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Public Health Service

Food and Drug Administration


Rockville MD 20857

Lilly A. Johnson
4041 Lauri Jo Drive
Marietta, Georgia 30060

Re: Docket No. 78N-0065


Comment No. C23

Dear Miss Johnson:

This is in response to your letter received by the agency on


June 24, 1996, regarding skin cream products containing
hydroquinone.

Your letter states your frustration with the cream containing 2%


hydroquinone. You explained that creams containing a higher
percentage of hydroquinone helped you for many years, but that
the 2% cream is not working at all. You stated that people
should be permitted to use products containing a higher
concentration of hydroquinone at their own risk, and compared the
situation to the use of cigarettes and alcohol. You further
pointed out that many people have adverse reactions to items
marketed legally, and removing everything that results in adverse
reactions from the market would leave nothing at all available.
You also suggested that the labeling could inform people on what
to do if adverse reactions should occur.

I am sorry to hear that you are unable to achieve satisfactory


results with the presently marketed products. However, taking
into consideration the benefit-risk assessment of hydroquinone,
based on the information available at this time, higher
concentrations of hydroquinone are unlikely. The enclosed
Federal Register notice, dated September 3, 1982, discusses our
concerns regarding the higher concentration of hydroquinone on
pages 39109-39110.

We are planning to have a public meeting before the end of the


year to consider additional safety aspects of hydroquinone.
.
Lilly A. Johnson Page 2

In addition, we will evaluate all the comments, including yours,


in response to the publication, and will publish a final rule at
some future date.

I regret that I cannot be more helpful at this time.

Sincerely yours,

Debra L. Bowen, M.D.


Director
Division of OTC Drug Products
Center for Drug Evaluation and Research

Enclosure
l
M E M 0 R A N D U M DEPARTMENTOF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
-----------------------------------------------------------------
DATE: OCT I 6 1996

FROM: Director
Division of OTC Drug Products, HFD-560
SUBJECT: Material for Docket No. t/f/v- (x%)5
TO: Dockets Management Branch, HFA-305 0f

The attached material should be placed on public


display under the above referenced Docket No.
This material should be cross-referenced to
Comment No. cJ.3 .

Bowen, M.D.

Attachment
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September 3, 1982

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Part V
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Department of
Health and Human
.

Services .
Food and Drug Administration

Skin Bleaching Drug Products for Over-


the-Counter Human Use; Tentative Final
Monograph
DEPARTMENT OF HEALTH AND $ 330.10(a)(G) (21 CFR 330.10(~)(G)), an display in the Dockets Management
HUMAN SERVICES . advance notice of proposed rulemriking Branch.
to establish a monograph for OTC skin This proposal to establish Part 356 (21
Food and Drug Administration bleaching drug products, together with CFR Part 358) constitutes FDA’S
21 CFR Part 358 the recommendations of the Advisory tentative adoption of the Panel’s
Review Panel on OTC Miscellaneous conclusions and recommendations on
[Docket No. 78N-00651
External Drug Products, which was the OTC skin bleaching drug products, as
Skin Bleaching Drug Products for advisory review panel responsible for modified on the basis of the comments
Over-the-Counter Human Use; elraluating data on the active ingredients received and the agency’s independent
Tentative Final Monograph in this drug class. Interested persons evaluation of the Panel’s report.
AGENCY: Food and Drug Administration. were invited to submit comments by Modifications have been made for
ACTION: Notice of proposed rulemaking. February 1,1979. Reply comments in clarity and regulatory accuracy and to
response to comments filed in the initial reflect new information. Such new
SUMMARY: The Food and Drug comment period could be submitted by information has been placed on file in
Administration (FDA) is issuing a notice March $1979. the Dockets Management Branch
of proposed rulemaking in the form of a In a notice published in the Federal (address above). These modifications
tentative final monograph that would Register of March 21,198O (45 FR 16464), are reflected in the following summary
establish conditions under which over- the agency advised that it had reopened of the comments and FDA’s responses to
the-counter (OTC) skin bleaching drug the administrative record for OTC skin them.
products (products that bleach or bleaching drug products to allow for FDA published in the Federal Register
otherwise lighten limited areas of consideration of data and information of September 29,198l (46 FR 47730) a
brownish skin through suppression of that had been filed in the Dockets final rule revising the OTC procedura1
melanin pigment formation within the Management Branch after the date the regulations to conform to the decision in
skin cells) are generally recognized as administrative record previously had Cutler v. Kennedy, 475 F. Supp. 838
safe and effective and not misbranded. officially closed. The agency concluded (D.D.C. 1979).The Court in Cutler held
FDA is issuing this notice of proposed that any new data and information filed that the OTC drug review regulations (21
rulemaking after considering the report prior to March 21.1986, should be CFR 330.10) were unlawful to the extent
and recommendations of Advisory available to the agency in developing a that they authorized the marketing of
Review Panel on OTC Miscellaneous proposed regulation in the form of a Category III drugs after a final
External Drug Products and public tentative final monograph. monograph had been established.
comments on an advance notice of In accordance with 0 330.10(a)(lO), the Accordin$y, this provision is now
proposed rulemaking that was based on data and information considered by the deleted from the regulations. The
those recommendations. This proposal Panel were put on public display in the regulations now provide that any testing
is part of the ongoing review of OTC Dockets Management Branch (HFA- necessary to resolve the safety or
drug products conducted by FDA. 3051, Food and Drug Administration effectiveness issues that formerly
DATES: Written comments, objections, or (address above), after deletion of a resulted in a Category III classification,
requests for oral hearing before the small amount of trade secret and submission to FDA of the results of
Commissioner of Food and Drugs on the information. Data and information that testing or any other data, must be
proposed regulation by November 2, received after the administrative record done during the OTC drug rulemaking
1982. New data by September 3,1983. was reopened also have been put on process, before the establishment of a
Comments on the new data by display in the Dockets Management final monograph (48 FR 47738).
November 3,1983. These dates are Branch. Although it was not required td do so
consistent with the time periods The advance notice of proposed under Cutler, FDA will no longer use the
specified in the agency’s final rule rulemaking, which was published in the terms “Category I,” “Category II,*’and
revising the procedural regulations for Federal Register on November 3,1978 “Category III” at the final monograph
reviewing and classifying OTC drugs, (43 FR 515461, was designated 8%a stage in favor of the terms “monograph
published in the Federal Register of “proposed monograph” in order to conditions” (old Category I) and
September 29,1981(46 FR 47730). conform to terminology used in the OTC “nonmonograph conditions” (old
Written comments on the agency’s ’ drug review regulations (21 CFR 330.10). Categories II and III). This document
economic impact determination by Similarly, the present document is retains the concepts of Categories I, II, _
January 3,1983. designated in the OTC drug review and III at the tentative final monograph
ADDRESS: Written comments, objections, regulation as a “tentative final stage.
or requests for oral hearing to the monograph.” Its legal status, however, is The agency advises that the
Dockets Management Branch (HFA- that of a proposed rule. In this tentative conditions under which the drug
305), Food and Drug Administration, Rrn. final monograph [proposed rule) tb8 products that are subject to this
4-62, 5606 Fishers Lane, Rockville. h4D FDA states for the first time its position monograph would be generally
20857. New data and comments on new on the establishnient of a monograph for recognized as safe and effective and not
data should also be addressed to the OTC skin bleaching drug products. Final misbranded (monograph conditions) will
dockets Management Branch. agency action on this matter will occur be effective 12 months after the date of
FOR FURTHER INFORMATION CONTACT: with the publication at a future date of a publication of the final monograph in the
William E. Gilbertson, National Center final monograph, which will be a final Federal Register. On or after that date,
for Drugs and Biologics (HFLMlO), Food rule establishing a monograph for OTC no OTC drug products that are subject
and Drug Administration. 5600 Fishers skin bleaching drug products. to the monograph and that contain
Lane, Rockville, MD 20857,301-443- - In response to the advance notick of nonmonograph conditions, i.e.,
4960. proposed rulemaking. one drug honditions that would cause the drug to
SUPPLEMENTARY INFORMATION: In the manufacturers’ association and five be not generally recognized as safe and
Federal Register of November 3,1978 (43 manufacturers submitted comments. effective or to be misbranded, may be
FR 51546) FDA published, under Copies of their comments are on public initially introduced or initially delivered
t ..
i
ifte; tl;e di;tk~6~“~~b~~~~~~~~~“si”’
for introduction into interstate ’
commerce unless they are the subject of manufaciurers can order neiv labeling
an approved new drug application. atidreformul& their produc’ts ‘&nd have expo&re and the disfiguring skin effects
Further, any OTC drug products subject them inoomPlian&‘in the marketplace. ‘observed after prolonged use of high
to this monograph that are repackaged H&&Gei;;:if the agency deteri&& that ~cohqe&itio.tis and exposure to the sun
or relabeled after the effective date of any labeling-‘for’s condition iiidluded in have not been reported for products
the monograph must be in-compliance the final monograph should be containing’conckntrations un’der 5
with the monograph regardless of the implemented sboner. a shorter deadline percent hydroquinone. .- ._The comment
date the product was initially introduced may be e$tablished.SimiIarly, if a safety ciied‘several references ie&~%&lbv’ the
or initially delivered for introduction problem is identified foia particular Panel in support of its argument (Refs. 1
into interstate commerce. Manufacturers nonmonograph condition, a shorter through’$‘and stated that 4 percent
are encouraged to comply voluntarily deadiixie may be set for removal of that hydroquinone skim bleridhing Rroducts
with the monograph at the earliest condition from OTC drug products.
. ; .(__” heve/yo
been
_;.” ~,marketed _i ;- ii*for
. *.:, ,.a, ,.* years without
possible date, I. The Agency’s Tentative Conclusions consumer complaints of any effects of
In the advance notice of proposed on the Comments the k&i ~~~~e~ti”~~~~~e~~~fiiins,
p~rcent’ reported from the use of 5
rulemaking for @l!C‘sk~mbleaching drug
products (published in the Federal A, Geneml Commentson Skin The agency has reviewed the’
Register of November 3.1978 (43 FR BleachingDFg Products available data and agrees with the Panel
51548)), the agency suggested that the 1. *e comment stated&at the QTC ” :igd “&~~&$i$ii<jifi~t the eye and skin
conditions included in the monogrfiph Panel lacked the juris&&n to make damage cited in the comment,have,pot
(Category I) be effective 20 days after recommendations with respect to ” ‘been renorted from use of .
the date of publication of the final cosmetic claims Andythii”i”the legal conce&ations ef’hy.droquinone less
monograph in the Federal Register and standards applicable to cosmetic claims ~~ii”~‘i;erce;lF’~owever, the agency
that the conditions. excluded from the are dierent from those applicable to does not agree with the comment’s
monograph (Cateogory$)‘be eliminated drug claims. req&est to fncreaiie the concentration to
from OTC drug products effective 8 The iigency agrees that the legal 4 percent because itlias been
months after the date of publication of standards applicable to cosmetic claims demonstrated’th~t concentr&ons of ’
the final monograph, regardless of are
whether further testing was undertaken dl;igdifferent from those Applicable to _
cl.i..s i~x~.&-...~~a~ey~ ‘hydroq;iinonebet&% 2 and.4-perhent
are not”sij@cantly more effective and
to justify their future use. Rxpedende jurisdiction extended only & drug’ pose ‘a @nifmantly higher risk of
has shown that relabeling of products claims for @I blea&ing products and adverse‘effects. Arndt and Fitzpcitrick
covered by the monograph is necessary not to cosmetic claims. The distinction (Ref. 6) obihp’tied 2 and 5 percent
_ , in order for manufacturers to comply between dr$‘&d cosmetic claiiris is’ hydroqnlnone Cream in 56 patients with
. with the monograph. New labels discussed further indoiif6d~~d
.2. One co&&rit comment &$t’
18 below.
@yyy hyperpl&iGnted skin. They concluded
containing tbe. monograph labeling have
.I’ i, to be written, ordered, received, and ~g monogriihg aij,%f~$~E~6;~~ / <.l^ thiit the Z-percent cream w&s as’
eff&t& but caused less primary
( incorporated into the marmfacturing opposed to substantive, regulations. The i&tat&n th* the &percent cream.
., process. The agency has determined that comment referred to statements uTy~.
on thl?
it is impractical to ,expect new labeling issue s~bmiCt3d.e’ ~Ii~~“~~~~~~ ,* 4x1a stndy,by Spencer (Ref. 4) cited by
\ the comment iii sGp&& of the the safety
to be in effect 30,dsys after the date of rulema& proceedings.
publication of the final m&ograph. of hydroqulimne, derivatives of
The agency addressed this issue in hydroq&none wereused in a &&al
Experience has shown also that if the paragraphs 85 through 91 of the
deadline for relabeling is tea short, the study of 142 white and 8 black subjects
preamble @ ‘the procedures, for for a period of 2”months. Nii’significant
agency is burdened with extension classification of OTC drug products,
requests and related paperwork. re@ioris er iieirsit&ition‘developed
published
**; f@q$y”pJ ‘iif thegggy~~tn
Pe&%aIReglster of May
paragraph 3 using conc&rationS’of 1,4, or 7 percent,
’ In addition, .some prod&s will have
to be reformulated’to comply with the, The ige;iicv belleves .tl+t this Study ’
of the preamble to the tent&v8 final pi@t be usedto sppport the safety of
monograph. Reformulatjon often monograph for ant@id drug prOduets,
involves the need to do stability testing published in the FederaIRe&t&of hydroqulnone because it involved
on the new product. An accelerated November 12,1972 (& PR 3%2t@)~_tr*r)A hydroquinone derivatives of hydroquinone, not
aging process may .be used to test a neti reaffis the dbnclusfons stiied there; itself. The derivatives
..~. ,. _ of
formulation; however, if the stability Subsequent court decisions heve, hydroq&ione used in the,study were the
testing is not successful, and if further confirmed the agendy’G%l&ity to tertiary butyldfmethyl ether of
reformulation is required, tbere.could be hydr&$nbne and the monotertiary ’
issue substantive
lulemak;~i-~~~‘ National by ,’
regulatmns
~.@;., buty~onomethyl ether of
a further delay in having a new product -r.
available for manufa&ne. Ntitri&nal FoodsASsociafi% ti.
The agency wishes to establish a Weinbergei;’ dii fi.“;id &.&59&98 (&I
reasonable period of time for relabeling Cir. 1975) and Natioi&%.&?ation of reported that u&g 5-pitient
end reformulation in order to,avoid an PharmaceuticblM%$actu&% 6. FDA, hydroqiiiiione, alone ‘or in combination
‘unnecessary disruption’of the 487 F. Supp. 412 (S.D.N.Y.‘198b], tiff% With the tertiary butyldiiiethyl ether of
marketplace that could not only result m 837 F. 2d 887 (2d Cir. 398%). hydroquinone,
.&(@ study df‘was effedtive
&$irrfiite &j in &)‘ci+‘4-
+a& ’
edonemic loss, butalso interfere with
consumers’ access to safe and effedtive B. Commentioix‘Hjrdroquino& “’ a~ males, vvho completed the study.
^ $;Jy~ g~‘-~&~ffe~iieited .&ihat ae
drug products. Therefore, the age&y id However, the concentr@ion of 5 percent
proposing that the. final monograph be 1.5 to 2-per&3 rdc6me&dk$’
co~~%w~i.db”+~’ hydroquinone in $ +p”jid liydroqlfinone
percent afiei’g %is’ Gduced
.wekki to 1.5 and 2
6~,;~<~&y~q
effective 12 months after the date of its tie“.{ti;i;<i~d ‘id conce~Gat&& of *;$ td :‘
,.: ,. dernmiitii
publication in the Federal Re&l&er. The iu&jecti in’iiYXti;f
ih*e’;&y,t&a p&.&l 12.2
agency believes that within 12 months 4 percent: Thk’comment,argued that the
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,,:,, ..-;;.,, ,<, “- i
, r.
0 39109
Federal Register / Vol. 47, ~Jo. 172 1 Friday, September 1 Proposed Rules

for introduction into interstate after the date of publication most Panel itself concluded that the eye
commerce unless they are the subject of manufacturers can order new labeling damage reported from industrial
an approved new drug application. and reformulate their products and have exposure and the disfiguring skin effects
Further, any OTC drug products subject them in compliance in thi marketplace. observed after prolonged use of high
to this monograph that are repackaged However, if the agency determines that concentrations and exposure to the sun
or relabeled after the effective date of any labeling for a condition included in have not been reported for products
the monograph must be in compliance the final monograph should be containing concentrations under 5
with the monograph regardless of the implemented sooner, a shorter deadline percent hydroquinone. The comment
date the product was initially introduced may be established. Similarly, if a safety cited several references reviewed by the
or initially delivered for introduction problem is identified for a particular Panel in support of its argument (Refs. 1
into interstate commerce. Manufacturers nonmonograph condition, a shorter through 5) and stated that 4 percent
are encouraged to comply voluntarily deadline may be set for removal of that hydroquinone skin bleaching products
with the monograph at the earliest condition from OTC drug products. have been marketed for years without
possible date. I. The Agency’s Tentative Conclusions consumer complaints of any effects of
In the advance notice of proposed on the Comments the kind reported from the use of 5
rulemaking for OTC skin bleaching drug percent or greater concentrations.
products [published in the Federal A. General Comments on Skin The agency has reviewed the
Register of November 3.1978 (43 FR Bleaching Drug Products available data and agrees with the Panel
5X46)), the agency suggested that the 1. One comment stated that the OTC and the comment that the eye and skin
conditions included in the monograph Panel lacked the jurisdiction to make damage cited in the comment have not
(Category I) be effective 30 days after recommendations with respect to been reported from use of
the date of publication of the final cosmetic claims and that the legal concentrations of hydroquinone less
monograph in the Federal Register and standards applicable to cosmetic claims than 5 percent. However, the agency
that the conditions excluded from the are different from those applicable to does not agree with the comment’s
monograph (Cateogory II) be eliminated drug claims. request to increase the concentration to
from OTC drug products effective 6 The agency agrees that the legal 4 percent because it has been
months after the date of publication of standards applicable to cosmetic claims demonstrated that concentrations of
the final monograph, regardless of are different from those applicable to hydroquinone between 2 and 4 percent
whether further testing was undertaken drug claims atid that the Panel’s are not significantly more effective and
to justify their future use. Experience jurisdiction extended only g drug pose a significantly higher risk of
has shown that relabeling of products claims for skin bleaching products and adverse effects. Arndt and Fitzpatrick
covered by the monograph is necessary not to cosmetic claims. The distinction (Ref. 6) compared 2 and 5 percent
,_ in order for manufacturers to comply between drug and cosmetic claims is hydroquinone cream in 56 patients with
with the monograph. New labels discussed further in comment 18 below. hyperpigmented skin. They concluded
containing the monograph labeling have 2. One comment contended that OTC that the t-percent cream was as
to be written, ordered, received, and drug monographs are interpretive, as effective but caused less primary
incorporated into the manufacturing opposed to substantive, regulations. The irritation than the I-percent cream.
process. The agency has determined that comment referred to statements on this
it is impractical to expect new labeling In a studyby Spencer (Ref. 4) cited dy
issue submitted earlier to other OTC the comment In support of the the safety
to be in effect 30 days after the date of rulemaking proceedings.
publication of the final monograph. of hydroquinone, derivatives of
The agency addressed this issue in hydroquinone were used in a clinical
Experience has shown also that if the paragraphs 85 through ~1 of the
deadline for relabeling is too short, the study of 142 white and 6 black subjects
preamble to the procedures for for a period of 2 months. No significant
agency is burdened with extension classification of OTC drag products,
requests and related paperwork. reactions or sensitization developed
published In the Federal Register of May using concentrations of 1,4, or 7 percent.
In addition, some products will have 11.1972 (37 FR 9464) and in paragraph 3
to be reformulated to comply with the The agency believes that this study
of the preamble to the tentative final cannot be used to support the safety of
monograph. Reformulation often monograph for antacid drug products,
involves the need to do stability testing published In the Federal RegIsteZof hydroquinone because it Involved
on the new product. An accelerated November X&l973 (ZieFR 31260).FDA derivatives of hydroquinone, not
aging process may be used to test a new reaffirms the conclusions stated there. hydroquinone itself. The derivatives of
formulation; however, if the stability Subsequent court decisions hqve. hydroquinone used in the study were the
testing is not successful, and if further confirmed the agency’s authority to tertiary butyldimethyl ether of
reformulation is required, there could be issue substantive regulations by hydroquinone and the monotertiary
a further delay in having a new product rulemaking. See, e.g.. National butylmonomethyl ether of
available for manufacture. Nutritional Foods Association v. hydroquinone.
The agency wishes to establish a Weinberger, 512 F. 2d 688,6%-98 (2d Significantly, Spencer (Ref. 4) also
reasonable period of time for relabeling Cir. 1975) and National Association of reported that using 5-percent
and reformulation in order to avoid an Pharmaceutical Manufacturers v. FDA, hydroquinone, alone or in combination
‘unnecessary disruption of the 487 F. Supp. 412 (S.D.N.Y. 19801,alcfd, with the tertiary butyldimethyl ether of
marketplace that could not only result in 637 F. zd 887 (zd Cir. 1981). hydroquinone, was effective in a 4-
economic loss, but also interfere with month study of 53 white and 45 black
consumers’access to safe and effective B. Comments on Hydroquinone males who completed the study.
drug products. Therefore, the agency is 3. One comment requested that the However, the concentration of 5 percent
proposing that the final monograph be 1.5- to Z-percent hydroquinone hydroquinone was reduced to 1.5 and 2
effective 12 months after the date of its concentrations recommended in 5 358.10 percent after 3 weeks because of contact
publication in the Federal Register. The be increased to concentrations of 1.5 to dermatitis in 33 of the original 122
agency believes that within 12 months 4 percent. The comment argued that the subjects in the study.
Spencer (Ref. 5) studied the effects of of the ointment surface to air, or (2) the because Arndt and Fitzpatrick used
2. 3, and s percent hydroquinone in 64 use of a stabrlizing agent such as sodium substantially lower concentrations of
white and 43 black men. Although there bisulfite. hydroqumone (2 and 5 percent) and for
was only a slight increase in the number The agency does not disagree with the lesser periods of time (1 to 3 months
of patients in whom depigmentation Panel’s suggestions for stabilizing with treatment discontinued if no effect
developed, there was a dramatic hydroquinone products. However, was seen after 3 months). Additionally,
increase in the number of inflammatory questions relating to the stability of drug patients were instructed to avoid
reactions as the concentrations products are more appropriately sunlight. During the summer months
increased. addressed under the regulations for patients were advised to use a
With respect to the comment’s current good manufacturing practice sunscreen (15 percent aminobenzoic
argument regarding the lack of consumer (CCMP) for finished pharmaceuticals in acid) to block the rays of the sun. The
complaints, the agency believes that Part 211 (21 CFR Part 211). Under these agency notes that there is some variance
market experience alone is not sufficient regulations, marketed drug products are as to the percent of hydroquinone
evidence of safety in light of the reouired to meet am&cable standards of discussed in the Findlay, Morrison, and
available data. identity. strength, &ality. and purity at Simson study (Ref. 1). In one place the
The agency concurs with the Panel the time of use. To insure stabilitv. drue study mentions creams “with
that 1.5 to z percent hydroquinone is products are required by I 211.137 to ” approximately 5 percent hydroquinone
safe and effective for use as a skin bear an expiration date which is and more,” while in another place the
bleaching agent when used over limited determined by appropriate testing authors state that “certain commercial
areas of the body. The agency sees no described in 0 211.166. In the Federal preparations, containing 3 percent
reason to permit an increase in, Register of September 28,1878 (43 PR hydroquinone were strengthened td 6
concentration when the 2-percent 45088), PDA proposed a regulation that and 8 percent.” In either case the Panel’s
concentration is effective because the would grant an exemption from required description of “high concentrations (5
increased risk of adverse effects likely expiration dating for OTC human drug percent or more) of hydroquinone” is not
to occur with concentrations above 2 products that are marketed without misleading. For these reasons, the
percent hydroquinone would not be dosage limitations and are stable for at agency does not propose to delete this
offset by a sufficient proven increase in least 3 years as supported by statement.
effectiveness. appropriate stability data. A final
regulation has not been published yet, References
References however. Because hydroquinone skin (1) Findlay. G. H.. J. G. L Morrison. and I.
(1) Stern, G. S., et al., “Further Chronic bleaching pro&r&s must meet the W. Simson. ‘Exogenous Ochronosis and
Toxicitv Studies of Hvdrooutnone.” stability requirements of the CGMP pigmented Co!loid hIilium from
Federaiion Proceedin& Qi21-12i. 1956. Hydroquinone Bleaching Cream,” British
(2) Lang. S., N. R. Brawer. and A. I. Carlson, regulations in Part 211. PDA has no
objection to the addition of a stabilizer Journal of Dermatology 93:613-622,1975.
“Chronic Studies of Effect of Hyclroquinone (2) Arndt, K. A., and T. B. Fitzpatrick.
on Man,” Fedemtion Proceedings, W74.1950. to skin bleaching drug products
(3) Fiidlay, G. H., J. G. L Morrison, and I. containing hydroquinone. However, “Topical Use of Hychoqutnone as a
W. Simson. “Exogenous Ochronosis and FDA believes that there is no basis in Depigmentina Azent,” lournal of the /
Pigmented Colloid Milium from Ame&an Mid&I Association; 194965-967. !
the record to establish in the monograph 1965.
Hyclroquinone Bleaching Cream.” British a requirement that skin bleaching drug
Journal of Dermatology. Q3:6’13-8221975. products contain a stabilizer. C. Labeling Comments
(4) Spencer, hf. C.. “Hydroquinona
Bleaching.” Archives of Dermatology, &4:131- 5. One comment stated that the
Panel’s statement that “prolonged use of 6. One comment objected to the
134,1961. age. cy’s policy of specifying a limited
(5) Spencer. M. C. “Tooical Use of high concentrations [8 percent or more)
Hydroquinone for Depigfnentation,” Journal of hydroquinone with exposure to the list of terms as the only permissible
of the American Medical Association, sun may produce disfiguring effects” is expressions of indications for use for
194:962+64.1965. potentially misleading and should be skin bleaching drug products,
(6) Amdt K. A, and T. B. Fitzpatrick, deleted. The comment argued that the specifically only those set forth in
“Topical Use of Wydroquinone as a Panel based its statement upon reports 9 358.56(b). The comment recommended .
Depigmenting Agent”JoumaI of the that 0 358.50(b) be revised as follows:
American Medical Association. 194:96&967. of disfiguring effects in a single study by
Findlay. ~Morzison, and Simson (Ref. 1) “Zr~Yicotions. the labeling of the product -
1965. contains a statement of the indications.
while a similar study’by Arndt and
4. One comment requested that the Fitzpatrick (Ref. 2) reported no such under the heading ‘fndications’ making
monograph for skin bIeac% drug effects, even though a I-percent use of one or more of the following
products be amended to require that any concentration was used phrases, or similar terms conveying
product containing hydroquinone as a The agency agrees with the Panel’s substantially the same meaning.” The
skin bleaching agent contain a stabilizer view that high concentrations of comment argued that as long as a
to retard the oxidation of the hydroquinone with exposure to the sun product’s indications are accurately
hydroquinone and thus maintain the. may produce disfiguring effects. This described on the labeling, the product
potency of the product. fact was substantiated by FindIay, cannot be deemed to be misbranded
The agency points out that the Panel Morrison, and Simson (Ref. l), who simply because the labeling terms differ
recognized that the ease of oxidation of documented the pathologic changes in from those specifically approved by the
hydroquinone is an important factor in 35 cases of hyd+oquinone damage to the Panels.
reducing its effectiveness as a skin- dermis of South African women. L Since the inception of the OTC drug
lightening agent. The Panel Damage followed ‘the prolonged use (Z review, the agency has maintained that
recommended two methods to reduce years and over) of 8 to 8 percent a monograph describing the conditions
the oxidation of hydroqufnone: (1) hydroquinone bleaching creams. The under which an OTC drug will be
Packaging of the product in a small- Arndt and Fitzpatrick study (Ref. 2) is generally recognized as safe and
sized tube (one-half to one ounce) with a not comparable to the Findlay. effective and not misbranded must -
small opening to minimize the exposure Morrison, and Simson study pef. 1) include both specific active ingredients
. 0 l
Federal Register / Vol. 47, No. 172 / Friday, September 3, 1982 / Proposed Rules 39111

anh specifid labeling. \T his policy has along with the indications for the in the skin to produce a more even skin
become known as the “exclusivity product contained in Q 358.50(b) tone,” “helps produce even tone of the
rule.“) The agency’s position has been accurately describe for consumers the skin.” ”evens (out) skin tone,” “lightens
that it is necessary to limit the pharmacologic results to be obtained skin tone,” ”helps achieve an eyen-
acceptable labeling language to that from using these products. The term toned complexion,” “skin color
developed and approved through the “skin lightener” is an allowable blotches,” ”for skin that appears blotchy
OTC drug review process in order to alternative for the term “skin bleaching due to uneven pigmentation,” “fades
ensure the proper and safe use of OTC agent” as it accurately describes the dark blotches,” “blotches,” “blotchy
drugs. The agency has never contended, expected action of these products. Tbe skin.” “hand spots,” “for fading
however, that any list of terms terms “bleaching cream” and “skin hyperpigmented areas of the skin,”
developed during the course of the cream which lightens” also adequately “helps fade away dark spots,” and
review literally exhausts all the describe the identity of a cream product “fades dark areas, or blotches, on the
possibilities of terms that appropriately which contains a skin bleaching agent. skin.” The comments argued that these
can be used in OTC drug labeling. Because skin bleaching products may terms would permit many consumers,
Suggestions for additional terms or for not be marketed necessarily in cream particularly Blacks, to understand better
other labeling changes may be formulations but also are marketed in the intended action of these products.
submitted as comments to proposed or lotion and ointment formulations‘, the The agency does not find the terms
tentative final monographs within the agency will modify these terms to read “tone” and “hyperpigmented” and the
specified time periods or through “skin bleaching (insert dosage form, e.g., concept of making skin color f’even”
petitions to amend monographs under 21 cream, lotion or ointment),” or “skin acceptable for inclusion in the
CFR 330.10(a)(12); For example, the lightening (insert dosage form, e.g.. indications for an OTC skin bleaching
labeling proposed in this tentative final cream, lotion, or ointment).” Section drug product. Nor does the agency find
monograph has been expanded and 358.50(a) will be modified to allow the acceptable any terms that would imply
revised in response to comments use of any of these terms. that use of these products should be
received. Section 330.10(a)(4)(v) (2l CFR limited to a particular area of the body,
During the cour6e of the review, 830.10(a)(4)(v)) states that “Labeling e.g., “hand spots.” The word “tone” ha3
FDA’s position on the “exclusivity rule” shall be clear and truthful in all respects a number of meanings, two of which are
has been questioned may times in and * l lshall state the intended uses apt to be confused when applied to
comments and objections filed in and results of the product l l l .” products for use on the skim “color
response to particular proceedings and Accordingly, the agency finds that quality or value” and “healthy
in correspondence with the agency. The general terms such as “skin cream,” elasticity” (Ref. I). The agency believes
agency has also been asked by The “medicated skin cream,” and “skin that substantial confusion can be _
Proprietary Association to reconsider its treatment” are inadequate as a prevented by excluding the word “tone”
position. To assist the agency in statement of identity because they do from the labeling of a skin bleaching ,
resolving this issue, FDA plans to not describe the action of the product. drug product. The word
conduct an open public forum on Terms such as “skin toner,” “skin color “hyperpigmented” is apt not to be well
September 29,1982 where all interested toning,” and “skin color toner” describe understood by the majority of
parties can present their views. The the tinting or shading of skin color or consumers, and the agency proposes to
forum will be a legislative type may suggest a direct action on the skin use language that is clearer and more
administrative hearing under 21 CFR such as improvement in skin elasticity meaningful for this purpose. Statements
Part 15 that will be held in response to a or resiliency, but they fail to describe that refer to making skin color “even”
request for a hearing on the tentative clearly the pharmacologic action of a are not acceptable because they imply
fiial monograph for nighttime sleep-aid3 skin bleaching agent. that skin bleaching agents have a
(published in the Federal Register of The term “lightening bmwnish skin selective action on concentrations of
June l&1978; 43 FR 25544). Details of the discolorations” is a term that best pigment and would produce even color
hearing were announced in a notice describes an indication and not a if applied indiscriminately to wide areas
published in the Federal Register of July statement of identity for skin bleaching’ of ,skin. In fact. an effective skin
2,1982 (47 FR 29002). In proposed and products. This term will be addressed’ bleaching agent would exert its action
tentative final monographs issued in the under the comments that relate to the ’ on all pigment so that the result of
meantime, the agency will continue to labeling indications for skin bleachiiig indiscriminate application would be a
state its longstanding policy. products under 8 358.50(b). (See ’. .,- lightening of the color of the total area,
7. Several comment3 recommended comment 8 below.) _* !- not just the portion3 in which the .
that the term “skin bleaching” not be The agency’proposes that the&&p- pigment is concentrated.
used as a statement of identity to “skin depigmenting agent”. not bk used In considering the remainder of the
describe this class of products because to identify the intended use of these language recommended by the Panel
the products do not-actully “bleach” the products because it does not believe and by the comments for use in OTC
skin. Alternate terms were suggested that depigmentation is a word that is skin bleaching drug product indications,
such as “skin’cream.” “skin cream understood by the ordinary lay the agency believes it is important to
which lightens,” “medicated skin consumer under customary conditions of clarify that these products should be
cream, ” “skin treatment.” “skin toner,” purchase and use. For this reason, the used on skin areaa that are brownish-in
“skin color toning,” “skin color toner,” agency also proposes to delete the word color. Reddish or bluish areas, such as a
“lightening brownish skin “depigmentation” from 5 358.5O(c)(l)(vi). diffuse port-wine stain or mark, are not
discolorations,” “skin depigmenting 8. Several comments requested amenable to lightening by the use of
agent, ” “skin lightener,” and “bleaching amending the Panel’s recommended skin bleaching agents (Ref. 21.The word
cream.” indic&ions in B 358.50(b) to include the “brownish” will be added in
The agency believes that consumers following. “skin discolorations.” parentheses after the word “dark,”
are familiar with the term “skin “light&ing brownish skin which was recommended by the Panel
] bleaching” and that the use of this term discolorations,” ‘lightens dark p&m&t and which the agency believes may not
Q Y
, .
39112
0
Federal Register / Vol. 47, No. 172 / Friday, September
0
3. 1982 / Proposed Rules

be sufficiently specific by itself to assure limited” or “avoid overexposure to take up to 3 months before the onset of
proper use of the product. So long as a sunlight.” One comment recommended depigmenting effects (Ref. 1).
brownish color is specified, the agency that the statement be included in the The agency agrees that the statement \
finds the words “discolorations, ” monograph as part of the directions for in 5 358.50(c)(l)(iv),would be more
“pigment,” “spots,” “blotches,” and use rather than as a warning. appropriate as part of the directions for \ L)-’
“areas” are acceptable for use in The Panel determined, and the agency use. The agency also agrees with the
designating appropriate places on the agrees, that information about the comments that the 2-month limitation
skin to which an OTC skin bleaching reversal of the hydroquinone skin may not provide sufficient time for some
agent might be applied. Thus, the bleaching effect due to exposure to the individuals to obtain results and that
indications for OTC skin bleaching sun should be conveyed to consumers. there is clinical evidence that for some
products recommended by the Panel is However, repigmentation of the users results are not obtained until after
0 388.80(b) (1) and (2) have been bleached skin by the sun’s ultraviolet 3 months of use (Ref. 1). Accordingly,
combined, revised, and redesignated as light is not considered by the agency to the agency proposes that
Q 358.50(b) in the tentative final be a safety problem, but relates 0 35859(c)(l)(iv) be revised to provide
monograph to read as follows: substantially to the effectiveness of the for up to “3 months of treatment” and
Zndicu~ions. The labeling of the product. Therefore, the agency does not that it be incorporated into “Directions”
product contains a statementof the believe that a boxed warning or red in 5 388.50(d)(l) in the tentative final
indication5 under the heading letters are necessary to inform the monograph.
“Indications” as follows: (Select one of. * consumer that repigmentation may
the following: “For the gradual fading Reference
occur if the area is exposed to the sun.
of’ or “Lightens”) “dark (brownish)” In addition, the agency agrees with (1) Arndt, K. A., and T. B.. Fitzpatrick,
(select one of the following: ‘Topical Use of Hydroquinonea5 a
the comments that labeling information Depigmenting Agent,” Jourd of the 2
“discolorations,” “pigment,” “spots,” should advise the consumer to “limit American Medical Association, 194:985-967,
“blotches,” or “areas”) “in the skin such exposure” or “avoid overexposure” to 196.5.
as” (select one or more of the following: sunlight and that the best means of
“freckles,” “age and liver spots,” or achieving this are through the use of a 11. Several comment5 argued that the
“pigment in the skin that may occur in sunscreen agent, a sunblocking agent or Panel had no evidence or rationale to
pregnancy or from the use of oral protective clothing. The agency also support its recommended limitation of
contraceptives.“) agree5 that it is more appropriate for use of hydroquinone for children under
References . this information to appear under the 12 years of age in 8 35a5o(c)(i)(v) and
directions for use. Accordingly, the (d)(l). Another comment‘suggested that
(1) “Webster’s CollegiateDictionary,”G. it was sufficient that the limitation
and C. Merriam Co.. Springfield, MA, 1!?76, agency proposes to incorporate
5 v “tone ” Q 35a5o(c)(i) from the Panel’s appear only under “Directions” in
. (2) HolGey, D. N., editor, “Hemangiomas,” recommended monograph into Q 358.50(d)(l) and not under “Wur~&gs”
in ‘The Merck Manual,” 12th Ed., Merck “Directiond’in Q 358.89(d) in the in 8 358.50(c)(l)(v). One comment
Sharp and Dohme, Research Laboratories, tentative final monograph and modify suggested that Q 35889(c)(l)(v), “Not
Rahway. NJ, p. 1483.1~2. this statement to read “Sun exposure recommended for use in children under
9. Several comment5 objected to the should be limited by using a sunscreen 12 years of age,” be changed to read
requirement that the Panel’s agent, a sun blocking agent, or “Not recommended for use on children
recommended warning statement in protective clothing to cover bleached under 12 years of age.” Another
8 358.50(c)(l), “WARNING: Sun skin when using and after using this comment suggested that 8 388.89(d)(l)
exposure should be avoided indefinitely product in order to prevent darkening be revised to read as follows: “* l For
l

by using a sunscreen agent, a sun from reoccurring.” For products children under 12, it should only be used
blocking agent, or protective clothing to containing a sunscreen, the statement on the advice and direction of a
cover bleached skin in order to prevent will be changed slightly to read “Sun physician.”
darkening from reoccurring,” be exposure should bedfmited by using a The agency points out that the Panel
conspicuously boxed and in red letters. sunscreen agent, a sunblocking agent, or reviewed the literature and could find
The comments argued that this protective clothing to cover bleached no data for either the safety or
statement merely seeks to caution the skin after treatment is completed in effectiveness of hydroquinone for use on
consumer of the accelerated reversal of order to prevent darkening from children under 12 years of age. Because
the skin lightening effect wsulting from reoccurrfng.” The tentative final . of the absence of data, the Panel could
sun exposure and that such information monograph does not require that this not responsibly conclude that these
does not justify the prominent display information be boxed and in red letters. products were generally recognized as
recommended by the Panel. One 10. Three comments argued that the safe and effective for this age group.
comment cited section 502(f)@) of the warning statement recommended by the Based on the indications for these
Federal Food, Drug, and Cosmetic Act Panel in 9 358.59(c)(l)(iv), “If no products being proposed in this
and argued that the provisions of this improvement is seen after 2 months of tentative final monograph, the agency
section of the act do not support the treatment, use of this product should be believe5 that OTC skin bleaching drug
warning statement recommended by the discontinued,” should be deleted or products are marketed primarily for
Panel because the warning is not moved to “Directions” under 8 388.88(d). adult use. The agency concurs with the
necessary for the protection of the One comment claimed that the warning Panel that these products should not be
public health. Another comment argued was unnecessary because consumers used on children under 12 years of age
that this warning is addressed not to an automatically would discontinue use if unless a doctor is consulted first.
issue of safety but to one of efficacy. the product did not work for them. The The agency disagrees that it is
Some comments suggested that the other comments argued that the Panel sufficient that such a limitation on use
warning be changed to read “to help had no rationale for the z-month appear only under ‘Directions” and not
prevent reversal of the effects of this ltmitation, and that there was clinical . under “Wurnings,” but believes that this
product. exposure to sunlight should be evidence that in some persons it may information should be presented in both
sections. The agency agrees with the (3) Arndt. K. A., and T. 8. Fitzpatrick. word “warning” is more likely to ?ag
comments that the word “on” children “Topical Use of Hydroquinone as a potential dangers so that consumers will
rather than “in” children should be used Depigmenting Agent.“/ourna/ ofthe read the information being conveyed.
;’ American Medical Association 194:965-967. Therefore, FDA has determined that the
in the warning statement and that the 1965.
t warning statement should recognize that signal word “warning,” rather than the
(4) Spencer,M. C., “Topical Useof
the product may be used on the advice Hydroquinonefor Depigmentation,”
fournol work “caution,” will be used routinely in
and direction of a doctor. Accordingly, of the American Medical Association, OTC drug labeling that is intended to
the agency proposes that the warning lb4962-964.1965. alert consumers to potential safety
under $ 358.50(c) “Not recommended for (5) Spencer, M. C.. “Hydroquinone problems.
use in children under 12 years of age” be Bleaching,” Archives of Dermatology, 64:131- 15. One comment recommended
revised to read as follows: “Do not use 134,196l. changing the warning in
on children under 12 years of age unless 13. Several comments recommended § 358SO(c)(l)(iii) from “If skin irritation
directed by a doctor.” Likewise, the changing the directions in 0 358.50(d) to develops, use of this product should be
agency proposes that the statement in make them better understood and more discontinued or a physician should be
the “Directions” section 0 358.50(d)(l)) easily followed by lay consumers. They consulted,” to “If skin irritation persists,
be revised to read as follows: “Children recommended changing “adult topical discontinue use or consult a physician.”
under 12 years of age: do not use unless dosage is the thin application of a 1.5 to The comment argued that the Panel’s
directed by a doctor,” 2.0 percent preparation to the affected recommended warning seemed
12. Several comments requested area twice daily” to read “for adults, inconsistent with the observations or
deletion of the Panel’s recommended apply twice daily to the affected areas Arndt and Fitzpatrick [Ref. I) who
warning statement in 4 358.5O(c)(l)(vi) or use as directed by a physician.” observed, “The occurrence of
“Depigmentation (lightening) effect of The agency notes the original wording inflammation makes subsequent
this product may not be noticeable when of the directions for use contained the lightening more likely.”
used on very dark skin.” The comments allowable concentration of
argued that hyerpigmented patches The agency recognizes that the use of
hydroquinone. However, it is not likely hydroquinone products may be
(blotches) are the type of skin most that the Panels intended the exact
susceptible to treatment with accompanied by a mild inflammatory
wording in this section to be used in reaction after the first few weeks of
hydroquinone and that hydroquinone labeling as it was not contained in
showed noticeable changes when used treatment and that this inflammation
quotation marks in the advance notice makes subsequent lightening more
on the dark skin of pigs and on of proposed rulemaking. Moreover, FDA
pigmented cells of transplantable mouse likely. In some instances the reaction
believes that stating the concentration may be so mild as to go unnoticed. The
melanomas (Refs. 1 and 2). of hydroquinone in the directions is
The agency notes that the data agency believes that consumers should
referenced by the comments are unnecessary and might unintentionally be advised that a mild skin irritation is
supportive of the lightening effects of confuse the consumer. Because of the expected, but if sevew irritation occurs,
hydroquinone concentration is stated in use of the product should be
.. hydroquinone in certain animal models B 358.10,the agency proposes to delete it
(Refs. 1 and 2). Nevertheless, the agency discontinued. Accordingly, the agency
agrees with the Panel that there are from 3 358.50(d)and reword this section proposes that the warning in
c ~> ample clinical data to conclude that the in the tentative final monograph to read, 9 358.5O(c)(l)(iii) (which has been
lightening effect of hyclroquinone in “Adults: apply a small amount as a thin redesignated 4 358.5O(c)(l)(ii) in this
humans may not be noticeable when layer on the affected area twice daily, or tentative final monograph) be revised as
used 0x1very dark skin, and that lighter- use as directed by a doctor.” follows: “Some users of this product
skinned individuals are more likely to 14. One coinment requested that the may experience a mild skin irritation. If
experience a greater skin-lightening term “Caution” replace the term skin injtation becomes severe, stop use
effect (Refs. 3.4, and 5). However, the “Warning” in the preface to the and consult a doctor.”
agency believes that this information statement in P 358SO(c)(l)(ii). “Avoid
contact with eyes.” The comment argued Reference
more appropriately is presented under (1) Arndt K. A., and T. 8. Fitzpatrick,
the directions for use. Accordingly, the that this statement was more
appropriately classified as a “caution” “Topical Use of HvdroauInoneas a
agency proposes that the information rather than as a “warning.” DePjgmentingAge&” J&unal of the
recommended by the Panel in American Medical Association, 194S7.
0 358.5O(c)(l)(vi) be incorporated in The agency notes that historically 1965.
Q 358.50(d)(l) in the tentative final there has not been a consistent usage of
monograph. As discussed in comment 7 the signal words “warn@” and - 16. One comment asked whether the
above, the word “depigmentation” has “caution” in OTC drug labeling. For monograph would require labeling that
been deleted because it may not be well example, in 0 3 36%% and 369.21(21 would include a statement that patch
understood by the majority of CFR 389.20and 389X), which list testing should precede the use of
consumers under customary conditions “warning” and “caution” statements for hydroquinone-containing skin bleaching
of purchase and use. drugs, the signal words “warning” and prodticts. The comment pointed out the
“caution” are both used. In some Panel’s statement at 43 FR 51550 that
References instances, either of these signal words is “the use of hydroquinone for
(1) “An Evaluationof a CosmeticCream used to convey the same or similar depigmenting * should never be
l l

Containing2%W/W of Hydroquinoneas an precautionary information. considered without a cautious


Agent for Reducingthe Darknessof Black FDA has considered which of these therapeutic trial on a limited,
, Skin.”draft of unpublishedreport attachedto signal words would be most likely to inconspicuous area” (patch testing). The
CommentNo. Cooaoz.Docket No. 78N-0065. attract consumers*attention to that - comment questioned whether the ’
DocketsManagementBranch.
(2) Hu. F.. “The Influence of Certain information describing conditions under absence of a patch-testing requirement.
Hormonesand Chemicalson Mammalian which the drug product should not be in the Panel’s recommended-monograph
PigmentCells.”/ourno oflnvestiigolive used or its use should be discontinued. indicated that 1.5 and 2 percent
Dermatology, 46~7-124.1966. The agency concludes that the signal hydroquinone preparations do not
c
I., 1 l 0
- am4 Podera) Register / Vol. 47, No. 172 / Friday. September 3, 1982 / Proposed Rules

Prmt @ ident rtek of sensitivity the comment3 asked that a distinction cosmetic claims appearing in any
reectfoxUb Wffy patch-testlng be drawn between claim3 that use of portion of the labeling that is required
*ahe% ‘The comment requested the skin bleaching product3 results in by the monograph could be misleading.
am to re5o)ve tht5 uncertainty by not healthier, younger, or rejuvenated skin Cosmetic claims may appear elsewhere
reqotrhV Wch-teettng labeling under (which are drug claims) and claim3 that on the label.
t~~WUaDh use of the products results in healthier 19. One comment requested ’
The agin+ believes that the comment or younger looking skin (which are clarification of the Panel’s placement in
tititerpnted the Panel’s cosmetic claims and should not be Category II of claims such as “* l l

recommendation ae to when a patch test prohibited). The comment added that where skin has become discolored.
5hoaddbe employed. III making the skin bleaching product3 are used spotted, or darkened from bad weather
sWtmen1 uoted above by the essentially for cosmetic purpose5 (to or natural aging,” while it placed claims
comment, 91e Panel was advising that achieve visual effects) and that these for “age spots, liver spots, freckles, and
the lrre of hydroqulnone for products are best judged by the melasma” in Category I. The comment
deWntfng certain conditions i e consumer’s perception of whether the argued that the Category II claim might
Pbstorensttlzatton reacti&e, h&en” depigmenting effects promote serve as a basis for prohibiting the
phum3 (an fnflammatory skin disease), attractiveness. The second comment Category I &aim and stated that it was
or &nnatBf3 aeused by reaction to argued that since these products are unliiely that this was the Panel’s intent.
, never rhould be considered used by consumers to improve the The agency points out that the claim
?ill
Wl t a ~auttow trtal (patch testing). appearance of the skin. cosmetic claims “for stubborn cases where skin has
The agency believes that the Panel did which merely refer to this effect should become discolored, spotted or darkened
not mean to Imply by tht5 statement that not be proscribed a5 Category ff. from bad weather or natural aging,“’
PatCfItertfng should be done for normal The agency agrees with the comments which was placed in Category fI by the
CO~<UUOIU of use of hydroqutnone skin that a distinction between drug and Panel, was cited as an example of a
b)eachlng prodtmt3, cosmetic claims must be made because claim that is not clinically defined or
The agency does not believe that OTC drug monograph5 contain labeling that would imply use of the skin
tabehng that suggests the consumer requirement3 only for the drug use of bleaching product on injured skin or
erform a patch test before using a skin products. The Panel recommended that
ii leuhtng product Is justifted for 1.5 to 2 burns. In reviewing this claim, the
the following kinds of claims be agency concludes that only that portion
percent hydroqufnone preparations. regarded as Category II: claims that are of the claim dealing with bad weather
unsupported by scientific data and would imply that a skin bleaching
tt%?t~::;:::: ~~;:;a::;‘& beyond the known pharmacologic
re5t&ted use has not been shown ti product was for use on injured skin or
properties of hydroquinone: claims that burns. The natural aging referred to in
Prodti , a 8ignlficant risk of sensitivity are not clinically defmed or which
reactto% @en dtrecttone for use of the the claim very likely could be confused
would imply use of the product on with age and livers spots, for which a
Product ara,,followed. Sensitivity injured skin or burns: claims that use
reaction -ally does not occur at the skin bleaching product may be used
poorly defined terms that would confuse safely. The agency therefore proPose to
2Penxnt u&entratlon. Accordingly. the consumer because the words have a
the agency wt)lrtrpt propose patch- remove from Category If that portion of
different significance for different the above claim that reads, “or n&ural
te5ttng labeltng f+l.g to 2 percent people: claim5 that imply through use of
hydroqutnone sktdbleaching drug aging.” The Category I labeling
certain terms an immediate rather than indications for skin bleaching drug
products. Purther, tli&gency believes a gradual skin bleaching effect; and
the 3kln irrtte tion wuhg ln product5 are discussed in comment 8
claims that tn any way negate, detract, above.
4 g~JW)(lj(tt) In the tentative final or deemphastze the warning statement3
monograph adequately inf&me the ’ in the labeltng. The agency generally D. Commentson Combination Products
consumer what course of action to take agrees with the PanePs
should 5ennItIzatton occur. (See 20. One comment recommended that
comment 16 above.) recommendations, but does not agree 0 356.20be expanded to include
with all of the examples provided by the hydroquinone formulations in a base
17. One comment suggested that an Panel at 43 PR 51554, for example,
effort be mado to limit the number of “natural aging,” which is discussed in that is opaque to ultraviolet radiation.
wuJntng5 In 9 358.60(c).The comment comment 19 below, and “blotches,” The comment specifically mentioned a
felt that a minlmum of concern for safe hydrophilic opaque base containing 10
which are discussed tn comment 8 percent talc as a light-scattering and
u5e exist5 with hydroquinone products above.
und, therefore, to promote effective While the monograph for skin reflecting agent. The comment included
c()mmuntcatlon with the consumer an bleaching products does not include data to illustrate the Sun Protection
effort should be mado to limit domestic labeling of skin bleaching Factor (SPF)values of its hydroquinone
..^---.
ustrJcCeR501y warnjnp. products, the agency has no objection to 2 and 4 percent formulations in this base
‘I%e awncy hns reviewed the cosmetic labeling appearing on these (Ref. 1).
wr’rn’ngs recommended by the Panel in products along with the required drug The agency notes that the Panel found
0 :jt6.60(c) and praposes that the labeling. Cosmetic claims that refer to hydroquinone combined with a
irlrormahn conlotnod in three of these improving the appearance of the skin or sunscreen to be a rational combination
wJtrnhv be ~hccd under Direcijon3, to more attractive or beautiful skin are and therefore recommended in 8 358.20
T’huH~ the wncy prop05~5 to rcduce the acceptable provided they conform to the that hydroquinone be combined with
n’imber Of warnings from stx to three. cosmetic labeling requirements of the any generally recognized safe and
h-~ commmtn 9, lo, and 12 above 1 Federal Food, Drug. and Cosmetic Act effective sunscreen active ingredient
lo* *Wo comments urged that the (21 U.S.C. 362). Consistent with the identified in 21 CFR 352.10 (see the
“rtaEorY 11lah?hlg Section bo modified provisions of 5 701.3(d) (21 CF’R701.3(d)) Federal Register of August 25,1978; 43
*’ f15not to prohibit co5mettc cttrtm5 regarding declaration in labeling of FR 36206) provided that the product is
and that a distinction be mad0 between active drug ingredient5 and cosmetic labeled only as a skin bleaching agent
coHmetic ctalms and drug ~t,,~,,,5~one of ingredients. it is the agency’5 view that and not as a sunscreen. The agency
p
. Federal Registe 01. 47, No. 172 / Friday, September 3, 2 1 Proposed Rules 39115

points out that many different reoccurrence of darkening of the skin by are not for the prevention of sunburn.
ingredients-have been recommended in sunlight. The Panel recognized that The Panel recommendedat Q 358(c)(2)
0 352.10 as Category I sunscreens. incorporating a sunscreenin a the warning, “This product will bleach
However, talc is not one of the hydroquinone product would be skin and is not for use for the prevention
ingredients listed in 8 352.10and beneficial only as long as the sunscreen of sunburn.” The agency concurs with
therefore is not presently a Category I was present on the surface of the skin. the intent of the warning, but proposes
sunscreen active ingredient. The agency W h e n the sunscreenwas washed off, or to shorten it in the tentative final
believes that the sunscreen rulemaking when the consumer stopped using the monograph to read “This product is not
and not the skin bleaching rulemaking is combination product, the consumer still for use in the prevention of sunburn.”
the proper forum in which to consider would be confronted with the problem
talc for sunscreen use. of reoccurrence of skin darkening when II. The Agency’s Tentative Adoption of
the treated area was exposed to the Panel’s Report
Reference sunlight. Accordingly, the Pane1advised
(1) Comment No. COOOO~.
Docket No. 78N- that continual protection of the bleached A. Summary of Ingredient Categories
0065,Dockets Management Branch. area was necessary regardless of and Testing of CatugoxyII and Category
whether hydroquinone was used alone 111Conditions.
21. One comment requested that the
phrase “provided that the product is or whether a hydroquinone-sunscreen 1. Summary of ingredient categories.
labeled only as identified in 0 358.50”be combination drug product was used. The The agency has reviewed all claimed
deleted from 8 358.20, which would have agency concurs, but believes that active ingredients submitted to the
permitted combinations of hydroquinone consumers should be informed of the Panel, as well as other data and.
with any generally recognized safe and difference between products containing information available at this time, and
effective sunscreen active ingredient a sunscreen and those not containing a concurs with the Panel’s categorization
provided that the product is labeled only sunscreen.As discussed in comment 9 of hydroqutnone in concentrations of 1.5
as a skin bleaching drug product. The above, this information will now be to 2.0 percent in Category I and
comment argued that the phrase could included in the monograph as part of the ammoniated mercury in Category II. The
possibly be interpreted to mean that directions for use rather than as a
warning. Panel placed ammoniated mercury in
nonmedical claims, which are permitted Category II because it felt that
on products that contain hydroquinone 23. One comment requested that
0 358.20 and 8 358.50 be revised to allow ammonitated mercury is not safe for
alone, may not likewise be permitted on OTC use. Mercury can pass through the
products that contain both hydroqutnone-sunscreencombination
products to bear a labeling statement skin. especially in an ointment base, and
hydroquinone and a sunscreen. chronic application can cause systemic
The agency emphasizes that OTC indicating that the product contains an
effective sunscreen agent to minimize mercury intoxication. In addition, the
drug monographs contain appropriate Pane1was unable to locate data relevent
drug labeling claims to be used on OTC the effect of sunlight in reversing the
skin bleaching effect of hydroquinone. to the efficacy of ammoniated mercury
drug products and do not preclude the in OTC skin bleaching drug products.
use of acceptable cosmetic claims if the Two comments requested deletion of
the warning for hydroquinone-sunscreen (See 43 FR 51553.)The Panel placed no
product is both a drug and a cosmetic. skin bleaching agents in Category III as
The phrase that the comment requested combination products in P 358.50(c)(2),
be deleted was intended to relate only i.e., “This product will bleach skin and single ingredients, and the agency
to the drug aspects of skin bleachlng- is not for use for the prevention of concurs.
sunscreen combination products and sunburn.” The comments reasoned that The recommended monograph
was not intended to preclude thk use of the absence of a sunburn prevention reflected the Panel’s view that
cosmetic claims. claim for these products would limit hydroquinone may be combined with
21%One comment awed that the their use as sunburn preventatives, and any generally recognized safe and
warning under 8 358.50(c)(l), thus a statement not to use the product effective sunscreenactive ingredient.
“WARNING: Sun exposure should be for the prevention of sunburn was The agency concurs but is proposing
unwarranted. revised labeling for all such
avoided indefinitely by using a Although the Panel found the
sunscreen agent, a sun blocking agent, combinations in the tentative final
combination of hydroquinone and a monograph.
or protective clothing to cover bleached sunscreenrational, it did not provide
skin in order to prevent darkening from sufficient information regarding the 2. Testing of Category II and Category
reoccurring,” is inconsistent because the labeling of such a combination. The ZZZconditions. Becausethe Panel did not
warning fails to differentiate between Panel recommended that such place any ingredients in Category III, it
single ingredient hydroqutnone products combination products not be labeled as did not recommend any testing
and products containing hydroqutnone sunscreensin order to avoid specific guidelines for Category III skin
combined with sunscreen agents. The reference to their use in preventing bleaching conditions. Interested persons
comment argued that formulations sunburn and permitting tanning. The may communicate with the agency
including a sunscreen or sun blocking agency agrees but believes that about the submission bf data and
agent already satisfy the requirement of consumers should be informed that the information to demonstrate the safety or
avoidance of sun exposure by the use of combination product “contains a effectiveness of any skin bleaching
a sunscreen, and the warning statement ’ sunscreen to help prevent darkening ingredient or condition included in the
should not be required on hydroquinone- from reoccurring”. The agency therefore review by following the procedures
sunscreen combination drug products. is proposing to include this language tn outlined in the agency’s policy statement
In its review of hydroquinone and the “Indications” section in this published in the Federal Register of
hydroquinone-sunscreen combinations, tentative final monograph at September 2 % 1981(48 FR 47740). This
the Panel recognized that the inclusion 8 358.50(b)(2). Because the term policy statement includes procedures for
of a sunscreen tn a hydroquinone- “sunscreen” is proposed for inclusion in the submission and review of proposed
sunscreen combination drug product the labeling, it is especially important to protocols, agency meetings with
was not sufficient to forestall the inform consumers that these products industry or other interested persons, and

,
0
Federal Register / Vol. 47, No. -172 / Friday, September 3, 1982 1 Proposed Rules
39116

agency communications on submitted 5. fn light of evidence that for some submitted. The agency will evaluate any
test data and other information. users 3 months are required in order to comments and supporting data that are
obtain results, the agency proposes to received and will reassess the economic -\
3. Summary of the Agency’s Changes in increase the Z-month use limitation in impact of this rulemaking in the
the Panel’s Recommendations. 8 358SO(c)(l)(iv) to 3 months and to preamble to the final rule. 5 /
FDA has considered the comments incorporate this limitation in The agency has determined that under
and other relevant information and 3 358.50(d)(l) as part of the “Directions.” ZI CFR 25,24(d)(9)(proposed in the
concludes that it will tentatively adopt Further, the agency proposes to delete Federal Register of December 11.1979:
the Panel’s report and recommended the concentration of hydroquinone from 44 FR 71742) this proposal is of a type
monograph with the changes described the “Directions”recommended by the that does not individually or
in FDA’s responses to the comments Panel in Q 358.50(d)(l) as being cumulatively have a significant impact
above and with other changes described unnecessary and possibly confusing to on the human environment. Therefore,
in the summary below. A summary of consumers. The proposed allowable neither an environmental assessment
the changes made in the Panel’s concentration is included in 0 358.10in nor an environmental impact stateme&
conclusions and recommendations the tentative final monogaph. (See is required.
follows. comments 10 and 13 above.)
I. The agency proposes to add to the 6. The agency has proposed revised List of Subjects in 21 CPR Part 356
Panel’s statement of identity (“skin . labeling for the combination of a skin Over-the-counter drugs, Skin
bleaching agent”) in 0 358.50(a)the bleaching agent with a sunscreen. (See bleaching agents, Wart removers,
alternative trems “skin lightener,” “skin comments 22 and 23 above.) Nailbiting and thumbsucking deterrents,
bleaching (insert dosage form, e.g., The agency has examined the Ingrown toenail relief.
cream, lotion, or ointment),” and “skin economic consequences of this proposed
lightening (insert dosage form, e.g., rulemaking and has determined that it Therefore, under the Federal Food,
cream, lotion, or ointment).” (See does not require either a Regulatory Drug. and Cosmetic Act (sets. 201(p),
comment 7 above.) Impact,Analysis. as specified in 502,505,7M, 52 Stat. 1041-1042 as
2. The agency proposes to combine Executive Order 12291, or a Regulatory amended, 1050-1053 as amended, l055-
and revise the Panel’s recommended Fledbility Analysis,as defined in the lo56 as amended by 70 Stat. 919 and 72
indications in 0 358.50(b)(l) and (2) Regulatory Flexibility Act (Pub. L 98- Stat. 948 (21 U.S.C. 32l(p), 352.355,371)),
(redesignated-9 358.50(b)) to read as 354). Specifically, it would place and the Administrative Procedure Act
follows in the tentative final monograph: hydroquinone, the main ingredient used (sets. 4,5, and lo,80 Stat. 238 and 243 as
(Select one of the following: “For the in these products, in Catego@ I. and amended (5 U.S.C. 553,554,702,703,
gradual fading of” or “Lightens”) “dark ammoniated mer&ry in Category II, as 704)), and under 2l CFR 5.11 as revised
(brownish)” (select one of the following: recommended by the Panel. Minimal (see 47 FR 16010; April 14,1982), it is’
“disc6lorations,” “pigment,” “spots,” reformulation and some relabeling proposed that Subchapter D of Chapter I
“blotches,” or “areas”) “in the skin such would be necessary; however the of Title 2l of the Code of Federal
as” (select one or more of the following: agency has expanded the labeling Regulations be amended by adding new
“freckles,” “age and liver spots,” or recommended by the Panel, so that Part 358, to read as.follows:
“pigment in the skin that may occur in manufacturers would have a wide
pregnancy or from the use of oral choice of language which could be PART 3584tlISCELLANEOlJS
contraceptives.“) (See com,ment8 incorporated into their labels at minimal EXTERNAL DRUG PRODUCTS FOR
above.) cost in the normal course of reordering. OVER-THE-COUNTER HUMAN USE
3. The warning in Q 358JO(c)(l)(iii), “If Therefore. the agency concludes that the Bubpart A-Skin Bleaching Drug Products
skin irritation develops, use of this proposed rule is not a major rule as
product should be discontinued or a General Provisions
defined in Executive Order 12291.
physician should be consulted,” has Further, the agency certifies that the Sec.
been tentatively redesignated proposed rule, if implemented, will not 358.1 Scope.
0 358.5O(c)(l)(ii) and revised as follows: have a significant economic impact on a 358.3 Definition.
“Some users of this product may substantial number of small entities, as Active legmdient
experience a mild skin irritation. If skin defined in the Regulatory Flexibility Act. 358.10 Skin bleachingactive ingredient.
irritation becomes severe, stop use and The agency invites public comments 356.20Permittedcombtnationsof active
consult a doctor.” (See comment 15 regarding any substantial or significant ingredients.
above.) economic impact that this rulemaking
4. The agency proposes to reword the would have on OTC skin bleaching drug Labeling
information in the Panel’s warnings in products. Types of impact may include, 358.50 Labelingof skin bleachingdrug
0 358.50(c)(l)(i), (iv), and (vi) and move but are not limited to, costs associated products.
this information to the “Directions”in with product testing, relabeling, Authority: 6~s. m(D], 502 505. 701. 52
B,358.50(d)(l). This includes information repackaging, or reformulating. Stat.lo+iw2 as a&&led, 1050-1053 as
to the effect that sun exposure should be Comments renardinn the imnact of this amended,IO!%-1056as amendedby 70 Stat.
limited by using a sunscreen agent, a rulemaking 0; 0TC”skin ble’aching drug 919 and 72 Stat.948(Zl U.S.C.321(p],352.355.
sun blocking agent, or protective products should be accompanied by 371):sets.4.5, and 10.60 Stat. 2313and 243as
clothing to cover bleached skin when appropriate documentation. Because the amended(5 U.S.C.553.554,702.703,704).
using and after using the product in agency has not previously invited
order to prevent darkening from Subpart A-Skin Bleaching Drug
specific comment on the economic Products
reoccurring; a statement that the impact of the OTC drug review on skin
lightening effect of hydroquinone may bleaching drug products, a period of 120 General Provisions
not be noticeable on very dark skin; and days from the date of publication of this
a statement specifying a use limitation proposed rulemaking in the Federal $ 358.1 SCOp8.

period. (See comments 9, IO. and 12 Register will be provided for comments (a) An over-the-counter skin bleaching
above.) on this subject to be developed and drug product in a form suitable for
/ Vol. 47, No. 172 / Friday, Septembe

topical administration is generally (2) For products confaining any time requested. Written comments on
recognized as safe and effective and is combination identified in J 358.20. the agency’s economic impact
not misbranded if it meets each of the “Contains a sunscreen to help prevent determination may be submitted on or
conditions in this subpart in addition to darkening from reoccurring.” before January 3.1983. Three copies of
each of the general conditions (c) Warnings. The labeling of the all comments, objections, and requests
established in Q 330.1. product contains the following warnings are to be submitted, except that
(b) References in this subpart to under the heading “Warnings”: individuals may submit one copy.
regulatory sections of the Code of (I) For products containing the Comments, objections, and requests are
Federal Regulations are to Chapter I of ingredient identified in 8 358.10 or any to be identified with the docket number
Title 21 unless otherwise noted. combination identified in J 358.20. found in brackets in the heading of this
(i) “Avoid contact with eyes.” document and may be accompanied by
5 358.3 Definition. (ii) “Some users of this product may
experience a mild skin irritation. If skin a supporting memorandum or brief.
As used in this subpart: Comments. objections, and requests
Skin bieoching active ingredient. An irritation becomes severe, stop use and
consult a doctor.” may be seen in the above office between
agent designed to bleach or otherwise 9 a.m. and 4 p.m., Monday through
lighten limited areas of hyperpigmented (iii) “Do not use on children under 12
years of age unless directed by a Friday. Any scheduled oral hearing will
skin through the suppression of melanin be announced in the Federal Register.
pigment formation within skin cells. doctor.”
(2) For products containing any Interested persons, on or before
Active Ingmdient combination identified in 3 358.20. “This September 3,X983. may also submit in
product is not for use in the prevention writing new data demonstrating the
8 358.10 Skin bleaching active ingredient.
of sunburn.” safety and effectiveness of those
The active ingredient and its (d] Directions. The labeling of the conditions not classified in Category I.
concentration in the product is as product contains the following Written comments on the new data may
follows: hydroquinone 1.5 to 2.0 percent. statements under the heading be submitted on or before November 3,
9 358.20 Permitted combititfons of active “Directions”: 1983. These dates are consistent with
Ingredients. (1) For products con tuining the the time periods specified in the
Hydroquinone identified in 8 358.10 ingredient identified in J 358.10 or uny agency’s final rule revising the
combination identified in $358.?0. procedural regulations for reviewing and
may be combined with any generally
recognized safe and effective sunscreen “Adults: apply a small amount as a thin classifying OTC drugs, published in the
active ingredient identified in 0 352.10 layer on the affected area twice daily, or Federal Register of September 29,198x
provided that the product is labeled use as directed by a doctor. If no (46 FR 47730). Three copies of all data
according to 0 358.50. improvement is seen after 3 months of and comments on the data are to be
treatment, use of this product should be submitted, except that individuals may
Labeling discontinued. Lightening effect of this submit one copy, and all data and
product may not be noticeable when comments are to be identified with the
0 358.50’ Labelfng of skin bleaching drug used on very dark skin.
products. docket number found in brackets in the
“Children under 12 years of age: do heading of this document. Data and
(a) Statement ofidentity. The labeling not use unless directed by a doctor.”
of the product contains the established comment3 should be addressed to the
(2) For products containing the Dockets Management Branch (HFA-305)
name of the drug, if any, and identifies ingredient identified in 9 $52.10. “Sun
the product as a “skin bleaching agent,” [address above). Received data and
exposure should be limited by using a comments may also be seen in the
“skin lightener,” “skin bleaching (insert sunscreen agent, a sun blocking agent,
dosage form, e.g., cream, lotion, or above office between 9 a.m. and 4 p.m.,
or protective clothing to cover bleached Monday through Friday.
ointment),” or “skin lightening (insert skin when using and after using this
dosage form, e.g. cream, lotion, or product in oider to prevent darkening In establishing a final monograph, the
ointment).” from reoccurring.” agency will ordinarily consider only
(b) Indications. The labeling of the (3) For products contain& any data submitted prior to the closing of the
product contains a statement of the combination identified in 9 ZXJ.W. “Sun administrative record on November 3,
indications under the heading exposure should be limited by using a 1983. Data submitted after the closing of
“indications” that is limited to the sunscreen agent, a sun blocking agent, the administrative record will be
following phrases: or protective clothing to cover bleached reviewed by the agency bnly after a
(1) Forproducts containing the skin after treatment is completed in final monograph is published in the
ingnzdient identified in 8 358.10 or any order to prevent darkening from Federal Register unless the
combination identified in j 358.20. reoccurring.” Commissioner finds good cause has
(Select one of the following: “For the Interested persons may, on or before been shown that warrants earlier
gradual fading of’ or “Lightens”] “dark November 2,1982 submit to the Docket3 consideration.
(brownish)” (select one of the following: Management Branch (HFA-305), Food Mark Novitch.
“discolorations,” “pigment,” “spots,” and Drug Administration, Rm. 4-62,5800, Acting Commissioner of Food and ws.
“blotches,” or “areas”) “in the skin such Fishers Lane, Rockville, MD 20657,
as” (select one or more of the following: Dated: August 9,X%!.
written comments, objections, or
“freckles,” ‘Iage and liver spots,” or requests for oral hearing before the Richard S. Schweiker,
“pigment in the skin that may occur in Commissioner on the proposed Secretary of Health ond Human Sem*ces.
pregnancy or from the use of oral regulation. A request for ati oral hearing IFR Doe. 82-m Filed s-z-w %u am]
contraceptives.“) must specify points to be covered and BILlma WOE 416041-11