A review of toxicity from topical salicylic acid

preparations
Raman K. Madan, MD,a,b and Jacob Levitt, MDb
New York, New York

Topical salicylic acid is often used in dermatologic conditions because of its keratolytic, bacteriostatic,
fungicidal, and photoprotective properties. The bioavailability of salicylic acid differs depending on the
vehicle used and pH of transcellular fluids. Although rare, salicylic acid toxicity (salicylism) can occur from
topical application. Physicians should be mindful of the potential for salicylism or even death from topically
applied salicylic acid. ( J Am Acad Dermatol 2014;70:788-92.)

Key words: ichthyosis; psoriasis; salicylic acid; salicylism; skin absorption; topical; toxicity.

S alicylic acid is the most widely consumed to 40%. Prescription-strength creams and lotions
analgesic, antipyretic, and anti-inflammatory contain concentrations of 6% or above.
agent in the world.1 It is a natural product The potency and toxicity of salicylic acid is
found in the bark of a willow tree and has been used changed by substitutions on the carboxyl or
for centuries to relieve fever and pain.2 Salicylic acid hydroxyl groups of its chemical structure. Its action
is a precursor to acetylsalicylic acid, better known as is also influenced by the ortho position of the
aspirin (Fig 1).3 hydroxyl group. This structure allows for the effects
Salicylic acid is used topically for its keratolytic, of salicylic acid on pain, body temperature, respira-
bacteriostatic, fungicidal, and photoprotective prop- tion, acid-base balance, kidneys, heart, gastrointes-
erties. Topical application has been shown to reduce tinal tract, uric acid excretion, blood, and rheumatic,
the rate of keratinocyte proliferation. It also inhibits inflammatory, and immunologic processes as well as
cholesterol sulfotransferase, an enzyme responsible causing local irritation.1 The benzene ring of salicylic
for cholesterol sulfate formation within keratino- acid functions to transform ultraviolet radiation into
cytes. Salicylic acid directly solubilizes the stratum longer wave radiation that is emitted from the skin as
corneum by dissolving the intercellular cement. heat, thereby providing a sunscreen effect.6
Through these mechanisms, salicylic acid increases Salicylism, the syndrome of salicylic acid toxicity,
the elimination of squames from the stratum can be acute or chronic and develops when blood
corneum.4 concentrations of salicylate are greater than 35 mg/
The principal use of topical salicylic acid in dL. Symptoms of salicylism include nausea, vomit-
dermatology is as a keratolytic agent. Warts and ing, confusion, dizziness, delirium, psychosis,
localized hyperkeratosis can be treated with salicylic stupor, coma, and death. The medullary respiratory
acid concentrations of 10% to 40%. At lower concen- center is activated at these levels, which leads to
trations, it is used in the treatment of plaque psoriasis hyperventilation and respiratory alkalosis.6
and comedonal acne.4 Other indications include Metabolic abnormalities, including acidosis, hypo-
acanthosis nigricans, actinic keratosis, ichthyosis, glycemia in children and hyperglycemia in adults,
superficial chemical peels, and tinea nigra.5 In gen- can occur as well.1 Salicylate toxicity causes tinnitus
eral, over-the-counter preparations for treatment of because of increases in labyrinthine pressure and
acne and xerosis contain concentrations of 5% or effects on cochlear hair cells.6
less, and solutions or adhesive plasters for treatment When ingested orally, salicylic acid is absorbed
of warts and calluses contain concentrations of 10% rapidly and can reach a peak value in about 1 hour.

From the Beth Israel Medical Center, Mount Sinai Health Systema; Reprint requests: Jacob Levitt, MD, Department of Dermatology,
and Department of Dermatology, Icahn School of Medicine at Mount Sinai School of Medicine, 5 E 98th St, 5th Floor, Box
Mount Sinai.b 1048, New York, NY 10029. E-mail: jacob.levitt@mssm.edu.
Funding sources: None. Published online January 27, 2014.
Conflicts of interest: None declared. 0190-9622/$36.00
Accepted for publication December 5, 2013. Ó 2013 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2013.12.005

788
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VOLUME 70, NUMBER 4

Absorption from topical application is variable but endoplasmic reticulum and mitochondria. Half-life is
can be rapid.1 Percutaneous absorption may be dose-dependent and elimination occurs in the
vehicle-dependent. One study compared different urine.1,12
vehicles of topical salicylic acid administration. By The following scenario is an estimate of the
analyzing urine 26 hours after application, it was exposure to salicylic acid in a theoretical dermato-
found that salicylic acid 5% in magistral mineral oil/ logic case. If a patient applies lotion to 70% of the
petrolatum formulation was absorbed 2.5 times more body surface area (approximately most of the arms,
than salicylic acid 5% in a legs, and trunk), a single
solution containing polyeth- application is roughly 16
ylene glycol, glycerol, and CAPSULE SUMMARY g.13 If we assume the patient
petrolatum. The relative ab- applies 16 g of a 6% salicylic
Salicylic acid toxicity (salicylism) can
d

sorption of salicylic acid 5% acid lotion, this amounts to

occur with topical use of 6% salicylic acid
in the magistral mineral oil/ 1 g of salicylic acid. If 60% is
over as little as 40% body surface area.
petrolatum formulation was absorbed, the maximal
slightly more than that of A search of the literature from 1966 to
d
plasma level would be 0.6 g.
salicylic acid 10% in a similar the present found 25 cases of toxicity The volume of distribution is
solution. The total absorp- with 4 deaths attributed to the use of equal to the total amount
tion was greatest with the topical salicylic acid. of drug in the body divided
10% solution.7 There is a potential for salicylism or even
d by the drug plasma
The percutaneous absorp- death from topically applied salicylic concentration:
tion of salicylic acid is nor- acid. Vd = Total amount of drug
mally 60% with intact skin.8 in body/drug plasma
Systemic effects of topical concentration
salicylic acid are minimal when it is applied to intact 170 mL/kg11 = 0.6 g/Drug plasma concentration
skin in low to moderate doses. Conversely, with a Drug plasma concentration = 3.5 g/mL = 350 mg/
break in the stratum corneum, measurable levels of mL = 35 mg/dL
salicylic acid can be found in the body even after The level at which salicylic toxicity begins is 35
application of low concentrations in hydrophilic mg/dL.6 The half-life of salicylic acid can range from
ointment.9 Using cutaneous microdialysis, it was 2 to 12 hours depending on the dose. If 16 g of lotion
shown that salicylic acid with petrolatum or ethanol is applied twice a day, salicylic acid could accumu-
applied to tape-stripped skin is absorbed 150 times late in the body and levels could even become high
more than when applied to intact skin.10,11 enough to cause death.
Once absorbed, salicylates are distributed to body A PubMed search from 1966 to the present
tissues and transcellular fluids primarily by pH- revealed toxicity directly linked to topically applied
dependent processes. The volume of distribution is salicylic acid in 13 cases of psoriasis, 8 cases of
170 mL/kg in healthy individuals but can increase to ichthyosis, 2 cases of tinea imbricata, 1 case of
500 mL/kg at high therapeutic doses. In all, 80% to erythroderma, and 1 case of seborrheic dermatitis
90% of the salicylate in plasma is bound to protein (Table I). Toxicity often appeared within a few days
and a much smaller percentage can actually be of use. The most severe cases, leading to coma and
detected. It is biotransformed predominantly in the death, occurred in patients with psoriasis. The age at

Fig 1. Biochemical pathway demonstrating the formation of acetylsalicylic acid (aspirin) from
salicylic acid. Left to right: salicylic acid (C7H6O3); acetic anhydride (C4H6O3); acetylsalicylic
acid (C9H8O4); and acetic acid (C2H4O2).
Table I. Cases of toxicity from topically applied salicylic acid; PubMed search 1966 to present

790 Madan and Levitt

Plasma/serum concentration,
Year published Ageegender Concentration and vehicle mg/L (toxic = 350 mg/L) Day Underlying disease Symptoms Reference
22
2012 6 wkeNR 23% Salicylic acid in petroleum jelly, 580 3 Seborrheic dermatitis Tachypnea, impaired
under occlusion on scalp consciousness
2003 58 yeM 10% Ointment to [80% BSA 435 5 Psoriasis Death 23

2003 35 yeM 10% Ointment to [80% BSA 510 4 Psoriasis Death 23

24
2002 NewborneM 20% with Oral retinoid BID over whole 1190 7 Ichthyosis (collodion Tachypnea, renal and
body baby) heart failure
25
2002 31 yeM 30% Applied to back and 4 limbs 309 2 Psoriasis, HIV Coma
continuously
26
1997 5 yeF 10% Plus urea, entire body BID 290.5 1.5 Ichthyosis Fever, respiratory
alkalosis, comatose
state
27
1996 7 yeM 10% Ointment over large area, once a 985 28 Ichthyosis Wheezing, vomiting,
week tinnitus, vertigo,
hyperventilation, deep
somnolence
28
1996 80 yeF 2%-10%, 4 times day 465 6 Erythroderma Confusion, hyperpnea,
metabolic acidosis
29
1994 3 moeF 4% with 6% Sulfur over large area 550 2 Ichthyosis Diarrhea, vomiting,
metabolic acidosis
30
1994 79 yeF 2%-5% with Coal tar over large area 450 7 Psoriasis Unresponsive
1994 42 yeF 10% of 650 g a day 360 10 Psoriasis Nausea, deafness, 31

tachycardia
32
1992 27 yeM 40%-41% BSA once 836 1 Psoriasis Nausea, vomiting,
tachycardia, hyperthermia
33
1991 72 yeM 10% TID over 80% BSA 443 21-28 Psoriasis Confusion, hypoglycemia,
metabolic acidosis,
chronically ill
34
1990 NeonateeM 2% in Aqueous cream Q3-4 h 429 3 Collodion-like Vomiting, metabolic acidosis
membrane
34
1990 12 yeM 2%-10% BID to whole body 457 8 Ichthyosis Salicylate toxicity
35
1989 NeonateeF 1% Q3 h to whole body 587 1 Harlequin fetus Tachypnea, fever
36
1986 45 yeM 3% TID with coal tar to whole body 252 5 Psoriasis Tinnitus

J AM ACAD DERMATOL
37
1980 48 yeM 20% Salicylic acid in petrolatum 810 6 Psoriasis Coma
38
1979 30 yeM 4%-12% BID to trunk and limbs 455 20 Ichthyosis Malaise, nausea, tinnitus,
deafness
39
1975 62 yeF 10% BID to 75% BSA 2234 15 y Psoriasis Dry mouth, headache, tinnitus

APRIL 2014
40
1968 NReM 50% BSA with 20.7% salicylic acid NR 1 Tinea imbricata Comatose, death
solution BID
J AM ACAD DERMATOL Madan and Levitt 791
VOLUME 70, NUMBER 4

which toxicity occurred was evenly distributed be-

tween adults and children. Toxicity with application
40

14

14

14
of as little as 1% to 2% salicylic acid has been reported
in neonates. In every case salicylic acid was applied
agitation, hallucinations, fever
headache, dizziness, tinnitus

to a large body surface area. In addition, before 1964

Anorexia, dizziness, vomiting,
Dyspnea, nausea, vomiting,

there was mention of 13 deaths caused by topical

salicylic acid toxicity. Of those, 3 patients had pso-
Dyspnea, nausea, thirst,
headache, dizziness,

riasis, 5 scabies, 3 dermatitis, 1 lupus vulgaris, and 1

congenital ichthyosiform erythroderma.14
Comatose, death

Toxicity from other topical salicylate medications

has been described. Although 10% topical methyl
agitation

salicylate and 3% menthol had no side effects when

used for back pain, toxicity developed when higher
concentrations were applied for longer times.15 The
plasma concentration of a commercially available
topical pain reliever containing methyl salicylate was
29.5 6 10.5 ng/mL when applied for 8 hours.16 Oil of
Tinea imbricata

wintergreen containing 98% methyl salicylate has

been associated with toxicity when applied topi-
Psoriasis

Psoriasis

Psoriasis

cally.17 Examples of toxicities reported include

reversible constriction of fetal ductus arteriosus after
maternal use, salicylism in a patient with psoriasis,
local necrosis and interstitial nephritis, and potenti-
1

ation of warfarin anticoagulation.18-21

Formal dose-response and toxicity studies are
BID, Twice a day; BSA, body surface area; F, female; M, male; NR, not reported; Q, every; TID, 3 times a day.

warranted to establish the maximum safe topical

dose of salicylic acid, particularly for patients with an
impaired skin barrier. Special care should be exer-
640

460

470

cised when prescribing topical salicylic acid for

conditions that involve large body surface areas,
such as psoriasis and ichthyosis, and for children.
NR

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