Final Report on the Safety Assessment of
Trihydroxystearin I

Trihydroxystearin is the triester of glycerin and hydroxystearicacid. It is used as a skin conditioning agent, a solvent, and as a viscosity increasing agent in cosmetic formulations at concentrations
up to 5%. In acute oral toxicity studies in rats, no deaths were reported at a dose of 5 g/kg. Trihydroxystearin was reported to be amild ocular irritant, but not a skin irritant in animal tests. Ames test
results indicate that the ingredient is not mutagenic. Clinical testing
found no skin irritation. Although the data on Trihydroxystearin
are limited, the Cosmetic Ingredient Review (CIR) Expert Panel
had previously conducted a safety assessment of Glyderyl Stearateand Hydroxystearic Acid. These data indicate no mutagenic, carcinogenic, or teratogenic effects in animals, and no irritation or
sensitization in clinical tests. The data on these two ingredients are
considered relevant to the assessment of Trihydroxystearin becauseof the chemical similarity of the ingredients. The data on Glyceryl
Stearate and Hydroxystearic Acid are also consistent with the limited data that are available on 1~ihydroxystearin itself. Therelbre,
based on the available animal and clinical data in this report, which
includes study summaries from earlier safety assessments of Hydroxystearic Acid and Glyceryl Stearate and Glyceryl Stearate/SE,
the Expert Panel concludes that Trihydroxystearin is safe as usedin cosmetic formulations.

INTRODUCTION
Trihydroxystearin is the triester of glycerin and hydroxystearic acid that is used as a skin-conditioning agent--occ~,usiYe,a solvent, and a viscosity increasing agent--nonaqueous in cosmetics. Although safety test data were not found in the publishedliterature for this ingredient, unpublisfied data were provided andare described in this report. In addition, the Cosmetic Ingredient
Review (CIR) Expert Panel considered that data on Hydroxystearic Acid and Glyceryl Stearate are relevant to the safetyassessment of Trihydroxystearin. Hydroxystearic Acid is oneof the chemical building blocks of Trihydroxystearin. Glyceryl
Stearate is the esterification product of glycerine and stearic acid,making it closely related to Trihydroxystearin. Both Hydroxystearic Acid (Andersen 1999) and Glyceryl Stearate (Elder 1982)
were previously reviewed by the Expert Panel and found to be

Received 3 February 2000; accepted 3 May 2000.
Reviewed by the Cosmetic Ingredient Review Expert Panel. Wilbur
Johnson, Senior Scientific Analyst, prepared this report. Address correspondence to him at Cosmetic Ingredient Review, 1101 17th Street,
NW, Suite 310, Washington, DC 20036, USA.

International Journal of Toxicology. 19(Suppl. I):89-94, 2000
Copyright © 2009 CosmeticIngredientReview
1071-7544/00 $12.00 + .00

safe as used in cosmetic products. A summary of the findings ofeach of those reports is provided in the summary section. The
Panel relied upon those findings in this safety assessment.

CHEMISTRY
C h e m i c a l A n d Physical Properties

Trihydroxystearin (CAS No. 139-44-6) is the triester of glycerin and hydroxystearic acid that conforms generally to the formula shown in Figure 1 (Wenninger, Canterbery, and McEwen
2000).
Other names for this chemical are as follows: Glyceryl
Tri(12-Hydroxysteamte; 12-Hydroxyoctadecanoic Acid, 1,2,3Propanetriyl Ester; Octadecanoic Acid, 12-Hydroxy-, 1,2,3-Propanetriyt Ester; and 1,2,3-Propanetriol Tri(12-Hydroxystearate)(Wenninger, Canterbery, and McEwen 2000); and Glycerol,
Tris(12-Hydroxyoctadecanoate); Octadecanoic Acid, 12Hydroxy-, triester with glycerol; 12-Hydroxystearic Acid Triglyceride; Glycerol 12-Hydroxystearate; Glycerol Tris(12Hydroxystearate); Glyceryl Tris(12-Hydroxystearate); andTri-12-Hydroxystearin (Scientific & Technical Information
Network International 1996a).
Trihydroxystearin has a formula weight of 939.49 and a melting point of 86°C (Scientific & Technical Information Network
International 1996b). Properties of two commercial grades of
Trihydroxystearin are summarized in Tables I and 2, res,~ectively. The commercial grade noted in Table 2 (Thixcin w E)
is another grade of Thixcin ® R that has a larger particle size
(Rheox, Inc. 1996a).

Methods Of Production

One melhod of production of Trihydroxystearin involved thehydrogenation of castor oil, in the presence of the reagent nickel,
at a temperature of 200°C. Another method of production is the
reduction of triricinolein (Scientific & Technical Information
Network International 1996b).

Reactivity

Regarding the reactivity of Trihydroxystearin, sources of ignition and strong oxidizers should be avoided (Rheox, Inc. 1995b;
1996b).

89

90

COSMETIC INGREDIENT REVIEW

0
H

OH
I

CH20-- C(CH2)loCH(CH2)sCHa
0
II

OH
I

CHO--C(CH2)loCH(CH2)sCHa
0
II

OH
I

CH20-- C(CH2)loCH(CH2)sCH3
FIGURE 1
Chemical formula for Trihydroxystearin (Wenninger,
Canterbery, and McEwen 2000).

USE
Purpose in Cosmetics
Trihydroxystearin has the following functions in cosmetics: Skin-conditioning agent--occlusive; solvent; and viscosity increasing agent--nonaqueous (Wenninger, Canterbery, andMcEwen 2000)

Scope and Extent of Use in Cosmetics
United States
The product formulation data submitted to the Food andDrug Administration (FDA) in 1997 indicated that Trihydroxystearin was used in as many as 4 [ cosmetic product lbrmu[ations(Table 3) (FDA 1997).
Concentration of use values are no longer reported to FDA
by the cosmetics industry (FDA 1992). However, 1984 productformulation data submitted to the FDA indicated that the highest reported use concentration range for Trihydroxystearin was

TABLE 1
Properties ofTrihydroxystearin--THIXCIN ® R(Rheox, Inc. 1995a)
Property

Description

Composition
An organic derivative of castor oil
Form and color
Finely divided white powder
Specific gravity,
1.O23
250°C/250°C
Density, 250~C, Ib/U.S. gal
8.51
Bulking value, U.S. gal/lb
0.1175
Melting point, °C
86
Fineness, through No. 200
99.8 minsieve, %Ash content, %NoneProcessing temperature, °F
95-130 (35°-55"C)
Recommended solvent
Aliphatic only

TABLE 2
Properties of Trihydroxystearin--THIXCIN ® E(Rheox, Inc. 1994)
Property

Description

Color
Form
Melting point, °C
Density (Ibs./U.S. gallon)
Passing #200 screen, %Ash content
Specific Gravity at 25°C

White
Finely divided powder
85
8.51
100
None
1.023

5% to 10% (FDA 1984). Current concentration of use data indicate that Trihydroxystearin is typically used at concentrationsof 0.5% to 5.0% (Rheox, Inc. 1996a).
Cosmetic products containing Trihydroxystearin are applied
to the skin, hair, and most parts of the body, and could comein contact with the ocular and nasal mucosae. These products
could he used on a daily basis, and have the potential for being
applied frequently over a period of several years.

TABLE 3
Product formulation data on Trihydroxystearin (FDA 1997)

Product category
Eye shadow
Eye makeup remover
MascaraOther eye makeup
preparations
Blushers (all types)
Face powders
Foundations
Lipstick
Makeup bases
Body and hand skincare preparations(excluding shaving
preparations)
Moisturizing skin care
preparations
Paste masks (mud packs)
Other skin care
preparations
Suntan gels, creams,
and liquids
Other suntan preparations
1997 Totals

Total no. of
formulations in
category

Total no.
containing
ingredient

501
80
158
I 16

1
I
5
3

229
245
283
758
125
776

1
4
9
6
I
I

743

2

247
683

2
3

134

I

43

1
41

TRIHYDROXYSTEARIN

International
Trihydroxystearin is listed in the Japanese Comprehensive
Licensing Standards of Cosmetics by Category. (CLS) (Rempeand Santucci 1997). This ingredient, which conforms to thespecifications of the Japanese Cosmetic Ingredients Codex, hasprecedent for use without restriction in most CLS categories. It
is not used in the following four CLS categories: eyeliner, lip,
oral, and bath preparations.
Trihydroxystearin also is not included among the substances
listed as prohibited from use in cosmetic products marketed in
the European Union (European Economic Community 1995).

91

substance (0.1 ml or 0.1 g) was instilled into the conjunctival sac of one eye of each animal. Untreated eyes served ascontrols. Reactions were scored at 24, 48, and 72 hours and at
7 days postinstillation according to the Draize scale: 0 to 110.
Ocular irritation (score = 1) was observed in five rabbits, andall reactions cleared during the 7-day observation period. It was
concluded that Trihydroxystearin (Thixcin ® R) was a mild, transient ocular irritant (Food and Drug Research Laboratories, Inc.
1975c). Identical results were reported in another study in which
Trihydroxystearin (Thixcin ® E) was instilled into the conjunctival sac of the eyes of six albino rabbits according to the same
experimental procedure (Food and Drug Research Laboratories,
Inc. 1975d).

Noncosmetlc Use
Trihydroxystearin has been used as a thickening agent for
Skin Irritation
peanut butter (Elliger, Guadagni, and Dunlap 1972). FDA has
The skin irritation potential of Trihydroxystearin (Thixcin ®
listed the following indirect food additive uses in the CodeR)
was evaluated using six adult albino rabbits. The test subof Federal Regulations (CFR): components of adhesives (21stance(0.5 ml or0.5 g) was applied to shaved and abraded sites,
CFR 175.105), components of resinous and polymeric coatrespectively,on the back of each animal. An occlusive patch
ings (21 CFR 175.300), components of paper and paperboard
wasappliedtoeach test site for 24 hours; reactions were scoredin contact with aqueous and fatty foods (21 CFR 176.170),
at
the
time
of
patch
removal. Erythema was observed at intact
components of paper and paperboard in contact with dry foodandabradedsites
onone animal, and only at the abraded site
(21 CFR 176.180), defoaming agents used in the manufactureinanother;edema
was
not observed. It was concluded that Triof paper and paperboard (21 CFR 176.210), cellophane (21CFR 177.1200), closures with sealing gaskets for food contain- hydroxystearin (Thixcin ® R) was not irritating to the skin ofers (21 CFR 177.1210), polyester resins cross-linked (21 CFR rabbits (primary irritation index = 0.17) (Food and Drug Re. search Laboratories, Inc. 1975e). Identical results were reported
177.2420), and textiles and textile fibers (21 CFR 177.2800).
Trihydroxystearin is among the inert ingredients that are ex- in another study in which Trihydroxystearin (Thixcin ® E) was
empt from the requirement of a tolerance under the Federal Food, applied to six albino rabbits according to the same test procedure
Drag, and Cosmetic Act when used in pesticide formulations that (Food and Drug Laboratories, Inc. 1975f).
are applied to crops (FDA 1975).

TOXICOLOGY

Acute Oral Toxicity
The acute oral toxicity of Trihydroxystearin (Thixcin ® R)
was evaluated using 10 Wistar-derived, young albino rats
(5 males, 5 females; weights = 200-300 g). The animals were
fasted prior to administration of a single oral dose (intragastricintubation) of 5 g/kg. The test substance was administered as a
25% corn oil solution. Dosing was followed by a 14-day nontreatment period. The LDso was not achieved at the administereddose of 5 g/kg; no deaths were reported (Food and Drug Research Laboratories, Inc. 1975a). Identical results were reported
in another study in which Trihydroxyslearin (Thixcin ® E, another grade of Thixcin® R) was administered to l0 albino rats
(same weights) according to the same procedure (Food and Drug
Research Laboratories, Inc. 1975b).

Ocular Irritation
The ocular irritation potential ofTrihydroxystearin (Thixcin ®
R) was evaluated using six young adult, albino rabbits according to the procedure described in 16 CFR 1500.42. The test

GFNOTOXICITY
The mutagenicity of Trihydroxystearin (Thixcin ® R) was
evaluated in the Ames test (Ames, McCann, and Yamasaki 1975)
using the following strains of Salmonella typhimurium: TA 1535,
TA 1537, TA 1538, TA 98, and TA 100. Two independent mutation tests were conducted. The test substance (suspension inethanol) was tested at concentrations of 3, l 0, 33, 100, 333, and1000 ~g per plate with and without metabolic activation. Control
cultures were treated with ethanol and the following substances
served as positive controls: 2-Aminoanthmcene, sodium azide,
9-aminoacridine, and 2-nitrofluorene. Except for sodium azide(dissolved in sterile, ultrapure water), all positive controls weredissolved in DMSO. 2-Aminoanthracene served as the positive
control for metabolically activated cultures, and the remaining chemicals served as positive controls for cultures without
metabolic activation. The results noted in the positive-control
cultures were within the normal ranges expected for each bacterial strain and activation condition. Vehicle-control values weregenerally within the normal ranges experienced at the testing
facility and reported in the literature for the bacterial strainstested. Thixcin® R was not toxic or mutagenic, with or without metabolic activation, to any of the bacterial strains whentested (in ethanol) to the limit of its solubility over the range

92

COSMETICINGREDIENTREVIEWof concentrations tested. Precipitation of the test substance wasnoted at a concentration of 1000/zg/plate (lnveresk ResearchInternational Limited 1995).

CLINICAL ASSESSMENTOF SAFETY

Skin Irritation
The skin irritation potential of Trihydroxystearin (Thixcin ®
R) was evaluated using 106 subjects (17 males, 89 females;
ages = 1 I---65). Three subjects did not complete the study (reasons not stated). An occlusive patch containing a small amountof the test substance (volume not stated) was applied either tothe inner aspect of the upper ann or to the back of each subject. Patches (secured with occlusive tape) remained in place for48 hours. Reactions were scored 48 and 72 hours after patch
removal according to the Schwartz-Peck scale: 0 (no erythema)
to 4+ (erythema and edema with vesiculation and ulceration).
Skin irritation was not observed in any of the 103 subjects whocompleted the study. It was concluded that Trihydroxystearin(Thixcin ® R) is not a primary irritant as long as the conditionsof contact do not exceed those indicated in this study (Foodand Drug Research Laboratories, Inc. 1975g). The results wereidentical for the same 103 subjects patch-tested with Trihydroxystea r in (Thixcin ® E) according to the same test procedure (Foodand Drug Research Laboratories, Inc. 1975 h).

SUMMARY
Hydroxystearic Acid Report (Andersen 1999)
Hydroxystearic Acid is a fatty acid that is used as a surfactantcleansing agent in cosmetic products. One method of production
involves the catalytic hydrogenation of castor oil.
Product formulation data submitted to FDA in 1996 indicatedthat Hydroxystearic Acid was used in two cosmetic products
categorized as body and hand skin care preparations (excluding
shaving preparations).
In male rats fed a diet containing hydrogenated castor oil,Hydroxystearic Acid was deposited in abdominal fat, as well asother body lipids, along with its metabolites (hydroxypalmitic
acid, hydroxymyristic acid, and hydroxylauric acid). Hydroxystearic Acid has also been detected in the feces of twelve subjects
who presumably ate a normal mixture of foods.
Reduced growth rate was noted in rats fed diets containing
8.7% and 17.3% 12-Hydroxystearic Acid, but not in rats fed
4.3% Hydroxystearic Acid, in a 90-day subchronic oral toxicity
study. The results of a second 90-day experiment (no reduction in growth rate) confirmed that the reduction in growth rate
previously observed was due to the lower caloric density of diets consisting of 8.7% and 17.3% Hydroxystearic Acid. In bothexperiments, the results of hematological and microscopic evaluations were unremarkable.
In an in vitro study, Hydroxystearic Acid interfered withoxidative phosphorylation in rat liver mitochondria. Oxidative
phosphorylation was uncoupled and mitochondria were damaged.

Hydroxystearic Acid was not mutagenic in strains TA 1535,
TA100, TA1537, TAI538, and TA98 ofS. typhimurium. However, Hydroxystearic Acid was classified as mutagenic in strain
Hs30 of Escherichia coll.
Hydroxystearic Acid was not mutagenic in the L5178Y
T K + / - mouse lymphoma assay, with or without metabolic activation; nor did it produce chromosome aberrations in Chinese
hamster ovary cells, with or without metabolic activation.
In an 18-month careinogenicity study (subcutaneous study),
Hydroxystearic Acid was classified as tentatively carcinogenic
in Swiss-Webster mice. Subcutaneous sarcomas were observedat the site of injection in 9 of the 28 mice (14 per dose group)that were alive at 6 months. All of the sarcomas were observedin the low-dose group (total dose of 4 mg delivered in a total of
8 ml tricaprylin for 80 weeks). The high dose group received a
total dose of 80 mg delivered in a total of 8 ml of tricaprylin.
In a second study in which nine A/He male mice received a
total intraperitoneal dose of 60 mg Hydroxystearic Acid over a
period of 4 weeks, the frequency of lung tumors was within the
spontaneous occurrence.
The dermal teratogenicity of two antiperspirant prototype formulations containing 7% Hydroxystearic Acid was evaluatedusing two groups of 30 Charles River CrhCD VAF/Plus female
rats. There were no test article-related or statistically significant
differences in the incidence of fetal malformations or fetal developmental variations between experimental and control groups.
Skin irritation reactions, however, were observed in greater than
50% of the dams in both experimental groups. No deaths werereported during the study.
Skin irritation reactions to each of three antiperspirant prototype formulations, each containing 7% Hydroxystearic Acid,
were observed in a human primary irritation patch test using
35 volunteers. Semiocclusive patches produced reactions in as
many as nine of the subjects, whereas occlusive patches produced reactions in as many as 17 individuals. Only two reactions were noted in the semiocclusive patch controls and only
one in the occlusive patch controls. Although the formulations
reportedly contained the same concentration of Hydroxystearic
Acid, there were small differences in the numbers of individuals
reacting to each.

Glyceryl Stearate Report (Elder 1982)
Glyceryl Stearate and Glyceryl Stearate/SE are the esterification products of glycerine and stearic acid. Glyceryl Stearate/SE
contains excess stearic acid reacted with potassium hydroxide to
produce a self-emulsifying product. Both Glyceryl Stearate andGlyceryl Stearate/SE are white to cream-colored waxlike solids.
Either ingredient may contain mono-, di-, and triglyceride impurities and fatty acid impurities.
Glyceryl Stearate and Glyceryl Stearate/SE are widely used incosmetic formulations as emollients, auxiliary emulsifiers, viscosifiers, stabilizers, bases, and surfactants. Glyceryl Stearate
is used in more than 1200 cosmetic formulations at concentrations of >0.1% to 50%; Glyceryl Stearate/SE is used in over 200
cosmetic products at concentrations of >0.1% to 50%.

TRIHYDROXYSTEARIN
Glyceryl Stearate is also widely used in foods as a surfactant,emulsifier, and thickener. Glyceryl Stearate is an antistalant anddough conditioner in breads and is also used in pharmaceuticalbases. Glyceryl Stearate has been granted regulatory status as a
Generally Recognized as Safe (GRAS) ingredient, an indirectfood additive, a direct food additive, and as an over-the-counter(OTC) substance.
In acute oral toxicity studies in rats, Glyceryl Stearate andGlyceryl Stearate/SE at concentrations up to 100% were mildly
toxic. In chronic studies, 15% to 25% Glyceryl Stearate in thediet of rats for three consecutive generations had no adverse
effects. Rats fed a diet containing 25% Glyceryl Stearate for
2 years developed renal calcifications.
Glyceryl Stearate and Glyceryl Stearate/SE at concentrationsof up to 100% were mildly irritating or nonirritating to the skinof rabbits. In subchronic and chronic dermal toxicity tests, 4%
to 5% Glyceryl Stearate was nontoxic to rabbits but did cause
moderate irritation (slight to moderate erythema, edema, atonia,
desquamation, and/or fissuring). In seven guinea pig sensitization studies, it was concluded that neither Glyceryl Stearate nor
Glyceryl Stearate/SE was capable of inducing sensitization.
In primary eye irritation studies, Glyceryl Stearate and Glyceryl Stearate/SE at concentrations up to 100% were mildly irritating or nonirritating when instilled into the conjunctival sac of
the eyes of rabbits.
Glyceryl Stearate, fed to mice in doses of 50 to 100 mg/day or
1.5% in the diet until they died did not induce significant brainor gastric tumor formation, respectively. Five percent Glyceryl
Stearate did not promote the carcinogenicity of DMBA in mouseskin.
Results of single and repeated insult patch tests (RIPTs)
used to evaluate human skin irritation and sensitization potentialof Glyceryl Stearate and Glyceryl Stearate/SE confirmed thatboth ingredients were nonsensitizing and nonirritating. Glyceryl Stearate was tested at concentrations up to 20% in RIPTs.
Products containing 2% Glyceryl Stearate were nonphototoxic
and nonphotoallergenic. Worker experience was that Glyceryl
Stearate and Glyceryl Stearate/SE are nonirritating to humanskin.

Trihydroxystearln
Trihydroxystearin is the triester of glycerin and hydroxystearic acid that is used as a skin-conditioning agent---occlusive,a solvent, and a viscosity increasing agent--nonaqueous in cosmetics. According to one source, the typical use concentration
range for this ingredient (marketed as Thixcin® R and Thixcin®
E grades that differ only in particle size) in cosmetics is 0.5% to
5.0%. Frequency of use data submitted to FDA in 1997 indicatedthat Trihydroxystearin has been used in as many as 41 cosmetic
products.
In acute oral toxicity studies in which Trihydroxystearin(Thixcin ® R and Thixcin® E grades) was tested using albino
rats, the LDs0 was not achieved at a dose of 5 g&g and no deaths
were reported.

93

Trihydroxystearin (Thixcin ® R and Thixcin® E grades tested)
was classified as a mild, transient ocular irritant in albino rabbits, but was not irritating to the skin of albino rabbits in 24-hour
occlusive patch tests.
Ames test results indicated that Trihydroxystearin (Thixcin ®
R grade) was not mutagenic to the following S. typhimurium
strains, with or without metabolic activation, when tested at concentrations ranging from 3 to 1000 #g/plate: TA1535, TA1537,
TA1538, TA98, and TA 100.
In 48-hour occlusive patch tests, Trihydroxystearin (Thixcin ®
R and Thixcin® E grades tested) did not induce skin irritationin any of the 103 subjects tested.
DISCUSSION
Although the data on Trihydroxystearin are limited, the C1R
Expert Panel had previously conducted a safety assessment of
Glyceryl Stearate and Hydroxystearic Acid. These data indicate
n o mutagenic, carcinogenic, or teratogenic effects in animals,
and no irritation or sensitization in clinical tests. The data on
these two ingredients is considered relevant to the assessmentof Trihydroxystearin because of the chemical similarity of theingredients. The data on Glyceryl Stearate and Hydroxystearic
Acid are also consistent with the limited data that are available
on Trihydroxystearin itself.
During the open, public comment period on the Tentative Report, a comment was made regarding the absence of sensitization
data. The CIR Expert Panel agrees that data on sensitization potential are important in assessing the safety of an ingredient. In
this case, there are data on a related ingredient. When tested atconcentrations up to 20.0% in human RIPTs involving a large
number of subjects, Glyceryl Stearate was neither an irritant
nor a sensitizer. Thus, in the absence of sensitization data on
Trihydroxystearin, it was concluded that this ingredient is not
likely a sensitizer based on data on a chemically similar ingredient. All of the available data suggest that Trihydroxystearin
and its component chemical species are safe as used in cosmetic
formulations.

CONCLUSION
Based on the available animal and clinical data in this report, which includes study summaries from C I R Safety Assessments of Hydroxystearic Acid and Glyceryl Stearate andGlyceryl Stearate/SE, the Expert Panel concludes that Trihydroxystearin is safe as used in cosmetic formulations.
REFERENCES
Ames.B. N., J. McCann.and E. Yamasaki. 1975.Methodsfordetectingcarcinogensand mutagenswiththe Salmonella/mammalianmicrosomemutagenicity
test. Murat. Res. 31:347-364.
Andersen, F. A., ed. 1999. Finalreport on the safetyassessmentof Hydroxystearic Acid.Int. Z Toxicol. 18(Suppl1):1-10.
Elder, R. L., ed. 1982.Finalreport on the safety assessmentof glycerylstearate
and glycerylstearate/SE.J. Am. Coil Toxicol. I: 169-192.
Elliger,C. A., D. G. Guadagni,and C. E. Dunlap. 1972.Thickeningactionofhydroxystearates in peanut butter. Z Am. Oil Chem. Soc. 49:536-537.

94

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STN International. 1996b. Properties of Trihydroxystearin. Beilstein databasefile. Columbus, OH: STN International.
Wenninger, J. A., R. C. Canterbery, and G. N. McEwen, eds. 2000. International cosmetic ingredient dictionary and handbook, 8th ed,, Vol 2. 1522.
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