Cutaneous Reactions to Topical Application of Hydroquinone

9 Augustus 1975 SA MEDIESE TYDSKRIF 1391
Cutaneous Reactions to Topical Application
of Hydroquinone
RESULTS OF A 6-YEAR INVESTIGATION
B. BENTLEY-PHILLIPS,
SUMMARY
The investigation was designed to assess the safety of
hydroquinone in cosmetic skin-lightening products, and to
determine the optimal concentration f.or the purpose. The
840 volunteers who took part in the 6-year trial were drawn
from various race groups with skins varying from very fair
to very dark. They were subjected to open tests, 'normal
usage' tests, and standard 48-hour closed-patch tests. In
all, over 7000 test areas were examined.
The results show that concentrations of hydroquinone
of 3% and less produced negligible adverse effects,
irrespective of the base or the colour of the user's skin.
It is stressed that any confusion of hydroquinone with
the hazardous monobenzyl ether of hydroquinone (monobenzone,
MBH) should be avoided.
S. Afr. Med. l., 49, 1391 (1975).
Vast quantIties of skin lighteners, estimated officially at
R12,8 million per annum, are sold in South Africa where
they are used for facial improvement and the elevation
of social standing. The additional 'smoothening' effect,
as the Blacks call it, is highly prized by both men and
women.
Until 1973 mercurials were popular, but have since
been banned after the recognition that they may become
nephrotoxic from the absorption of mercury through the
skin. Monobenzyl ether of hydroquinone was also in use,
but was recently prohibited by Government edict after
the disastrous epidemic of patchy leucomelanoderma
reported by Dogliotti et al.' We have seen many cases at
our outpatient clinic (Fig. 1). Hydroquinone remains the
only suitable substance, although it is well known that it
may produce skin reactions. Another disadvantage is its
tendency to produce hyperpigmentation of a postinflammatory
nature after contact with it in high concentrations
in cosmetic preparations which are used to excess (Fig 2).
Users believe that if a product bums or stings on application,
it is 'working well', and they continue using stronger
Department of Dermatology, University of Tatal and King
Edward VID Hospital, Durban
B. BENTLEY-PHILLIPS, M.D.
MARGARET A. H. BAYLES, M.B. CH.B.
Date received: 27 March 1975.
Reprint request< 10: Dr B. Bentley-Phillips. 708 Eagle Building, West
Street, Durban 4001.
14
MARGARET A. H. BAYLES
and yet stronger preparations, more and yet more vigorously,
to produce inflammation followed by hypermelanosis.
Thereafter they demand an even more potent skin
lightener.'
A world-wide search over the years for an effective
and non-irritating chemical agent capable of inducing
cutaneous depigmentation, has been fruitless, and a
comprehensive review of 33 different chemicals by Bleehan
et al.' illustrates the problem.
More recently, we have investigated butylated hydroxytoluene
as a skin lightener:,5 but the substance is a skin
irritant and produces no lightening. Until a more effective
skin lightener is discovered, hydroquinone will continue
to be used and the present investigation was undertaken
to determine the optimal concentration for general use.
SUBJECTS AND METHODS
In Durban we had the opportunity of selecting volunteers
from several races with skins varying from the lightest to
the darkest. These were: Blacks (Zulu), Asians (Indian)
and Coloureds (mixed Black and White). The following
investigations were undertaken: (a) open-patch tests; (b)
normal usage tests; (c) closed, 48-hour standard patch tests
using different concentrations of hydroquinone in different
bases.
Open-Patch Tests
Two hundred unselected Indian factory workers were
tested with 5%, 6% and 7% hydroquinone in soft paraffin.
A 30-second standard rub was applied to the sides of the
neck and the postauricular regions. The test areas were
examined after 24 hours and the preparations re-applied
as before. A second examination was made after 72 hours.
Normal Usage Tests
Fifty-two Black women were instructed to apply 7,5%
hydroquinone cream, twice daily, to one side of the face
only and to attend for examination at regular intervals
for 3 months.
Ten Black hospital nurses were to apply the same
cream each evening to the flexor surface of the left
forearm for 6 weeks, and to remain under observation.

1394 SA MEDICAL JOURNAL 9 August 1975
TABLE Ill. PERCENTAGE POSITIVE REACTIONS AT 48 HOURS TO HYDROQUINONE CREAMS AND LOTIONS IN 256
BLACK FEMALES
Concentration
of
hydroquinone
C%)
1
2,5
3,5
5,0
7,0
Closed 48-Hour Patch Tests
Cream
Number treated % pos.
100 1
100 1
166 10,8
206 25,7
140 35,0
Table Il shows the results of testing the various
concentrations of hydroquinone on 578 volunteers drawn
from the different racial groups. Table III demonstrates
the different reactions to creams and lotions containing
the same concentrations of hydroquinone.
DISCUSSION
Because hydroquinone is the only effective skin lightener
available in South Africa, we considered that an attempt
should be made to determine the optimal concentration
for use in cosmetics. Preparations on sale have a content
of hydroquinone between I % and 7,5"b in various bases
and it was anticipated that the higher the concentration
the more likely would be adverse reactions. Table II
clearly demonstrates this point and even allowing for
the severity of a 48-hour closed-patch test, it was thought
that a high content of hydroquinone should be avoided
and that about 3°{, is the optimal amount for all pigmented
skins.
Hydroquinone is regarded as a mild primary irritant and
likely to produce a sensitivity and a contact dermatitis in
those previously exposed to it. This probably accounts
for the big difference in response of the various races
to closed-patch tests (Table 11). Indians are usually content
with the colour of their skin, but the other races are
not and, consequently, large numbers of Blacks and
Coloureds would have been sensitised prior to our testing.
We were unable to assess the effects of hydroquinone on
Whites, who generally prefer bronzed to pale faces.
Only I White patient with contact dermatitis from skin
lighteners has been seen during the past 7 years. This was
an 82-year-old English woman who had preserved her
lily-white complexion for over 50 years with a mercurial
preparation without ill effect until, without her knowledge,
the formula was altered and MBH substituted for the
mercury. Within a month she developed a typical MBH
leucomelanoderma.
A salutary lesson needs to be learned from Fitzpatrick
et al.,' who in 1966 detailed the chemistry and the entirely
different modes of action of hydroquinone and MBH and
pointed out that the 'confetti-like depigmentation' which
develops frequently with MBH, had never been observed
with hydroquinone.
Number treated
Nil
116
66
116
Nil
Lotion
';10 pos.
Preparation not available
0,9
1,5
15,5
Preparation not available
Had all the manufacturers of cosmetics been aware of
this, the recent disastrous epidemic of leucomelanoderma
could have been prevented by banning MBH years ago.
Bases also make a difference and the figures shown in
Table III illustrate this point. In the Black women tested
it was clear that the 3,5% and 5% creams produce
considerably more reactions than lotions of the same
strength. No significant difference was observed between
creams and lotions containing 2,5% hydroquinone, or less.
In all cases, adequate control patches were applied and·
all the ingredients constituting the bases of creams and
lotions were exonerated· from any irritant effects by
48-hour patch tests, as previously mentioned.
Hyperpigmentary reactions of a delayed type without
preceding erythema, and contact-type erythema progressing
to hyperpigmentation, were the most frequently seen
adverse effects. The latter was obviously a postinflammatory
type of hyperpigmentation seen frequently in our hospital
outpatient department. The former, however, might be
explained by the binding of hydroquinone to keratin and
the subsequent oxidation to a brown tint, as described
by Fitzpatrick et al." Without further applications, both
types of hyperpigmentation disappear gradually.
CONCLUSIONS
Firstly, from these investigations it is evident that hydroquinone
is a suitable substance for incorporation in
cosmetics designed for skin lightening, if the content is
kept below a certain limit. We conclude that 3% hydroquinone
is the optimal strength, irrespective of the base
used or the colour of the user's skin.
Secondly, from our clinical observations there is an
impression that most of the adverse effects occur from
misuse, excessive use and the application of multiple
preparations. In order to prevent these harmful practices
it is imperative for manufacturers to enclose a suitably
worded warning in each pack.
Finally, in order to prevent harm, it is essential that
manufacturers and medical practitioners be aware of the
difference between hydroquinone itself, and the. monobenzyl
ether of hydroquinone. This is of paramount
importance, since MBH may be used either illegally or
ignorantly in countries where skin lighteners are in vogue.