Article

International Journal of Toxicology

32(Supplement 1) 59S-83S
Safety Assessment of Triethanolamine and ª The Author(s) 2013
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Triethanolamine-Containing Ingredients as DOI: 10.1177/1091581813488804
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Used in Cosmetics

Monice M. Fiume1, Bart Heldreth2, Wilma F. Bergfeld3,

Donald V. Belsito3, Ronald A. Hill1, Curtis D. Klaassen3, Daniel Liebler3,
James G. Marks Jr3, Ronald C. Shank3, Thomas J. Slaga3,
Paul W. Snyder3, and F. Alan Andersen4

Abstract
The Cosmetic Ingredient Review Expert Panel assessed the safety of triethanolamine (TEA) and 31 related TEA-containing
ingredients as used in cosmetics. The TEA is reported to function as a surfactant or pH adjuster; the related TEA-containing
ingredients included in this safety assessment are reported to function as surfactants and hair- or skin-conditioning agents. The
exception is TEA-sorbate, which is reported to function as a preservative. The Panel reviewed the available animal and clinical
data. Although data were not available for all the ingredients, the panel relied on the information available for TEA in conjunction
with previous safety assessments of components of TEA-containing ingredients. These data could be extrapolated to support the
safety of all included ingredients. The panel concluded that TEA and related TEA-containing ingredients named in this report are
safe as used when formulated to be nonirritating. These ingredients should not be used in cosmetic products in which N-nitroso
compounds can be formed.

Keywords
triethanolamine

Introduction TEA-cocoate
TEA-hydrogenated cocoate
In 1983, the Cosmetic Ingredient Review (CIR) Expert Panel
TEA-tallate
issued a report on the safety of triethanolamine (TEA), dietha-
TEA-glyceryl dimaleate
nolamine, and monoethanolamine. In 2010, the panel decided to
Hydroxy acid salts
reopen that safety assessment as 3 separate reports and to include
TEA-lactate*
related ingredients in each of the new reviews. This assessment
Organo-substituted sulfates
addresses TEA and the following 31 related TEA-containing
Magnesium/TEA-coco-sulfate
ingredients:
Sodium/TEA C12-13 pareth-3 sulfate
TEA-lauryl sulfate*
Inorganic salts TEA-laureth sulfate
TEA-hydrochloride TEA-oleyl sulfate
TEA-sulfate TEA-C10-15 alkyl sulfate
Organic acid salts TEA-C11-15 alkyl sulfate
TEA-laurate
TEA-laurate/myristate
TEA-myristate 1
Cosmetic Ingredient Review, Scientific Analyst/Writer, Washington, DC, USA
TEA-palmitate 2
Cosmetic Ingredient Review, Chemist, Washington, DC, USA
3
TEA-stearate* Cosmetic Ingredient Review, Expert Panel Member, Washington, DC, USA
4
TEA-isostearate Cosmetic Ingredient Review, Director, Washington, DC, USA
TEA-undecylenate
Corresponding Author:
TEA-sorbate F. Alan Andersen, Cosmetic Ingredient Review, 1101 17th Street, NW, Suite
TEA-oleate 412, Washington, DC 20036, USA.
TEA-canolate Email: [email protected]

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60S International Journal of Toxicology 32(Supplement 1)

Table 1. Conclusions of Previously Reviewed Ingredients and Components.

Ingredient Conclusion Reference

Previously reviewed ingredients

1
TEA Safe for use in cosmetic formulations designed for discontinuous, brief use followed by
thorough rinsing from the surface of the skin; in products intended for prolonged
contact with the skin, the concentration of diethanolamine should not exceed 5%;
should not be used with products containing N-nitrosating agents.
69
TEA-lactate Safe for use in cosmetic products at concentrations 10%, at final formulation pH  3.5,
when formulated to avoid increasing sun sensitivity or when directions for use include
the daily use of sun protection. These ingredients are safe for use in salon products at
concentrations 30%, at final formulation pH  3.0, in products designed for brief,
discontinuous use followed by thorough rinsing from the skin, when applied by
trained professionals, and when application is accompanied by directions for the daily
use of sun protection
70
TEA-lauryl sulfate Can be used without significant irritation at a final concentration thereof not exceeding
10.5%; greater concentrations may cause irritation, especially if allowed to remain in
contact with the skin for significant periods of time
71
TEA stearate Safe as used in cosmetic formulations designed for discontinuous, brief use followed by
thorough rinsing; in products intended for prolonged contact with the skin, the
concentration should not exceed 15% in formulation; should not be in products
under conditions resulting in N-nitrosation reactions

Previously reviewed components

72
Alkyl PEG ethers Safe as used when formulated to be nonirritating
73
Ammonium lauryl sulfate and sodium Safe in formulations designed for discontinuous, brief use followed by thorough rinsing
lauryl sulfate from the surface of the skin; in products intended for prolonged contact with skin,
concentrations should not exceed 1%
74
Coconut ingredients Safe as used
75
Isostearic acid Safe as used
76,77
Lauric acid, myristic acid, oleic acid, Safe as used
palmitic acid, and stearic acid
78
Plant-derived fatty acid oils Safe as used
79
Sodium cetearyl Sulfate and related Safe as used
alkyl sulfates
80,81
Sodium laureth sulfate and sulfated Safe as used when formulated to be nonirritating
ethoxylated alcohols
82
Sorbic acid Safe as used
83
Tall oil acid Safe as used
Abbreviations: PEG, polyethylene glycol; TEA, triethanolamine.

TEA-C12-13 alkyl sulfate rinsing from the surface of the skin.1 In products intended for
TEA-C12-14 alkyl sulfate prolonged contact with the skin, the concentration of TEA
TEA-C12-15 alkyl sulfate should not exceed 5%. The TEA should not be used in products
TEA-coco-sulfate containing N-nitrosating agents. In the 1983 assessment, data
TEA-C11-15 pareth sulfate demonstrated that TEA was a mild skin and eye irritant and that
TEA-C12-13 pareth-3 sulfate irritation increased with increasing ingredient concentration.
TEA-PEG-3 cocamide sulfate The TEA-containing ingredients are reported to function in
cosmetics as surfactants, skin-conditioning agents, or hair-
The ingredients marked with an asterisk have been reviewed conditioning agents. The TEA-sorbate is reported to function
previously by the CIR, and the conclusions on safety of these only as a preservative.
ingredients are provided in Table 1. The safety of many of the
‘‘components’’ of these ingredients has been reviewed by the
CIR, and these conclusions are also provided in Table 1. Chemistry
The TEA, an ingredient reported to function as a surfactant As given in CIR’s earlier safety assessment of TEA,1 this
or pH adjuster in cosmetic products, had been reviewed previ- ingredient is an amino alcohol commercially produced by
ously by the CIR Expert Panel. In 1983, the Expert Panel aminating ethylene oxide with ammonia. The replacement of
concluded that TEA is safe for use in cosmetic formulations 3 hydrogens of ammonia with ethanol groups produces TEA
designed for discontinuous, brief use followed by thorough (Figure 1). The TEA contains small amounts of diethanolamine

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Fiume et al 61S

O
OH
N H 3C O
HO OH
OH
Figure 1. Triethanolamine. NH
HO OH

and ethanolamine. The TEA is reactive and bifunctional, com- Figure 2. Triethanolamine (TEA) stearate.
bining the properties of alcohols and amines. The reaction of
ethanolamines and sulfuric acid produces sulfates. The TEA
can act as an antioxidant against the autoxidation of fats of both O
animal and vegetable origin.
H 3C O S O
Of concern in cosmetics is the conversion (N-nitrosation) of
secondary amines (R1-NH-R2), such as diethanolamine (wherein O
R1 and R2 are each ethanol), into N-nitrosamines that may be
carcinogenic. Tertiary alkyl amines (NR1R2R3), such as TEA OH
(wherein R1, R2, and R3 are each ethanol), however, do not tend NH
to react with N-nitrosating agents to directly form nitrosamines. HO OH
However, tertiary amines can act as precursors in nitrosamine
formation by undergoing nitrosative cleavage (eg, 1 ethanol Figure 3. Triethanolamine (TEA)-lauryl sulfate.
functional group can be cleaved off from TEA to generate
diethanolamine).2 The resultant secondary amine (ie, diethano- approximately one-third of each ethanolamine, diethanolamine,
lamine) can then be N-nitrosated (ie, to N-nitrosodiethanolamine and TEA. The crude mixture is later separated by distillation.
[NDELA]). Accordingly, TEA can react, in a formulation or in
vivo, with nitrites or oxides of nitrogen to form a nitrosamine. TEA-stearate. TEA-stearate was produced by mixing partially
Nitrous anhydride is the oxide of nitrogen that most commonly neutralized stearic acid and TEA at temperatures above 80 C
initiates nitrosation in vivo.3–6 and then cooling.8 It was determined that the acid–soap com-
plex at a 2:1 fixed stoichiometric ratio was formed between
TEA stearate and stearic acid.
Acid Salts
The acid salts (inorganic salts, organic acid salts, and hydroxy TEA-lauryl sulfate. As given in the original CIR safety assess-
acid salts), mentioned previously, are ion pairs that freely dis- ment of TEA-lauryl sulfate,9 this ingredient is manufactured by
sociate in water (eg, Figure 2). Therefore, these salts are closely neutralizing lauryl sulfuric acid with aqueous (aq) TEA.
related to the corresponding free acids and TEA. In other Commercial alkyl sulfates are produced by the sulfation of
words, TEA stearate is closely related to stearic acid and TEA. primary alcohols using sulfur trioxide or chlorosulfonic acid
followed by neutralization with a base to produce the corre-
sponding salt.9
Organo-Substituted Sulfates
The sulfates consist of organic acid salts that have the addi-
tional functional group of sulfate. For example, TEA lauryl Stability
sulfate is a 12-carbon alkyl chain (ie, lauryl) bonded to a sulfate
TEA-stearate. TEA stearate was produced as described previ-
anion, balanced with a triethanolammonium cation (Figure 3).
ously. On cooling, a lamellar gel phase formed.10 Solid crystals
were observed after 5 hours. Upon storage, the sample gradu-
Definition and Structure ally separated into 2 phases; after a few weeks, a separate liquid
phase and a solid-pearly crystalline phase were observed.
The definitions and structures of TEA and TEA-containing
ingredients are provided in Table 2. Chemical and physical prop-
erties are described in Table 3.
Impurities
Method of Manufacture Triethanolamine. Based on the unpublished survey data col-
lected by the Food and Drug Administration (FDA), a dietha-
Triethanolamine. The TEA is produced by reacting 3 moles of nolamine impurity level of 0.3% was found in TEA samples.11
ethylene oxide with 1 mole of ammonia; additional ethylene (Additional details were not provided.)
oxide will continue to react to produce higher ethylene oxide
adducts of TEA.7 Typically, ethylene oxide is reacted with TEA-lauryl sulfate. As previously reported by the CIR,9 impuri-
ammonia in a batch process to produce a crude mixture of ties in TEA-lauryl sulfate may include TEA, TEA-sulfate,

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62S
Table 2. Definitions and Structures.

Ingredient CAS No. Definition Formula/Structure

TEA and inorganic salts

TEA 102-71-6 TEA is a tertiary amine with 3 ethanol
OH
functional groups.
N
HO OH

TEA-hydrochloride 637-39-8 TEA-hydrochloride is the TEA salt of

Cl OH
hydrochloric acid.
NH
HO OH

TEA-sulfate 7376-31-0 TEA-sulfate is the TEA salt of sulfuric O

acid. OH
HO S OH
N
HO OH O
m n
Organic acid salts
TEA-laurate 2224-49-9 TEA-laurate is the TEA salt of a 12 carbon O
fatty acid, lauric acid.
H 3C O

OH

NH
HO OH
TEA-laurate/myristate TEA-laurate/myristate is the TEA salt of O
a mixture of a 12 carbon fatty acid,
lauric acid and a 14 carbon fatty acid, H 3C O
myristic acid. OH
NH
HO OH

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O

H3C O

OH
NH
HO OH
TEA-myristate 41669-40-3 TEA-myristate is the TEA salt of a 14 car- O
bon fatty acid, myristic acid.
H3C O
OH
NH
HO OH

(continued)
 Table 2. (continued)

Ingredient CAS No. Definition Formula/Structure

TEA-palmitate 49719-60-0 TEA-palmitate is the TEA salt of a 16 O

carbon fatty acid, palmitic acid.
H 3C O

OH

NH
HO OH

TEA-stearate 4568-28-9 TEA-stearate is the TEA salt of an 18 O

carbon fatty acid, stearic acid.
H 3C O

OH

NH
HO OH
O
TEA-isostearate 88120-12-1 TEA-isostearate is the TEA salt of a
branched, 18 carbon fatty acid, iso- H 3C
O
stearic acid.
CH 3
OH
NH
HO OH
one example of an ‘‘iso’’
TEA-undecylenate TEA-undecylenate is the TEA salt of a O
terminally unsaturated, 11 carbon
H 2C
fatty acid, undecylenic acid. O

OH
NH
HO OH

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TEA-sorbate TEA-sorbate is the TEA salt of an a, b, O
g, and d unsaturated 6 carbon acid,
sorbic acid. H3C CH CH CH CH O

OH
NH
HO OH
O

TEA-oleate 2717-15-9 TEA-oleate is the TEA salt of an 18 H3C

CH CH O
carbon, O-9 fatty acid, oleic acid.
OH
NH
HO OH

(continued)

63S
64S
Table 2. (continued)

Ingredient CAS No. Definition Formula/Structure

O
TEA-canolate TEA-canolate is the TEA salt of the fatty
acids derived from canola oil. R O

OH
NH
HO OH
wherein RC(O)O ¼ the fatty acid anions derived from Canola Oil
TEA-cocoate 61790-64-5 TEA-cocoate is the TEA salt derived O
from coconut fatty acids.
R O

OH
NH
HO OH

wherein RC(O)O ¼ the fatty acid anions derived from coconut
TEA-hydrogenated cocoate TEA-hydrogenated cocoate is the TEA O
salt of hydrogenated coconut fatty
acids R O

OH
NH
HO OH

wherein RC(O)O ¼ the fatty acid anions derived from hydrogenated coconut
TEA-tallate 8043-27-4 67784- TEA-tallate is the TEA salt of tall oil acid. O
78-5
R O

OH

NH
HO OH

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wherein RC(O)O ¼ the fatty acid anions derived from Tall Oil Acid
TEA-Glyceryl dimaleate TEA-glyceryl dimaleate is the TEA salt Not enough information for a structure
[63358-71-4] per CAS of the diester of glycerin and maleic
acid.
Hydroxy acid salt O
TEA-lactate 20475-12-1 TEA-lactate is the TEA salt of the 3 H3C
carbon, a-hydroxy acid, lactic acid. O
OH
OH
NH
HO OH
Organo-substituted sulfates

(continued)
 Table 2. (continued)

Ingredient CAS No. Definition Formula/Structure

O
Magnesium/TEA-coco-sulfate Magnesium/TEA-coco-sulfate is the
mixed magnesium and TEA salt of O S O
coco-sulfate. R O

OH
NH
HO OH

O
O
O S O
2 O S O
R O Mg
R O
where R represents the alkyl groups derived from coconut oil

Sodium/TEA C12-13 pareth-3 Sodium/TEA C12-13 pareth-3 sulfate is

sulfate the mixed sodium and TEA salt of the
sulfate ester of C12-13 pareth-3. O
O O S O Na
H3C O O
O
O OH
H3C O O S O NH
O O HO OH
O
O
TEA-lauryl sulfate 139-96-8 TEA-lauryl sulfate is the TEA salt of
H3C O S O
lauryl sulfuric acid.
O

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OH
NH
HO OH
TEA-laureth sulfate TEA-laureth sulfate is the TEA salt of O
27028-82-6 polyethoxylated lauryl sulfate. O O
S
H3C O
O
n

OH
NH
HO OH
where n ¼ 1-4
(continued)

65S
 Table 2. (continued)

66S
Ingredient CAS No. Definition Formula/Structure
O
TEA-oleyl sulfate TEA-oleyl sulfate is the TEA salt of O-9
unsaturated 18 carbon alkyl sulfate, CH CH O S O
H3C
oleyl sulfate. O
OH
NH
HO OH

TEA-C10-15 alkyl sulfate TEA-C10-15 alkyl sulfate is the mixture O

OH
of 10 to 15 carbon alkyl sulfate TEA H3C O S O
salts. NH
O HO OH
O
OH
O S O
H3C NH
O HO OH
O
OH
H3C O S O
NH
O HO OH
O
OH
O S O
H3C NH
O HO OH
O
OH
H3C O S O
NH
O HO OH
O
OH
O S O
H3C NH
O HO OH

TEA-C11-15 alkyl sulfate TEA-C11-15 alkyl sulfate is the mixture O

OH
of 11 to 15 carbon alkyl sulfate TEA O S O

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salts. H3C NH
O HO OH
O
OH
H3C O S O
NH
O HO OH
O
OH
O S O
H3C NH
O HO OH
O
OH
H3C O S O
NH
O HO OH
O
OH
O S O
H3C NH
O HO OH

(continued)
 Table 2. (continued)

Ingredient CAS No. Definition Formula/Structure

TEA-C12-13 alkyl sulfate TEA-C12-13 alkyl sulfate is the mixture O

OH
of 12 to 13 carbon alkyl sulfate TEA H3C O S O
salts. NH
O HO OH
O
OH
O S O
H3C NH
O HO OH
TEA-C12-14 alkyl sulfate TEA-C12-14 alkyl sulfate is the mixture O
of 12 to 14 carbon alkyl sulfate TEA OH
H3C O S O
salts. NH
O HO OH
O
OH
O S O
H3C NH
O HO OH
O
OH
H3C O S O
NH
O HO OH

TEA-C12-15 alkyl sulfate TEA-C12-15 alkyl sulfate is the mixture O

OH
of 12 to 15 carbon alkyl sulfate TEA H3C O S O
salts. NH
O HO OH
O
OH
O S O
H3C NH
O HO OH
O
OH
H3C O S O
NH

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O HO OH
O
OH
O S O
H3C NH
O HO OH

TEA-coco-sulfate TEA-coco-sulfate is the TEA salt of O

sulfated coconut alcohol. O S O
R O

OH
NH
HO OH
where R represents the alkyl groups derived from coconut oil
(continued)

67S
68S
Table 2. (continued)

Ingredient CAS No. Definition Formula/Structure

TEA-C11-15 pareth sulfate TEA-C11-15 pareth sulfate is the TEA O

OH
salt of the sulfate ester of a mixture of H3C O S O
monoethoxylated, 11 to 15 carbon O NH
O HO OH
fatty alcohols.
O
OH
O S O
H3C O NH
O HO OH
O
OH
H3C O S O
O NH
O HO OH
O
OH
O S O
H3C O NH
O HO OH
O
OH
H3C O S O
O NH
O HO OH
TEA-C12-13 pareth-3 sulfate TEA-C12-13 pareth-3 sulfate is the TEA
salt of the sulfate ester of a mixture of
triethoxylated, 12 to 13 carbon fatty
O
alcohols. OH
O O S O
H3C O O NH
O HO OH
O
OH
H3C O O S O

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O O NH
O HO OH

O O
TEA-PEG-3 cocamide sulfate TEA-PEG-3 cocamide sulfate is the TEA
salt of the sulfate ester of triethoxy- O O S O
R N O
lated cocamide. H O

OH
NH
HO OH

where RCO– represents the fatty acids derived from coconut oil

Abbreviations: PEG, polyethylene glycol; TEA, triethanolamine.

Fiume et al 69S

Table 3. Physical and Chemical Properties. inoculum) media. (The percentage of nitrosation was deter-
mined using values that were corrected for diethanolamine
Property Value Reference
impurity-related NDELA formation.)
TEA In vivo, female B6C3F1 mice were dosed dermally or orally
1
Physical form Clear viscous liquid with 1000 mg/kg TEA, in conjunction with oral exposure to
28
Color Colorless to pale yellow
1
sodium nitrite.12 Following 7 days of dermal dosing, no NDELA
Odor Ammonia-like was detected in the blood, ingesta, or urine of test, vehicle control,
1
Molecular weight 149.19
28 or sodium nitrite control mice. (The limits of detection for the
Melting point 21.6 C
Boiling point 335.4 C at 760 mm Hg 28 blood, ingesta, and urine were 0.001, 0.006, and 0.47 mg/mL,
Water solubility Miscible in water 28 respectively.) With a single oral dose, the concentrations of
1 NDELA found in the blood and ingesta of mice 2 hours postdos-
Other solubility Insoluble in benzene, ether, and
petroleum distillates ing were 0.001 + 0.0005 and 0.044 + 0.059 mg/g, respectively.
84
Miscible with methanol or
acetone; sparingly soluble in
hydrocarbon solvents; readily
forms salts with organic and
Use
inorganic acids Cosmetic
17
log Kow 1.59 at 20 C
36 The TEA is reported to function in cosmetics as a surfactant or
pKa 7.76 at 25 C
Viscosity 590.5 cP at 25 C 84
pH adjuster, and it can be used in fragrances.13 Most of the other
TEA-hydrochloride TEA ingredients are reported to function in cosmetics as surfac-
85
Melting point 177 C tants, skin-conditioning agents, or hair-conditioning agents.
TEA-lactate
86 TEA-sorbate is reported to function only as a preservative.
Melting point 54.9 C
Density 1.222 g/cm3 86 Voluntary Cosmetic Registration Program (VCRP) data
TEA lauryl sulfate obtained from the FDA in 2011 indicate that TEA is used in
Density Approximately 1 g/cm3 (20 C) 9 3756 formulations; 3034 of those products are leave-on formula-
tions, and 3106 formulations involve dermal exposure.14 Accord-
Abbreviation: TEA, triethanolamine.
ing to the data submitted by industry in response to a survey
conducted by the Personal Care Products Council (Council), TEA
unsulfated alcohol, TEA chloride, and formaldehyde (some is used at concentrations of 0.0002% to 19%.15 In leave-on prod-
grades). ucts, the reported use concentrations range from 0.0002% to 6%.
Sodium sulfate and residual alcohols may be present as With the exception of TEA-lauryl sulfate (302 uses) and TEA-
impurities in commercial alkyl sulfate products.9 Typically, stearate (130 uses), all other in-use TEA-containing ingredients
industrial alkyl sulfates contain 1% to 4% sodium sulfate and had less than 20 reported uses.14 TEA-lauryl sulfate had the high-
0.5% to 18% residual alcohol. est concentrations of use, with 40% being reported for rinse-off
and 8% for leave-on formulations.16 The available use data on
all in-use ingredients are provided in Table 4. Ingredients not
N-Nitrosodiethanolamine Formation reported to be in use, according to the VCRP data and the Council
Nitrosamines are compounds containing the R1R2N-NO func- survey, are listed in Table 5.
tional group.2 N-nitrosation is the process of converting organic Typical exposure to TEA was calculated. Using an evolu-
compounds (eg, alkyl amines) into N-nitroso derivatives (eg, tionary computation algorithm method,17 the dermal exposure
nitrosamines) by reaction with nitrosating agents. These agents of consumers to TEA in an eye make-up powder is 0.0125 mg/kg
include nitrous acid (HNO2), oxides of nitrogen (eg, nitrous body weight (bw)/d and to TEA in a body lotion is 6.25 mg/kg
anhydride or nitrite), and other compounds capable of generating bw/d. Using a DERMAL program method, the dermal potential
a nitrosonium ion, NO2þ. dose rate of a bar soap containing 2.5% TEA is 5.182 mg/d.
The formation of a specific nitrosamine, NDELA, from Some of the ingredients reviewed in this assessment may be
reaction of TEA with nitrite was examined in vitro and in applied to baby skin, used near the eye area or mucous mem-
vivo.12 The TEA used in these studies had an impurity content branes, or could possibly be ingested. The TEA, TEA-lauryl
of 0.4% diethanolamine. In an aq matrix, approximately 3% sulfate, and TEA-stearate are reported to be in products that
TEA was converted to NDELA at a pH of 4.0 in the presence of could be inhaled. In practice, 95% to 99% of the aerosols
acetic acid. At the same pH, in the presence of sulfuric or released from cosmetic sprays have aerodynamic equivalent
hydrochloric acid, only about 1% of the TEA was nitrosated. diameters in the 10 to 110 mm range.18,19 Therefore, most
At pH 7, the greatest nitrosation to NDELA, 0.5%, occurred in aerosols incidentally inhaled from these sprays are deposited
the presence of sulfuric acid. No conversion of TEA to NDELA in the nasopharyngeal region and are not respirable.20,21 There
was detected at pH 2 or 10. In nutrient broth cultures (neutral is some evidence indicating that deodorant spray products can
pH), 0.08% and 0.68% of the TEA were nitrosated to NDELA release substantially larger fractions of particulates having
in a diluted (high-cecal inoculum) and full-strength (low-cecal aerodynamic diameters in the range considered to be

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70S International Journal of Toxicology 32(Supplement 1)

Table 4. Frequency and Concentration of Use According to the Duration and Type of Exposure.

TEA TEA-Cocoate TEA-Hydrochloride

No. of Uses14,87 Conc of Use, %15 No. of Uses14,87 Conc of Use, %15 No. of Uses14,87 Conc of Use, %15

Totalsa 3756 0.0002-19 2 NR NR 0.5

Duration of use
Leave-on 3034 0.0002-6 1 NR NR NR
Rinse-off 697 0.0003-19 1 NR NR 0.5
Diluted for (bath) use 25 0.4-0.7 NR NR NR NR
Exposure type
Eye area 413 0.2-4 NR NR NR NR
Incidental ingestion 18 0.2-1 NR NR NR NR
Incidental inhalation—spray 120b 0.001-2 NR NR NR NR
Incidental inhalation— 14 0.06-2 NR NR NR NR
powder
Dermal contact 3106 0.0002-19 2 NR NR NR
Deodorant (underarm) 11c 0.1-0.4 NR NR NR NR
Hair noncoloring 373 0.0003-6 NR NR NR 0.5
Hair coloring 5 1-13 NR NR NR NR
Nail 14 0.2-3 NR NR NR NR
Mucous membrane 203 0.2-19 1 NR NR NR
Baby products 16 0.2-2 NR NR NR NR

TEA-Isostearate TEA Lactate TEA Laurate

No. of Uses14,87 Conc of Use, %15 No. of Uses14,87 Conc of Use, %15 No. of Uses14,87 Conc of Use, %15

Totalsa 1 NR 13 0.06 NR 8
Duration of use
Leave-on 1 NR 13 0.06 NR NR
Rinse off NR NR NR NR NR 8
Diluted for (bath) use NR NR NR NR NR NR
Exposure type
Eye area NR NR NR NR NR NR
Incidental ingestion NR NR NR NR NR NR
Incidental inhalation—spray NR NR NR NR NR NR
Incidental inhalation— NR NR NR NR NR NR
powder
Dermal contact 1 NR 13 0.06 NR 8
Deodorant (underarm) NR NR NR NR NR NR
Hair noncoloring NR NR NR NR NR NR
Hair coloring NR NR NR NR NR NR
Nail NR NR NR NR NR NR
Mucous membrane NR NR NR NR NR NR
Baby products NR NR NR NR NR NR

TEA-Laureth Sulfate TEA-Lauryl Sulfate TEA-Myristate

No. of Uses14,87 Conc of Use, %15 No. of Uses14,87 Conc of Use, %15 No. of Uses14,87 Conc of Use, %15

Totalsa 17 3-14 302 0.0009-40 2 NR

Duration of use
Leave-on NR NR 29 0.0009-8 NR NR
Rinse-off 1517 3-14 241 0.0009-40 2 NR
Diluted for (bath) use NR 3 32 12-15 NR NR
Exposure type
Eye area NR NR NR NR NR NR
Incidental ingestion NR NR NR NR NR NR
Incidental inhalation—spray NR NR 1c 4-8 NR NR
Incidental inhalation—powder NR NR NR NR NR NR
Dermal contact 3 3-9 236 0.2-40 2 NR

(continued)

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Fiume et al 71S

Table 4. (continued)
TEA-Laureth Sulfate TEA-Lauryl Sulfate TEA-Myristate

No. of Uses14,87 Conc of Use, %15 No. of Uses14,87 Conc of Use, %15 No. of Uses14,87 Conc of Use, %15

Deodorant (underarm) NR NR NR NR NR NR
Hair noncoloring 14 14 65 0.0009-40 NR NR
Hair coloring NR 6 NR 2 NR NR
Nail NR NR NR NR NR NR
Mucous membrane 1 3-9 179 5-30 NR NR
Baby products NR NR 2 NR NR NR

TEA-Palmitate TEA-Stearate TEA-Sulfate

No. of Uses14,87 Conc of Use, %15 No. of Uses14,87 Conc of Use, %15 No. of Uses14,87 Conc of Use, %15

Totals 5 14 130 9 6 0.2

Duration of use
Leave-on 3 NR 108 NR NR NR
Rinse off 2 14 22 9 6 0.2
Diluted for use NR NR NR NR NR NR
Exposure type
Eye area 1 NR 9 NR NR NR
Incidental ingestion NR NR 1 NR NR NR
Incidental inhalation—spray NR NR 2c NR NR NR
Incidental inhalation— NR NR 2 NR NR NR
powder
Dermal contact 4 14 109 9 NR NR
Deodorant (underarm) NR NR NR NR NR NR
Hair noncoloring NR NR 16 NR 6 0.2
Hair coloring NR NR 1 NR NR NR
Nail NR NR NR NR NR NR
Mucous membrane NR NR 4 NR NR NR
Baby products NR NR NR NR NR NR
Abbreviations: Conc, concentration; NR, no reported uses; TEA, triethanolamine.
a
Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure types my not equal the sum of total uses.
b
Includes suntan products, in that it is not known whether or not the product is a spray.
c
It is not known whether or not the product is a spray.

Table 5. Ingredients Not Reported to be Used. respirable.21 However, the information is not sufficient to deter-
mine whether significantly greater lung exposures result from
Magnesium/TEA-coco-sulfate the use of deodorant sprays, compared to other cosmetic sprays.
Sodium/TEA C12-13 pareth-3 sulfate Internationally, data were available from the European Com-
TEA-C10-15 alkyl sulfate mission (EC) and Canada. In the EC, Annex III Part 1 of the
TEA-C11-15 alkyl sulfate
TEA-C12-13 alkyl sulfate
CosIng database, which is the list of substances that cosmetic
TEA-C12-14 alkyl sulfate products must not contain except subject to the restrictions and
TEA-C12-15 alkyl sulfate conditions laid down, states that trialkylamines, trialkanola-
TEA-C11-15 pareth sulfate mines, and their salts are allowed at concentrations of up to
TEA-C12-13 pareth-3 sulfate 2.5% in nonrinse-off products; ‘‘other’’ product types do not
TEA-canolate have a concentration limit for TEA.22 However, the following
TEA-coco-sulfate additional limitations apply to leave-on and rinse-off products
TEA-glyceryl dimaleate
TEA-hydrogenated cocoate
containing TEA: do not use with nitrosating systems; minimum
TEA-laurate/myristate allowable purity is 99%; maximum allowable secondary amine
TEA-oleate content is 0.5% in raw material; maximum allowable nitrosa-
TEA-oleyl sulfate mine content is 50 mg/kg; and must be kept in nitrite-free con-
TEA-PEG-3 cocamide sulfate tainers. Additional relevant information from the EC is that
TEA-sorbate sorbic acid and its salts and undec-10-enoic acid and its salts,
TEA-tallate including their ethanolamine salts, are listed by the EC for use as
TEA-undecylenate
preservatives, with maximum concentrations of use of 0.6% and
Abbreviations: PEG, polyethylene glycol; TEA, triethanolamine. 0.2%, respectively, based on the free acid.23

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72S International Journal of Toxicology 32(Supplement 1)

According to the data obtained from Health Canada, some in the receptor fluid after 24 hours. The authors speculated that
leave-on-type products reportedly use TEA as high as 10% and the penetration rate of the TEA molecule was dependent on the
30%, with some reporting concentration ranges of 30% to penetration of its salts.
100% (Health Canada, personal communication).
Non-human
Triethanolamine. The blood kinetics and absorption, distri-
Noncosmetic bution, metabolism, and excretion (ADME) of [14C]triethano-
The TEA is used in the manufacture of emulsifiers and dispersing lamine were determined following dermal application of 2000
agents for textile specialties, agricultural chemicals, waxes, mg/kg neat [14C]triethanolamine without occlusion to 24 male
mineral and vegetable oils, paraffin, polishes, cutting oils, petro- C3H/HeJ mice and with occlusion to 3 male mice.27 (Nonra-
leum demulsifiers, and cement additives.1 It is an intermediate for diolabeled TEA was 99.6% pure; radiochemical purity was
resins, plasticizers, and rubber chemicals. It is used as a lubricant 98.6%.) The TEA was extensively and rapidly absorbed fol-
in the textile industry, as a humectant and softening agent for lowing a single open application of 2000 mg/kg neat
hides, as an alkalizing agent and surfactant in pharmaceuticals, [14C]triethanolamine. The majority of the radioactivity, 49%
as an absorbent for acid gases, and in organic syntheses. to 62% of the total dose (*58%-72% of the absorbed dose),
The TEA, TEA-myristate, TEA-palmitate, TEA-oleate, was excreted in the urine, primarily as unmetabolized TEA.
TEA-cocoate, and TEA-tallate have been used as an indirect Diethanolamine and ethanolamine were not detected in the
food additive.24 The TEA is used as a rust inhibitor in water- urine. Approximately, 18% to 28% of the total dose
based metalworking fluids.25 (*20%-32% of the absorbed dose) was excreted in the feces.
The amount of radioactivity remaining in the body after 48
hours ranged from 3.3% to 6.1%, and the amount recovered at
Toxicokinetics the application site ranged from 1.2% to 2.1% for the open
application and 6% to 11% for the occluded application.
Dermal The National Toxicology Program (NTP) examined the
In vitro ADME of TEA following dermal administration to B6C3F1 mice
Triethanolamine and TEA-stearate. The penetration of oil-in- and F344 rats.28 Groups of 4 female mice were given a single dose
water (o/w) emulsions containing TEA was determined in vitro of 79 or 1120 mg/kg [14C]triethanolamine in acetone; the dose
using human skin samples.26 Emulsions were prepared using contained 12 to 15 mCi, with the appropriate amount of nonla-
1% TEA and 5% stearic acid and using 5% TEA and 10.5% beled TEA in a volume of 190 mL/dose. (Radiochemical purity of
stearic acid; the pH values of these emulsions were 8.0 and 8.2, [14C]triethanolamine was 97%; the purity of nonlabeled TEA was
respectively. Because the pH values of commercial lotions confirmed, but the purity was not stated.) The dose was applied to
containing TEA were reported to be *7.0, emulsions were a 1.44 cm2 area of clipped skin, and a nonocclusive cover was
also prepared with the pH adjusted to 7.0. The test samples used. Approximately 60% to 80% of the dose was absorbed, and
were applied to the skin for 24 hours at a concentration of 3 absorption increased with increasing dose. In the urine, 22.5% to
mg/cm2, and the area of the exposed skin was 0.64 cm2. Pene- 27.5% and 48% to 56% of the dose were recovered after 24 and 72
tration and absorption were measured at 24 hours using the hours, respectively, and TEA was excreted mostly unchanged.
emulsions with a pH of *8 and at 24 and 72 hours using the Approximately 5% to 9% and 8% to 13% of the dose were recov-
emulsions with a pH of 7.0. The 24-hour skin sample was tape ered in the feces at the same time periods.
stripped, while the 72 hours sample was not. Groups of 4 female rats were given a single dermal dose of
Using the emulsions with a pH of *8, there was no statis- 68 or 276 mg/kg [14C]triethanolamine in acetone; the dose
tically significant difference in penetration between a 1% and a contained 65 mCi, with the appropriate amount of nonlabeled
5% TEA emulsion. Using the emulsion with a pH of 7 and TEA in a volume of 190 mL/dose. The dose was applied to a 12
concentration of 1% TEA, there was no statistically significant cm2 area of clipped skin, and a nonocclusive cover was used.
difference in penetration observed when comparing the 24 and Only 19% to 28% of the dose was absorbed over 72 hours;
72 hours values. There was a statistically significant difference absorption increased with increasing dose but not significantly.
in the total recovery of TEA using the 5% emulsion, pH 7, with In the urine, 13% to 24% of the dose was recovered in 72 hours
the recovery at 24 hours less than that recovered at 72 hours. as mostly unchanged TEA. The amount recovered in the feces
The authors suggested that all the TEA in a TEA/stearic acid after 72 hours was <0.25%. Very little radioactivity, <1%, was
emulsion existed as the TEA stearate salt, since an excess of present in the tissues; a number of tissues had elevated con-
stearic acid was used. Radiolabeled TEA stearate was prepared centrations of radiolabel relative to blood.
by mixing stearic acid with a radiotracer dose of 0.64 mCi
[14C]triethanolamine (5 mg TEA) in an o/w emulsion; the ratio
of TEA to stearic acid was 1:4. Using this emulsion, at pH 8.2,
Oral
50.1% of the applied dose of TEA-stearate was found in the Non-human
skin, and 0.51% in the receptor fluid after 24 hours. With pH Triethanolamine. The TEA (purity not specified) was admi-
7.0, 29.1% of the applied dose was found in the skin and 0.46% nistered orally to male and female rats as a single dose or as a

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Fiume et al 73S

repeated dose for 5 to 6 days.29 (Dosing details were not The exposure to actual TEA was 2 g/kg. None of the animals
described.) At 24 hours after administration of the single dose, died. Mild erythema and edema were reported at 24 hours.
the excretion ratio of unchanged TEA in the urine and feces
was 53% and 20% of the dose, respectively. With repeated Oral
administration, the excretion ratio/day remained constant. Gen- Triethanolamine. As reported previously,1 the acute oral toxi-
der did not affect the ratios. TEA glucuronide was detected but city of TEA was determined using guinea pigs and rats. In
in a very small amount (actual concentration not specified). guinea pigs, undiluted TEA has an median lethal dose (LD50)
The TEA was rapidly absorbed in the gastrointestinal tract and of 8 g/kg, and the LD50 of TEA in a gum arabic solution was
excreted mostly in the urine in unchanged form. between 1.4 and 7.0 g/kg. Using rats, the oral LD50 of undiluted
TEA ranged from 4.19 to 11.26 g/kg. The purity ranged from
78.6% TEA (with 8.6% diethanolamine and 1.7% ethanola-
Other mine) to unspecified high purity.
Non-human
TEA-lauryl sulfate. As reported previously, 9TEA-lauryl sul-
Triethanolamine. A group of 27 male C3H/HeJ mice was
fate was moderately to slightly toxic in acute oral studies with
given an intravenous (iv) injection of 1 mg/kg [14C]triethano-
rats, LD50 values ranged from 0.27 to >1.95 g/kg. In a more
lamine as an aq solution (0.5 mg/mL), and the dose volume was
recent study, the oral LD50 of TEA-lauryl sulfate in male and
2 mL/kg.27 (Nonradiolabeled TEA was 99.6% pure; radioche-
female Wistar rats was >2 g/kg.30
mical purity was 98.6%.) Radioactivity in the blood declined in
a biphasic exponential manner for 24 hours, with a relatively Other
rapid initial phase of [14C] elimination followed by a slower Triethanolamine. As reported previously,1 the intraperitoneal
terminal phase. The majority of the radioactivity, approxi- LD50 of TEA was 1.45 g/kg for mice.
mately 69%, was excreted in the urine, primarily as unmetabo-
lized TEA. Diethanolamine and ethanolamine were not
detected in the urine. Some of the radioactivity, *17%, was Repeated Dose Toxicity
excreted in the feces. The average amount of radioactivity Dermal
recovered in the tissues after 24 hours was 3.1%. Triethanolamine. As given in the original CIR safety assess-
The NTP examined the ADME of TEA following iv admin- ment of TEA,1 toxicity was reported in a closed-patch contin-
istration to B6C3F1 mice and F344 rats.28 Groups of 4 female uous exposure test using 10 guinea pigs in which commercial
mice and 4 female rats were given a single iv dose of 3 mg/kg and high-purity TEA, 8 g/kg, was applied daily 5 d/wk. All
[14C]triethanolamine in isotonic saline. For mice, the dose con- guinea pigs died by the 17th application; adrenal, pulmonary,
tained 6 mCi, with the appropriate amount of nonlabeled TEA, hepatic, and renal damage were observed. In a 13-week study, 1
for a dosing volume of 2 mL/kg. (Radiochemical purity of mg/kg of a hair dye formulation containing 0.1% to 0.15% or
[14C]triethanolamine was 97%; the purity of nonlabeled TEA 1.5% TEA was applied to the backs of 12 rabbits for 1 hour,
was confirmed, but the purity was not stated.) At 24 hours, 26% twice weekly. The test site skin was abraded for half of the
and 14% of the dose were excreted in the urine and feces, animals. No systemic toxicity was observed, and there was no
respectively, while at 72 hours, these values were 62% and histomorphologic evidence of toxicity. In a 6-month study in
28%, respectively. The TEA was excreted mostly unchanged. which TEA was applied caudally to rats for 1 h/d, 5 days/wk,
Little, <0.5%, was detected in expired carbon dioxide. For rats, no toxic effects were observed with a 6.5% solution. However,
the dose contained 47 mCi, with the appropriate amount of using a 13% solution, changes (not specified) were seen in liver
nonlabeled TEA, for a dosing volume of 1 mL/kg. Much more and central nervous system function. The addition of 1.4 mg/L
of the radioactivity was excreted in the urine of rats compared TEA to the drinking water of the rats dosed dermally with 13%
to mice, and excretion was more rapid. Approximately 90% of TEA did not increase the toxic effects.
the dose was recovered in the urine in 24 hours, and 98% in 72 In a 2-week study, undiluted TEA (purity not specified) was
hours, mostly as unchanged TEA. Similar to mice, <0.5% was applied dermally to B6C3F1 mice and F344 rats, 5 days/wk.31
detected in expired carbon dioxide. Only 0.9% of the radio- Dose levels of TEA were 0.21, 0.43, 0.84, 1.69, and 3.37 g/kg
activity was detected in the tissues after 72 hours. for the mice and 0.14, 0.28, 0.56, 1.13, and 2.25 g/kg for rats.
Chronic active necrotizing inflammation of the skin at the
application site occurred at a greater frequency and severity
Toxicological Studies in rats than in mice. No renal or hepatic lesions were detected
with either species.
Acute (Single) Dose Toxicity In a preliminary study, 50 mL of 1% to 100% TEA was
Dermal applied to the backs of male C3H mice, 5 days/wk for 2 weeks,
Triethanolamine. As reported previously,1 the acute dermal and mild epidermal hyperplasia was observed in mice treated
toxicity of TEA was examined using groups of 6 rabbits. Undi- with 25%, 50%, or 100% TEA.32 Based on these results, a 13-
luted TEA, 91.8% and 88.1% active, was applied to the intact week study was completed in which 50 mL of 0%, 10%, 33%, or
and abraded skin of 3 rabbits under a 24 hours occlusive patch. 100% TEA (99.3% pure) in acetone was applied 3/wk to a

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74S International Journal of Toxicology 32(Supplement 1)

clipped site on the backs of 15 male and female C3H/HeJ mice. due to severe dehydration. No treatment-related changes were
(The approximate daily doses were 0, 0.14, 0.46, or 2.0 g/kg for observed in mice given 4% TEA or rats given 2% TEA in the
males, respectively, and 0, 0.16, 0.54, or 2.3 g/kg for females, drinking water.
respectively.) No treatment-related clinical signs of toxicity, skin
irritation, or mortality were observed during the study. A mild Inhalation
epidermal hyperplasia was observed in treated male and female Triethanolamine. In a dose-range finding inhalation study, 5
mice at all 3 concentrations tested, and this reaction was consid- male and 5 female Wistar rats were exposed, nose only, for 5
ered to be evidence of mild irritation associated with repeated consecutive days to 100, 200, or 400 mg/m3 TEA (target con-
application of TEA. centrations; 98.9% pure) for 6 hours.36 Concentration-dependent
In a 13-week NTP dermal study using male and female laryngeal inflammation and edema were observed at micro-
B6C3F1 mice, application of 250, 500, 1000, or 2000 mg/kg scopic examination, and the no-observed adverse effect concen-
bw TEA in acetone or 4000 mg/kg neat resulted in decreased tration (NOAEC) was 100 mg/m3. The full, 28-day/20-day
mean body weights and body weight gains for some male exposure study used target concentrations of 0, 20, 100, and
mice.33 (Purity of TEA was 99%. Functional group titration 500 mg/m3, and the mass median aerodynamic diameter was
indicated <0.4% ethanolamine or diethanolamine.) Irritation was 0.7 to 1.1 mm. A functional observational battery was conducted
observed for the highest dose group. Microscopically, inflamma- using 7 rats/sex/group. Minimal-to-moderate focal inflammation
tion was observed for this dose group and acanthosis was noted in the submucosa of the larynx was observed; effects were con-
for all dose groups, with severity increasing with dose. Absolute centration dependent. No systemic toxicity was observed, and
kidney and liver weights of males and females of the 4000 mg/ there were no effects on organ weights. There were no indica-
kg group and relative kidney to body weights of males dosed tions of neurotoxicological effects. Based on the results of this
with 1000 mg/kg were increased compared to controls. Abso- study, the 90-day NOAEC for local irritation was calculated to
lute and relative spleen weights were also significantly increased be 4.7 mg/m3. (The extrapolation of the 28-day laryngeal irrita-
in high dose female mice compared to controls. tion used the calculation of benchmark concentrations for a 5%
In a 13-week dermal study using male and female F344/N incidence of mucosal inflammation, without consideration of
rats, application of 125, 250, 200, or 1000 mg/kg body weight severity, using a multistage model.)
TEA (99% pure) in acetone or 2000 mg/kg neat resulted in In 14-day inhalation studies, B6C3F1 mice and F344 rats
significant decrease in mean body weights and body weight were exposed to 125, 250, 500, 1000, or 2000 mg/m3 TEA
gains in the high-dose animals.33 (Functional group titration (purity not specified) 6 h/d, 5 d/wk, for 2 weeks.37,38 Female
indicated <0.4% ethanolamine or diethanolamine present.) Irri- mice and male and female rats of the high-dose group had
tation was observed at the application site. Microscopic lesions decreased body weights, and male mice of the high-dose group
included acanthosis and inflammation. Kidney weights of had increased kidney weights. Increased kidney weights in rats
males and females dosed with 500 mg/kg were increased dosed with 500 mg/m3 and decreased thymus and heart
compared to controls, and dosed females, but not males, had weights in mice at all doses were not clearly associated with
greater incidences of nephropathy, when compared to controls. TEA. The only histopathologic observation was a minimal
acute inflammation of the laryngeal submucosa in both mice
TEA-lauryl sulfate. As reported previously,9 in a 28-day der- and rats; however, this occurred sporadically, and there was no
mal study, application of a diluted shampoo containing 1% dose response associated with this lesion.
TEA-lauryl sulfate to rabbit skin caused erythema, edema,
wrinkling, eschar formation, and severe desquamation. In a
13-week dermal study in rabbits with a diluted shampoo con-
taining 2.4% TEA-lauryl sulfate, mild erythema and dryness
Reproductive and Developmental Studies
were observed. Dermal
Triethanolamine. As reported previously,1 hair dyes containing
Oral 0.1% to 0.15% or 1.5% TEA were applied topically to the
Triethanolamine. As reported previously,1 oral studies were shaved skin of groups of 20 gravid rats on days 1, 4, 7, 10,
conducted in which groups of 8 to 20 rats were dosed with 0.2 13, 16, and 19 of gestation, and the rats were killed on day 20 of
to 2.61 g/kg/d TEA for 60 days to 6 months, and groups of 8 gestation. No developmental effects were observed.
guinea pigs were dosed with 0.2 to 1.6 g/kg/d TEA for 60 or The TEA, 0.5 g/kg in acetone (purity not stated), was
120 doses. Repeated oral ingestion of TEA produced evidence applied dermally to clipped skin on the back of male and
of hepatic and renal damage in both the species. Some deaths female F344 rats.39 A volume of 1.8 mL/kg was applied daily
occurred in groups of rats fed with 0.3 g/kg/d TEA. for 10 weeks prior to mating, during mating, and through gesta-
More recently, male and female B6C3F1 mice and F344 rats tion and lactation. No effect on mating or fertility or offspring
were given drinking water containing 2% to 8% TEA (purity growth or survival was observed. A similar study was per-
not specified) for 14 days.34,35 Male and female high-dose mice formed in which Swiss CD-1 mice were given daily applica-
and male and female rats given 4% TEA had decreased body tions of 2 g/kg TEA at a volume of 3.6 mL/kg.40 No adverse
weights. All but 1 of the high-dose rats were euthanized early developmental effects were observed.

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Fiume et al 75S

Oral 1000 mg/kg/d to female B6C3F1 mice.47 Purity of TEA was

99þ%. Using high-performance liquid chromatography/mass
Triethanolamine. A Chernoff-Kavlock teratogenicity screening
spectrometry, 0.491% diethanolamine was detected as impure.
test was performed using mated female CD-1 mice, in which
A slight increase in diethanolamine was seen in acetone and
the animals were dosed by gavage with 1125 mg/kg/d TEA on
ethanol solutions after 11 days of storage; the dose formula-
days 6 to 15 of gestation.41 (It was stated that the TEA was the
tions were prepared approximately every 2 weeks. The body
‘‘purest grade commercially available.’’) No adverse develop-
weights of high-dose males were decreased compared to con-
mental effects were observed.
trols during weeks 17 to 37 and at the end of the study. Dermal
irritation increased with increasing dose and was more severe
Genotoxicity in males than in females. At necropsy, treatment-related epi-
dermal hyperplasia, suppurative inflammation, and ulceration
In Vitro
and dermal chronic inflammation occurred at the application
Triethanolamine. As reported previously,1 TEA, at the concentra- site in most test groups, and the incidence and severity
tions of 100 mg/plate, was not mutagenic in Salmonella typhi- increased with increasing dose. Lesions were found, and it was
murium with or without metabolic activation. The TEA with concluded that there was equivocal evidence of carcinogenic
sodium nitrite, but not TEA alone, was mutagenic in Bacillus activity of TEA in male mice, based on the occurrence of liver
subtilis without metabolic activation. The NDELA, which is not hemangiosarcoma, and some evidence of carcinogenic activity
mutagenic in B subtilis without metabolic activation, was found in female mice, based on increased incidences of hepatocellular
in the mixture. In an unscheduled DNA synthesis test in which adenoma.
primary rat hepatocyte cultures were exposed to 108 to 101 The carcinogenic potential of TEA was evaluated using a
mol/L TEA and [3H]thymidine, simultaneously, TEA did not TgAC transgenic mouse model.48 Groups of 10 to 15 female
appear to cause DNA-damage-inducible repair. homozygous mice were dosed dermally with 3 to 30 mg TEA/
In more recent reports, TEA, in distilled water or dimethyl- mouse in acetone, 5/wk for 20 weeks. The TEA was inactive
sulfoxide, was not mutagenic to Escherichia coli42 or S typhi- in Tg.AC mice.
murium, with or without metabolic activation, at doses of 0 to
20 000 mg/plate.42–44 The TEA (88.2% purity) did not cause
gene conversion in Saccharomyces cerevisiae.43 The TEA was Oral
negative in a rec assay at doses of 0 to 4000 mg/disk. No Triethanolamine. The oral carcinogenic potential of TEA was
induction of sister chromatid exchanges occurred in Chinese examined by administering 1% or 2% TEA in drinking water
hamster ovary cells at 0 to 1010 mg/mL without metabolic to groups of male and female B6C3F1 mice for 82 weeks.49
activation or 0 to 10 100 mg/mL with metabolic activation,45 Diethanolamine was present as an impurity at 1.9%. Body
and chromosomal aberrations were not induced in cultured rat weights of male mice of the 2% group were decreased during
liver cells43 or at doses of 5 to 100 mg/mL in cultured Chinese weeks 1 to 20 when compared to controls. No significant
hamster cells.42,45 The TEA, 25 to 500 mg/mL, was negative in changes in organ weights were observed. No dose-related
a cell transformation assay using hamster embryo cells.42 increase in the incidence of any tumors was observed in the
treated groups, and there was no evidence of carcinogenic
In Vivo potential of TEA upon oral administration.
Drinking water containing 1% or 2% TEA was given to
Triethanolamine. A mouse peripheral blood micronucleus test was groups of male and female F344 rats for 2 years.50 Diethano-
performed using samples collected from mice, which were dosed lamine was present as an impurity at 1.9%. From week 69
dermally for 90 days with 0 to 4 g/kg TEA in an NTP study.46 onward, the dose concentrations for females were reduced by
Results were negative in both male and female mice. half because of associated nephrotoxicity. A dose-related
decrease in body weight gain was reported for male and female
Carcinogenicity test group rats, and a dose-dependent increase in mortality,
starting at week 60, was observed. Absolute and relative kidney
Dermal to body weights were significantly increased in males and
Triethanolamine. As reported previously,1 in a series of 3 experi- females, and the increase was dose related. Severe chronic
ments using a total of 560 CBA  C57Bl6 male mice, the nephropathy was statistically significantly increased in males
carcinogenic effects of 99%þ pure TEA and 80%þ industrial of the high-dose group and females of both the dose groups. No
grade TEA and the cocarcinogenic effects of TEA and syntanol treatment-related effects were found in the liver. There was no
DC-10 (alcohols C10-18 ethoxylated) were examined over a increase in the incidence of any tumors in the treated groups
14- to 18-month time frame. The TEA was not carcinogenic or compared to controls when using the chi-square test. Since
cocarcinogenic. increased nephrotoxicity appeared to affect the life span of the
More recently, a 2-year study was performed in which TEA treated animals, especially the females, an age-adjusted statis-
in acetone was applied dermally at doses of 200, 630, or 2000 tical analysis was performed on the incidences of main tumors
mg/kg/d to male B6C3F1 mice and at doses of 100, 300, or or tumor groups for males and females, and a positive trend was

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76S International Journal of Toxicology 32(Supplement 1)

noted in the occurrence of hepatic tumors (neoplastic nodule/ patch test.55 The tissues used in the in vitro tests were fully
hepatocellular carcinoma) in males and of uterine endometrial differentiated 3-dimensional reconstituted human epidermal
sarcomas and renal-cell adenomas in females. The researchers cultures. Each in vitro test was performed in triplicate. In the
stated that because these tumors have been observed sponta- first test, the in vitro patch test, TEA was applied to the skin
neously in F344 rats, and since their incidences in the control samples for 4 hours using a 0.95-cm2 polypropylene chamber.
group was lower than that of historical controls, the occurrence In the second in vitro test, the direct topical application test,
of the tumors may not be attributable to TEA. Instead, 100 mL TEA was applied directly to a 0.63-cm2 area of the
increased incidence of renal tumors in the high-dose group may epidermal surface for 4 hours. Histology, cell viability was
have been associated with renal damage. The researchers con- determined via 3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyl tet-
cluded that TEA was toxic to the kidneys, especially in razolium bromide reduction, and interleukin 1a (IL-1a) release
females, but it was not carcinogenic to F344 rats. end points were measured in both the tests, and a combination
of the outcomes of these end points was used to determine the
Possible Mode of Action for Carcinogenic Effects of TEA potential for irritation. The TEA, which was described as ‘‘non-
classified’’ in the Draize and human patch tests, was classified
It has been reported that choline deficiency induces liver cancer as a nonirritant in the in vitro patch test, and as an irritant in the
in rodents51,52; therefore, the potential of TEA to cause choline direct topical application test. The irritant classification was
deficiency in the liver of female B6C3F1 mice was investigated based on tissue necrosis and a higher amount of released IL-
as a mode of tumorigenesis.53 Female mice were dosed der- 1a compared to the negative control (water). The concentration
mally with unoccluded applications of 10, 100, 300, or 1000 of TEA tested for each of the studies was not specified.
mg/kg/d TEA in acetone, 5 d/wk for 3 weeks, and female CDF
rats were dosed in a similar manner with 250 mg/kg/d TEA. Non-human
(Purity of TEA was 99þ%; diethanolamine impurity levels Triethanolamine. As reported previously,1 the primary skin
were 0.04% and 0.45%.) No clinical signs of toxicity were irritation potential of undiluted TEA was determined using rab-
noted for mice or rats. Phosphocholine and betaine levels were bits. After 10 open applications of 0.1 mL to rabbit ears and 10
statistically significantly decreased in the high-dose mice, and unoccluded applications to the intact skin of the abdomen, and 3
the levels were decreased in these mice. The decrease in phos- semioccluded 24-hour applications to abraded skin, it was con-
phocholine levels was variable but dose related. (More pro- cluded that TEA was slightly-to-moderately irritating, and pro-
nounced effects were observed when the TEA having 0.45% longed or repeated exposure may be irritating. Twenty-four
diethanolamine impurity was used.) In rats, no changes in cho- hours occluded patch tests using groups of 8 male rabbits were
line or its metabolites were noted. The potential of TEA to performed in 22 laboratories; the primary irritation score ranged
inhibit the uptake of [3H]choline by Chinese hamster ovary from 0 to 5.5 of 24, and the total score for all 22 laboratories was
cells was also investigated, and a dose-related decrease was 27.3 of 400. In a preliminary study, occlusive dermal applica-
observed. The researchers concluded that TEA may cause liver tions of 50% to 100% aq TEA to pairs of guinea pigs resulted in
tumor in mice via a choline depletion mode of action, and this 1 erythematic reaction to undiluted TEA, and in another prelim-
effect is likely caused by the inhibition of choline uptake by the inary study, no irritation was observed when 5%, 10%, or 25%
cells. The researchers stated that although diethanolamine TEA was applied to the backs of guinea pigs.
impurity may contribute to choline depletion, a choline- In a more recent study, the irritancy potential of TEA (purity
deficiency mode of tumorigenesis appears to be a property of not specified) was evaluated in an ear-swelling test using
TEA, exclusive of any diethanolamine impurity. female BALB/c mice.56 A significant increase in irritancy was
observed with 25% and 50% TEA compared to the vehicle (4:1
Carcinogenic Potential in Humans acetone–olive oil).

Triethanolamine. According to an evaluation of TEA by the TEA-lauryl sulfate. As reported previously,1 the dermal irrita-
International Agency for Research on Cancer (IARC) Working tion of TEA-lauryl sulfate ranged from not irritating to moder-
Group, there is inadequate evidence in humans, as well as in ately irritating in rabbit skin at concentrations up to 46%.
animals, for the carcinogenicity of TEA.54 The overall evalua- Concentrations of up to 10% produced slight-to-mild irritation,
tion of the IARC is that TEA is not classifiable as to its carci- while concentrations of 25% and 39% produced moderate irrita-
nogenicity to humans (group 3). tion. Mild irritation was reported with 40% TEA-lauryl sulfate,
while testing with 46% TEA-lauryl sulfate produced nonirritant
results in some laboratories and irritant results in others.
Irritation and Sensitization
Human
Dermal Irritation Triethanolamine. As reported previously,1 clinical studies
In vitro were performed with formulations containing TEA. In a few
Triethanolamine. The dermal irritation potential of TEA was studies on formulations containing 0.45% to 2.4% TEA, the
determined in 2 in vitro assays, and these results were com- researchers concluded that no irritation was observed, while
pared to results obtained in the in vivo Draize test and human short-lived acute irritation was reported for formulations

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Fiume et al 77S

containing 1.9% to 2.6% TEA. However, according to the groups of 5 BALB/c mice.56 This study was performed in
Expert Panel’s interpretation of the results of a number of other conjunction with the ear-swelling test described previously.
studies, formulations containing 0.83% to 20.04% TEA were Lymphocyte proliferation increased with dose, but the
irritating. In clinical provocative testing using 5 to 10 ‘‘hyper- increases were not statistically significant. The TEA was not
reactors,’’ 100% TEA produced an irritant reaction on nonscar- identified as a sensitizer in the LLNA.
ified skin, 10% TEA in ethanol was a marked irritant on scar- Also, the hypersensitivity of mice to TEA (99þ% pure) was
ified skin, whereas 5% in ethanol was a slight irritant on determined.59 The TEA, in an acetone–olive oil mixture (4:1)
scarified skin. at the concentrations of 3%, 10%, or 30%, was applied daily for
More recently, a patch test with TEA (purity not specified) 5 consecutive days to groups of 8 female B6C3F1 mice, and the
was performed on 20 subjects, and erythema and transepidermal animals were challenged 7 days later with a 30% solution. For
water loss (TEWL) were measured, and the contents of suction some animals, dermabrasion, as well as intradermal injections
blister fluids (SBFs) were evaluated for primary proinflamma- of Freund complete adjuvant (FCA), was used. There were no
tory mediators.57 The aq TEA, 50% to 100%, was applied occlu- treatment-related effects on survival or body weights. There
sively for 24 hours; 100 to 200 mL, concentrated to 20 mL with were no statistically significant or dose-related hypersensitivity
drying, were applied. The percentage of nonresponders to 100% responses to TEA observed with a radioisotopic method or in
TEA was 80%; those that did respond had weak and nonuniform an ear-swelling test, with or without FCA.
erythema. The incidence was below or about that found with the Results were negative in 3 maximization studies examining
solvent controls. For the challenge phase, 765 mmol/cm2 TEA the sensitization potential of TEA.25 In the first test, performed
was applied occlusively to 12 subjects for 6 to 24 hours. No using Pirbright-White guinea pigs, induction consisted of intra-
increase in TEWL or change in eicosanoid profile of the SBF dermal injections of 2% TEA (98.9% pure) in isotonic saline
was observed. The TEA was a nonirritant. and epicutaneous application of undiluted TEA, and challenge
used 10% TEA in isotonic saline. In the second test using 20
TEA-lauryl sulfate. As reported previously,9 in clinical studies,
Dunkin-Hartley guinea pigs, intradermal and epicutaneous
shampoos containing 10.5% TEA-lauryl sulfate caused no irri-
inductions used 1.5% technical grade TEA and 25% technical
tation with semiocclusive patches or ‘‘use’’ testing, while
grade TEA with 10% sodium lauryl sulfate pretreatment,
diluted shampoos containing 0.15% to 7.5% produced no-to-
respectively, and challenge doses consisted of 1%, 5%, and
moderate irritation. In an occlusive patch test, a diluted sham-
10% technical and analytical grade TEA. In the third study,
poo containing 4.4% TEA-lauryl sulfate was highly irritating in
with 15 animals and the same induction protocol just described
a 21-day cumulative irritation test.
(grade of TEA not specified), 2 of the 15 reacted to 10% TEA
More recently, the dermal irritation potential of a 10% solu-
after 1 day but not 3 days.
tion of TEA-lauryl sulfate (vehicle not identified) at neutral pH
was determined using 10 subjects.58 Duhring chambers were Human
applied to the forearm of each subject for 5 days. A 10% Triethanolamine. As reported previously,1 TEAs studied in
solution of TEA-lauryl sulfate caused intense erythema in patch tests conducted over a number of years had positive
nearly all subjects by day 4. Testing was terminated (additional reactions for contact dermatitis. The expert panel interpreted
details were not provided). these findings as sensitizing.
In 1 patch test with 64 subjects in which 0.5 mL of 1% TEA
(containing 88.6% TEA and 6% diethanolamine) was used, the
Sensitization test solution was not sensitizing. Overall, the majority of formu-
Non-human lations containing 0.83% to 4.2% TEA were not sensitizing, and
Triethanolamine. As reported previously,1 TEA was not a a formulation containing 20.04% TEA, tested on 26 subjects,
sensitizer in guinea pigs when 20 guinea pigs were given der- was not considered sensitizing when it produced 2 slight reac-
mal applications of undiluted TEA 1/wk for 3 weeks, fol- tions upon challenge. However, according to the interpretation
lowed by challenge applications 14 and 21 days after dosing. of the CIR Expert Panel, there were a few cosmetic formulations
No sensitization was seen when 4 lots of TEA were evaluated containing 2.1% and 2.4% TEA that the panel determined to be
using groups of 20 guinea pigs; induction applications were sensitizing. In other studies with cosmetic formulations contain-
applied for up to 6 hours, 1/wk, for 3 weeks, and the chal- ing 2.1% TEA, the researchers concluded that reactions
lenge was performed after 14 days. One of the studies used observed at challenge were probably due to skin fatigue.
undiluted TEA during induction, while the other 3 studies used TEA-lauryl sulfate. As reported previously,9 undiluted sham-
50% TEA at induction. All 4 studies used challenge patches poo formulations containing 10.5% TEA-lauryl sulfate and
with 90% TEA. No sensitization was observed in a similar dilutions of formulations containing 0.15% to 7.5% TEA-
study in which induction patches contained a 25% active TEA lauryl sulfate were not sensitizers in clinical studies.
solution, and a challenge patch with the 25% solution was
applied after 1 week of nontreatment. Provocative testing. A group of 737 patients was patch tested with
More recently, the sensitization potential of TEA was eval- 6 different emulsifiers, including 2.5% TEA (purity not spec-
uated in a local lymph node assay (LLNA) performed with ified) in petrolatum (pet).60 The patch tests were performed

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78S International Journal of Toxicology 32(Supplement 1)

according to International Contact Dermatitis Research Group classified as non/mildly irritating at these concentrations. In the
(ICDRG) recommendations. A total of 39 patients had positive luminescent bacterial toxicity test (ie, the Microtox test), TEA
reactions to the emulsifiers, and 20 of those patients, 5 males had an half maximal effective concentration (EC50) of 110 mg/
and 15 females, had positive reactions to TEA. There were 106 L, corresponding to non/moderate irritant potential.64 In the
irritant reactions reported. The results were clinically relevant EYTEX assay, undiluted TEA had an EYTEX/Draize equiva-
in 7 patients. Many of the patients allergic to TEA were also lent of 42.1, corresponding to a prediction of severe ocular
allergic to other ingredients. irritant.65
Over a 4-year period, the incidences of positive patch test
reactions to the same TEA-containing cream were 69 of 171 Non-human
patients in 1 clinic and 49 of 191 in another.61 It was hypothe- Triethanolamine. As reported previously,1 the ocular irrita-
sized that the difference between the clinics was due to the tion potential of 0.005 to 0.1 mL undiluted TEA was evaluated
differences in sampling methods; the first clinic tested only in a number of studies using rabbits. With high concentrations
those patients that had recently used the TEA-containing cream and long contact time, TEA may be irritating to rabbit eyes.
or who had suspected reactions. In the follow-up patch testing Using rabbits, 10% aq TEA produced essentially no irritation
with a total of 54 patients from the 2 clinics, 15 of which were with or without rinsing. A formulation containing 12.6% TEA,
controls, 19 patients had a positive allergic response to the 0.1 mL, was evaluated in a study using 6 rhesus monkeys. Slit
TEA-containing cream, 40 had a positive irritant response, and lamp examination revealed some corneal effects in 2 monkeys
13 had negative responses. With 1.45% to 5% TEA, 6 patients at 24 hours and slight positive fluorescein staining in 1 monkey
had a positive response. However, with 5% to 20% TEA stea- at 72 hours.
rate, 8 of 8 patients and 15 of 15 controls had a positive irritant
TEA-lauryl sulfate. As reported previously,9 the ocular irrita-
response. (TEA stearate was tested because it was demon-
tion potential of TEA-lauryl sulfate was evaluated in rabbit
strated that TEA stearate was formed from the combination
eyes; irritation ranged from not irritating to severely irritating
of TEA and stearic acid in formulation.) The researchers pos-
at concentrations up to 40%. The severity of irritation observed
tulated the reactions were irritant reactions to TEA stearate.
with each concentration varied among the studies, as illustrated
(The amount of TEA stearate present in formulation was esti-
by 5% TEA lauryl sulfate causing no ocular irritation in 1
mated to be 4.8%, and 6 of 23 patients patch tested with 5%
study, but significant irritation in another.
TEA stearate had irritant reactions).
Over a 15-year period, provocative patch testing using TEA
was performed on 85 098 dermatological patients.25 There
were 323 positive reactions to TEA, and most of the reactions Clinical Assessment
(289) were weak positives. The researchers stated that occupa-
tional exposure was not a risk factor for TEA contact allergy.
Case Reports
Metalworkers that were patients with dermatitis were patch Triethanolamine. Eczema of the face of 2 female patients was
tested with 2.5% TEA in pet.62 The patches were applied for 1 exacerbated by a cream that contained TEA.66 Patch testing
to 2 days. On day 3, 1 (0.5%) of the 216 patients had a positive was performed using the ICDRG standard series, a cosmetic
reaction. battery, the TEA-containing cream, and TEA at 1%, 2%, and
Patch testing was performed with 2.5% TEA in pet in 184 5% in pet. Both the patients reacted to the TEA-containing
patients with suspected metalworking fluid contact dermatitis.63 cream (þreaction) and to 5% TEA pet (þþreaction). One
(All patients were metalworkers.) Patches were applied for 1 or 2 patient reacted to 2% TEA (þreaction), and neither reacted
days. On day 3, 4 patients had any type of positive reactions, 2 to 1% TEA pet. Patch tests were negative for all other com-
(?), and 2 (þ). The percentage of positive reactions was 1.1. pounds. In a control group of 50 patients, patch testing with 5%
TEA pet was negative.
Two cases of occupational asthma in metal workers exposed
Phototoxicity/Photoallergenicity to cutting fluid containing TEA were reported.67 Exposure to
As reported previously,1,9 TEA at cosmetic use concentrations TEA at temperatures higher than that of ambient air was a
was not phototoxic or photoallergenic in non-human and common feature.
human studies, and TEA-lauryl sulfate was not photoallergenic
in human studies. TEA-PEG-3 cocamide sulfate. Two patients with a reaction to a
shampoo were patch tested with the ICDRG standard series and
a 1% aq solution of the shampoo.68 Both the patients had pos-
Ocular Irritation itive patch results to the shampoo only. Subsequent patch test
In vitro with 1% aq TEA-PEG-3 cocamide sulfate (as well as 1% coca-
Triethanolamine. The ocular irritation potential of TEA was midopropyl betaine) produced positive results in both the
evaluated in several in vitro studies. The ocular irritation poten- patients. A total of 20 patients with eczema patch used as
tial of TEA was evaluated in the rabbit corneal epithelium controls had negative patch test results to 10% aq TEA-PEG-
model at concentrations of 0.05%, 0.5%, and 1%; TEA was 3 cocamide sulfate.

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Fiume et al 79S

Summary 2% or 4% TEA in their water. In inhalation studies with TEA in

rats (400 mg/m3) and mice (2000 mg/m3), no observations
This report is a safety assessment of TEA and TEA-containing
were reported that were indicative of a toxic pulmonary effect.
ingredients as used in cosmetics. The TEA is reported to func-
No adverse developmental effects were seen in dermal stud-
tion as a surfactant or pH adjuster, and the other TEA-
ies in which rats and mice were dosed with 0.5 and 2 g/kg TEA,
containing ingredients such as surfactants, skin-conditioning
respectively, in acetone from before mating through lactation
agents, or hair-conditioning agents. TEA-sorbate is reported
or in an oral teratogenicity screening test in mice with 1125 mg/
to function only as a preservative. The TEA is reported to be
kg/d TEA on days 6 to 15 of gestation.
used in 3756 cosmetic ingredients at concentrations of up to 6%
The TEA was negative for genotoxic effects in an Ames test
in leave-on formulations, 19% in rinse-off formulations, and
with or without metabolic activation, gene conversion assay,
0.7% in products that are diluted for (bath) use. All the other
rec assay, sister chromatid exchange assay with or without
ingredients named in this safety assessment that are in use, with
metabolic activation, chromosomal aberration assay, and cell
the exception of TEA-lauryl sulfate (302 uses) and TEA-
transformation assay.
stearate (130 uses), are reported to have less than 20 uses. The
In 2-year dermal carcinogenicity studies with doses of up to
TEA may contain diethanolamine as an impurity.
1000 and 2000 mg/kg/d TEA for male and female mice, respec-
Internationally, data were available from the EU and
tively, and up to 125 and 250 mg/kg/d TEA for male and female
Canada. In the EU, trialkylamines, trialkanolamines, and their
rats, respectively, it was concluded that TEA produced equivocal
salts are allowed for use by the EU at concentrations of up to
evidence of carcinogenic activity in male mice based on the
2.5% in leave-on products; ‘‘other’’ product types do not have a
occurrence of liver hemangiosarcoma, some evidence of carci-
concentration limit for TEA. There are additional restrictions
nogenic activity in female mice based on increased incidences of
regarding conditions for the use of TEA in leave-on and rinse-
hepatocellular adenoma, equivocal evidence of carcinogenic
off products, including a maximum allowable secondary amine
activity in male rats based on a marginal increase in the inci-
content of 0.5% in raw material and a maximum allowable
dence of renal tubule cell adenoma, and no evidence of carcino-
nitrosamine content of 50 mg/kg. According to Health Canada,
genic activity in female rats. In oral carcinogenicity studies in
some leave-on products contain TEA at concentrations of 10%
rats and mice, TEA was not carcinogenic to rats or mice, but it
to 30%, with some reporting concentrations in the range of 30%
was toxic to the kidneys of rats, especially females. Based on the
to 100%.
preliminary data, it has been hypothesized that TEA may cause
Dermal absorption studies of TEA were performed in vitro
liver tumors in mice via a choline-depletion mode of action.
using human skin samples and in vivo using mice and rats. In
The TEA can be a dermal irritant in both animals and
vitro, the absorption of TEA through human skin was low
humans, but it has not been shown to be a sensitizer. Many
under conditions simulating perceived cosmetic use, that is,
of the ingredients in this report are surfactants, which can be
1% to 5% at pH 7.0; approximately 5.5% to 9.5% of the dose
irritating to skin and eyes.
was recovered in the skin after 24 or 72 hours; however, only
*0.5% was recovered in the receptor fluid. In mice,
[14C]triethanolamine in acetone was rapidly absorbed, and
absorption increased with increasing dose. The majority of the Discussion
radioactivity was excreted in the urine, 48% to 56% in 72 Although the CIR Expert Panel noted gaps in the available
hours, primarily as unchanged TEA. The TEA was absorbed safety data for the 31 TEA-containing ingredients included in
more slowly and less extensively in rats than in mice. In rats, this group, the panel relied on the information available for
19% to 28% of the dose was absorbed over a 72-hour period, TEA in conjunction with previous safety assessments of the
and 13% to 24% of the dose was recovered in the urine, mostly components of TEA-containing ingredients. Those data could
as unchanged TEA. In an oral dosing study with rats, TEA was be extrapolated to support the safety of these ingredients. For
rapidly absorbed in the gastrointestinal tract and excreted example, myristic acid has been found safe as used, and the
mostly in the form of unchanged TEA. panel was able to extrapolate these data to support the safety of
In 2- and 13-week repeated dose dermal toxicity studies in TEA-myristate (ie, the TEA salt of myristic acid). Addition-
mice with 250 to 2000 mg/kg bw TEA in acetone or 4000 mg/ ally, some of the ingredients reviewed in this assessment, such
kg bw neat, dermal irritation was observed in the highest dose as TEA-lauryl sulfate, have been previously reviewed by the
group, and kidney and liver weights were increased with the CIR and found to be safe for use in cosmetics.
higher doses. In rats, 125 to 1000 mg/kg bw TEA in acetone or The panel was concerned with the levels of free diethano-
2000 mg/kg bw neat was applied to rats for 13 weeks, and lamine that could be present as an impurity in TEA or TEA-
irritation was observed at the dosing site. Kidney weights were containing ingredients. The panel stated that the amount of free
increased in male and female rats dosed with 500 mg/kg diethanolamine available must be limited to the present prac-
TEA, and dosed females had higher incidences of nephropathy. tices of use and concentration of diethanolamine itself, as
In a 14-day drinking water study, animals given 8% TEA were described in the CIR safety assessment of diethanolamine.
all killed due to severe dehydration before study termination. Dermal carcinogenicity studies performed by the NTP on
Treatment-related changes were not observed for animals given TEA reported equivocal evidence of carcinogenic activity in

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80S International Journal of Toxicology 32(Supplement 1)

male mice based on the occurrence of liver hemangiosarcoma, TEA-C12-15 alkyl sulfate*
some evidence of carcinogenic activity in female mice based on TEA-C11-15 pareth sulfate*
increased incidences of hepatocellular adenoma, and equivocal TEA-C12-13 pareth-3 sulfate*
evidence of carcinogenic activity in male rats based on a mar- TEA-canolate*
ginal increase in the incidence of renal tubule cell adenoma. It TEA-cocoate
has been hypothesized that TEA may cause liver tumors in mice TEA-coco-sulfate*
via a choline-depletion mode of action. Humans are much less TEA-glyceryl dimaleate*
sensitive to this deficiency, and these hepatic findings are con- TEA-hydrochloride
sidered to have little relevance to humans regarding the safety of TEA-hydrogenated cocoate*
the use of TEA in personal care products. TEA-isostearate
The panel was concerned that the potential exists for dermal TEA-lactate
irritation with the use of products formulated using TEA or TEA-laurate
TEA-related ingredients. The panel specified that products TEA-laurate/myristate*
containing these ingredients must be formulated to be TEA-laureth sulfate
nonirritating. TEA-lauryl sulfate
Tertiary alkyl amines such as TEA do not react with N- TEA-myristate
nitrosating agents to directly form nitrosamines. However, ter- TEA-oleate*
tiary amines can act as precursors in nitrosamine formation by TEA-oleyl sulfate*
undergoing nitrosative cleavage. The resultant secondary TEA-palmitate
amine (ie, diethanolamine) can then be N-nitrosated to prod- TEA-PEG-3 cocamide sulfate*
ucts that may be carcinogenic. Because of the potential for this TEA-sorbate*
process to occur, TEA and TEA-containing ingredients should TEA-stearate
not be used in cosmetic products in which N-nitroso com- TEA-sulfate
pounds can be formed. TEA-tallate*
The TEA, TEA-lauryl sulfate, and TEA-stearate can be used TEA-undecylenate*
in products that may be sprayed, and so the panel discussed the
issue of potential inhalation toxicity. In the absence of suffi- *Were the ingredients not in current use (as indicated by *)
cient safety test data to evaluate this end point directly, the to be used in the future, the expectation is that they would be
panel considered other data that were available to characterize used in product categories and at concentrations comparable to
the potential for these ingredients to cause systemic toxicity, others in this group.
ocular or dermal irritation or sensitization, and other effects.
The panel noted that 95% to 99% of particles produced in Author’s Note
cosmetic aerosols are not respirable. Coupled with the small Unpublished sources cited in this report are available from the Direc-
actual exposure in the breathing zone and the concentrations at tor, Cosmetic Ingredient Review, 1101 17th St, Suite 412, Washing-
which the ingredients are used, this information suggested that ton, DC 20036, USA.
inhalation would not be a significant route of exposure that
might lead to local respiratory or systemic toxic effects. Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Conclusion
The CIR Expert Panel concluded that TEA and the 31 related Funding
TEA-containing ingredients, listed below, are safe in the pres-
The author(s) disclosed receipt of the following financial support for
ent practices of use and concentration described in this safety
the research, authorship, and/or publication of this article: The articles
assessment when formulated to be nonirritating and when the in this supplement were sponsored by the Cosmetic Ingredient
levels of free diethanolamine do not exceed the present prac- Review. The Cosmetic Ingredient Review is financially supported
tices of use and concentration of diethanolamine itself. These by the Personal Care Products Council.
ingredients should not be used in cosmetic products in which
N-nitroso compounds can be formed.
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