
entire package of dentifrice was a real public safety risk. The comment 
concluded that consumers would benefit from an increase in the package 
size fluorine limitation because of the added convenience of a larger 
package size and more economical products on a cost per oz basis.
    The comment stated that the issue in establishing a package size 
limitation is to prevent acute toxicity that may result from a single 
individual ingesting the entire contents of a fluoride dentifrice 
package on a single occasion, rather than to prevent the long-term 
adverse effects of fluoride ingestion. The comment submitted a list of 
21 published animal toxicology studies (Ref. 1) that were submitted in 
support of the NDA for the 1,500-ppm fluoride dentifrice product. The 
comment stated that a review of its marketing experience records over 
an 18-month period (during which tubes as small as 1.4 oz were 
marketed) indicated that no one in the United States had ingested an 
entire tube of toothpaste regardless of size during that period of 
time. The comment added that it has marketed a 1,450-ppm fluoride 
(theoretical total fluorine) dentifrice extensively outside the United 
States in tube sizes that exceed the proposed monograph package size 
limitations without any special warnings or closures. The comment 
stated that no incidents or issues have been raised with respect to the 
safety of such package sizes. The comment concluded that the proposed 
260-mg package size limitation is unnecessary to protect the safety or 
health of the American public and that the limitation should be raised 
to 350-mg.
    After the tentative final monograph was published in 1985, the 
agency evaluated and approved an NDA (19-518) for an OTC fluoride 
dentifrice containing 1,500-ppm theoretical total fluoride (Ref. 2). As 
part of that evaluation, the agency reconsidered, as noted by the 
comment, the package size limitation of 260 mg total fluorine that had 
been recommended by the Panel and proposed by the agency in the 
tentative final monograph. The agency approved marketing of a 6.4 oz 
(actually containing 276 mg total fluorine) and a 8.2 oz (containing 
350 mg total fluorine) package size. Since that time, the agency has 
reviewed the confidential sales distribution data submitted under the 
NDA for the extra-strength dentifrice. The data indicate extensive 
marketing experience for the 6.4 oz package size and limited marketing 
of the 8.2 oz package size. Furthermore, the manufacturer of the extra-
strength dentifrice has discontinued marketing the 8.2 oz package size 
(Ref. 3). The agency concludes that it has insufficient marketing 
experience and an inadequate safety profile to support general 
recognition of an 8.2 oz package size containing 350 mg total fluorine 
per package. The agency has sufficient data to support the 6.4 oz 
package size of 1,500 ppm dentifrice (containing 276 mg total 
fluorine). Therefore, the agency is limiting monograph dentifrices to a 
package size containing no more than 276 mg total fluorine per package.

References-

    (1) Comment No. CP4, Docket No. 85N-0554, Dockets Management 
Branch.
    (2) Copy of FDA-approved Labeling from NDA 19-518, OTC Vol. 
08AFM, Docket No. 80N-0042, Dockets Management Branch.
    (3) Memorandum of telephone conversation between C. Martin, FDA, 
and L. Cancro, Consultant to Chesebrough-Pond's Co., dated August 9, 
1993, OTC Vol. 08AFM, Docket No. 80N-0042, Dockets Management 
Branch.
    46. One comment requested that the proposed package size 
limitations for dentifrices, treatment rinses, and treatment gels in 
Sec. 355.20(a) and (b) not be limited to 260 mg (dentifrices) and 120 
mg (rinses and gels) total fluorine per package when the products are 
intended for professional use. Noting that the package size limitations 
were proposed because of potential toxicity that might be caused by 
accidental ingestion of these products, the comment contended that 
these package size restrictions are inappropriate for professional 
packages used by dental practitioners in their practice. The comment 
stated that dentists routinely administer these products to their 
patients as part of their treatment and, thus, require a larger 
container than the proposed OTC package sizes. The comment concluded 
that professional package sizes would have limited distribution, would 
not be available to consumers and, therefore, would not be a safety 
concern.
    The package size limitations established for OTC fluoride 
dentifrices, treatment rinses, and preventive treatment gels in 
Sec. 355.20 of this final monograph are intended for products used by 
the general public and not for products used only under professional 
supervision. The agency does not believe that safety problems will 
occur when a larger package size is distributed for professional office 
use only, provided the package is not intended to be distributed by the 
dentist to the consumer for home use. A product marketed in this manner 
would present potential safety problems similar to an OTC product. 
Therefore, the agency is not limiting the package size for dentifrices, 
treatment rinses, and preventive treatment gels labeled for 
professional office use only. The agency is including in Sec. 355.60 of 
the monograph (professional labeling) the following statements for 
products marketed to health professionals in package sizes larger than 
those specified in Sec. 355.20: ``For Professional Office Use Only'' 
and ``This product is not intended for home or unsupervised consumer 
use.'' For clarity, the agency is adding paragraph (a)(3) to 
Sec. 355.20 as follows: ``Package size limitations do not apply to 
anticaries drug products marketed for professional office use only and 
labeled in accord with Sec. 355.60.''

II. Summary of Significant Changes From the Proposed Rule

A. Summary of Ingredient Categories

    The agency has reviewed all claimed active ingredients submitted to 
the Panel and to the tentative final monograph, as well as other data 
and information available at this time. For the convenience of the 
reader, the following table is a summary of the agency's categorization 
of OTC anticaries active ingredients.

                                                                                                                
----------------------------------------------------------------------------------------------------------------
     Anticaries Active                                                                                          
        Ingredients                       Monograph (M)                            Nonmonograph (NM)            
----------------------------------------------------------------------------------------------------------------
Hydrogen fluoride:........                                                                                      

[[Page 52504]]
                                                                                                                
  Rinse--In an appropriate                                                                                      
   formulation with 0.02                                                                                        
   percent fluoride ion...                                                                                   NM 
Phosphate preparations:...                                                                                      
  Calcium sucrose                                                                                               
   phosphate..............                                                                                   NM 
  Dicalcium phosphate                                                                                           
   dihydrate..............                                                                                   NM 
  Disodium hydrogen                                                                                             
   phosphate..............                                                                                   NM 
  Phosphoric acid.........                                                                                   NM 
  Sodium dihydrogen                                                                                             
   phosphate..............                                                                                   NM 
  Sodium dihydrogen                                                                                             
   phosphate monohydrate..                                                                                   NM 
  Sodium phosphate........                                                                                   NM 
  Sodium phosphate,                                                                                             
   dibasic anhydrous                                                                                            
   reagent................                                                                                   NM 
  Sodium bicarbonate......                                                                                   NM 
Sodium fluoride:..........                                                                                      
  Dentifrice--paste: 0.188                                                                                      
   to 0.254 percent (with                                                                                       
    650                                                                                              
   available fluoride ion)                                         M                                            
Dentifrice--powder: 0.188                                                                                       
 to 0.254 percent (with                                                                                         
  850 ppm                                                                                            
 available fluoride ion                                                                                         
 and poured-bulk density                                                                                        
 of 1.0 to 1.2 g/mL)......                                         M                                            
  Rinse--0.05 percent.....                                         M                                            
  Rinse--0.02 percent.....                                         M                                            
  Rinse--Acidulated                                                                                             
   phosphate fluoride with                                                                                      
   0.02 percent fluoride                                                                                        
   ion....................                                         M                                            
  Rinse--Acidulated                                                                                             
   phosphate fluoride with                                                                                      
   0.01 percent fluoride                                                                                        
   ion....................                                         M                                            
Sodium fluoride and                                                                                             
 hydrogen fluoride:.......                                                                                      
  Rinse--Acidulated                                                                                             
   phosphate fluoride with                                                                                      
   1.23 percent fluoride                                                                                        
   ion....................                                                                                   MN 
Sodium monofluorophosphate                                                                                      
 (850 to 1,150 ppm):......                                                                                      
  Dentifrice: 0.654 to                                                                                          
   0.884 percent (with  800 ppm                                                                                              
   available fluoride ion                                                                                       
   as PO3F= and F-                                                                                              
   combined)..............                                         M                                            
  Rinse--6.0 percent......                                                                                   NM 
Sodium monofluorophosphate                                                                                      
 (1,500 ppm):.............                                                                                   NM 
  Dentifrice--1.153                                                                                             
   percent (with  1,275 ppm available                                                                                      
   fluoride ion as PO3F=                                                                                        
   and F- combined).......                                         M   .........................................
Stannous fluoride:........                                                                                      
  Dentifrice--0.351 to                                                                                          
   0.474 with an available                                                                                      
   fluoride ion                                                                                                 
   concentration of:......                                                                                      
     700 ppm                                                                                         
     for products                                                                                               
     containing abrasive                                                                                        
     other than calcium                                                                                         
     pyrophosphate........                                         M                                            
    or....................                                                                                      
     290 ppm                                                                                         
     for products                                                                                               
     containing the                                                                                             
     abrasive calcium                                                                                           
     pyrophosphate........                                         M                                            
  Rinse--0.1 percent......                                         M                                            
  Gel--0.4 percent in an                                                                                        
   anhydrous glycerin gel.                                         M                                            
----------------------------------------------------------------------------------------------------------------



B. Summary of the Agency's Changes

    1. The agency is revising the definitions proposed for anticaries 
drug, dentifrice, and treatment gel in Sec. 355.3(c), (e), and (i), 
respectively. The agency is adding a definition for anhydrous glycerin 
in Sec. 355.3(b), as used in Sec. 344.3(a) (21 CFR 344.3(a)) of the 
final monograph for OTC topical otic drug products. Also, in 
Sec. 355.3(h), the agency is adding a definition for a fluoride 
supplement that is intended to be swallowed. Because of these 
additions, proposed Sec. 355.3(b) through (f) have been redesignated as 
paragraphs (c) through (g), and Sec. 355.3(g) through (k) have been 
redesignated as paragraphs (i) through (m), respectively, in this final 
monograph. (See section I.B., comments 5, 6, and 7 of this document.)
    2. The agency is including fluoride dentifrices that contain 1,500 
ppm theoretical total fluorine in Sec. 355.10(b)(2) of this final 
monograph. Because of concerns about dental fluorosis, the agency is 
requiring that dentifrices containing these fluorine concentrations be 
clearly labeled for use only by children 6 years of age and older and 
is including directions for adults and children 6 years of age and 
older in Sec. 355.50(d)(1)(ii) of this final monograph. The agency is 
also including an optional additional labeling statement that will 
inform consumers of the benefits of these products. (See section I.B., 
comment 10 of this document.)
    3. The agency is adding sodium fluoride/sodium bicarbonate powdered 
dentifrices in Sec. 355.10(a)(2) of this final monograph. Directions 
for these products appear in Sec. 355.50(d)(1)(iii). (See section I.B., 
comments 13 and 14 of this document.)
    4. The agency is increasing the package size limitations in 
Sec. 355.20(a) for dentifrice (toothpastes and tooth powders) packages 
up to 276 milligrams total fluorine per package. The agency is also 
adding a new paragraph in Sec. 355.20 for fluoride powdered dentifrices 
that provides for tight container packaging in accordance with the 
definition in the U.S.P. (See section I.B., comment 15 and section 
I.G., comment 45 of this document.)
    5. The agency notes that there is a U.S.P. monograph for Sodium 
Fluoride and Phosphoric Acid Topical Solution (Ref. 1). This monograph 
applies to acidulated phosphate sodium fluoride topical solutions 
having a pH between 3.0 and 4.0. Therefore, this monograph 

[[Page 52505]]
would apply to the aqueous solution of acidulated phosphate fluoride 
described in Sec. 355.10(a)(3)(ii) of the final monograph for OTC 
anticaries drug products and could apply to the aqueous solution of 
acidulated phosphate fluoride described in Sec. 355.10(a)(3)(i) if the 
pH range of the U.S.P. monograph were to be expanded to 4.5. The agency 
and an interested manufacturer (Ref. 2) are working with U.S.P. to 
develop a revision in the compendial monograph for these rinse 
products. The agency anticipates that this revision will be completed 
before this final monograph for OTC anticaries drug products becomes 
effective. In accord with Sec. 355.50(a) of the final monograph, 
manufacturers marketing these products should include the compendial 
name, Sodium Fluoride and Phosphoric Acid Topical Solution, as the 
established name in the labeling of such products.

References-

    (1) The United States Pharmacopeia 23--The National Formulary 
18, United States Pharmacopeial Convention, Inc., Rockville, MD, p. 
1423, 1994.
    (2) Memorandum of telephone conversation between C. Martin, FDA, 
and P. Okarma, Colgate-Palmolive Co., dated December 9, 1993, OTC 
Vol. 08AFM, Docket No. 80N-0042, Dockets Management Branch.-
    6. The agency is redesignating several paragraphs and is providing 
the following table of changes for the convenience of the reader:

                                                                        
------------------------------------------------------------------------
 Paragraph number in this     Paragraph number in the tentative final   
      final mongraph                         monograph                  
------------------------------------------------------------------------
355.3(b).................  .............................................
355.3(c) through (g).....                           355.3(b) through (f)
355.3(h).................                                               
355.3(i) through (m).....                           355.3(g) through (k)
  .......................                                               
355.10(a)(2).............  .............................................
355.10(a)(3)(i)..........                                   355.10(b)(1)
355.10(a)(3)(ii).........                                   355.10(b)(2)
355.10(a)(3)(iii)........                                   355.10(b)(3)
355.10(a)(3)(iv).........                                   355.10(b)(4)
355.10(a)(3)(v)..........                                   355.10(b)(5)
355.10(b)(1).............                                   355.10(a)(2)
355.10(b)(2).............  .............................................
355.10(c)(1)(i)..........                                   355.10(a)(3)
355.10(c)(1)(ii).........                                   355.10(a)(4)
355.10(c)(2).............                                      355.10(c)
355.10(c)(3).............                                   355.10(b)(6)
  .......................                                               
355.20(a)(1)1............                                      355.20(a)
355.20(a)(2).............                                      355.20(b)
355.20(a)(3).............  .............................................
355.20(b)................  .............................................
                                                                        
355.50(d)(1)(i)..........                                355.50(d)(1)(i)
355.50(d)(1)(ii).........  .............................................
355.50(d)(2)(i)..........                                   355.50(d)(2)
355.50(d)(2)(ii).........  .............................................
355.50(d)(2)(iii)........                               355.50(d)(2)(ii)
355.50(d)(5).............  .............................................
355.50(e)(2).............                                   355.50(e)(3)
355.50(f)(1)2............                                      355.50(f)
355.50(f)(2).............  .............................................
  .......................                                      355.50(g)
------------------------------------------------------------------------
\1\ Because Sec.  355.20(b) has been revised, the heading of Sec.       
  355.20 has been changed to ``Packaging conditions.''                  
\2\ Because Sec.  355.50(f)(2) has been added, the word ``statement'' in
  the heading of Sec.  355.50(f) has been changed to ``statements.''    

    7. The agency is revising and expanding Sec. 355.50(a) to provide 
the option of using the additional terms ``mouthwash,'' ``tooth 
powder,'' and ``tooth polish'' in the statement of identity. The agency 
is also requiring that the term ``preventive treatment'' be included in 
the statement of identity for nonabrasive fluoride gels. The agency is 
providing that the word ``treatment'' be optional in the statement of 
identity for fluoride rinse products. (See section I.C., comments 17 
and 18 of this document.)
    8. The agency has moved the statement ``Do not use before mixing 
with water'' from the warnings in proposed Sec. 355.50(c) to the 
directions for use in Sec. 355.50(d)(5) of this final monograph. This 
statement is to be the first sentence of the directions for 
concentrated treatment rinse solutions, powders, and effervescent 
tablets. (See section I.C., comment 26 of this document.)
    9. The agency is modifying the general warning in Sec. 330.1(g), 
which states: ``Keep this and all drugs out of the reach of children,'' 
to read as follows for fluoride dentifrice drug products: ``Keep out of 
the reach of children under 6 years of age.'' This warning appears in 
Sec. 355.50(c)(1) of this final monograph. However, in 
Sec. 355.50(c)(2), the agency continues to require the general warning 
in Sec. 330.1(g) for all other OTC anticaries drug products. (See 
section I.B., comment 22 of this document.)
    10. The agency is revising the directions for anticaries dentifrice 
drug products proposed in Sec. 355.50(d) and is including the revised 
directions in Sec. 355.50(d)(1)(i), (d)(1)(ii), and (d)(1)(iii) 

[[Page 52506]]
of this final monograph. The agency is also revising the directions for 
use of anticaries preventive treatment gels by children in 
Sec. 355.50(d) to read: ``Instruct children under 12 years of age in 
the use of this product (to minimize swallowing). Supervise children as 
necessary until capable of using without supervision.'' The agency is 
including the revised directions in Sec. 355.50(d)(4) in this final 
monograph.
    11. The agency is revising the directions for use of anticaries 
treatment rinses by children, proposed in Sec. 355.50(d)(2)(i), to 
read: ``Instruct children under 12 years of age in good rinsing habits 
(to minimize swallowing). Supervise children as necessary until capable 
of using without supervision.'' The agency is including the revised 
directions in Sec. 355.50(d)(2)(i) and (d)(2)(ii) in this final 
monograph. (See section I.C., comment 25 of this document.)
    12. The agency is not including proposed Sec. 355.50(e)(2) in this 
final monograph. In its place, the agency is including new Sec. 355.55, 
as follows: ``Principal display panel of all fluoride rinse drug 
products. In addition to the statement of identity required in 
Sec. 355.50, the following statement shall be prominently placed on the 
principal display panel: 'IMPORTANT: Read directions carefully before 
using'''. Because proposed Sec. 355.50(e)(2) is not included in this 
monograph, the agency is redesignating proposed Sec. 355.50(e)(3) as 
Sec. 355.50(e)(2) in this final monograph. (See section I.C., comment 
20 of this document.)
    13. The agency is not including proposed Sec. 355.50(g) (which 
states: ``The word 'physician' may be substituted for the word 'doctor' 
in any of the labeling statements in this section.'') in this final 
monograph because the agency has amended Sec. 330.1 to permit the 
interchangeability of certain terms, including ``physician'' and 
``doctor,'' in all OTC drug monographs. (See 59 FR 3998, January 28, 
1994.)
    14. The agency is modifying the introductory language in the 
professional labeling in Sec. 355.60 to read: ``The labeling for 
anticaries fluoride treatment rinses identified in Sec. 355.10(b) that 
are specially formulated so they may be swallowed (fluoride 
supplements) and are provided to health professionals (but not to the 
general public) may contain the following additional dosage 
information: * * *.'' (See section I.C., comment 28 of this document.)
    15. The agency is including in Sec. 355.60 (professional labeling) 
the following statements for products marketed to professionals in 
package sizes larger than those specified in Sec. 355.20: ``For 
Professional Office Use Only'' and ``This product is not intended for 
home or unsupervised consumer use.'' The agency is also amending 
Sec. 355.20 by revising paragraph (b) to read: ``Package size 
limitations do not apply to anticaries drug products marketed for 
professional office use only and labeled in accord with Sec. 355.60.'' 
(See section I.G., comment 46 of this document.)
    16. The agency is revising the biological testing requirements in 
this final monograph to require that all OTC anticaries dentifrice drug 
product formulations be tested in an animal caries reduction test 
rather than allowing this type of biological test to be optional as 
proposed in the tentative final monograph (53 FR 22430 at 22434). 
Accordingly, the first sentence in Sec. 355.70 of the testing 
procedures for fluoride dentifrice drug products reads: ``A fluoride 
dentifrice drug product must meet the biological test requirements for 
animal caries reduction and one of the following tests: Enamel 
solubility reduction or fluoride enamel uptake.'' The agency has 
further revised the proposed testing guidance for parameters other than 
available fluoride ion and biological test requirements and is citing 
these revised parameters as testing intended as guidance, e.g., for use 
in determining expiration dating. The agency is including a revised LTP 
chart in the preamble of this document for informational purposes. (See 
section I.F., comments 37, 39, and 40 of this document.)
    17. The agency is revising the testing procedures in Sec. 355.70 to 
include information about the available U.S.P. fluoride dentifrice 
reference standards. (See section I.F., comments 43 and 44 of this 
document.)

III. The Agency's Final Conclusions on OTC Anticaries Drug Products

    Based on available evidence, the agency is issuing a final 
monograph establishing conditions under which OTC anticaries drug 
products (aid in the prevention of dental cavities) are generally 
recognized as safe and effective and not misbranded. Specifically, the 
agency has determined that the following active ingredients meet 
monograph conditions: Sodium fluoride, sodium monofluorophosphate, and 
stannous fluoride. All other ingredients considered in this rulemaking 
have been determined to be nonmonograph conditions. Four of these 
ingredients are presently listed in Sec. 310.545(a)(2) (21 CFR 
310.545(a)(2)) as not generally recognized as safe and effective for 
anticaries use, i.e., hydrogen fluoride, sodium carbonate, sodium 
monofluorophosphate (6 percent rinse), and sodium phosphate. In this 
final rule, the agency is amending Sec. 310.545(a)(2) by adding the 
ingredients calcium sucrose phosphate, dicalcium phosphate dihydrate, 
disodium hydrogen phosphate, phosphoric acid, sodium dihydrogen 
phosphate, sodium dihydrogen phosphate monohydrate, and sodium 
phosphate, dibasic anhydrous reagent to this list of nonmonograph 
conditions. These ingredients appear in new Sec. 310.545(a)(2)(ii), 
while previous Sec. 310.545(a)(2) is redesignated 
Sec. 310.545(a)(2)(i).
    The agency is removing the existing warning and caution statement 
required in Sec. 369.21 (21 CFR 369.21) and exemptions for certain 
drugs limited by NDA's to prescription sale in Sec. 310.201(a)(10) and 
(a)(15) (21 CFR 310.201(a)(10) and (a)(15)) for anticaries drug 
products because most portions of those regulations are superseded by 
the anticaries final monograph (21 CFR part 355). The items being 
removed include: (1) Sec. 310.201(a)(10)(i) through (a)(10)(vi); (2) 
Sec. 310.201(a)(15)(i) through (a)(15)(vi); and (3) paragraphs in 
Sec. 369.21 applicable to sodium fluoride dentifrice powder and sodium 
monofluorophosphate dentifrice solution. The agency is reserving 
paragraphs (a)(10) and (a)(15) in Sec. 310.201 for future use.
    Any drug product labeled, represented, or promoted for use as an 
OTC anticaries drug product that contains any of the ingredients listed 
in Sec. 310.545(a)(2) or that is not in conformance with the monograph 
(21 CFR part 355) may be considered a new drug within the meaning of 
section 201(p) of the act (21 U.S.C. 321(p)) and misbranded under 
section 502 of the act (21 U.S.C. 352) and may not be marketed for this 
use unless it is the subject of an approved application or abbreviated 
application under section 505 of the act (21 U.S.C. part 355) and part 
314 of the regulations (21 CFR part 314). In appropriate circumstances, 
a citizen petition to amend the monograph may be submitted under 21 CFR 
10.30 in lieu of an application. Any OTC anticaries drug product 
initially introduced or initially delivered for introduction into 
interstate commerce after the effective dates of Sec. 310.545(a)(2) or 
the effective date of this final rule that is not in compliance with 
the regulations is subject to regulatory action.
    An analysis of the cost and benefits of this regulation, conducted 
under 

[[Page 52507]]
Executive Order 12291, was discussed in the tentative final monograph 
of September 30, 1985 (50 FR 39854) and in the amendment of the 
tentative final monograph of June 15, 1988 (53 FR 22430). No comments 
were received in response to the agency's request for specific comment 
on the economic impact of this rulemaking (50 FR 39854 at 39871 and 53 
FR 22430 at 22447), and the substance of that analysis has not changed. 
Executive Order 12291 has been superseded by Executive Order 12866. FDA 
has examined the impacts of the final rule under Executive Order 12866 
and the Regulatory Flexibility Act (Pub. L. 96-354). Executive Order 
12866 directs agencies to assess all costs and benefits of available 
regulatory alternatives and, when regulation is necessary, to select 
regulatory approaches that maximize net benefits (including potential 
economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this final rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the final 
rule is not a significant regulatory action as defined by the Executive 
Order and, thus, is not subject to review under the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. All major anticaries drug products already contain 
monograph ingredients, and no reformulations should be necessary. This 
final rule will require some relabeling for these products. 
Manufacturers will have 1 year to implement this relabeling. 
Accordingly, the agency certifies that the final rule will not have a 
significant economic impact on a substantial number of small entities. 
Therefore, under the Regulatory Flexibility Act, no further analysis is 
required.
    The agency has determined under 21 CFR 25.24(c)(6) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

List of Subjects

21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.

21 CFR Part 355

    Labeling, Over-the-counter drugs.

21 CFR Part 369

    Labeling, Medical devices, Over-the-counter drugs.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR 
chapter I is amended as follows:

PART 310--NEW DRUGS

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

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


Sec. 310.201  [Amended]

    2. Section 310.201 Exemption for certain drugs limited by new-drug 
applications to prescription sale is amended by removing and reserving 
paragraphs (a)(10) and (a)(15).
    3. Section 310.545 is amended by redesignating the text of 
paragraph (a)(2) as paragraph (a)(2)(i); by adding new (a)(2)(i) 
heading and paragraphs (a)(2)(ii) and (d)(24); and by revising 
paragraph (d) introductory text and paragraph (d)(1) to read as 
follows:


Sec. 310.545  Drug products containing certain active ingredients 
offered over-the-counter (OTC) for certain uses.

    (a) * * *
    (2) Anticaries drug products--(i) Approved as of May 7, 1991. * * *
    (ii) Approved as of October 7, 1996.
Calcium sucrose phosphate
Dicalcium phosphate dihydrate
Disodium hydrogen phosphate\1\

    \1\ These ingredients are nonmonograph except when used to 
prepare acidulated phosphate fluoride treatment rinses identified in 
Sec. 355.10(a)(3) of this chapter.
---------------------------------------------------------------------------

Phosphoric acid1
Sodium dihydrogen phosphate
Sodium dihydrogen phosphate monohydrate
Sodium phosphate, dibasic anhydrous reagent1
 * * * * *
    (d) Any OTC drug product that is not in compliance with this 
section is subject to regulatory action if initially introduced or 
initially delivered for introduction into interstate commerce after the 
dates specified in paragraphs (d)(1) through (d)(24) of this section.
    (1) May 7, 1991, for products subject to paragraphs (a)(1) through 
(a)(2)(i), (a)(3) through (a)(4), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7) 
(except as covered by paragraph (d)(3) of this section), (a)(8)(i), 
(a)(9) through (a)(10)(iii), (a)(12)(i) through (a)(12)(iv), (a)(14) 
through (a)(15)(i), and (a)(16) through (a)(18)(i) of this section.
 * * * * *
    (24) October 7, 1996, for products subject to paragraph (a)(2)(ii) 
of this section.
    4. Part 355 is added to read as follows:

PART 355--ANTICARIES DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE

Subpart A--General Provisions

Sec.
355.1    Scope.
355.3    Definitions.

Subpart B--Active Ingredients

355.10    Anticaries active ingredients.
355.20    Packaging conditions.

Subpart C--Labeling

355.50    Labeling of anticaries drug products.
355.55    Principal display panel of all fluoride rinse drug 
products.
335.60    Professional labeling.

Subpart D--Testing Procedures

355.70    Testing procedures for fluoride dentifrice drug products.

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

Subpart A--General Provisions


Sec. 355.1  Scope.

    (a) An over-the-counter anticaries drug product in a form suitable 
for topical administration to the teeth is generally recognized as safe 
and effective and is not misbranded if it meets each condition in this 
part and each general condition established in Sec. 330.1 of this 
chapter.
    (b) References in this part to regulatory sections of the Code of 
Federal Regulations are to Chapter I of Title 21 unless otherwise 
noted.


Sec. 355.3   Definitions.

    As used in this part:
    (a) Abrasive. Solid materials that are added to dentifrices to 
facilitate mechanical removal of dental plaque, debris, and stain from 
tooth surfaces.
    (b) Anhydrous glycerin. An ingredient that may be prepared by 
heating glycerin U.S.P. at 150 -C for 2 hours to drive off the moisture 
content.
    (c) Anticaries drug. A drug that aids in the prevention and 
prophylactic treatment of dental cavities (decay, caries). 

[[Page 52508]]

    (d) Dental caries. A disease of calcified tissues of teeth 
characterized by demineralization of the inorganic portion and 
destruction of the organic matrix.
    (e) Dentifrice. An abrasive-containing dosage form for delivering 
an anticaries drug to the teeth.
    (f) Fluoride. The inorganic form of the chemical element fluorine 
in combination with other elements.
    (g) Fluoride ion. The negatively charged atom of the chemical 
element fluorine.
    (h) Fluoride supplement. A special treatment rinse dosage form that 
is intended to be swallowed, and is promoted to health professionals 
for use in areas where the water supply contains 0 to 0.7 parts per 
million (ppm) fluoride ion.
    (i) Preventive treatment gel. A dosage form for delivering an 
anticaries drug to the teeth. Preventive treatment gels are formulated 
in an anhydrous glycerin base with suitable thickening agents included 
to adjust viscosity. Preventive treatment gels do not contain 
abrasives.
    (j) Treatment rinse. A liquid dosage form for delivering an 
anticaries drug to the teeth.
    (k) Treatment rinse concentrated solution. A fluoride treatment 
rinse in a concentrated form to be mixed with water before using to 
result in the appropriate fluoride concentration specified in the 
monograph.
    (l) Treatment rinse effervescent tablets. A fluoride treatment 
rinse prepared by adding an effervescent tablet (a concentrated solid 
dosage form) to water before using to result in the appropriate 
fluoride concentration specified in the monograph.
    (m) Treatment rinse powder. A fluoride treatment rinse prepared by 
adding the powder (a concentrated solid dosage form) to water before 
using to result in the appropriate fluoride concentration specified in 
the monograph.

Subpart B--Active Ingredients


Sec. 355.10   Anticaries active ingredients.

    The active ingredient of the product consists of any of the 
following when used in the concentration and dosage form established 
for each ingredient:
    (a) Sodium fluoride--(1) Dentifrices containing 850 to 1,150 ppm 
theoretical total fluorine in a paste dosage form. Sodium fluoride 
0.188 to 0.254 percent with an available fluoride ion concentration 
 650 parts per million (ppm).
    (2) Dentifrices containing 850 to 1,150 ppm theoretical total 
fluorine in a powdered dosage form. Sodium fluoride 0.188 to 0.254 
percent with an available fluoride ion concentration of  850 
ppm for products containing the abrasive sodium bicarbonate and a 
poured-bulk density of 1.0 to 1.2 grams per milliliter.
    (3) Treatment rinses. (i) An aqueous solution of acidulated 
phosphate fluoride derived from sodium fluoride acidulated with a 
mixture of sodium phosphate, monobasic, and phosphoric acid to a level 
of 0.1 molar phosphate ion and a pH of 3.0 to 4.5 and which yields an 
effective fluoride ion concentration of 0.02 percent.
    (ii) An aqueous solution of acidulated phosphate fluoride derived 
from sodium fluoride acidulated with a mixture of sodium phosphate, 
dibasic, and phosphoric acid to a pH of 3.5 and which yields an 
effective fluoride ion concentration of 0.01 percent.
    (iii) Sodium fluoride 0.02 percent aqueous solution with a pH of 
approximately 7.
    (iv) Sodium fluoride 0.05 percent aqueous solution with a pH of 
approximately 7.
    (v) Sodium fluoride concentrate containing adequate directions for 
mixing with water before using to result in a 0.02-percent or 0.05-
percent aqueous solution with a pH of approximately 7.
    (b) Sodium monofluorophosphate--(1) Dentifrices containing 850 to 
1,150 ppm theoretical total fluorine in a paste dosage form. Sodium 
monofluorophosphate 0.654 to 0.884 percent with an available fluoride 
ion concentration (consisting of PO3F= and F- combined) 
 800 ppm.
    (2) Dentifrices containing 1,500 ppm theoretical total fluorine in 
a paste dosage form. Sodium monofluorophosphate 1.153 percent with an 
available fluoride ion concentration (consisting of PO3F= and 
F- combined)  1,275 ppm.
    (c) Stannous fluoride--(1) Dentifrices containing 850 to 1,150 ppm 
theoretical total fluorine in a paste dosage form. (i) Stannous 
fluoride 0.351 to 0.474 percent with an available fluoride ion 
concentration  700 ppm for products containing abrasives 
other than calcium pyrophosphate.
    (ii) Stannous fluoride 0.351 to 0.474 percent with an available 
fluoride ion concentration  290 ppm for products containing 
the abrasive calcium pyrophosphate.
    (2) Preventive treatment gel. Stannous fluoride 0.4 percent in an 
anhydrous glycerin gel, made from anhydrous glycerin and the addition 
of suitable thickening agents to adjust viscosity.
    (3) Treatment rinse. Stannous fluoride concentrate marketed in a 
stable form and containing adequate directions for mixing with water 
immediately before using to result in a 0.1-percent aqueous solution.


Sec. 355.20   Packaging conditions.

    (a) Package size limitation. Due to the toxicity associated with 
fluoride active ingredients, the following package size limitations are 
required for anticaries drug products:
    (1) Dentifrices. Dentifrice (toothpastes and tooth powders) 
packages shall not contain more than 276 milligrams (mg) total fluorine 
per package.
    (2) Preventive treatment gels and treatment rinses. Preventive 
treatment gel and treatment rinse packages shall not contain more than 
120 mg total fluorine per package.
    (3) Exception. Package size limitations do not apply to anticaries 
drug products marketed for professional office use only and labeled in 
accord with Sec. 355.60.
    (b) Tight container packaging. To minimize moisture contamination, 
all fluoride powdered dentifrices shall be packaged in a tight 
container as defined as a container that protects the contents from 
contamination by extraneous liquids, solids, or vapors, from loss of 
the article, and from efflorescence, deliquescence, or evaporation 
under the ordinary or customary conditions of handling, shipment, 
storage, and distribution, and is capable of tight reclosure.

Subpart C--Labeling


Sec. 355.50   Labeling of anticaries drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as the 
following: ``anticavity fluoride'' (select one of the following as 
appropriate: ``dentifrice,'' ``toothpaste,'' ``tooth polish,'' ``tooth 
powder;'' (optional: ``dental'') ``preventive treatment gel;'' or 
(optional: ``treatment'' or ``dental'')) (select one of the following: 
``rinse,'' ``concentrated solution,'' ``rinse powder,'' or ``rinse 
effervescent tablets''). The word ``mouthwash'' may be substituted for 
the word ``rinse'' in this statement of identity if the product also 
has a cosmetic use, as defined in section 201(i) of the Federal Food, 
Drug, and Cosmetic Act (the act) (21 U.S.C. 321(i)).
    (b) Indication. The labeling of the product states, under the 
heading ``Indication,'' the following: ``Aids in the prevention of 
dental (select one of the following: ``cavities,'' ``decay,'' ``caries 
(decay),'' or ``caries (cavities)''). Other truthful and nonmisleading 
statements, describing only the 

[[Page 52509]]
indication for use that has been established and listed in this 
paragraph (b), may also be used, as provided in Sec. 330.1(c)(2) of 
this chapter, subject to the provisions of section 502 of the Federal 
Food, Drug, and Cosmetic Act (the act) relating to misbranding and the 
prohibition in section 301(d) of the act against the introduction or 
delivery for introduction into interstate commerce of unapproved new 
drugs in violation of section 505(a) of the act.
    (c) Warning. The labeling of the product contains the following 
warning under the heading ``Warning'':
    (1) For all fluoride dentifrice (toothpastes and tooth powders) 
products. ``Keep out of the reach of children under 6 years of age.'' 
This warning shall be used in place of the first general warning 
statement required by Sec. 330.1(g) of this chapter.
    (2) For all fluoride rinse and gel products. The first general 
warning statement in Sec. 330.1(g) of this chapter shall be used.
    (d) Directions. The labeling of the product contains the following 
statements under the heading ``Directions'':
    (1) For anticaries dentifrice products--(i) Paste dosage form with 
a theoretical total fluorine concentration of 850 to 1,150 ppm 
identified in Sec. 355.10(a)(1), (b)(1), and (c)(1). Adults and 
children 2 years of age and older: Brush teeth thoroughly, preferably 
after each meal or at least twice a day, or as directed by a dentist or 
doctor. Instruct children under 6 years of age in good brushing and 
rinsing habits (to minimize swallowing). Supervise children as 
necessary until capable of using without supervision. Children under 2 
years of age: Consult a dentist or doctor.
    (ii) Paste dosage form with a theoretical total fluorine 
concentration of 1,500 ppm identified in Sec. 355.10(b)(2). Adults and 
children 6 years of age and older: Brush teeth thoroughly, preferably 
after each meal or at least twice a day, or as directed by a dentist or 
doctor. Instruct children under 12 years of age in good brushing and 
rinsing habits (to minimize swallowing). Supervise children as 
necessary until capable of using without supervision. Children under 6 
years of age: Do not use unless directed by a dentist or doctor.
    (iii) Powdered dosage form with a theoretical total fluorine 
concentration of 850 to 1,150 ppm identified in Sec. 355.10(a)(2). 
Adults and children 6 years of age and older: Apply powder to a wet 
toothbrush; completely cover all bristles. Brush for at least 30 
seconds. Reapply powder as before and brush again. Rinse and spit out 
thoroughly. Brush teeth, preferably after each meal or at least twice a 
day, or as directed by a dentist or doctor. Instruct children under 12 
years of age in good brushing and rinsing habits (to minimize 
swallowing). Supervise children as necessary until capable of using 
without supervision. Children under 6 years of age: Do not use unless 
directed by a dentist or doctor.
    (2) For anticaries treatment rinse products--(i) For acidulated 
phosphate fluoride solution containing 0.02 percent fluoride ion, 
sodium fluoride 0.05 percent, sodium fluoride concentrate, and stannous 
fluoride concentrate identified in Sec. 355.10(a)(3)(i), (a)(3)(iv), 
(a)(3)(v), and (c)(3). Adults and children 6 years of age and older: 
Use once a day after brushing your teeth with a toothpaste. Vigorously 
swish 10 milliliters of rinse between your teeth for 1 minute and then 
spit out. Do not swallow the rinse. Do not eat or drink for 30 minutes 
after rinsing. Instruct children under 12 years of age in good rinsing 
habits (to minimize swallowing). Supervise children as necessary until 
capable of using without supervision. Children under 6 years of age: 
Consult a dentist or doctor.
    (ii) For acidulated phosphate fluoride solution containing 0.01 
percent fluoride ion and sodium fluoride 0.02 percent aqueous solution 
identified in Sec. 355.10(a)(3)(ii) and (a)(3)(iii). Adults and 
children 6 years of age and older: Use twice a day after brushing your 
teeth with a toothpaste. Vigorously swish 10 milliliters of rinse 
between your teeth for 1 minute and then spit out. Do not swallow the 
rinse. Do not eat or drink for 30 minutes after rinsing. Instruct 
children under 12 years of age in good rinsing habits (to minimize 
swallowing). Supervise children as necessary until capable of using 
without supervision. Children under 6 years of age: consult a dentist 
or doctor.
    (3) For stannous fluoride treatment rinse products. (i) ``Use 
immediately after preparing the rinse.''
    (ii) For powder or effervescent tablets used to prepare treatment 
rinses. ``Do not use as a rinse until all the'' (select one of the 
following: ``powder'' or ``tablet'') ``has dissolved.''
    (4) For anticaries preventive treatment gel products. Adults and 
children 6 years of age and older: Use once a day after brushing your 
teeth with a toothpaste. Apply the gel to your teeth and brush 
thoroughly. Allow the gel to remain on your teeth for 1 minute and then 
spit out. Do not swallow the gel. Do not eat or drink for 30 minutes 
after brushing. Instruct children under 12 years of age in the use of 
this product (to minimize swallowing). Supervise children as necessary 
until capable of using without supervision. Children under 6 years of 
age: consult a dentist or doctor.
    (5) For all concentrated treatment rinse solutions, powders, and 
effervescent tablets. The following statement shall appear as the first 
statement under directions: ``Do not use before mixing with water.''
    (e) Additional labeling statements for anticaries drug products. 
The following statements need not appear under warnings, but are 
required to appear on the label of anticaries drugs products as 
applicable.
    (1) For all preventive treatment gels. ``This is a(n)'' (select one 
or both of the following: ``anticavity'' or ``fluoride'') ``preventive 
treatment gel, not a toothpaste. Read directions carefully before 
using.''
    (2) For all stannous fluoride treatment rinse, preventive treatment 
gel, and dentifrice products. ``This product may produce surface 
staining of the teeth. Adequate toothbrushing may prevent these stains 
which are not harmful or permanent and may be removed by your 
dentist.''
    (f) Optional additional labeling statements--(1) For fluoride 
treatment rinses and preventive treatment gels. The following labeling 
statement may appear in the required boxed area designated ``APPROVED 
USES'': ``The combined daily use of a fluoride preventive treatment'' 
(select one of the following: ``rinse'' or ``gel'') ``and a fluoride 
toothpaste can help reduce the incidence of dental cavities.''
    (2) For dentifrice products containing 1,500 ppm theoretical total 
fluorine. ``Adults and children over 6 years of age may wish to use 
this extra-strength fluoride dentifrice if they reside in a 
nonfluoridated area or if they have a greater tendency to develop 
cavities.''


Sec. 355.55   Principal display panel of all fluoride rinse drug 
products.

    In addition to the statement of identity required in Sec. 355.50, 
the following statement shall be prominently placed on the principal 
display panel: ``IMPORTANT: Read directions for proper use.''


Sec. 355.60   Professional labeling.

    (a) The labeling for anticaries fluoride treatment rinses 
identified in Sec. 355.10(a)(3) and (c)(3) that are specially 
formulated so they may be swallowed (fluoride supplements) and are 
provided to health professionals (but not to the general public) may 
contain the following additional dosage information: Children 3 to 
under 14 

[[Page 52510]]
years of age: As a supplement in areas where the water supply is 
nonfluoridated (less than 0.3 parts per million (ppm)), clean the teeth 
with a toothpaste and rinse with 5 milliliters (mL) of 0.02 percent or 
10 mL of 0.01 percent fluoride ion rinse daily, then swallow. When the 
water supply contains 0.3 to 0.7 ppm fluoride ion, reduce the dose to 
2.5 mL of 0.02 percent or 5 mL of 0.01 percent fluoride ion rinse 
daily.
    (b) The labeling for products marketed to health to health 
professionals in package sizes larger than those specified in 
Sec. 355.20 shall include the statements: ``For Professional Office Use 
Only'' and ``This product is not intended for home or unsupervised 
consumer use.''

Subpart D--Testing Procedures


Sec. 355.70   Testing procedures for fluoride dentifrice drug products.

    (a) A fluoride dentifrice drug product shall meet the biological 
test requirements for animal caries reduction and one of the following 
tests: Enamel solubility reduction or fluoride enamel uptake. The 
testing procedures for these biological tests are labeled Biological 
Testing Procedures for Fluoride Dentifrices; these testing procedures 
are on file under Docket No. 80N-0042 in the Dockets Management Branch 
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., 
Rockville, MD 20857, and are available on request to that office.
    (b) The United States Pharmacopeia fluoride dentifrice reference 
standards along with reference standard stability profiles (total 
fluoride, available fluoride ion, pH, and specific gravity) required to 
be used in the biological tests are available to any purchaser upon 
written request to the United States Pharmacopeial Convention, Inc., 
1260 Twinbrook Parkway, Rockville, MD 20852.
    (c) Alternative testing procedures may be used. Any proposed 
modification or alternative testing procedures shall be submitted as a 
petition in accord with Sec. 10.30 of this chapter. The petition should 
contain data to support the modification or data demonstrating that an 
alternative testing procedure provides results of equivalent accuracy. 
All information submitted will be subjected to the disclosure rules in 
part 20 of this chapter.

PART 369--INTERPRETATIVE STATEMENTS RE WARNINGS ON DRUGS AND 
DEVICES FOR OVER-THE-COUNTER SALE

    4. The authority citation for 21 CFR part 369 continues to read as 
follows:

    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701 of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 
352, 353, 355, 356, 357, 371).


Sec. 369.21   [Amended]

    5. Section 369.21 Drugs; warning and caution statements required by 
regulations is amended by removing the entries for ``SODIUM FLUORIDE 
DENTIFRICE POWDER'' and ``SODIUM MONOFLUOROPHOSPHATE DENTIFRICE 
SOLUTION.''

    Dated: September 18, 1995.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 95-24693 Filed 10-5-95; 8:45 am]
BILLING CODE 4160-01-F