International Journal of Toxicology

29(Supplement 2) 84S-97S
Final Report of the Safety Assessment of ª The Author(s) 2010
Reprints and permission:
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Allantoin and Its Related Complexes DOI: 10.1177/1091581810362805
http://ijt.sagepub.com

Lillian C. Becker1, Wilma F. Bergfeld, MD, FACP2,

Donald V. Belsito, MD2, Curtis D. Klaassen, PhD2, James G. Marks, Jr MD2,
Ronald C. Shank, PhD2, Thomas J. Slaga, PhD2,
Paul W. Snyder, DVM, PhD2, and F. Alan Andersen, PhD3

Abstract
Allantoin is a heterocyclic organic compound. Allantoin ascorbate, allantoin biotin, allantoin galacturonic acid, allantoin
glycyrrhetinic acid, allantoin panthenol, and allantoin polygalacturonic acid are complexes of allantoin. All of the ingredients in
this review act as skin-conditioning agents. Allantoin was reported to be used in 1376 cosmetic products at concentrations up
to 2%. There are data gaps regarding use and concentration of the remaining allantoin complexes. Ascorbic acid, biotin, glycyr-
rhetinic acid, and panthenol have been determined by the CIR Expert Panel to be safe. Galacturonic acid and polygalacturonic acid
have not been reviewed by the CIR Expert Panel, and substantial data on these chemicals were not available. The safety test data in
this safety assessment and in previous safety assessments were considered sufficient to support the safety of allantoin and the
allantoin complexes in product categories and at concentrations reviewed in this safety assessment.

Keywords
safety, cosmetics, allantoin

This is a safety assessment of the cosmetic ingredient allantoin organic compound that conforms to the formula in Figure 1A.
and the related complexes allantoin ascorbate, allantoin biotin, Its source in cosmetics is synthetic. Allantoin is also known as
allantoin galacturonic acid, allantoin glycyrrhetinic acid, allan- (2,5-dioxo-4-imidazolidinyl)urea; glyoxyldiureid; glyoxyldiur-
toin panthenol, and allantoin polygalacturonic acid. eide; glyoxylic diureide; urea, (2,5-dioxo-4-imidazolidinyl);
There was a paucity of data in the literature on the related allan- and 5-ureidohydantoin7 and 6-ureidohydantoin.8 Other names
toin complexes. The safety of ascorbic acid, biotin, glycyrrhetinic are alantan; alloxantin; ureidohydantoin; hemocane; paxyl;
acid, and panthenol, however, has already been assessed by the allantol; cordianine; hydantoin, 5-ureido-; and 2,5-dioxo-4-
Cosmetic Ingredient Review (CIR) Expert Panel. These previ- imidazolidinyl-urea.9
ously reviewed cosmetic ingredients are summarized in Table 1. Allantoin ascorbate (CAS No. 57448-83-6) is the organic
Galacturonic acid and polygalacturonic acid have not been compound that conforms to the formula in Figure 1B. Its
reviewed by the CIR Expert Panel. A search of the literature chemical classes are heterocyclic compounds and organic salts.
revealed no safety test data relevant to these 2 compounds. It is also known as L-ascorbic acid, compounded with (2,5-
Galacturonic acid is a sugar that is, in the form of polygalac- dioxo-4-imidazolidinyl)urea.7
turonic acid, a major component of pectin. The US Food and Allantoin biotin (CAS No. 4492-73-3) is the organic com-
Drug Administration (FDA)6 has designated pectin as gener- pound that conforms to the formula in Figure 1C. Its chemical
ally recognized as safe (GRAS) as a food additive. classes are heterocyclic compounds and organic salts. It is also
Data in the safety assessments of allantoin and the related known as 1H-thieno(3,4-)imidazole-4-pentanoic acid,
complexes and further data about pectin allow conclusions to
be drawn about the safety of allantoin ascorbate, allantoin bio-
tin, allantoin glycyrrhetinic acid, allantoin panthenol, allantoin
galacturonic acid, and allantoin polygalacturonic acid. 1
Cosmetic Ingredient Review Scientific Analyst/Writer
2
Cosmetic Ingredient Review Expert Panel Members
3
Cosmetic Ingredient Review Director
Chemistry
Definition and Structure Corresponding Author:
Lillian C. Becker, Cosmetic Ingredient Review, 1101 17th Street, NW, Suite
According to the International Cosmetic Ingredient Dictionary 412, Washington, DC 20036, USA.
and Handbook,7 allantoin (CAS No. 97-59-6) is a heterocyclic Email: [email protected]

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Becker et al 85S

Table 1. Previously Reviewed Ingredients Complexed to Allantoin

Use
Concentration,
Ingredient Uses % Conclusion

Ascorbic 431 <0.01-10 Safe as used in cosmetic

acida products.
Biotinb 75 0.6 Safe as used in cosmetic
formulations.
Glycyrrhetin 65 2 Safe for use in cosmetic
acidc formulations in the practices
of use and concentration as
described in this safety
assessment.
Panthenold,e 284 0.1-5 Safe as presently used
in cosmetics.
a
Andersen 2005.1
b
Andersen 2001.2
c
Andersen 2007.3
d
Elder 1987.4
e
Andersen 2006.5

hexahydro-2-oxo-, compd. with (2,5-dioxo-4-imidazolidinyl)

urea (1:1).7
Allantoin galacturonic acid (CAS No. 5119-24-4) is the
complex of allantoin and galacturonic acid that conforms to the
formula in Figure 1D. Its chemical classes are heterocyclic
compounds and organic salts. It is also known as allantoin a-
D-galacturonic acid; allantoin, monogalactopyranuronat; and
galactopyranuronic acid, compd. with allantoin (1:1).7
Allantoin glycyrrhetinic acid (CAS No. 4572-09-2) is a
complex of allantoin and glycyrrhetinic acid and has the
empirical formula: C30H46O4  C4H6N4O3. Its chemical
classes are heterocyclic compounds and organic salts. It is also
known as olean-12-en-29-oic acid, 3b-hydroxy-11-oxo-,
compd. with allantoin (1:1).7
Allantoin panthenol (no CAS No.) is a complex between
allantoin and panthenol. Its chemical classes are alcohols,
amides, and heterocyclic compounds. A technical name is
allantoin DL-pantothenyl alcohol.7 Figure 1. (A) Allantoin, (B) allantoin ascorbate, (C) allantoin biotin,
Allantoin polygalacturonic acid (CAS No. 29659-38-9) is a and (D) allantoin galacturonic acid.7
complex of allantoin and polygalacturonic acid. Its chemical
classes are heterocyclic compounds and organic salts. Allan-
Allantoin is soluble in hot water; slightly soluble in cold
toin polygalacturonic acid has the empirical formula
water, glycerin, and propylene glycol; very slightly soluble in
(C6H10O7)x  xC4H6N4O3.7
alcohol; and practically insoluble in apolar solvents (ie, mineral
oil, dimethylisosorbide, ether, and chloroform).11
Allantoin ascorbate is a white-yellowish powder that is
Physical and Chemical Properties water soluble.17
Allantoin is a white powder8,9 that is odorless and tasteless10,11 Allantoin a-D-galacturonic acid is soluble at 3% to 5%. It
and does not stain.12 Allantoin is an amphoteric substance.13 contains *41.6% + 4.0% allantoin and *58.4% + 4.0% a-
Chemical properties of allantoin are listed in Table 2. D-galacturonic acid.18
Akema Fine Chemicals11 stated that allantoin exists in solu- Allantoin glycyrrhetinic acid, as described in a product data
tion as a tautomeric mixture of ketonic and enolic forms in sheet by Active Ingredients Ltd,19 is the combination of allan-
equilibrium. With 1 chiral center, the 2 enantiomeric forms R toin and glycyrrhetinic acid in molar ratios of 1:1, 1:2, or 1:3.
and S are a 50:50 mixture that is optically inactive. Optically The product specification states that allantoin, measured as
active forms can be obtained by extraction procedures. nitrogen, is 30% + 2% and glycyrrhetinic acid is 70% +

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86S International Journal of Toxicology 29(Supplement 2)

Table 2. Chemical Properties of Allantoin Sznitowska and Janicki23 measured the release of allantoin
from various ointments using a modified Mutimer apparatus.
Property Reference At 150 minutes, more than 80% of the allantoin from the oil/
Molecular weight 158.12 Sheker et al8 water ointment (15% wt/wt oily phase and 84% wt/wt aqueous
Melting point,  C 234.6-235.2 Buzard et al14 ethanol phase) was released with a solubility of 1.12 g/cm3. At
225-230 Akema Fine 300 minutes, *50% of the allantoin from the water/oil oint-
Chemicals11 ment (73% wt/wt oily phase and 26% wt/wt aqueous ethanol
230 Chemical LAND219 phase) was released with a solubility of 0.78 g/cm3. At 300
239 ChemIDplus Lite15 minutes, *50% of the oil/water ointment (no wt/wt oily phase
Solubility 1 g per 190 mL of distilled Sheker et al8
water and 94% wt/wt aqueous ethanol phase) was released with a
5260 mg/L of water ChemIDplus Lite15 solubility of 0.97 g/cm3.
0.5% at 25 C in water Chemical LAND219 Allantoin glycyrrhetinic acid has a shelf life of 5 years in the
(freely dissolves in alkalis) original packaging.19
pH 4-6 (0.5% solution) Chemical LAND219
Stability range pH 4-9 Mecca16
Vapor pressure 4.32E-09 mm Hg ChemIDplus Lite15 UV Absorption
Lukasiak et al24 reported that the absorption of allantoin in aqu-
eous solution is most stable at a pH range of 10.5 to 11.5 at
2% of the complex. It is a yellowish-white powder with a mild, lmax ¼ 225 nm.
characteristic odor. Allantoin glycyrrhetinic acid is soluble in
propylene glycol, dimethylisosorbide, and alcohol; it is practi-
cally soluble in water and mineral oil. Methods of Manufacture
In a product data sheet, Akema Fine Chemicals17 states that Allantoin can be extracted from blow-fly larvae25 and maize
allantoin glycyrrhetinic acid is a white-yellowish powder that is silk.26
alcohol soluble but not water soluble. It has a working tempera- According to Hartman et al,27 allantoin is prepared from the
ture of up to 80 C. heated combination of uric acid and sodium hydroxide with
Allantoin panthenol, as described in a product data sheet by the addition of potassium permanganate to the cooled flask.
Akema Fine Chemicals,17 is a white powder that is water The solution is filtered to remove manganese dioxide, and
soluble. acetic acid is added. After standing for several hours, allantoin
Allantoin polygalacturonic acid, as described in a product crystallizes and can be filtered. To further purify the filtrate, the
data sheet by Akema Fine Chemicals,17 is a white-yellowish allantoin is dissolved in boiling water, treated with Norite, and
powder. It forms a clear thin gel in sodium citrate solution. then rapidly filtered again.
Akema Fine Chemicals28 reported that it manufactures
allantoin by chemical means and does not use any animal
Stability sources.
Akema Fine Chemicals11 also reported that allantoin is
Allantoin degrades when dissolved in distilled water. At 0.13% synthetically obtained by oxidation of uric acid with permanga-
allantoin (0.6556 g per 500 mL), 6.3% was lost after 620 nate, heating of dichloroacetic acid and urea, and a condensa-
days; at 0.45% (1.1396 g per 250 mL), 1.5% was lost after tion process between glyoxylic acid and urea.
415 days; at 0.24% (2.421 g per 1000 mL), 6.4% was lost after The International Cosmetic Ingredient Dictionary and
24 days. At 0.13% allantoin in tap water, 6.4% was lost after 24 Handbook stated that allantoin has a synthetic source for use
days. When 2 samples of allantoin (25 mL) were mixed with in cosmetics.7
23.94 mL of potassium hydroxide (KOH) and let stand for a
month, there was a 90.2% loss and a 91.1% loss. When 2 samples
of allantoin (25 mL) were incubated in KOH (20 mL) for 24 hours Analytical Methods
(at ‘‘body temperature’’), there was a 43.4% loss of allantoin.20
Analytical methods for measuring allantoin under different cir-
Kaliszan and Halkiewicz21 used infrared (IR) analysis to
cumstances and conditions are listed in Table 3.
look for deterioration in stored allantoin. After 3 months, the
samples differed at *720 cm–1 in the position of V amide band
of the hydrogen-bonded secondary amides and in the formation Impurities
of the III amide band at 1275 cm–1. The samples also differed at Allantoin. Kahn and Nolan41 reported that [4,514C]allantoin
the region of N-H rocking vibrations (666-800 cm–1). was 96.0% pure by thin-layer chromatography (TLC) and
Allantoin is unstable in alkaline conditions and hydrolyzes 96.3% pure by high-performance liquid chromatography
to urea and glyoxylic acid, possibly via allantoic acid.22 How- (HPLC).
ever, it is stable in ordinary conditions.9 It should be stored at Wang et al42 gave the purity of allantoin powder from
room temperature away from sunlight.12 Jiangsu Huanghai Pharmaceutical Factory as 99.6%.

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Becker et al 87S

Table 3. Methods for the Analysis of Allantoin

Analytical Method Application Reference

Potentiometric titration in a mixed solvent Measure the amount of allantoin in a cream formulation Weber and Higgins29
system
IR analysis Measure deterioration in stored allantoin Kaliszan and Halkiewicz21
RP-HPLC Determine allantoin in human body fluids Tiemeyer and Giesecke30
HPLC Determine allantoin in human body fluids or cosmetic products Grootveld and Halliwell,31
Kawase et al32
Chromatographic assay Determine allantoin and uric acid in plasma ultrafiltrate Lux et al33
simultaneously
Direct spectrophotometry Determine presence of allantoin Chen et al34
Alkalimetric titration with pH indicator Determine presence of allantoin Chen et al34
TLC and LC Determine presence of allantoin Chen et al,34 Berthemy
et al35
Modified HPLC Measure allantoin and urate simultaneously Benzie et al36
HPLC Simultaneously determine the levels of hypoxanthine, uric Marklund et al37
acid, and allantoin in small (4 mL) microdialysis samples
GC-MS Determine presence of serum allantoin. Pavitt et al38
RP-HPLC Analyze allantoin extracted from maize Maksimović et al26
Enzymatic assay Measure serum allantoin in experimental animals Muratsubaki et al39
TLC Identify allantoin United States Pharmacopeia40

GC-MS, gas chromatography–mass spectrometry; IR, infrared; LC, liquid chromatography; RP-HPLC, reversed-phase high-performance liquid chromatography;
TLC, thin-layer chromatography.

Impurities have been reported to include sulfated ash 0.0001% to 2%.46 Allantoin ascorbate was reported by industry
(0.1%-0.2%), sulfate (200 ppm), chloride (50 ppm), heavy metals to be used at concentrations of 0.001% and 0.05% for allantoin
(10 ppm), lead (<20 ppm), iron (10 ppm), arsenic (3 ppm), urea biotin and allantoin galacturonic acid. Table 4 summarizes the
(0.5%), glyoxylic acid (0.5%), and glycoluril (<0.2%).9,11,19 available cosmetic use data on frequency of use and concentra-
tions of use of allantoin and allantoin complexes.
Natural Occurrence in Plants and Food Allantoin glycyrrhetinic acid was reported to be used in
6 cosmetic products, allantoin panthenol in 2 cosmetic prod-
Allantoin is found naturally in the leaf buds of Platanus orien- ucts, and allantoin polygalacturonic acid in 2 cosmetic prod-
talis (oriental plane tree), Acer pseudoplatanus (sycamore), and ucts47; concentrations of use were not reported to CTFA.
Acer campestre (hedge maple) and in the bark of Aesculus hip- The Ministry of Health, Labor and Welfare48 of Japan lists
pocastanum (horse chestnut) and A pseudoplatanus. Allantoin allantoin as an acceptable medicinal ingredient to be used in
is also found in the embryos of wheat separated in the milling cosmetics.
process and in beet juice.43 Allantoin has been found in trace Allantoin is used in 11 sprays and fixatives. The potential
amounts in other plants and in foods.11,26,44 adverse effects of inhaled aerosols depend on the specific
chemical species, the concentration, the duration of the expo-
sure, and the site of deposition within the respiratory system.49
Use In general, the smaller the particle, the farther into the respira-
tory tree the particle will deposit and the greater the impact on
Cosmetic
the respiratory system.50
According to the International Cosmetic Ingredient Dictionary Anhydrous hair spray particle diameters of 60 to 80 mm have
and Handbook,7 allantoin functions as a skin-conditioning been reported, and pump hair sprays have particle diameters of
agent - miscellaneous and a skin protectant. Allantoin ascorbate, 80 mm or larger.51 The mean particle diameter is around 38 mm
allantoin biotin, allantoin galacturonic acid, allantoin glycyrrhe- in a typical aerosol spray.52 In practice, aerosols should have at
tinic acid, allantoin panthenol, and allantoin polygalacturonic least 99% of particle diameters in the 10- to 110-mm range. This
acid also act as skin-conditioning agents - miscellaneous.7 means that most aerosol particles are deposited in the nasophar-
According to information supplied to the FDA by industry yngeal region and are not respirable.
as part of the Voluntary Cosmetic Ingredient Reporting Pro-
gram (VCRP), allantoin is used in a total of 1376 cosmetic
products.45 A survey of current use concentrations conducted
Noncosmetic
by the Cosmetic, Toiletry, and Fragrance Association (CTFA) Allantoin is FDA approved for use as a skin protectant at 0.5%
reported that allantoin is used at concentrations ranging from to 2.0%.53 It is considered safe for use as an oral wound healing

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88S International Journal of Toxicology 29(Supplement 2)

Table 4. Frequency of Use and Concentration of Allantoin, Allantoin Ascorbate, Allantoin Glycyrrhetinic Acid, Allantoin Panthenol, and
Allantoin Polygalacturonic Acid

Product Category (no. of products in each category)45 Frequency of Use45 Concentration of Use, %46

Allantoin
Baby products
Lotions, oils, powders, and creams (67) 6 0.05-2
Other (64) 3 —
Bath products
Oils, tablets, and salts (207) 3 —
Soaps and detergents (594) 28 0.1-0.2
Bubble baths (256) 2 0.3
Other (276) 3 0.0001-0.1
Eye makeup
Eyebrow pencils (124) — 0.1
Eyeliners (639) 3 0.2
Eye shadow (1061) 2 —
Eye lotions (32) 12 0.1-0.2
Eye makeup remover (114) 15 0.0005-0.1
Mascara (308) 4 —
Other (229) 17 0.001-0.2a
Fragrance products
Powders (324) 4 —
Other (187) 20 —
Noncoloring hair care products
Conditioners (5) 34 0.001-0.1
Sprays/aerosol fixatives (294) 11 —
Straighteners (61) 1 —
Permanent waves (169) 4 —
Rinses (46) 1 —
Shampoos (1022) 31 0.1
Tonics, dressings, etc (623) 24 0.0001-0.1
Other (464) 4 0.3b
Makeup
Blushers (459) 8 —
Face powders (447) 13 2
Foundations (530) 10 0.02-0.5
Lipsticks (1681) 51 0.01-0.8
Makeup bases (273) 6 0.02
Rouges (115) 1 —
Other (304) 17 0.5
Nail care products
Cuticle softeners (20) 1 0.1
Creams and lotions (13) 1 —
Other (58) 1 0.005-0.1
Oral hygiene products
Dentifrices (54) 5 0.1-0.2
Mouthwashes and breath fresheners (57) — 0.1-0.2
Personal hygiene products
Underarm deodorants (281) 10 0.001-0.1
Douches (8) 1 —
Other (390) 25 0.001-0.1
Shaving products
Aftershave lotions (260) 110 0.05-0.5
Shaving cream (135) 9 0.01-0.5
Other (64) 10 0.001-0.2
Skin care products
Skin cleansing creams, lotions, liquids, and pads (1009) 92 0.001-0.2
Face and neck creams, lotions, powders, and sprays (546) 102 0.002-0.4
Body and hand creams, lotions, powders, and sprays (992) 146 0.002-0.4
Foot powders and sprays (43) 2 —
Moisturizers (1200) 241 0.005-0.5

(continued)
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Becker et al 89S

Table 4 (continued)

Product Category (no. of products in each category)45 Frequency of Use45 Concentration of Use, %46

Night creams, lotions, powders, and sprays (229) 55 0.1-0.2

Paste masks/mud packs (312) 35 0.001-0.1
Skin fresheners (212) 39 0.1-0.2
Other (915) 116 0.005-0.2c
Suntan products
Suntan gels, creams, liquids, and sprays (138) 19 0.2-0.5
Indoor tanning preparations (74) 5 0.1
Other (41) 13 0.002
Total uses/ranges for allantoin 1376 0.0001-2
Allantoin ascorbate
Personal hygiene products
Underarm deodorants (281) — 0.001
Shaving products
Aftershave lotions (260) — 0.05
Total uses/ranges for allantoin ascorbate — 0.001-0.05
Allantoin glycyrrhetinic acid
Shaving products
Shaving cream (135) 2 —
Skin care products
Skin cleansing creams, lotions, liquids, and pads (1009) 1 —
Moisturizers (1200) 2 —
Night creams, lotions, powders, and sprays (229) 1 —
Total uses/ranges for allantoin glycyrrhetinic acid 6 —
Allantoin panthenol
Skin care products
Face and neck creams, lotions, powders, and sprays (546) 1 —
Moisturizers (1200) 1
Total uses/ranges for allantoin panthenol 2 —
Allantoin polygalacturonic acid
Shaving products
Aftershave lotions (260) 1 —
Skin care products
Body and hand creams, lotions, powder and sprays (992) 1 —
Total uses/ranges for allantoin polygalacturonic acid 2 —
Dashes indicate not reported.
a
0.2% in an eye pencil and an eye cream.
b
0.3% in a hair-straightening balm.
c
0.2% in skin wipes and skin toner.

agent, but there are inadequate data to establish the effective- The oxidation of uric acid by cytochrome c produced allan-
ness.45 Allantoin for a variety of other skin uses has been toin. This may be a possible source of allantoin in human tissues
described.25,54-57 and may be of significance in patients with Reye’s syndrome, in
The safety and effectiveness of allantoin for use in dandruff/ whom elevated uric acid has been demonstrated.61
seborrheic dermatitis psoriasis drug products have not been
established.58
Use of allantoin ascorbate, allantoin polygalacturonic acid, Animals and Humans
allantoin glycyrrhetinic acid, and allantoin polygalacturonic Allantoin is found in blood or serum in humans in the range of
acid in various skin treatments has been described by 7.2 to 48.2 mmol/L.31,33,36,62-65
manufacturers.18,19,59
Absorption, Distribution, Metabolism, and Excretion
Sznitowska and Janicki66 applied allantoin (1%) in 3 different
General Biology
vehicles to the inner forearm of volunteers (n ¼ 6) to test skin
Most mammals process purines to allantoin, as shown in penetration. The vehicles were a hydrophilic gel (5% wt/wt
Figure 2. However, higher apes and humans do not possess aqueous solution of methyl cellulose with added glycerol and
urate oxidase, the final step in the process; thus, purines in propylene glycol), an oil/water cream (sodium lauryl sulfate
humans become uric acid, which is excreted in urine.60 and cetostearyl alcohol), and a water/oil ointment (cetyl

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90S International Journal of Toxicology 29(Supplement 2)

absorption of allantoin. Allantoin penetration with the hydro-

philic gel at 3 and 6 hours was 5.00% + 1.25% and 6.9% +
Purine Catabolism 1.4%, respectively; with the oil/water cream 13.0% + 1.8%
and 15.4% + 2.7%, respectively; and with the water/oil oint-
ment 12.5% + 2.1% and 20.0% + 2.3%, respectively.
Allantoin (600 mg) was administered by stomach tube to
dogs.67 Elimination was complete in *4 hours. Urine allantoin
peaked at *260 mg per 100 mL in less than 30 minutes and
declined rapidly. Blood allantoin peaked at *90 mg per 100
Hypoxanthine
mL in less than 1 hour and declined steadily. Recovery was
674 mg (112%).
Friedman and Byers68 performed clearance studies on male
albino rats (n ¼ 20; 1 was used twice) and male dogs (n ¼ 4; 9
runs were done) following intravenous (IV) administration
Xanthine Oxidase
of allantoin. The renal clearance of endogenous allantoin
in rats was 33.7 mL/h per 100 g (range, 25.8-41.7 mL/h per
100 g). The mean plasma allantoin concentration was 1.76
mg% (range, 1.20-2.23 mg%) during clearance. The renal
clearance of endogenous allantoin in dogs was 85.5 mL/
min/m2 (range, 1.46-7.55 mL/g per 100 g). The mean
Xanthine
plasma allantoin concentration was 0.66 mg% (range,
0.40-1.03 mg%).
Wallenburg and van Kreel69 tested the transference of
allantoin from the fetus to the dam in a pregnant rhesus mon-
Xanthine Oxidase
key (Macaca mulatta). The dam was anesthetized. After fast-
ing, a lower midline laparotomy was performed and the uterus
exposed and delivered from the abdominal cavity. A fetal leg
was delivered through a small incision and dissected for the
application of catheters to the fetal femoral artery and vein.
The fetal groin was sutured and returned to the amniotic cav-
Uric Acid* ity after draining the urinary bladder. The uterus was returned
to the abdominal cavity and the incision partially closed. The
maternal aorta, through a femoral artery, and the vena cava,
through a saphenous vein, were catheterized. [14C]Allantoin
was infused into the fetal femoral artery (10 mL/g of body
Urate Oxidase weight for 30 minutes and then 3 mL/h). Samples were col-
lected from the fetal femoral artery (0.4 mL) and from the
maternal aorta (1.0 mL) at 15-minute intervals and stored in
heparinized vials. After centrifugation, fetal red cells were
suspended in an equal volume of dilute heparin-normal saline
and reinjected into the fetal circulation. The fetus was deliv-
ered by Cesarean section and killed, and the urinary bladder
was emptied.
ALLANTOIN
(urinary excretion) The total fetal clearance of allantoin was 3.8 mL/min/kg;
renal clearance of allantoin was 0.09 mL/min/kg and of creati-
nine 0.29 mL/min/kg. The total clearance of allantoin was sim-
ilar to that of uric acid clearance. Unlabeled uric acid in the
Figure 2. Mechanism of purine catabolism to allantoin in most fetal plasma was 60 mmol/L at the beginning of the experiment
animals. *Normal end point in higher apes and humans.60 and rose 2- to 3-fold; steady concentration levels were never
observed. Maternal renal uric acid and creatinine clearances
were 3.2 + 0.6 and 3.0 + 0.5 mL/min/kg, respectively, and
maternal plasma unlabeled uric acid remained stable at a low
alcohol and cholesterol). Two applications of each vehicle level (1.54 + 0.30 mmol/L). Less than 5% of the available uric
were made, 1 removed after 3 hours and the other after 6 hours. acid metabolized to allantoin. The authors stated that it is
The remaining allantoin in the removed portion was measured unlikely that fetal uric acid contributes to the maternal uric acid
and subtracted from the original amount to determine the load in pre-eclamptic pregnancies.69

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Animal Toxicology with the hydrogen peroxide. When allantoin was added 1.5
hours before and after hydrogen peroxide, the mutations
No short-term or subchronic toxicity data were available. Chronic
decreased (P < .001 and .01, respectively).
toxicity data are presented in the Carcinogenicity section.
Akema Fine Chemicals11 reported that allantoin was not
mutagenic in an Ames test.
Oral Acute Toxicity
In a toxicology assessment,70 an acute oral toxicity test on Dermal Irritation
Wistar rats (n ¼ 10, 5 males and 5 females) was performed. The
Akema Fine Chemicals11 reported that allantoin (0.5% in
rats were orally administered a single dose of allantoin (5000
water) was not a primary skin irritant when applied to the intact
mg/kg) and observed for 14 days. No clinical signs were
and abraded skin of rabbits (details not provided).
observed during the observation period. No mortality occurred.
Shiseido Research Center74 applied allantoin (10% in water)
No abnormalities were noted at necropsy.
to the clipped and shaved flanks of guinea pigs (n ¼ 3) daily for
Akema Fine Chemicals11 reported the oral median lethal
3 days. The skin was evaluated 24 hours after each application.
dose (LD50) of allantoin in rats to be more than 5000 mg/kg and
The cumulative irritation score index was 0.2. The authors con-
considered allantoin to be slightly toxic.
cluded that allantoin is classified as a ‘‘none to weak irritant’’
and is safe for use as a cosmetic ingredient.
Acute Dermal Toxicity The authors treated the germinated roots of Allium cepa L.
Akema Fine Chemicals11 reported the LD50 of allantoin on the (onion) with hydrogen peroxide after treating them with allan-
intact and abraded skin of rabbits (n ¼ 10) to be 5000 mg/kg or toin (10–6 to 10–5 M). After 18 hours, the seedlings were fixed
higher. and examined for aberrant cells, and chromosomal aberrations
were quantified and compared with untreated seedlings. The
treated seedlings decreased the level of Fe2þ-induced chromo-
Ocular Irritation somal aberrants (P < .001). The level of chromosomal aberra-
Centre International de Toxicoligie71 performed a primary ocu- tions decreased after 42 hours (P < .01). The authors stated that
lar irritancy test of allantoin (100 mg) on 1 eye of New Zealand allantoin is neither cytotoxic nor cytostatic while exerting anti-
rabbits (n ¼ 6). The other eye served as the control. The eyes mutagenic effects at concentrations corresponding to physiolo-
were examined 1, 24, 72, and 96 hours after instillation. No gical values (ie, blood plasma 6.5  10–6).75
ocular reactions were observed. The authors concluded that
allantoin was not irritating to eyes. Akema Fine Chemicals11
Carcinogenicity
reported that no eye irritation was observed in a Draize test
on rabbits without washout (details not provided). Lijinsky76 fed F344 rats (males and females) rat chow with
and without 0.2% allantoin with or without 0.2% sodium nitrite
ad libitum for 106 weeks (n ¼ 20). The rats were necropsied
Phototoxicity
and all gross lesions and major organs and tissues were exam-
No phototoxicity or photosensitization data were available. ined histologically. Controls (n ¼ 24) were fed untreated chow
and tap water.
The approximate total doses of allantoin were calculated to be
Reproductive and Developmental Toxicity 42 g per male rat and 28 g per female rat. Most of the rats were
No reproductive or developmental toxicity data were available. alive at the end of the 2-year treatment; there was no difference in
the life spans of the rats in any group. The incidence of nonneo-
plastic lesions of the organs did not differ between treated and
Genotoxicity control rats. There was no difference in the incidence of tumors
Allantoin was not mutagenic to Salmonella typhimurium between groups. There was an increase in papillomas of the for-
strains TA1535, TA1538, TA98, and TA100, with or without estomach in male rats fed allantoin plus nitrite compared with
S9 up to 1000 mg.72 controls (P < .047). The incidence of pituitary tumors was lower
Gus’kov et al73 measured the frequency of rifampicin- in females, but not males, fed allantoin without nitrite than in the
resistant mutants in the Escherichia coli SOS-lux test to mea- untreated or nitrite-treated controls (P not provided).76
sure the mutagenicity of allantoin. Allantoin (1 mL) was added
to the test plates 1.5 hours before hydrogen peroxide (10–7 and Clinical Assessment of Safety
10–6 M) was added to plates containing E coli (PT-1 strain
transformed with plasmid pPls-1 carrying the Lux operon con-
Absorption, Distribution, Metabolism, and Excretion
trolled by an SOS-responder). Water was the control. Allantoin Young et al67 administered allantoin to male subjects orally,
decreased the mutant frequency at both hydrogen peroxide con- intravenously, and subcutaneously. Almost all of the allantoin
centrations (P < .05). In further testing, allantoin did not affect administered by IV and subcutaneous injection was recovered
the induction of the SOS response when added simultaneously by urinary excretion within 2 days; less was recovered

91
92S International Journal of Toxicology 29(Supplement 2)

following oral administration. The authors suggest that allan- detected with a normalized score of 0.00 out of 630. In a second
toin goes through decomposition in the intestine prior to test of the same product, with volunteers with self-perceived
absorption. sensitive skin (n ¼ 35), no skin irritation was detected with a
Friedman et al77 measured the clearance of orally adminis- normalized score of 8.9 out of 630.
tered allantoin in 5 men and 1 woman. The volunteers were In a repeated-insult patch test of baby talc containing allan-
administered 10 g of allantoin. The average plasma clearance toin (0.5%), the product was applied to volunteers with normal
of allantoin at 3.0, 3.5, and 4.0 hours after ingestion was 5.9, skin (n ¼ 214). There were no reactions to 212 volunteers dur-
5.9, and 6.2 mg per 100 mL, respectively, and the average renal ing induction (2 volunteers with a minimal or doubtful
clearance of allantoin was 123, 123, and 123 mL/min, respec- response). There were no reactions during the challenge phase.
tively. No adverse effects were observed as a result of allantoin This study was repeated with volunteers with normal skin (n
ingestion.77 ¼ 213). During the induction phase, there were no reactions for
Freidman et al78 repeated the above experiment on healthy 211 volunteers (2 volunteers with minimal or doubtful
volunteers (n ¼ 9; 1 female, 8 males) and patients with hyper- responses). There were no reactions during the challenge phase.
tension (n ¼ 8; 3 female, 5 male), coarctation (n ¼ 1 male), or This study was repeated with volunteers with normal skin (n ¼
nephritis (n ¼ 2; 1 female, 1 male). The procedure was repeated 206). During the induction phase, there were no reactions in all
with inulin (10 g in saline intravenously). The authors con- volunteers. There were no reactions during the challenge phase.82
cluded that allantoin clearance was a measure of glomerular fil-
tration rate; allantoin is absorbed by the gastrointestinal tract at
a stable rate. There were no signs of toxicity following inges- Other Dermal Tests
tion of allantoin.78 Mecca83 stated that when allantoin is used in shampoos, not all
of the allantoin is washed away, but rather some is left on the
scalp and in the hair.
Dermal Irritation and Sensitization Henning84 tested the effects of allantoin on stratum corneum
Mecca79 reported a personal communication from R.W. Gould renewal by applying a cream containing allantoin (0.5%) twice
that allantoin was not a primary skin sensitizer in a Schwartz a day to untreated skin on forearms (number of subjects not
patch test on 200 people. Allantoin was nontoxic, nonirritating, stated). Another area was treated with a placebo and another
and nonallergenic. Allantoin was not a primary skin irritant or was untreated. A suspension of dansyl chloride in petrolatum
primary sensitizer in a repeated-insult test of 12 people. was applied to the forearm skin, and the level of fluorescence
Akema Fine Chemicals11 reported no irritation and no sen- was assessed every second day under UV light. The time taken
sitization using allantoin on healthy volunteers (n ¼ 200; for dansyl chloride to disappear provided a measure of stratum
details not provided). corneum renewal time. Untreated skin had a renewal time of
Tronnier80 performed a skin irritation test on volunteers (n *23 days, placebo *21 days, and allantoin-treated skin
¼ 50; 31 females, 19 males; 18-72 years old). Eleven of the *19 days. No adverse effects were reported.
subjects had allergies and 7 had sensitive skin. A plaster of In a second experiment, irritation on the volar skin of fore-
allantoin (2-5 mg/cm2) was applied to the backs of the volun- arms (number of subjects not stated) was induced by sodium
teers. The test plaster was removed after 24 hours. The test area dodecyl sulfate–tape stripping and UV radiation. Redness
was observed at removal of the plaster and after 72 hours. was measured with a chromatometer before irritation and after
There were no signs of irritation. 2 hours and 1, 3, and 5 days. The skin was untreated, treated
Consumer Product Testing Co81 performed a repeated-insult with a placebo (*2 mg/cm2), or treated with the cream con-
patch test of a product containing allantoin (0.095%) on human taining allantoin (0.5%; *2 mg/cm2). Before irritation, redness
subjects (n ¼ 105; age 16-78 years). The product (*0.2 mL) was measured at *8.4. Allantoin-treated skin had lower red-
was applied to the upper back under an absorbent pad 3 times ness scores at all observation times (no statistics were
a week for 9 applications. The pad was left in place for 24 reported). No adverse effects were reported.
hours. After *2 weeks’ rest, a challenge pad was applied to In a third experiment, transepidermal water loss (TEWL)
a naive site and read 24 and 72 hours after application. There was measured before treatment with sodium dodecyl sulfate,
were scattered, transient, barely perceptible to moderate after treatment, and then after treatment as in the above experi-
responses with occasional dryness and/or edema noted ments (number of subjects not stated). TEWL was closer to
throughout the test period. No evidence of induced allergic normalized in the allantoin-containing cream-treated group
contact sensitization was observed. The authors concluded that on day 5 than in the other 2 groups.84
the results did not indicate a clinically significant potential for Vinson and Proch85 tested the use of an allantoin-based pro-
dermal irritation or allergic contact sensitization. tectant as a moisture barrier in 12 subjects. The product con-
The Personal Care Products Council82 submitted summaries taining allantoin (concentration not provided) was applied to
of tests of products containing allantoin. In a 21-day cumula- 1-inch-square areas of the forearm and then covered with a ban-
tive irritation study, baby talc containing allantoin (0.5%) was dage treated with a saline solution that simulated the density
repeatedly applied, under occlusion, to volunteers with and ionic strength of urine and contained a dye solution. No
self-perceived sensitive skin (n ¼ 33). No skin irritation was reactions were reported from the allantoin barrier product at

92
Becker et al 93S

4 or 8 hours. The allantoin barrier product began to lose its

effectiveness in both groups after 1 hour.

Skin Disease Treatment

Topical agents containing allantoin and other ingredients were
tested for effectiveness in treatment of diaper rash in infants.
No adverse effects were reported in the studies.86,87 Studies
of topical agents containing allantoin and refined coal tar
extract in treating psoriasis or other skin conditions reported
no adverse effects.88-92
In another study, 22 patients were treated with an ointment
containing allantoin, coal tar extract, and other ingredients.93
One adverse side effect (acute dermatitis) was reported.
Almeyda and Wood94 compared an allantoin (2%)–coal tar
(5%) cream-based treatment to a fluorinated steroid prepara-
tion for the treatment of psoriasis on 33 patients (17 male, 16
female; age 16-74 years). The former was applied to the left Figure 3. The structure of pectin. Galacturonic acid is the major
component of all three types of polylsaccharide: A) homogalactur-
arm and the latter to the right arm 2 or 3 times a day after an
onan, B) rhamnogalacturonan I, C) rhamnogalactrunan.
initial evaluation. The progress was evaluated after 2 and 4
weeks. Two patients dropped out because of deteriorating con-
Summary
ditions. The allantoin–coal tar preparation performed better in
8 cases, worse in 13 cases, and equally well in 7 cases, and it This safety assessment includes the cosmetic ingredient allan-
failed equally in 7 cases. Six patients dropped out after the 2- toin and its related complexes: allantoin ascorbate, allantoin
week evaluation, 1 because of worsening of the condition with biotin, allantoin galacturonic acid, allantoin glycyrrhetinic
the allantoin–coal tar preparation that included a secondary acid, allantoin panthenol, and allantoin polygalacturonic acid.
infection. No other adverse effects were reported. The safety of ascorbic acid, biotin, glycyrrhetinic acid, and
panthenol has already been assessed by the CIR Expert Panel,
and these agents were found to be safe. Galacturonic acid and
polygalacturonic acid have not been reviewed by the CIR
Wound Treatment Expert Panel. Galacturonic acid is a sugar that is a component
Creams, gels, and ointments containing allantoin (alone or in of pectin.
combination with other ingredients) have been tested for Polygalacturonic acid is the polysaccharide of the acid. Pectin
wound healing and treatment of other skin conditions.56,94-97 was deemed GRAS as a direct human food additive by FDA.
No adverse effects attributed to allantoin were reported. Allantoin is a heterocyclic organic compound that may be
prepared by several methods, including uric acid oxidation in
the presence of permanganate. The other ingredients in this
Galacturonic acid and polygalacturonic acid. No relevant safety assessment are organic salts of this compound, except for allan-
test data were found on galacturonic acid and polygalacturo- toin panthenol, which is an alcohol/heterocyclic compound
nic acid. Galacturonic acid, in the form of polygalacturonic complex. Multiple analytical methods for allantoin are
acid, is a major component of the polysaccharides that form reported, including HPLC. Impurities include sulphated ash,
pectin. Pectin is a group of polysaccharides rich in galacturo- sulphate, chloride, lead, arsenic, urea, and glycoluril.
nic acid. Galacturonic acid is present in the following major All of the ingredients in this review act as skin-conditioning
structural features that form the backbone of polysaccharide agents - miscellaneous.
domains that are thought to be found in all pectin species: Allantoin was reported to be used in 1376 cosmetic products
homogalacturonan, rhamnogalacturonan-I, and rhamnogalac- at concentrations ranging from 0.0001% to 2%. Allantoin
turonan-II.98,99 ascorbate was reported to be used at concentrations of
Homogalacturonan is a homopolymer of (1-4)-a-D- 0.001% and 0.05%. Allantoin glycyrrhetinic acid was
galacturonic acid residues that may be methylesterfied and reported to be used in 6 cosmetic products, allantoin panthenol
acetylated. Rhamnogalacturonan-I has a repeating backbone in 2 cosmetic products, and allantoin polygalacturonic acid in
of (1-2)-a-L-rhamnose-(1-4)-a-D-galacturonic acid. Rhamno- 2 cosmetic products. There were no reported uses for allantoin
galacturonan-II has a homogalacturonan backbone with oligo- biotin or allantoin galacturonic acid. Allantoin, allantoin
saccharide side chains, as in Figure 3.98,99 The FDA has glycyrrhetinic acid, allantoin panthenol, and allantoin polyga-
deemed pectin as GRAS when used as a direct human food lacturonic acid were reportedly used in hair sprays. Noncos-
additive.47 metic uses included wound treatment and skin protectant.

93
94S International Journal of Toxicology 29(Supplement 2)

Allantoin is found in plants and foods. Mammals process Discussion

purines to allantoin with the exception of higher apes and
The CIR Expert Panel noted that none of the sensitization and
humans because of their lack of urate oxidase. Only small
irritation safety test studies were conducted at the 2% level,
amounts of allantoin are produced by oxidation of uric acid
which is reported to be used in cosmetics. However, the thera-
by cytochrome c and other oxidation pathways.
peutic use studies were conducted at 2% to 4% on damaged
There was 98% recovery of allantoin in urine in dogs 5 hours
skin with no adverse effects. These clinical data were consid-
after intravenous administration. When allantoin was administered
ered to support the safety of allantoin in cosmetics.
orally, elimination was complete at 4 hours. Recovery averaged
The panel noted that allantoin is a natural metabolic product
66% when allantoin was administered in feed. No urinary allantoin
for which no reproductive/developmental toxicity has been
was recovered from rabbits with allantoin in the diet. In sheep, most
suggested.
of the intravenously administered allantoin was excreted in the
The ingredients in the complexes were found to be safe in
urine; degradation in the gut occurred post ruminally.
previous safety assessments. Pectin is a GRAS substance that
Acute oral toxicity of allantoin was greater than 5000 mg/kg
is mostly made up of galacturonic and polygalacturonic acid.
in rats. Acute dermal toxicity of allantoin was equal to 5000
These allantoin complexes, as well as allantoin polygalacturo-
mg/kg in rabbits with intact and abraded skin.
nic acid and allantoin galacturonic acid, were not expected to
Allantoin was nonirritating when instilled into the eyes of
be toxic.
rabbits. Allantoin at 0.5% is not a dermal irritant to the intact
The potential adverse effects of inhaled aerosols depend on
or abraded skin of rabbits.
the specific chemical species, the concentration and the dura-
Allantoin was not mutagenic in an Ames test.
tion of the exposure, and their site of deposition within the
When fed to rats at 28 g per female and 42 g per male over
respiratory system. The reported mean diameter of particles
2 years, allantoin did not increase the instances of neoplastic
in hair sprays is 38 mm, with other reported diameters of 60
lesions and tumors compared with controls. Allantoin with
to 80 mm. Because the aerodynamic diameters of respirable
nitrite increased the incidence of papillomas of the foresto-
particles are less than 10 mm, most aerosol particles found in
mach in males and reduced the incidence of pituitary tumors
hair sprays are not respirable. In the absence of inhalation toxi-
in females without nitrite. There was no difference in life
city data, the panel determined that allantoin and its related
spans between rats fed allantoin and controls.
complexes can be used safely in hair sprays, because the ingre-
In a fasting blood clinical test, serum allantoin levels were
dient particle size is not respirable.
10.8 + 1.7 mmol/L for women and 13.4 + 1.6 mmol/L for men.
The CIR Expert Panel recognizes that there are data gaps
Individual urinary recovery of orally administered allantoin to
regarding use and concentration of these ingredients. However,
human males was 18.6% in 24 hours and 33.8% in 72 hours.
the overall information available on the types of products in
Intravenously administered allantoin recovery in the urine was
which these ingredients are used and at what concentrations
98% in 72 hours and 94.5% and 88.8% in 12 hours. Subcuta-
indicates a pattern of use, which was considered by the Expert
neously administered allantoin recovery in the urine was
Panel in assessing safety.
81.2% in 6 hours and 73.2% in 24 hours.
Allantoin (1%) penetration of human skin after 3- and 6-hour
exposures was 5.00% + 1.25% and 6.9% + 1.4% in a hydro- Conclusion
philic gel, 13.0% + 1.8% and 15.4% + 2.7% for an oil/water
cream, and 12.5% + 2.1% and 20.0% + 2.3% for a water/oil The CIR Expert Panel concluded that allantoin and its related
ointment, respectively. complexes, allantoin ascorbate, allantoin biotin, allantoin
Allantoin was found to be clinically nonirritating and non- galacturonic acid, allantoin glycyrrhetinic acid, allantoin
sensitizing in multiple tests at various concentrations in various panthenol, and allantoin polygalacturonic acid, are safe as cos-
vehicles up to 0.5%. metic ingredients in the practices of use and concentrations as
Allantoin-containing medications were tested for effective- described in this safety assessment. Were ingredients in this
ness and were successful in treating and preventing diaper rash group not in current use to be used in the future, the expectation
in infants. No adverse effects were reported for the babies or is that they would be used in product categories and at concen-
the persons applying the medication. Medications containing trations comparable to others in the group.
allantoin (2%)–coal tar successfully treated patients with psor-
iasis with no adverse effects. Allantoin-containing treatments, Authors’ Note
up to 4%, successfully treated psoriasis patients; 1 of 22 patients Unpublished sources cited in this report are available from the Direc-
using an allantoin–coal tar lotion developed acute dermatitis tor, Cosmetic Ingredient Review, 1101 17th Street, Suite 412,
after 1 week. Application of a coal tar lotion with allantoin Washington, DC 20036, USA.
(2%) 1 to 4 times daily for 6 months resulted in no adverse
effects. A treatment containing allantoin (0.35%) in 40 patients Declaration of Conflicting Interests
with seborrheic dermatitis reported 1 adverse event. There No potential conflict of interest relevant to this article was reported.
were no adverse effects in the treatment of skin conditions with F. Alan Andersen, PhD, and Lillian C. Becker are employed by the
allantoin up to 2%. Cosmetic Ingredient Review.

94
Becker et al 95S

Funding 19. Active Ingredients Ltd. Glyceratoin. 2004. http://www.activein-

The articles in this supplement were sponsored by the Cosmetic Ingre- gredient.plus.com/glyceratoin.pdf.
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