Journal of Dermatological Treatment

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Exogenous ochronosis

Pa Burke & Hi Maibach

To cite this article: Pa Burke & Hi Maibach (1997) Exogenous ochronosis, Journal of
Dermatological Treatment, 8:1, 21-26, DOI: 10.3109/09546639709160504

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Published online: 12 Jul 2009.

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 Journal of Dermatological Treatment (1997) 8, 21 -26 (' 1997 Journalof Dermatological Treatment. All rights reserved. ISSN 0954-6634 21

Exogenous ochronosis: an overview

PA Burke' & HI Maibach2 Exogenous ochronosis/colloid milium hydroquinone concentrations to-

'Sara Lee D/E, Household and Personal
Care Division - Americas Region,
PA, USA
'Department of Dermatology, School of
Medicine, University of San Francisco,
CA, USA
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in Blacks is a relatively unknown
condition in the USA, but a relatively
high incidence has been observed in
South Africa. Physicians reporting
adverse reactions, observe these effects
almost exclusively in the facial areas
exposed to sunlight. These effects can
gether with other preparations con-
taining ochronotic agents such as
phenol and resorcinol provided the
basis for the high incidence of ochro-
nosis (pre-1984) in South Africa.
Thirdly, the use of hydroalcoholic
lotions in South Africa permitted

be attributed to several causative formulations with higher hydroqui-

factors to explain the striking differ-
ence in the incidence between the USA
and South Africa. Prior to 1984,
neither the type nor concentration of
skin lightening compounds sold in
general commerce in South Africa
were regulated. Therefore, it was not
uncommon for products to contain
G - 8% hydroquinone as opposed to
the 2% hydroquinone level utilized in
over-the-counter skin discoloration
fade creams available in the USA.
Secondly, the combination of higher
none concentration and increased the
bioavailability of hydroquinone rela-
tive to normal oil-in-water emulsion
creams. Therefore, the high incidence
of exogenous ochronosis in South
Africa may be directly related to
higher concentrations of hydroqui-
none, combination with other drugs,
and increased bioavailability as a
result of the predominance of hydro-
alcoholic lotions. (J Dennutol T r m
(1997) 8: 21 - 2 6 )

Received 25th March 1996 Keywords: Exogenous ochronosis - Colloid milium - Hydroquinone
Accepted 4th October 1996

Background seen a case.'3-'s It is clear that while a problem existed

Exogenous ochronosis/colloid milium in Blacks is a
relatively unknown condition in the USA; there have been
only 17 reported domestic cases outside the Republic of
South Africa associated with the use of products containing
hydroquinone (Table I).' - l 2 Most clinical cases have been
reported in South Africa which, up until 1984, did not
regulate the type or concentration of skin lightening
compounds sold in general commerce.
The physicians reporting adverse reactions have
observed these effects almost exclusively in the facial
areas exposed to sunlight. These effects are attributed to
the unrestricted utilization of products containing G - 8%
hydroquinone. Additionally, three panels of Board
Certified dermatologists in the USA with predominantly
black patient populations have stated that ochronosis is
rare with none of the dermatologists having personally
Correspondence:
HI Maiboch MD, Department of Dermatology, School of Medicine, University of
California, Son Francisco, Surge 770, Box 0989, Son Francisco, CA 941434989, USA
relative to skin toning creams in South Africa, it is largely
absent in the USA due to the regulatory restrictions on
hydroquinone concentration as well as limitation of
active ingredient combinations. Furthermore, the vehicle
effect upon percutaneous absorption and bioavailability
may play a role in the concentration gradient of
ochronotic agents in the dermis leading to ochronosis.
Epidemiology and safety
Hydroquinone-containing skin preparations have been sold
for over 50 years without any significant indications of
adverse reactions concerning hyperpigmentation. Approxi-
mately 10 - 15 million skin tone creams are sold annually
in the USA. Since limited quantities are utilized by the
consumer, this equates to more than 550 million potential
exposures annually and billions of exposures over the years.
However, in spite of this rate of exposure, only 17 cases of
ochronosis have been reported in the USA.
 22 PA Burke & HI Maibach Exogenous ochronosis: an overview

Review of the toxicology and pharmacology of hydro-
quinone took place during the examination by the US Food
and Drug Administration (FDA) Miscellaneous Panel prior
to publication of the 1982 Tentative Final Monograph.
Examination of the adverse reactions file of the FDA from
1961 through 1995 reveals less than 30 experiences since
1961 with only case which is referred to as hyperpigmenta-
tion. The remaining cases were either minor irritations or
possibly allergic reactions. Statistically, this equates to an
incident rate of approximately one case for every one billion
exposures.
Depigmentation agents
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resorcinol with hydroquinone while limiting the maximum
permissible concentration in skin lightening products to 2%
and requiring incorporation of a sunscreen. However, cases
of ochronosis were still occurring in substantial numbers in
South Africa in 1986 as reported by Phillips.'"-2" In a 1-year
period, 395 patients with ochronosis were presented to a
dermatology outpatient clinic in a Johannesburg hospital.
This equated to 7.7% of the total patient population. In all
cases, skin lightening preparations were being utilized. The
continued presence of ochronosis after only 2 years of
restrictive measures might not be unexpected owing to
several factors such as undiagnosed ochronosis, continued
use of restricted combination drugs, i.e. combining antiacne
preparations with hydroquinone products by consumers,

and slow reversal of the pigmentary disorder of the dermis.

Several reports emanated from South Africa in the late
1370s describing the presence of exogenous ochronosis/
colloid milium in the black population.'6- Allegedly,
these adverse reactions resulted from utilization of
products containing 6 - 8% hydroquinone. Engasser and
Maibach pointed out that a cause and effect relationship
was never established." However, as late as 1986, the
hazardous depigmentation agents t-butyl catechol and
mercuric compounds which are capable of irreversible
depigmentation were still in the marketplace. The extent
and degree of distribution is hard to pinpoint.
These reports led the South African government to ban
combinations of many compounds including phenol and
Anti-Acne Products
The position in the USA regarding ochronosis and
hydroquinone was stated in 1983 by O'Donoghue who
served on the FDA Miscellaneous Panel. The panel
recommended that hydroquinone be sold over-the-counter
in concentrations below 2%.
The Panel took into consideration Findlay's original
article in 1975 in which he stated the concentration of
hydroquinone was 5% or greater, and the people
using the products used them for 6 months to 3
years.2
Hence, there appears to be a substantial difference
between the South African and USA market with respect to
the development of ochronosis. To explain this difference,
the development of ochronosis is discussed below in terms
of: climatic conditions, effects of phenol and resorcinol, and
vehicle effects.

Development of ochronosis
Climatic conditions
1981 1982 1983 1984 1985 1986
Findlay et a1 suggested that the reason for the difference in
Year exogenous ochronosis between South Africa and the USA is
Million
Packs

Percent of Hydroquinone Versus Time in Hours

n
Skin Liahteners for Alcoholic Lotions and Oil-in-Water Cream

40 +Alcoholic

*O
.-
10 4
I 30
20
Soln.#l

--C Alcoholic

'0,41
1981 1982 1983 1984 1985 1986
10
0
Soln.#2

6Oil-in-
Million Year 10 20 30 40
Packs Time in Hours
Percent
Figure 1 Absorbed
South Afican sales of skin products (Nielsen Media Research, Market Figure 2
Trend Data for 1981 - 1386 as reported to Nicholas Laboratories, South In vitro penetration of hydroquinone across guinea pig skin of three
Africa) commercial South African skin lighteners
 PA Burke & HI Maibach Exogenous ochronosis: an overview 23

First Age (years)

author race Reported
year State sex exposure Treatment Outcome

Hoshaw Arizona 75 2% HQ No treatment for multiple Four years after the first visit,
1985 B/F 2 years pigmented papules on cheeks, improvement was in the size and
(1 976 case) and lateral to eyes number of forehead, pigmented
papules
Cullison Georgia 58 2% HQ 2.5% HC 18 months (twice daily) for sooty Remarkable clearing of the
1983 B/F 2.5 years blue-black, hyperpigmentation except for some
(1979 case) 5-6 x/d relatively uniform residual changes
hyperpigmentation of cheeks
Hoshaw Arizona 49 OTC skin Sunscreen and avoid sunlight No change several months
1985 B/F lightening for black-blue post-visit
(1982 case) creams hyperpigmentation of cheeks,
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2 months nose and chin

Penneys FIorida NC NC NC NG
1985
Lawrence Louisiana 62 1% HQ 2.5% HC for bilateral speckled Lost to follow-up
1988 B/F 2 - 3 years hyperpigmentation on malar
(1985 Case) regions of cheeks
Lawrence Louisiana 46 1% HQ 2.5% HC plus sunscreen for "The treatment resulted in some
1988 B/F duration hyperpigmentation macular decrease in the pigmentation of the
(1985 case) unknown eruption of nose, forehead and forehead, but the periorbital and
periorbital areas cheek hyperpigmentation remained
prominent." Note: the time at
which this assessment was made
was not given

Connor Maryland 72 1 month of Treatment not discussed, "In most cases the
1987 B/F darkening confluent hyperpigmented blue- hyperpigmentation will fade
after using black macular and patches on dramatically over a period of
skin forehead malar and temporal years, if the bleaching agent is
lightening regions discontinued."
creams
since
childhood

Fisher New 47 4% HQ 500 mg tetracycline for discrete "After one month decided
1988 York B/F 18 months nonpruritic papular eruption of improvement was apparent and in 3
"dark spots" on cheeks months, the lesions had entirely
cleared"

Carey All 3 NG NC NC
1988 cases in NG NC NG
(3 cases) North NC NG NC
Carolina

Howard Texas 36 2% HQ 1% HC; 0.1% retinoic acid; "Only minimal lightening of the
1990 MEX 4 months 5% BP; sunscreen for hyperpigmentation." Note: the
(1989 case) F symmetrical blue-black macular time at which this assessment was
hyperpigmentation of cheeks, made was not given.
chin, and forehead

Diven Texas 53 2% HQ Dermabrsion and C 0 2 laser for "The patient was pleased with the
1990 B/F 2 - 3 months "sooty blue-black macules and final result."
prior Hx patches," especially in malar
unknown and periorbital areas
~

Table 1
Reports published in the USA of exogenous ochronosis reportedly associated with use of hydroquinone-containing skin lightening preparations
 24 PA Burke & HI Maibach Exogenous ochronosis: an overview

First Age (years)

author race Reported
year State sex Exposure Treatment Outcome

Davis Texas 40 NC NC
1990 Cajun
male

Martin Puerto 44 2% HQ 1% HC and suncreens No change eight months

1992 Rico BIF 3-4 Years post-visit
(2 cases)
Puerto 56 OTC skin Sunscreens Lost to follow-up
Rico BIF lightening
creams -30
years
Snider
1993 South 59 2-4% HQ NG
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Carolina BIF many years

HC, hydrocortisone; HQ, hydroquinone; NC, not given; OTC, over-the-counter; MEX, Mexican-American; BP, Benzoyl Peroxide; Hx, History

Tuble 1 continued

attributable to climatic conditions.''-'" However, this has
not been substantiated, since parts of southeastern United
States are analogous to South Africa. Furthermore, Olumide
reported in 1987 that over a 10-year period at Lagos
University Teaching Hospital, only 15 cases had been
observed (0.1% of dermatologic cases)."'-" The climatic
conditions of Nigeria are similar to those of South Africa and
hydroquinone can be sold with virtually no restrictions. The
majority of preparations in Nigeria contained 4 - 8%
hydroquinone. Patel confirmed a low incidence in Kenya
(letter to Nicholas Kiwi on ochronosis in Nairobi). If climate
were a factor, then the equatorial climate of Nigeria and
Kenya would be expected to result in even a higher incidence
of ochronosis. Therefore, one could conclude climatic
conditions do not contribute significantly to the disease
process.
products, namely 'HE MAN Skin Lightening Cream' and 'HE
MAN Supamel Skin Clearing Cream' (the latter containing
resorcinol) are examples. Hence, many consumers mis-
takenly or intentionally used a known ochronotic agent
(resorcinol) o n hyperpigmented areas.
This hypothesis is supported by market data showing a
decline in sales of skin lightening compounds with a sharp
increase in sales of antiacne products following the
hydroquinone concentration restrictions in 1983 (Figure
I ) . The consumers were switching brands in an attempt to
find a more effective product. There was a growth of
products containing ingredients associated with ochrono-
sis, namely resorcinol, oxyquinoline and phenol. It is
therefore not surprising that there are reports of
ochronosis allegedly with 2% hydroquinone-containing
products.

Effects of phenol and resorcinol Vehicle effects

There is a well-established relationship between exogenous
ochronosis and chronic exposure to phenol or resorci-
14.2-3 The presence of these compounds in many skin
lightening products prior to 1983 was largely responsible
for the outbreak of ochronosis as a consequence of long-
term use of skin lighteners. Following the banning of
combinations containing these drugs in 1983, it is possible
that skin lightening products were mixed with antiacne
products. In South Africa, it was common practice to use
antiacne preparations (containing resorcinol) in conjunc-
tion with skin toning preparations to try to achieve a more
rapid and enhanced lightening. Many South African
companies marketed antiacne and skin lightening prepara-
tions under the same brand names. The marked leading
Hydroalcoholic lotions containing hydroquinone were a
predominant formulation type in South Africa and may
further explain why ochronosis is largely limited to that
country. This vehicle not only increases penetration but
importantly allows higher concentrations of hydroquinone
to be incorporated into the formulations. These hydroalco-
holic lotions accounted for 46% of the South African
market while they are not generally sold over the counter in
most countries. For instance, the only lotion in the LISA is
Melanex (Neutrogena Corp.), available only by prescription.
Studies performed in vivo have demonstrated that the
bioavailability profile depends upon the vehicle base and
species. Basically, it can be said that hydroquinone in an
aqeuous solution is poorly absorbedL4 but alcoholic
 PA Burke & HI Maibach
vehicles significantly increase skin penetration of hydro-
quin0ne.j‘ Bucks et al have reported that the bioavailability
of hydroquinone administered topically to the human
forehead reaches levels of GO - 70Y0.’~
Snell et al studied the penetration through guinea pig
skin in vitro of hydroquinone from two hydroalcoholic
lotions and an oil-in-water cream commercially available in
South Africa prior to the 1384 restrictions of combination
drugs (Figure 2).’” Chemical analysis of the lotions revealed
the presence of salicylic acid, methyl salicylate and phenol,
and they demonstrated greater penetration of hydroquinone
than the cream formulation. Preparations available after the
1384 restrictions did not contain these components, but it
was shown that the penetration of hydroquinone was five
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times greater over a 24-h period from hydroalcoholic
lotions than from oil-in-water emulsions.
Maibach has demonstrated the bioavailability of ‘‘C-
labeled hydroquinone in a 2% commercial oil-in-water
emulsion to be 45.3% with a flux rate of 1.8 pg/h cmz for
the forehead in humans (manuscript in preparation).
Slower penetration was seen in the same study utilizing
the forearm (1 0 pg/h cmL). This anatomical variation is
consistent with previous reports.” However, since the
forearm site was utilized for ipsilateral/contralateral blood
levels, it was not possible to determine the bioavailability
since the skin was washed 8 h following topical adminis-
tration.
Findlay’s hypothesis that ”ochronosis . . . requires an
initial glut of the substance in some part of the organism” is
consistent with the suggestion that the habitual use of
References
1. Hoshaw RA et al, Ochronosis-like pigmentation from
hydroquinone bleaching creams in American Blacks. Arch
Dc,r/pi(/r<)/(1985) 121: 105-8.
2. Cullison D et al, Localized exogenous ochronosis. J A m
A d Drrmotol (1983) 8: 882-9.
3 . Penneys NS, Ochronosis-like pigmentation from hydro-
quinone bleaching creams. Arch Deriiitrfnl ( 1985) 121:
I239 -40 (letter).
4. Lawrence N et al, Exogenous ochronosis in the United
States. J A m Actrtl D o n i n / o l ( 1988) 18: 1207 I I .
- 12. Snider RL, Thiers BH, Exogenous ochronosis. .I . 4 / r 1 . - I d
5. Connor T, Braunstein B, Hyperpigmentation following the
use of bleaching creams. A t d i D ~ r r i i ~ i t (1987)
ol
6. Fisher AA, Tetracycline treatment for sarcoid-like ochro-
nosis due to hydroquinone. Cirtis (1988) 42: 19-20.
7. Carey AB et al, Bleaching cream associated exogenous
ochronosis. Presented at the 26th Annual Meeting of the
American Society of Dermatopathology, Washington, DC,
30 November - 2 December 1988. J Cirta/7 Palliol (1988)
15(5): 299.
8. Howard KL, Furner BB, Exogenous ochronosis in a
Mexican-American woman. Cirtis ( 1990) 45: 180 - 2.
Exogenous ochronosis: an overview 25
hydroalcoholic lotions in South Africa is largely contribu-
tory to the high incidence of exogenous ochronosis. The
amount of hydroquinone in the skin would be enhanced by
the combination of higher hydroquinone concentrations
and increased bioavailability in hydroalcoholic lotions.
Therefore, perhaps the habitual use of hydroalcoholic
lotions leads to a glut not created by cream-based
formulations from which the hydroquinone penetrates
relatively moderately. The presence of phenol and resorcinol
would have exacerbated the condition in pre-1384
formulations. Therefore, a major reason for this striking
difference in exogenous ochronosis between the lISA and
South Africa probably can be attributed to the formulation
differences.
Conclusion
The extremely high incidence of exogenous ochronosis
observed in South Africa may be related to the following
factors:
1. High hydroquinone concentrations were concomitantly
used with ochronotic agents such as phenol and
resorcinol (pre-1384). This trend continued through
the use of home-made combinations as evidenced by
significant market growth.
2. Hydroalcoholic lotions permitted higher hydroquinone
concentrations and increased its bioavailability relative
to the normal creams.
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August 1987.
 26 PA Burke & HI Maibach
16. Findlay GH et al, Exogenous ochronosis and pigmented
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Exogenous ochronosis: an overview
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