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GREEN
MEA
CIR EXPERT PANEL MEETING
SEPTEMBER 26-27, 2011
Memorandum
TO: CIR Expert Panel Members and Liaisons FROM: Monice M. Fiume MMF Senior Scientific Analyst/Writer DATE: September 8, 2011 SUBJECT: Draft Amended Safety Assessment of Part I: Ethanolamine and Ethanolamine-Containing
Ingredients; Part II: Ethanolamides Enclosed is the draft amended safety assessment on ethanolamine and ethanolamine-containing ingredients. This is the first time you will be reviewing this document. At the December 2010 Panel meeting, the Panel made the decision to reopen the 1983 safety assessment of Triethanolamine (TEA), Diethanolamine (DEA), and Monoethanolamine (now named Ethanolamine), splitting the report in to three separate documents, and adding related ingredients to each. This is the last of the reports resulting from that split. As each of these split-off reports has been presented, the Panel has been given an exhaustive list of related ingredients and then decided which ingredients were appropriate for inclusion in the safety assessment and which were not. Since the Panel has excluded amides from the re-reviews of DEA and TEA, the draft report you are reviewing has been developed so that monoethanolamine and all ethanolamine-containing ingredients, except the ethanolamides, are presented in the first section of the report, and then the information on the ethanolamides is presented as a second section. The reasoning is that, if the ethanolamides are excluded from this reopened report, we wouldn’t want to lose this group entirely. CIR could then break the ethanolamides (total of 49 ingredients) out of this report and add them to a new re-review of the 1995 safety assessment on Isostearmide MEA, Myristamide MEA, and Stearamide MEA at a later date (maybe December). By creating a section that presents only the information on ethanolamides, we are hoping to facilitate such an approach, while leaving it up to the Panel to make the actual decision. As for the first section of the report, there are 21 ingredients being proposed for inclusion in the re-review of ethanolamine – 2 inorganic acid salts, 8 organic salts, 2 protein salts, 3 organic-substituted inorganic acid salts, and 6 alkyl substituted ethanolamines. In the review of DEA, the Panel did not find it appropriate to include the alkyl substituted diethanolamines. Since quite a bit of data was available on the alkyl-substituted ethanolamines, rather than summarize and include those data at this stage, it was decided that those data would be added only if the alkyl-substituted ethanolamines were actually included in the re-review of ethanolamine. Some of the ingredients included in this re-review include a “component” that has been reviewed by the CIR. For example, MEA-Cocoate is the ethanolamine salt of coconut acid; coconut acid has been reviewed by the CIR. Tables 2a and 2b provide the conclusions from the CIR reports on the component ingredients. The data profile indicates the types of data that were available in those reports. The Panel should consider whether read-across data from existing reports can be used.
MEA/Page 2
The following unpublished data have been summarized for this draft report, and these papers are included with this report package:
1. Concentration of Use by FDA Product Category: Ethanolamine and Ethanolamine Containing Ingredients. Memo dated July 5, 2011.
2. Ethanolamine hydrochloride. Two-generation reproduction toxicity study in Wistar rats; administration via diet.
3. Hepatic choline level in rats after repeated dose feeding of ethanolamine hydrochloride. At this meeting, the Panel should decide which ingredients to include. If the data are sufficient to assure the safety of those ingredients in cosmetics, the Panel should develop a rationale and a tentative conclusion and issue that for public comment.
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 1
History: Ethanolamine
Original Report: In 1983, the Expert Panel determined that TEA, DEA, and MEA were 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 ethanolamines should not exceed 5%. Ethanolamine (MEA) should be used only in rinse-off products. Triethanolamine (TEA) and diethanolamine (DEA) should not be used in products containing N-nitrosating agents. December 2010: a formal rereview package was presented to the Panel for the report on TEA, DEA, and MEA
- the report was split into 3 separate documents – DEA, TEA, and MEA, - appropriate new ingredients are to be added to each report
September 26-27, 2011: Re-Review Draft Report The Draft Amended Safety Assessment was presented to the Panel. The assessment was divided into two parts. The first part, entitled Ethanolamine and Related Ethanolamine-Containing Ingredients, included 21 ingredients for consideration for inclusion in the re-review of ethanol-amine Part II, entitled Ethanolamides, was created so that if the Panel determined that the ethanol-amides were not appropriate as part of the re-review of ethanolamine, the Panel could decide that it would be appropriate to re-review isostearamide, myristamide, and stearamide MEA (reviewed in 1995), and included these ethanolamides
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 2
MEA SEARCH STRATEGY – SCIFINDER – June 10, 2011
1. Searched all ingredients (except MEA) with CAS #s (38 substances) – 18,866 references a. Refined by document type – 7091 references b. Refined by removing documents in Chinese – 5701 references
2. Searched MEA by CAS # a. Refined by document type – 14229 references b. Refined by year 1980+ - 11440 references
3. Combined results of SS 1 and 2 above - 18968 references 4. Searched all ingredients without CAS #, refined by document type
a. MEA laureth carboxylate – 1 b. MEA steareth carboxylate – 0 c. MEA talloweth – 0 d. MEA hydrolyzed Silk – 0 e. MEA hydrolyzed collagen – 1 f. MEA distearyl phosphate – 0 g. Butylethanolamine – 128 h. Stearamidoethyl ethanolamine phosphate - 0 i. Lysophosphatidylethanolamine – 1982 j. Azelamide MEA – 0 k. Cocamide methyl MEA – 0 l. Deoxyphytantriyl Palmitamide MEA – 0 m. Hydroxyethyl pantotheamide – 0 n. Hydroxylpropyl MEA – 227 o. Myristoyl/palmitoyl/oxostearamide/arachamide DEA – 0 p. Oatamide MEA – 0 q. Palm kernelamide MEA – 0 r. Palmamide MEA – 0 s. Panthothenamide MEA – 0 t. Peanutamide MEA – 0 u. PEG Cocamide MEA – 0
5. Combined SS 3 and all results of SS 4 – 18413 references 6. Applied the following qualifiers to SS 5 above
a. Carcinogen – 593 b. Mutagen – 79 c. Teratogen – 15 d. Developmental toxicity – 56 e. Reproductive toxicity – 8 f. Dermal – 46 g. Toxicology – 728 h. Ocular – 164 i. Irritation – 86 j. Sensitization – 119 k. Photosensitization – 59 l. ADME – 7 m. Dermal absoroption – 4 n. Excretion – 70 o. Pharmacokinetics – 116 p. Kidney renal – 219 q. Choline deficiency – 20 r. Nitrosation – 53
7. Combined all of SS 6 – 2032 references Keep Me Posted Results are received weekly
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 3
SEARCH STRATEGY – TEA/DEA/MEA
TOXLINE PUBMED EU Jan 17. 2010 DEA not to be used 111-42-2 & choline 13 15 111-42-2 & carcinogen* 83 21
choline & deficiency & human & cancer
38
TEA restrictions 102-71-6 & carcinogen* 55 11 102-71-6 & choline 5 2 MEA restrictions Jan 25, 2010 102-71-6 OR 111-42-2 (1980-current)
1003 (downloaded 58)
UPDATED SEARCH May 31, 2010
(102-71-6 OR 111-42-2 OR 141-43-5) AND (REPRODUCTI* OR TERATOGEN*) – 142 (Toxline); 41 (DART)
(102-71-6 OR 111-42-2 OR 141-43-5) AND (DEVELOPMENT* OR FETOTOX*) – 378 (Toxline); 47 (DART) (102-71-6 OR 111-42-2 OR 141-43-5) AND TOX* (102-71-6 OR 111-42-2 OR 141-43-5) AND (GENOTOX* OR MUTAGEN* OR CLASTOGEN*) – 286 Toxline); 7 (DART); 9 (CCRIS) (102-71-6 OR 111-42-2 OR 141-43-5) AND (SENSITIZA* OR SENSITIZE* OR SENSITIS* OR IRRIT*) – 306 (Toxline); 6 (DART) (102-71-6 OR 111-42-2 OR 141-43-5) AND (METBOLI* OR ABSORB* OR ABSORP* OR DISTRIBUT* OR EXCRET*) – 403 (Toxline); 18 (DART) 141-43-5 AND CARCINOGEN* – 193 141-43-4 AND CHOLINE - 0
Total Download (most duplicates removed): 1218
UPDATED SEARCH – Sept 21, 2010 – last 12 mos 102-71-8 OR 111-42-2 OR 141-43-5 128 hits/1 useful
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 4
Eth
anol
amin
e, E
than
olam
ine-
Ingr
edie
nts
, an
d “
Com
pon
ents
” D
ata
Pro
file
* –
Sep
t 20
11 –
Wri
ter,
Mon
ice
Fiu
me
Previously Reviewed#
Reported Use
Method of Manufacture
Toxicokinetics
Animal Tox – Acute, Dermal
Animal Tox – Acute, Oral
Animal Tox, Acute, Inhalation Animal Tox – Rptd Dose, Dermal Animal Tox, Rptd Dose, Oral Animal Tox – Rptd Dose, Inhalation
Repro/Dev Tox
Genotoxicity
Carcinogeni-city
Dermal Irr/Sens
Ocular Irritation
Eth
anol
amin
e 19
83
X
X
X
X
X
X
X
X
X
X
X
X
X
Butylethanolam
ine
DibutylEthanolam
ine
DiethylEthanolam
ine
DimethylM
EA
EthanolamineHCl
X
X
X
EthylEthanolam
ine
MEAPPG‐6Laureth‐7Carboxylate
MEA‐Benzoate
MEA‐Cocoate
X
MEA‐DicetearylPhosphate
MEA‐HydrolyzedCollagen
X
MEA‐HydrolyzedSilk
MEA‐LaurethSulfate
X
MEA‐Laureth‐6Carboxylate
MEA‐LaurylSulfate
X
MEA‐PPG‐8‐Steareth‐7Carboxylate
MEA‐Salicylate
MEA‐Sulfite
MEA‐Tallowate
X
MEA‐Undecylenate
Methylethanolam
ine
“CO
MP
ON
EN
TS
”
Am
mon
ium
& S
odiu
m L
aury
l Sul
fate
19
83
X
X
X
X
X
X
X
X
X
X
X
BenzoicA
cid
curr
ent
X
X
X
X
X
X
X
X
X
X
X
X
X
C
ocon
ut I
ngre
dien
ts
2008
X
X
X
X
X
X
X
X
X
HydrolyzedCollagen
1985
X
X
X
X
X
X
Is
oste
aric
Aci
d 19
83
X
X
X
X
Laureths
2010
X
X
X
X
X
X
X
X
X
X
X
PP
G
2010
X
X
X
X
X
X
S
odiu
m L
aure
th S
ulfa
te/S
ulfa
ted
Eth
oxyl
ated
Alc
ohol
s 20
10
X
X
X
X
X
X
X
X
X
S
tear
eths
20
10
*“X
” in
dica
tes
that
dat
a w
ere
avai
labl
e in
a c
ateg
ory
for
the
ingr
edie
nt
# ye
ar th
e re
port
was
pub
lish
ed
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 5
1
Eth
aola
mid
es D
ata
Pro
file
* –
Sep
t 20
11 –
Wri
ter,
Mon
ice
Fiu
me
Previously Reviewed*
CIR Review on Component*
Reported Use
Info on Free MEA Content
log P value
Toxicokinetics Data
Animal Tox – Acute, Dermal
Animal Tox – Acute, Oral
Animal Tox, Acute, Inhalation Animal Tox – Rptd Dose, Dermal Animal Tox, Rptd Dose, Oral Animal Tox – Rptd Dose, Inhalation
Repro/Dev Tox**
Genotoxicity
Carcinogenicity - Dermal
Dermal Irr/Sens
Ocular Irritation
Ace
tam
ide
ME
A
1993
x x
x
x x
x
x
x
x A
zela
mid
e M
EA
2010
Bab
assu
amid
e M
EA
2011
Beh
enam
ide
ME
A
x
B
ehen
amid
e M
EA
C16‐22AcidAm
ideMEA
x
C
ocam
ide
ME
A
1999
20
08
x
x x
x
x
x
x
C
ocam
ide
Met
hyl M
EA
2010
x
Coc
amid
opro
pyl B
etai
nam
ide
ME
A
Chl
orid
e
2010
x
Deo
xyph
ytan
triy
l Pal
mit
amid
e M
EA
Hex
ylox
odec
anam
ide
ME
A
x
H
exyl
oxod
ecan
amid
e M
EA
Pho
spha
te
H
ydro
xyet
hyl P
anto
then
amid
e M
EA
1987
Hyd
roxy
prop
yl B
isis
oste
aram
ide
ME
A
H
ydro
xypr
opyl
Bis
laur
amid
e M
EA
Hyd
roxy
prop
yl B
ispa
lmit
amid
e M
EA
Hyd
roxy
prop
yl B
isst
eara
min
de M
EA
Hyd
roxy
stea
ram
ide
ME
A
19
99
x
Is
oste
aram
ide
ME
A
1995
19
86
L
acta
mid
e M
EA
1998
x
Lau
ram
ide
ME
A
19
87
x
x
x
x
x
x L
inol
eam
ide
ME
A
x
M
yris
tam
ide
ME
A
1995
19
87
x x
x
M
yris
toyl
/Pal
mit
oyl/
Oxo
stea
rmid
e/
Ara
cham
ide
ME
A
x
Oat
amid
e M
EA
2011
x
Ole
amid
e M
EA
1987
Oli
veam
ide
ME
A
20
11
P
alm
Ker
nela
mid
e M
EA
2011
Pal
mam
ide
ME
A
20
11
P
alm
itam
ide
ME
A
19
87
x
P
anto
then
amid
e M
EA
1987
Pea
nuta
mid
e M
EA
2001
x
Ric
inol
eam
ide
ME
A
20
07
x
x
S
tear
amid
e M
EA
19
95
1987
x
x x
x
x x
Stea
ram
ide
ME
A S
tear
ate
19
87
x
x
S
tear
amid
oeth
yl E
than
olam
ine
x
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 6
2
Eth
aola
mid
es D
ata
Pro
file
* –
Sep
t 20
11 –
Wri
ter,
Mon
ice
Fiu
me
Previously Reviewed*
CIR Review on Component*
Reported Use
Info on Free MEA Content
log P value
Toxicokinetics Data
Animal Tox – Acute, Dermal
Animal Tox – Acute, Oral
Animal Tox, Acute, Inhalation Animal Tox – Rptd Dose, Dermal Animal Tox, Rptd Dose, Oral Animal Tox – Rptd Dose, Inhalation
Repro/Dev Tox**
Genotoxicity
Carcinogenicity - Dermal
Dermal Irr/Sens
Ocular Irritation
Sun
flow
eram
ide
ME
A
20
11
T
allo
wam
ide
ME
A
T
ride
ceth
-2 C
arbo
xam
ide
ME
A
20
10
x
U
ndec
ylen
amid
e M
EA
x
x
PEG
-2 C
ocam
ide
20
10
P
EG
-3 C
ocam
ide
20
10
PE
G-4
Coc
amid
e
2010
PE
G-5
Coc
amid
e x
2010
PEG
-6 C
ocam
ide
x 20
10
P
EG
-7 C
ocam
ide
20
10
PE
G-9
Coc
amid
e M
EA
x
2010
x
PE
G-1
1 C
ocam
ide
20
10
PE
G-2
0 C
ocam
ide
20
10
P
EG
-20
Coc
amid
e M
EA
2010
*“X
” in
dica
tes
that
dat
a w
ere
avai
labl
e in
a c
ateg
ory
for
the
ingr
edie
nt
*yea
r of
rev
iew
is p
rovi
ded
**da
ta o
n th
e D
EA
am
ides
wer
e no
t ava
ilab
le; d
ata
from
pre
viou
s C
IR r
epor
ts o
n D
EA
and
fat
ty a
cids
wer
e su
mm
ariz
ed
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 7
Rep
ort
Draft Amended Report
MEA as Used in Cosmetics
September 26, 2011 All interested persons are provided 60 days from the above date to comment on this Draft Amended Report and to identify additional published data that should be included or provide unpublished data which can be made public and included. Information may be submitted without identifying the source or the trade name of the cosmetic product containing the ingredient. All unpublished data submitted to CIR will be discussed in open meetings, will be available at the CIR office for review by any interested party and may be cited in a peer-reviewed scientific journal. Please submit data, comments, or requests to the CIR Director, Dr. F. Alan Andersen. The 2011 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; Ronald A Hill, Ph.D. James G. Marks, Jr., M.D.; Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is F. Alan Andersen, Ph.D. This report was prepared by Monice Fiume, Senior Scientific Analyst/Writer.
© Cosmetic Ingredient Review 1101 17th Street, NW, Suite 412 " Washington, DC 20036-4702 " ph 202.331.0651 " fax 202.331.0088 "
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 8
ii
Table of Contents
PART I: ETHANOLAMINE and RELATED ETHANOLAMINE CONTAINING INGREDIENTS ...................................... 1 Introduction ................................................................................................................................................................................. 1 Chemistry ..................................................................................................................................................................................... 2
Method of Manufacture .......................................................................................................................................................... 3 Impurities ................................................................................................................................................................................ 3
Use ............................................................................................................................................................................................... 3 Cosmetic ................................................................................................................................................................................. 3 Non-Cosmetic ......................................................................................................................................................................... 4
Toxicokinetics.............................................................................................................................................................................. 4 In-Vitro ............................................................................................................................................................................... 5 Dermal ................................................................................................................................................................................ 5
Non-Human ................................................................................................................................................................... 5 Oral ..................................................................................................................................................................................... 5
Non-Human ................................................................................................................................................................... 5 Other ................................................................................................................................................................................... 6
Non-Human ................................................................................................................................................................... 6 Toxicological Studies .................................................................................................................................................................. 6
Acute (Single) Dose Toxicity ................................................................................................................................................. 6 Dermal ................................................................................................................................................................................ 6 Oral ..................................................................................................................................................................................... 6 Inhalation ............................................................................................................................................................................ 7 Other ................................................................................................................................................................................... 7
Repeated Dose Toxicity .......................................................................................................................................................... 7 Dermal ................................................................................................................................................................................ 7 Oral ..................................................................................................................................................................................... 7 Inhalation ............................................................................................................................................................................ 7
Reproductive and developmental Toxicity .................................................................................................................................. 7 Dermal ................................................................................................................................................................................ 7 Oral ..................................................................................................................................................................................... 8
Genotoxicity ................................................................................................................................................................................ 9 In Vitro .................................................................................................................................................................................... 9
Irritation and Sensitization ........................................................................................................................................................... 9 Irritation .................................................................................................................................................................................. 9
Skin .................................................................................................................................................................................... 9 Non-Human ................................................................................................................................................................... 9 Human ........................................................................................................................................................................... 9
Sensitization .......................................................................................................................................................................... 10 Non-Human ................................................................................................................................................................. 10 Human ......................................................................................................................................................................... 10
Provocative Testing .......................................................................................................................................................... 10 Ocular Irritation .................................................................................................................................................................... 10
Non-Human ................................................................................................................................................................. 10 In Vitro ........................................................................................................................................................................ 11
Occupational ExpoSure ............................................................................................................................................................. 11 Occupational Exposure Limits .............................................................................................................................................. 11
Miscellaneous Studies ............................................................................................................................................................... 11 Effect on Hepatic Choline ..................................................................................................................................................... 11 Effect on Bronchoconstriction .............................................................................................................................................. 11
Summary .................................................................................................................................................................................... 12 PART II: ETHANOLAMIDES ................................................................................................................................................ 14 Introduction ............................................................................................................................................................................... 14 Chemistry ................................................................................................................................................................................... 15
Method of Manufacture ........................................................................................................................................................ 15 Impurities .............................................................................................................................................................................. 15
Use ............................................................................................................................................................................................. 16 Cosmetic ............................................................................................................................................................................... 16
Toxicokinetics............................................................................................................................................................................ 16 Toxicological Studies ................................................................................................................................................................ 16
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 10
iii
Acute (Single) Dose Toxicity ............................................................................................................................................... 16 Dermal .............................................................................................................................................................................. 16 Oral ................................................................................................................................................................................... 17
Repeated Dose Toxicity ........................................................................................................................................................ 17 Dermal .............................................................................................................................................................................. 17 Oral ................................................................................................................................................................................... 17
Reproductive and developmental Toxicity ................................................................................................................................ 17 Genotoxicity .............................................................................................................................................................................. 18
In Vitro .................................................................................................................................................................................. 18 Irritation and Sensitization ......................................................................................................................................................... 19
Irritation ................................................................................................................................................................................ 19 Skin .................................................................................................................................................................................. 19
Non-Human ................................................................................................................................................................. 19 Human ......................................................................................................................................................................... 19
Sensitization .......................................................................................................................................................................... 19 Non-Human ................................................................................................................................................................. 19
Human .............................................................................................................................................................................. 19 Ocular Irritation .................................................................................................................................................................... 20
Non-Human ................................................................................................................................................................. 20 Summary .................................................................................................................................................................................... 20 Tables......................................................................................................................................................................................... 22
Table 1a. Definition and structures of ethanolamine and ethanolamine-containing ingredients ........................................ 22 Table 1b. Definition and structures of ethanolamides ......................................................................................................... 24 Table 2a. Conclusions of previously reviewed ingredients, as pertaining to the ethanolamine and ethanolamine-containing ingredients ........................................................................................................................................................... 29 Table 2b. Conclusions of previously reviewed ingredients, as pertaining to the ethanolamides ........................................ 30 Table 3a. Physical and chemical properties ........................................................................................................................ 31 Table 3b. Physical and chemical properties of ethanolamides ............................................................................................ 31 Table 4a. Frequency and concentration of use according to duration and type of exposure ............................................... 34 Table 4b. Ingredients not reported to be in use .................................................................................................................... 34 Table 4c. Status for use in Europe according to the EC CosIng Database for ethanolamine ingredients ........................... 34 Table 5a. Frequency and concentration of use according to duration and type of exposure – ethanolamides .................... 35 Table 5b. Ethanolamides not reported to be in use ............................................................................................................. 37
References ................................................................................................................................................................................. 38
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 11
1
PART I: ETHANOLAMINE AND RELATED ETHANOLAMINE CONTAINING INGREDIENTS
INTRODUCTION
In 1983, the Cosmetic Ingredient Review (CIR) Expert Panel issued a report on the safety of Triethanolamine,
Diethanolamine, and Monoethanolamine. In 2010, the Panel decided to reopen that safety assessment as three separate
reports and to include additional related ingredients in each of the new reviews.
The International Nomenclature Cosmetic Ingredient (INCI) name for monoethanolamine is now ethanolamine.
This assessment addresses ethanolamine and ethanolamine-containing ingredients. The acid salt ingredients (as recited
below) would be expected to dissociate into ethanolamine and the corresponding acid, some of which have been reviewed
separately. In most cases, this means that the composition of these salts is stoichiometrically half ethanolamine (i.e. as its
conjugate acid).
In 1983, the Expert Panel concluded that ethanolamine, an ingredient that functions in cosmetics as a pH adjuster, is
safe for use in cosmetic formulations designed for discontinuous, brief use followed by thorough rinsing from the surface of
the skin, and ethanolamine should only be used in rinse-off products.1 In that review, it was shown that ethanolamine is a
skin and eye irritant in animals, and clinical studies with formulations containing ethanolamine indicated that it is a human
skin irritant. Also, there was indication that the longer ethanolamine was in contact with the skin, the greater the likelihood
of irritation.
The following 21 ingredients are being proposed for inclusion in the re-review of ethanolamine:
Inorganic Acid Salts Ethanolamine HCl MEA-Sulfite Organic Acid Salts MEA-Benzoate MEA-Salicylate MEA-Cocoate MEA-Tallowate MEA-Undecylenate MEA-Laureth-6 Carboxylate MEA PPG-6 Laureth-7 Carboxylate MEA-PPG-8-Steareth-7 Carboxylate Protein Salts MEA-Hydrolyzed Silk MEA-Hydrolyzed Collagen Organic-Substituted Inorganic Acid Salts MEA-Lauryl Sulfate MEA-Laureth Sulfate MEA-Dicetearyl Phosphate Alkyl Substituted Ethanolamines Methylethanolamine Ethyl Ethanolamine Butylethanolamine Dimethyl MEA Diethyl Ethanolamine Dibutyl Ethanolamine
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 12
2
The organic salts and the organic-substituted inorganic salts mostly function as surfactants, with the exception of
MEA-benzoate and MEA-salicylate, which are preservatives. Many of the alkyl substituted ethanolamines, as well as
ethanolamine HCl, are reported to function as pH adjusters. Other reported functions in this category include anti-static
agent, skin conditioning agent, and skin protectant. MEA-sulfite is reported to function as a hair fixative.
MEA-salicylate also has been reviewed previously by the CIR Expert Panel. In 2003, the Panel concluded that
MEA-salicylate is safe as used when formulated to avoid skin irritation and when formulated to avoid increasing the skin’s
sun sensitivity, or, when increased sun sensitivity would be expected; directions for use include the daily use of sun
protection.2
The definitions and structures of ethanolamine and the ethanolamine-containing ingredients listed above are
provided in Table 1a. Since the ingredients included in this review consist of ethanolamine and one or more components, and
the safety of some of these components has been reviewed by the CIR, the conclusions of those relevant ingredients that have
been previously reviewed are provided in Table 2a.
CHEMISTRY
Ethanolamine is an amino alcohol. (Figure 1). Ethanolamine is produced commercially by aminating ethylene oxide with ammonia; the replacement of one hydrogen of ammonia with an ethanol group produces ethanolamine. Ethanolamine typically contains a small amount of diethanolamine (DEA).
Figure 1. Eethanolamine
Ethanolamine is reactive and bifunctional, combining the properties of alcohols and amines. At temperatures of 140°-160°C, ethanolamine will react with fatty acids to form ethanolamides. Additionally, the reaction of ethanolamines and sulfuric acid produces sulfates, and, under anhydrous conditions, ethanolamine may react with carbon dioxide to form carbamates. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine1
While many secondary amines and amides are readily nitrosated to form isolatable nitrosamines and nitrosamides,
primary amines, such as ethanolamine, ultimately yield diazonium salts instead of nitrosamines.3
Acid Salts The acid salts (inorganic acid salts, organic acid salts, sulfate salts, and phosphate salt), named above, are ion pairs
which freely dissociate in water (e.g., Figure 2). Therefore, these salts are closely related to the corresponding free acids and
ethanolamine. In other words, MEA-undecylenate is closely related to undecylenic acid and ethanolamine.
Figure 2. MEA-Undecylenate
Alkyl Substituted Ethanolamines The alkyl substituted ethanolamines consist of covalent, secondary (and sometimes tertiary) amines, whereby one of
the nitrogen substituents is ethanol and the second (and in some cases third) is an alkyl chain (e.g., a four carbon chain is the
alkyl substituent on butylethanolamine; Figure 3). These ingredients are not salts, do not readily dissociate in water, and are
not readily hydrolyzed. Since some of these ingredients are secondary amines, the conversion (nitrosation) of secondary
amines (R1-NH-R2), such as butylethanolamine (wherein R1 is butyl and R2 is ethanol), into N-nitrosamines that may be
carcinogenic is of concern in cosmetics is.4,5 Of the approximately 209 nitrosamines tested, 85% have been shown to
produce cancer in laboratory animals. Nitrosation can occur under physiologic conditions. Depending on the nitrosating
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agent and the substrate, nitrosation can occur under acidic, neutral, or alkaline conditions. Atmospheric NO2 may also
participate in the nitrosation of amines in aqueous (aq.) solution. Accordingly, alkyl substituted ethanolamines should be
formulated to avoid the formation of nitrosamines.
Figure 3. Butylethanolamine
Chemical and physical properties are summarized in Table 3a.
Method of Manufacture
Ethanolamine Ethanolamine is produced by reacting 1 mole of ethylene oxide with 1 mole of ammonia. Typically, ethylene oxide
is reacted with ammonia in a batch process to produce a crude mixture of approximately one-third each ethanolamine, DEA,
and TEA, which are then separated, achieving varying degrees of single component purity.6
Ethanolamine combines with long-chain fatty acids to produce neutral carboxylates or alkanolamine soaps.7
Impurities
Ethanolamine contains a small amount of DEA. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine1
USE
Cosmetic
Ethanolamine is reported to function in cosmetics as a pH adjuster.8 The organic salts and the organic-substituted
inorganic salts mostly function as surfactants, with the exception of MEA-benzoate and MEA-salicylate, which are
preservatives. Many of the alkyl substituted ethanolamines, as well as ethanolamine HCl, are reported to function as pH
adjusters. Other reported functions in this category include anti-static agent, skin conditioning agent, and skin protectant.
MEA-sulfite is reported to function as a hair fixative.
In 1981, data provided to the Food and Drug Administration (FDA) Voluntary Cosmetic Registration Program
(VCRP) indicated that ethanolamine was used in 51 formulations.1 All but 2 of those products were rinse-off formulations,
and 28 uses were in hair coloring products. Products contained ethanolamine at concentrations of ≤10%. VCRP data
obtained in 2011 indicate that the use of ethanolamine has increased significantly, as it is now reported to be used in 764
formulations.9 All of the uses, except 1, are rinse-off products, and 750 uses are in hair coloring formulations.10 A few of the
other ethanolamine-containing ingredients are in use, but all of those are reported to be used in less than 15 formulations.
According to data submitted by industry in response to a recent survey conducted by the Personal Care Products
Council (Council), ethanolamine is used only in rinse-off products, and at concentrations of 0.0002-18%.11 MEA-lauryl
sulfate has the highest reported concentration of use, with a concentration of 35% reported in rinse-off formulations. The
only leave-on use concentration reported is for MEA-hydrolyzed collagen, with a maximum use concentration of 0.2%. Use
data for ethanolamine and all other in-use ethanolamine-containing ingredients are provided in Table 4a. Ethanolamine
ingredients not reported to be in use, according to VCRP data and the Council survey, are listed in Table 4b.
Monoalkylamines, monoalkanolamines, and their salts are listed by the European Commission in Annex III Part 1:
the list of substances which cosmetic products must not contain, except subject to the restrictions and conditions laid down.12
These restrictions for these ingredients include an allowed maximum secondary amine content of 0.5% in finished product;
do not use with nitrosating agents; minimum purity of 99%; maximum secondary amine content of 0.5% for raw materials;
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maximum nitrosamine content of 50 µg/kg; and must be kept in nitrite-free containers. The ingredients named in this report
that have these restrictions are listed in Table 4c.
According to data obtained from Health Canada, ethanolamine is used at up to 10%.13 Most of the uses are rinse-
off, but some leave-on type products are reported. For example ethanolamine is reported to be included at 3-10% in an eye
make-up. However, other information provided by Health Canada indicate that ethanolamine is used primarily in hair
coloring products, with concentrations of use of ≤30% (Health Canada, personal communication). Ethanolamine is also
reported to be used in Canada at concentrations of ≤30% in non-coloring hair preparations and rinse-off formulations, and at
≤10% in leave-on formulations; this includes reported use at 0.3-3% in baby products and 3-10% in lipsticks.
Non-Cosmetic
Ethanolamine is used in the manufacture of emulsifiers and dispersing agents for textile specialties, agricultural chemicals, waxes, mineral and vegetable oils, paraffin, polishes, cutting oils, petroleum demulsifiers, and cement additives. It is an intermediate for resins, plasticizers, and rubber chemicals. It is also used as a lubricant in the textile industry, as a humectant and softening agent for hides, as an alkalizing agent and surfactant in pharmaceuticals, as an absorbent for acid gases, and in organic syntheses. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.1
Ethanolamine has uses as an indirect food additive; according to 21 CFR 175.105 ethanolamine is allowed for use as
a component of adhecives.14 Ethanolamine is also used as a rust inhibitor in water-based metalworking fluids.15
TOXICOKINETICS
Ethanolamine is the only naturally occurring ethanolamine in mammals; it occurs in phospholipids known as phosphatides. In an in vitro study, absorption of undiluted and aq. ethanolamine was much greater through mouse skin than it was through human, rat, or rabbit skin; human skin was the least permeable. The cumulative dose absorbed through mouse and human skin was greater with aq. ethanolamine compared to undiluted ethanolamine; 16.92%of the undiluted and 24.79% of the aq. ethanolamine absorbed through mouse skin while 0.61% undiluted and 1.11% aq. ethanolamine absorbed through human skin. In split-thickness pig skin, 5% of the dose of ethanolamine HCl in ethanol penetrated percutaneously. In a metabolism and distribution study, ethanolamine HCl was applied dermally to human skin-grafted and ungrafted athymic nude mice. Radioactivity was recovered in the skin (18.4% recovered in grafted skin; 12.1% in ungrafted skin), liver (~24-26%), and kidneys (~2%). Approximately 5% of the radioactivity was recovered in the urine; 10% of the radioactivity recovered in the urine was unchanged ethanolamine, and the major urinary metabolites were urea and glycine. In an oral study in Wistar rats fed a diet containing 100-1000 mg/kg ethanolamine HCl for 10 wks, plasma ethanolamine concentrations increased in a dose-dependent manner from <3 mg/kg in control animals and <4 mg/kg in low dose animals to 60-81 mg/kg in high-dose animals. Ethanolamine is the only naturally occurring ethanolamine in mammals, and it is excreted in the urine. Ethanolamine was converted to phosphatidylethanolamine (PE) in the liver, blood, and brain of female rats that were dosed intraperitoneally (i.p.) with radiolabeled ethanolamine. The step-wise methylation of PE that converts it to phosphatidylcholine (PC) did not occur in the brain. Labeled respiratory carbon dioxide has been found in rats after i.p. administration of labeled ethanolamine. A coenzyme-B12-dependent ethanolamine deaminase-mediated conversion of ethanolamine to acetaldehyle and ammonia was demonstrated. Intraperitoneal administration of ethanolamine to rats increased blood urea and blood glutamine, and the researchers suggested that ethanolamine was an ammonia source. Additional researchers, upon detection of labeled acetate in the urine of rats fed labeled ethanolamine, suggested that ethanolamine is phosphorylated by ATP in vivo, converted to acetaldehyde, ammonia, and inorganic phosphate, and the acetaldehyde is oxidized to acetate. The researchers further hypothesized that the removal of phosphorylated ethanolamine by its conversion to acetate may exert a regulatory effect on PE biosynthesis. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Ethanolamine.1
Ethanolamine occurs naturally in phospholipids known as phosphatides.7 Ethanolamine is a structural component of
the phospholipids as part of the headgroups in phospholipid bilayers. In man and other animals, the alcohol group of
ethanolamine is phosphorylated, and phosphorylated ethanolamine is transferred to cytidine monophosphate to form cytidine-
5’-diphosphoethanolamine and phospholipids via diacylglycerol.
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In-Vitro
Ethanolamine Three full thickness skin preparations from CD rats, CD-1 mice, and New Zealand White rabbits and 6 samples
from female mammoplasty patients were used to compare the dermal penetration of ethanolamine through skin of different
species.16 [14C]ethanolamine (98.8% purity; specific activity [sp. act.] 15.0 mCi/mmol) was applied to the skin sample
undiluted or as an aq. solution at a dose of 4 mg/cm2. Dose volumes of 7 µl undiluted [14C]ethanolamine or 32 µl of the aq.
solution (22% w/w) were applied to the exposed surface of the skin (1.77 cm2) for 6 h. With undiluted ethanolamine, the
cumulative dose absorbed was 5.98, 16.92, 8.66, and 0.61% through rat, mouse, rabbit, and human skin, respectively. With
aq. ethanolamine, 1.32, 24.79, 1.87, and 1.11%, was the cumulative dose absorbed through rat, mouse, rabbit, and human
skin, respectively. In vitro absorption of undiluted and aq. ethanolamine was much greater through mouse skin than human
skin, and human skin was the least permeable of all the skin samples. With human skin samples, the cumulative dose
absorbed was greater with aq. ethanolamine as compared to undiluted ethanolamine. The researchers hypothesized that
enhanced penetration of aq. ethanolamine may be attributable to elevated skin hydration.
Ethanolamine HCl The dermal penetration of [1,2-14C]ethanolamine HCl was evaluated in vitro using split-thickness skin from wean-
ling Yorkshire pigs.17 An ethanolic solution was prepared so that a 5 µl application to 0.8 cm2 of skin gave a chemical dose
of 4 µg/cm2 and a radioactive dose of approximately 0.05 µCi. After 50 h, 11% of the dose was lost to evaporation, 5%
penetrated percutaneously, and 62% was recovered in the skin residue. Seven to nine times more radioactivity was recovered
in the upper 100 µm layer, compared to recovery from the remaining dermis.
Dermal
Non-Human The distribution and metabolism of ethanolamine was determined using groups of 5 male athymic nude mice with
human skin grafts and ungrafted athymic nude mice.17 [1,2-14C]Ethanolamine HCl in ethanol was applied at a dose of 4.0 µg
(3.6 µCi) to a 1.45 cm2 area of grafted or non-grafted skin. Penetration appeared similar for both groups. Radioactivity in
expired carbon dioxide (CO2) appeared 30 min after dosing, and the amount recovered at 30 min was 0.76-0.83% of the dose
for grafted and ungrafted skin, respectively. After 24 h, 18.5-19% of the dose was in expired CO2. Distribution was also
similar for both groups. At 24 h after dosing, 24.3-25.8% of the dose was recovered in the liver and 2.24-2.53% in the
kidneys. At the application site, 18.4% of the radioactivity was recovered in the grafted skin, and 12.1% was recovered in the
ungrafted skin. The amount of radioactivity recovered in the urine was 4.6 and 5.2% for grafted and ungrafted nude mice,
respectively. Unchanged ethanolamine comprised 10.2% of the urinary radioactivity. The major urinary metabolites were
urea and glycine, comprising 39.9 and 20.4% of the urinary radioactivity. Minor urinary metabolites were serine, uric acid,
choline, and unidentified ninhydrin-positive compounds.
The radioactivity in proteins and amino acids isolated from the liver, human skin grafts, and mouse skin was deter-
mined as an evaluation of the metabolism of ethanolamine. The researchers stated that the appearance of 14C in skin and
hepatic amino acids and proteins, and the incorporation of ethanolamine into phospholipids, was evidence of extensive
metabolism of the absorbed ethanolamine. The liver was the most active site of ethanolamine metabolism.
Oral
Non-Human In a dietary two-generation reproductive toxicity study (described later in the ‘Reproductive and Developmental
Toxicity’ section), blood samples were taken from groups of 10 male and 10 female F0 and F1 Wistar rats that were fed 0,
100, 300, or 1000 mg/kg ethanolamine HCl in feed for 10 wks.18 Plasma levels of ethanolamine, calculated as ethanolamine
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HCl, increased in a dose-dependent manner. The plasma concentration of ethanolamine was <3 mg/kg for control male and
female F0 and F1 animals. In the low dose group, the plasma concentration values of ethanolamine were <4 mg/kg, in the
mid-dose animals, the levels were 8-11 mg/kg, and in the high dose animals, the plasma ethanolamine levels ranged from 60-
81 mg/kg.
Other
Non-Human Five male athymic nude mice were dosed intraperitoneally (i.p.) with 4.0 µg (3.6 µCi) of [1,2-14C]ethanolamine
HCl in ethanol, and the distribution and metabolism were examined following dosing.7 Radioactivity was detected in expired
CO2, increasing gradually over time. After 24 h, 18% of the radioactivity was detected in expired air.
TOXICOLOGICAL STUDIES
Single applications of 5 and 10% ethanolamine were mildly toxic to mouse skin. The dermal LD50 in rabbits was 1.0-2.5 g/kg ethanolamine. Oral LD50 values were 0.7-15.0 g/kg in mice and 1.0-2.9 g/kg in rabbits. The inhalation LC50 of a mixture containing ethanolamine, hydroxylamine, 1-aminopropanolo-2-ol, catechol, and water was 2.48 mg/l.
Acute (Single) Dose Toxicity
Dermal
Female C3H mice were used to determine the in vivo and in vitro morphological response of mouse skin exposed to
a single application of 1, 5, or 10% ethanolamine in acetone.19 In vivo, ethanolamine was applied to an area of skin 1 inch in
diameter, the animals were killed the next day, and the treated skin was removed and processed. In vitro, ethanolamine was
applied to a 1-inch diameter mouse skin disc for 1 min, and the skin discs were then cultured for 20 h. No lesions were
observed in vitro or in vivo at any concentration tested. Lactate dehydrogenase activity in in vitro samples was statistically
significantly elevated with 5 and 10% ethanolamine, suggesting that ethanolamine was mildly toxic to the skin at these
concentrations.
The dermal LD50 in rabbits was 1.0-2.5 g/kg ethanolamine.7
The acute dermal toxicity of a mixture containing ethanolamine (as well as hydroxylamine, diglycolamine,
propylene glycol, catechol, and water; percentages not specified) was determined by applying 2g/kg of the mixture to the
shaved back of 5 male and 5 female rabbits.20 The dermal LD50 of the mixture was >2 g/kg. In a similar study with a
formulation containing ethanolamine (and hydroxylamine, diglycolamine, gallic acid, and water; percentages not specified),
the LD50 of the mixture in rabbits was 1.24 g/kg bw.21
Oral
The acute oral toxicity of ethanolamine, concentration not specified, ranged from 1.72-2.75 g/kg for rats. Using 90-120 rats, 20% aq. ethanolamine had an LD50 of 2.14-2.74 g/kg, based on results of studies performed over a 10 yr time period. With groups of 10 rats, a hair preparation containing 5.9% ethanolamine had an LD50 of 14.1 g/kg when diluted and 12.9 ml/kg when undiluted. In a study using guinea pigs, all in the group of 2 or 3 guinea pigs survived oral dosing with 0.6 g/kg ethanolamine, while none survived dosing with 7.0 g/kg. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.1
In oral studies, the LD50 of ethanolamine was 0.7-15.0 g/kg in mice and 1.0-2.9 g/kg in rabbits.7
The acute oral toxicity of a mixture containing ethanolamine (as well as hydroxylamine, diglycolamine, propylene
glycol, catechol, glycolic acid and water; percentages not specified) was determined using groups of 5 male and 5 female
rats.22 The oral LD50 of the mixture was 0.95 g/kg. In a similar study with a formulation containing ethanolamine (and
hydroxylamine, diglycolamine, gallic acid, and water; percent in formulation not specified), the oral LD50 of the mixture was
0.815 g/kg bw.
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Inhalation
The acute inhalation toxicity of a mixture containing ethanolamine (as well as hydroxylamine, 1-amino-propano-2-
ol, catechol, and water; percent of each not specified) was determined using groups of 5 male and 5 female rats. The
inhalation LC50 of the mixture was estimated to be 2.48 mg/l.22
Other
The intraperitoneal (i.p.) LD50 of ethanolamine was 1.05 g/kg for mice. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.1
Repeated Dose Toxicity
Dermal
Percutaneous application of 4 mg/kg/day ethanolamine to rats resulted in nonspecific histological changes in the heart and lung, fatty degeneration of the liver parenchyma, and subsequent focal liver necrosis. The duration of dosing was not specified. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.1
Oral
Groups of 10 rats were fed 0-2.67 g/kg/day ethanolamine for 90 days. Heavy livers and kidneys were observed at ≥0.64 g/kg/day, and deaths and “major pathology” occurred with ≥1.25 g/kg/day. In a 2-yr dietary study in which groups of 12 beagle dogs were fed 0-0.0975 g/kg/day of a hair dye composite that contained 22% ethanolamine, no toxic effects were observed. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.1
Inhalation
The dominant effects of “continuous exposure” of dogs, guinea pigs, and rats to 5-6 ppm ethanolamine vapor were skin irritation and lethargy. No dogs or rodents exposed to 12-26 ppm ethanolamine vapor for 90 days died, but mortality was reported in dogs exposed to 102 ppm ethanolamine vapor for 2 days and rodents exposed to 66-75 ppm ethanolamine vapor for 24-28 days. Dogs and rodents exposed to 66-102 ppm ethanolamine vapor had behavioral changes, pulmonary and hepatic inflammation, hepatic and renal damage, and hematological changes. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.1
REPRODUCTIVE AND DEVELOPMENTAL TOXICITY
Dermal developmental toxicity studies were performed using rats and rabbits. In a study in which gravid rats were dosed with 10-225 mg/kg bw/day ethanolamine on days 6-15 of gestation, the no-observed effect level (NOEL) for maternal toxicity was 75 mg/kg/day and for embryonal/fetal toxicity was 225 mg/kg/day. In rabbits that were dosed with 10-75 mg/kg bw/day ethanolamine on days 6-18 of gestation, the NOEL for maternal toxicity was 10 mg/kg bw/day and for embryonal/fetal toxicity was 75 mg/kg bw/day. Significant skin irritation was observed in the high dose groups for both rats and rabbits. In a Chernoff-Kavlock post-natal mouse screening assay, oral dosing with 850 mg/kg/day ethanolamine on days 6-15 of gestation resulted in 16% mortality of maternal mice and a reduced number of viable litters. In a study in which Wistar rats were gavaged with 40-450 mg/kg bw/day aq. ethanolamine on days 6-15 of gestation, the NOEL for maternal toxicity was 120 mg/kg/day and for developmental toxicity was 450 mg/kg/day. In an oral study in which Long-Evans rats were dosed with 50-500 mg/kg aq. ethanolamine on days 6-15 of gestation, there was no significant maternal toxicity, but embryolethality was increased in the 500 mg/kg group, and more reproductive and developmental effects were observed involving male pups compared to female pups. There was an increase in malformed pups in all dose groups. In a dietary two-generation study in rats with 100-1000 mg/kg bw/day ethanolamine HCl, the no-observed adverse effect level (NOAEL) for systemic toxicity and for reproductive effects was 300 mg/kg bw/day, and the NOAEL for develop-mental toxicity was 1000 mg/kg bw/day.
Dermal
The developmental toxicity of dermally-applied aq. ethanolamine was evaluated using groups of 30-45 gravid
Sprague-Dawley rats and 15 gravid New Zealand White rabbits.23 Ethanolamine was applied at doses of 0, 10, 25, 75, and
225 mg/kg bw/day to the backs of rats on days 6-15 of gestation, with a dose volume of 1 ml/kg. Significant skin irritation,
consisting of erythema followed by necrosis, scabs, and scar formation, occurred with 225 mg/kg ethanolamine, but not at the
other dose levels. No effects on kidney or liver weights were reported. Despite maternal effects in the 225 mg/kg dose
group, no effects on reproductive parameters were observed at any dose, and there were no treatment-related increases in the
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visceral or skeletal malformations. In rats, the no-observed effect level (NOEL) for maternal toxicity was 75 mg/kg/day and
for embryonal/fetal toxicity, it was 225 mg/kg/day.
In rabbits, 0, 10, 25, and 75 mg/kg bw/day ethanolamine was applied to the back (2 ml/kg) on days 6-18 of
gestation. Severe skin irritation at the application site, consisting of necrosis, exfoliation, and crusting, was observed in the
75 mg/kg group, and crusting, transient erythema, and edema were observed in a few rabbits of the 25 mg/kg dose group. No
effects on kidney or liver weights were reported. As with the rats, no effects on reproductive parameters were observed at
any dose, and there were no treatment-related increases in the visceral or skeletal malformations. In rabbits, the NOEL for
maternal toxicity was 10 mg/kg bw/d and for embryonal/fetal toxicity, it was 75 mg/kg/day, the highest dose tested.
Oral
Ethanolamine No reproductive or developmental effects were observed in groups of gravid rats given a hair dye and base containing 22% ethanolamine in the diet at concentrations ≤7800 ppm on days 6-15 of gestation. No differences in reproductive or developmental parameters were observed when male rats were fed treated diet for 8 wks prior to and during mating with undosed females or when female rats were fed treated feed for 8 wks prior to dosing until day 21 of lactation. These females were mated with undosed males. Additionally, no teratologic effects were induced by dosing gravid rabbits with ≤19.5 mg/kg/day of the hair dye and base by gavage on days 6-18 of gestation. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Ethanolamine.1
The teratogenic potential of ethanolamine was evaluated in a Chernoff-Kavlock postnatal mouse screening assay.24
Gravid CD-1 mice were dosed orally with 850 mg/kg/day ethanolamine on days 6-15 of gestation, resulting in 16% mortality
of maternal mice and reduced numbers of viable litters. Litter size, percentage survival of pups, birth weight, and pup weight
gains were not affected.
A preliminary study was performed in which gravid Wistar rats were dosed orally with 0-500 mg/kg by/day aq.
ethanolamine; details not provided.25 Maternal effects were observed in the high dose animals, but no embryonal/fetal effects
were observed at any dose. Based on these results, groups of 40 Wistar rats were dosed by gavage with 0, 40, 120, or 450
mg/kg bw/day aq. ethanolamine on days 6-15 of gestation. On day 20 of gestation, 25 dams/group were killed and
necropsied, while the remaining 15 were allowed to litter, and then killed on day 21 of lactation. Despite evidence of
maternal toxicity in the 450 mg/kg group, as indicated by statistically significant decreases in maternal body weights and feed
consumption, no effects on reproductive parameters, incidences of visceral or skeletal malformations, or postnatal growth
were observed at any dose. The NOELs for maternal and developmental toxicity were 120 and 450 mg/kg/day, respectively.
Groups of 10 gravid Long-Evans rats were dosed by gavage with 50, 300, or 500 mg/kg aq. ethanolamine on days 6-
15 of gestation, and a negative control group of 34 gravid rats were dosed with water only.26 The animals were killed and
examined on day 20 of gestation. Significant maternal toxicity was not noted. Embryolethality was significantly increased in
the 500 mg/kg group, with male pups affected more than female pups. Male pups were more severely affected than female
pups at all dose levels in regards to intrauterine growth retardation and increased gross structural anomalies that were consid-
ered indicative of depressed fetal growth. However, pups of either sex who were contiguous to male siblings were more
adversely affected that those contiguous to one or more female siblings. Male pups contiguous to male siblings (mMm)
were, apparently, resorbed (mRm). The number of malformed pups per dam was significantly increased in animals dosed
with 300 mg/kg ethanolamine. The number of malformed pups, when evaluated as a percent of the litter affected, was
significantly increased for all 3 dose groups.
Ethanolamine HCl Groups of 25 male and 25 female Wistar rats (F0 parental generation) were fed 0, 100, 300, or 1000 mg/kg bw/d
ethanolamine HCl for at least 75 days prior to mating.18 Twenty-five male and 25 female F1 pups/group were continued on
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the test diets of their parents, and then mated, becoming the F1 parental generation. The study was terminated after the
weaning of the F2 pups. No test substance-related adverse reproductive, developmental, or toxic effects were observed in any
of the pups or parental animals of the 100 or 300 mg/kg bw/d groups. In the 1000 mg/kg group, adverse effects on fertility
and reproduction were evidenced by statistically significant decreases in absolute and relative weights of the epididymides
and cauda epididymidis in male and statistically significant decreased number of implantation sites, increased post-
implantation loss, and smaller litters in female F0 and F1 parents. Sperm head count in the cauda epididymidis and absolute
and relative liver weights were also statistically significantly decreased in male F0 parents. Body weight gains of both the F0
and F1 parental animals were statistically significantly decreased during gestation when compared to controls, as was feed
consumption during lactation. There were no test-related signs of developmental toxicity observed in F1 and F2 pups of this
dose group. The no-observed adverse effect level (NOAEL) for systemic toxicity and for reproductive effects was 300 mg/kg
bw/d, and the NOAEL for developmental toxicity was 1000 mg/kg bw/d, which was the highest dose tested.
GENOTOXICITY
In Vitro
ethanolamine, with and without metabolic activation using liver preparations from rats induced with a polychlorinated biphenyl mixture, was not mutagenic to Salmonella typhimurium TA100 or TA1535. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.1
Ethanolamine was negative in most Ames tests at concentrations ≤2000 μg/plate;27,28 however “weak mutagenic
effects” were reported in one study.29 Ethanolamine, 25-500 µg/ml, was negative in a cell transformation assay using
hamster embryo cells.30 Ethanolamine was clearly cytotoxic at 500 µg/ml. Ethanolamine did not produce chromosomal
aberrations in rat liver cells,27 but a “weak positive” response was reported in human lymphocytes.29 (Concentrations tested
were not provided.)
IRRITATION AND SENSITIZATION
Ethanolamine HCl did not have a sensitizing effect in a local lymph node assay. In a maximization study with intradermal and epicutaneous inductions of 0.6 and 10.3% aq. ethanolamine, respectively, in guinea pigs, positive reactions were observed at challenge. Possible cross-reactions to 5% TEA and 7% DEA were reported. In provocative testing of metalworkers with dermatitis, a higher reaction to ethanolamine was observed for the patients as compared to control subjects. In a study of hairdressers and clients, cosensitization to DEA was reported for 38% of the patients that reacted to ethanolamine. Ethanolamine was classified as a moderate irritant in in vitro studies of ocular irritation potential.
Irritation
Skin
Non-Human Ethanolamine was corrosive to rabbit skin with single semi-occlusive patches of 30, 85 and 100% on intact and abraded skin. When applied to rabbit ears using non-occlusive applications and to shaved skin of the abdomen under semi-occlusive patches, ≥10% was corrosive, >1% was extremely irritating, and 1% was irritating. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.1
Human In a study in which a formulation containing 5.9% ethanolamine was applied to the backs of 12 female subjects for 23 h/day for 21 days, the formulation was considered an experimental cumulative irritant. Results observed during the induction phase of a patch test of 165 subjects using a formulation containing 11.47% ethanolamine were interpreted by the Expert Panel as irritation. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.1
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Sensitization
Non-Human A local lymph node assay was performed to evaluate the sensitization potential of ethanolamine (as the hydro-
chloride salt).15,31 Groups of 6 female CBA/Ca mice were treated on the ear with 10, 40, or 70% w/w aq. ethanolamine HCl.
Ethanolamine HCl did not have a skin sensitizing effect.
In a maximization study using 15 Dunkin-Hartley guinea pigs, intradermal and epicutaneous inductions with 0.6%
and 10.3% aq. ethanolamine, respectively, were performed after 10% sodium lauryl sulfate pre-treatment.15 (Ethanolamine
contained less than 0.1% DEA and TEA.) At challenge with 0.41, 2.05, or 4.1% ethanolamine, 3, 2, and 3 animals,
respectively, reacted positively after 3 days. Two of the 15 test animals reacted to the vehicle, but none of the control
animals reacted to ethanolamine or the vehicle. Possible cross-reactions to 5% TEA occurred in 3 animals, and to 7% DEA
in 2 animals. In a second test using the same protocol, no animals reacted to 0.41% ethanolamine, 2 reacted to 2.05%
ethanolamine, and 1 reacted to 4.1% ethanolamine. Additionally, 1 animal reacted to 10% TEA and 2 reacted to 7% DEA.
The control animals did not react to any of the ethanolamines.
Human A formulation containing 5.9% ethanolamine, tested undiluted, and one containing 11.47% ethanolamine, tested at 5% in 25% alcohol, were not sensitizing in clinical studies. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.1
Provocative Testing
Metalworkers that were dermatitis patients were patch tested with 2% ethanolamine in pet.32 The patches were
applied for 1-2 days. On day 3, 3 of 155 patients (1.9%) had positive reactions.
Patch testing was performed with 2% ethanolamine in pet. in 199 patients with suspected metalworking fluid contact
dermatitis.33 (All patients were metalworkers.) Patches were applied for 1 or 2 days. On day 3, 40 patients had positive
reactions, 16 (?), 19 (+), 4 (++), and 1 (+++). The % positive reactions were 11.6%.
A patch test using 2% ethanolamine in petrolatum was performed on 370 patients with suspected dermatitis to
ethanolamine-containing metal-working fluids and on 452 control subjects.34 A 10-fold higher reaction was seen in the
patient group, with 12.2% of the patients having positive reactions, as compared to 1.3% in the control group.
Over a 3-yr period, 11/595 (1.9%) hairdresser clients and 7/401 (1.8%) female hairdressers reacted positively to 2%
ethanolamine pet.15 In 22 patients with suspected intolerance to oxidative hair dye components, 4 had a positive reaction to
2% ethanolamine pet. Over a 15-yr period, provocative patch testing using ethanolamine was performed on 9602 subjects.
There were 363 (3.8%) positive reactions to ethanolamine, and most of the reactions (277; 2.9%) were weak positives. There
were 55 (0.6%) irritant reactions reported. Cosensitization was reported; 38% of the patients that reacted to ethanolamine
also tested positive to DEA. Occupational sensitization was reported; of 5884 male patients, 2.9% that did not work in the
metal industry had positive reactions as opposed to 7.0 and 15.2% of those working in the metal industry and those exposed
to water-based metalworking fluids, respectively.
Ocular Irritation
Non-Human Using 6 rabbits, 30% aq. ethanolamine was moderately irritating to rabbit eyes. Undiluted ethanolamine, instilled as a volume of 0.005 ml, produced severe injury to rabbit eyes. A hair preparation containing 5.96% ethanolamine had a maximum avg. irritation score of 0.7/110 for rinsed and unrinsed eyes. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.1
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In Vitro Ethanolamine
The ocular irritation potential of ethanolamine was evaluated in several in vitro studies. The ocular irritation
potential of ethanolamine was evaluated in the rabbit corneal epithelium model at concentrations of 0.05, 0.5, and 1%;
ethanolamine was classified as a moderate irritant at these concentrations.35
OCCUPATIONAL EXPOSURE
Ethanolamine inhalation by humans has been reported to cause immediate allergic responses of dyspnea and asthma and clinical symptoms of acute liver damage and chronic hepatitis. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.1
A case of occupational asthma in an industrial worker exposed to a detergent containing 8% ethanolamine was
reported.36 Since the detergent was used in hot water, release of ethanolamine vapor was greater than if the detergent
temperature was lower. Exposure to vapors from ethanolamine in cleaning solutions can irritate the nose, throat, and lungs.37
Occupational Exposure Limits
The Occupational Safety and Health Administration permissible exposure level for ethanolamine is 3 ppm (8
mg/m3) as an 8-hr time-weighted average concentration.38 The National Institute for Occupational Health and Safety
(NIOSH) has a recommended exposure limit (REL) of 3 ppm (8 mg/m3) for a 10 h workday and 40 h work week; the short-
term exposure limit (STEL) is 6 ppm (15 mg/m3), for periods not to exceed 15 min.39 The threshold limit value set by the
American Conference of Governmental Industrial Hygienists is the same as the REL set by NIOSH, and the STEL is also the
same.38
MISCELLANEOUS STUDIES
Effect on Hepatic Choline
The effects of ethanolamine HCl on hepatic choline was determined in the F0 and F1 parental rats from the two-
generation feeding study described earlier in this report.40 Liver weights were determined for all parental rats at necropsy,
and the livers of control and high-dose animals (1000 mg/kg bw/day) were examined microscopically. Feeding ethanolamine
HCl to rats did not affect liver weights of any of the animals. No adverse microscopic affects in the livers of high-dose rats
were reported. Liver samples of F1 female rats of the test and control groups were analyzed for choline, phosphocholine,
glycerophosphocholine, and phosphatidylcholine. A statistically significant increase in phosphocholine and phosphatidyl-
choline was observed in the 100 and 300 mg/kg bw/day dose groups, but no other statistically significant difference in
choline content were reported. In that there was no dose-response, these effects were not considered dose-related. The
researchers concluded that “based on the combined hepatic observations, ethanolamine hydrochloride does not affect hepatic
choline metabolism in the rat.”
Effect on Bronchoconstriction
The effect of ethanolamine on bronchoconstriction was investigated using a group of 4 anesthetized male Hartley
guinea pigs.41 When an aerosol of 0.1 ml/kg of 3.3% ethanolamine solution was inhaled through a tracheal cannula,
bronchoconstriction was observed. The results were compared to those obtained using an aerosol of potassium hydroxide.
Bronchoconstriction induced by ethanolamine was greater than that induced by potassium hydroxide. Additional testing
suggested that ethanolamine-induced bronchoconstriction may not result from induction of acetylcholine or histamine
release, but that they may result partly from an agonistic effect of ethanolamine at the histamine-H1 receptor and the
muscarinic receptor.
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SUMMARY
This report assesses the safety of ethanolamine and ethanolamine-containing ingredients as used in cosmetics. The
ethanolamine salts are expected to dissociate into ethanolamine and the corresponding acid. Ethanolamine typically contains
a small amount of DEA. Ethanolamine functions in cosmetic formulations as a pH adjuster. The organic salts and the
organic-substituted inorganic salts mostly function as surfactants, with the exception of MEA-benzoate and MEA-salicylate,
which are preservatives. Many of the alkyl substituted ethanolamines, as well as ethanolamine HCl, are reported to function
as pH adjusters. Other reported functions in this category include anti-static agent, skin conditioning agent, and skin
protectant. MEA-sulfite is reported to function as a hair fixative.
In 2011, ethanolamine was reported to be used in 764 formulations, 750 of which are hair coloring formulations;
one use was in a leave-on formulation. Of the ethanolamine-containing ingredients that are in use, none have more than 15
uses. Ethanolamine is reported to be used at concentrations of 0.0002-18%. MEA-lauryl sulfate has the highest reported
concentration of use at 35% in rinse-off formulations. The only leave-on use concentration reported is for MEA-hydrolyzed
collagen, with a maximum use concentration of 0.2%. In Europe, monoalkylamines, monoalkanolamines, and their salts are
on the list of substances which must not form part of the composition of cosmetic products, except subject to restrictions and
conditions laid down. These restrictions include a maximum secondary amines contaminant content of 0.5% in finished
products, a maximum secondary amines content of 0.5% in raw materials, and a maximum nitrosamine content of 50 µg/kg.
Ethanolamine is the only naturally occurring ethanolamine in mammals; it occurs in phospholipids known as
phosphatides. In an in vitro study, absorption of undiluted and aq. ethanolamine was much greater through mouse skin than
it was through human, rat, or rabbit skin; human skin was the least permeable. The cumulative dose absorbed through mouse
and human skin was greater with aq. ethanolamine compared to undiluted ethanolamine; 16.92%of the undiluted and 24.79%
of the aq. ethanolamine absorbed through mouse skin while 0.61% undiluted and 1.11% aq. ethanolamine absorbed through
human skin. In split-thickness pig skin, 5% of the dose of ethanolamine HCl in ethanol penetrated percutaneously. In a
metabolism and distribution study, ethanolamine HCl was applied dermally to human skin-grafted and ungrafted athymic
nude mice. Radioactivity was recovered in the skin (18.4% recovered in grafted skin; 12.1% in ungrafted skin), liver (~24-
26%), and kidneys (~2%). Approximately 5% of the radioactivity was recovered in the urine; 10% of the radioactivity
recovered in the urine was unchanged ethanolamine, and the major urinary metabolites were urea and glycine. In an oral
study in Wistar rats fed a diet containing 100-1000 mg/kg ethanolamine HCl for 10 wks, plasma ethanolamine concentrations
increased in a dose-dependent manner from <3 mg/kg in control animals and <4 mg/kg in low dose animals to 60-81 mg/kg
in high-dose animals.
Single applications of 5 and 10% ethanolamine were mildly toxic to mouse skin. The dermal LD50 in rabbits was
1.0-2.5 g/kg ethanolamine. Oral LD50 values were 0.7-15.0 g/kg in mice and 1.0-2.9 g/kg in rabbits. The inhalation LC50 of a
mixture containing ethanolamine, hydroxylamine, 1-aminopropanolo-2-ol, catechol, and water was 2.48 mg/l. Percutaneous
application of 4 mg/kg/day ethanolamine to rats for an unspecified length of time resulted in nonspecific histological changes
in the heart and lung, fatty degeneration of the liver parenchyma, and subsequent focal liver necrosis. In a dietary study in
which rats were fed 0-2.67 g/kg/day ethanolamine for 90 days, heavy livers and kidneys were observed at ≥0.64 g/kg/day,
and deaths and “major pathology” occurred with ≥1.25 g/kg/day. In a 2-yr dietary study in which beagle dogs were fed 0-
0.0975 g/kg/day of a hair dye composite that contained 22% ethanolamine, no toxic effects were observed. In repeated-dose
inhalation studies, the dominant effects of “continuous exposure” of dogs, guinea pigs, and rats to 5-6 ppm ethanolamine
vapor were skin irritation and lethargy; mortality was observed in dogs exposed to 102 ppm ethanolamine vapor for 2 days
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and some rodents exposed to 66-75 ppm ethanolamine vapor for 24-28 days. Dogs and rodents exposed to 66-102 ppm
ethanolamine vapor had pulmonary and hepatic inflammation, hepatic and renal damage, and hematological changes.
Dermal developmental toxicity studies were performed using rats and rabbits. In a study in which gravid rats were
dosed with 10-225 mg/kg bw/day ethanolamine on days 6-15 of gestation, the no-observed effect level (NOEL) for maternal
toxicity was 75 mg/kg/day and for embryonal/fetal toxicity, it was 225 mg/kg/day. In rabbits that were dosed with 10-75
mg/kg bw/day ethanolamine on days 6-18 of gestation, the NOEL for maternal toxicity was 10 mg/kg bw/day and for
embryonal/fetal toxicity, it was 75 mg/kg bw/day. Significant skin irritation was observed in the high dose groups for both
rats and rabbits. In a Chernoff-Kavlock post-natal mouse screening assay, oral dosing with 850 mg/kg/day ethanolamine on
days 6-15 of gestation resulted in 16% mortality of maternal mice and a reduced number of viable litters. In a study in which
Wistar rats were gavaged with 40-450 mg/kg bw/day aq. ethanolamine on days 6-15 of gestation, the NOEL for maternal
toxicity was 120 mg/kg/day and for developmental toxicity was 450 mg/kg/day. In an oral study in which Long-Evans rats
were dosed with 50-500 mg/kg aq. ethanolamine on days 6-15 of gestation, there was no significant maternal toxicity, but
embryolethality was increased in the 500 mg/kg group, and more reproductive and developmental effects were observed
involving male pups compared to female pups. There was an increase in malformed pups in all dose groups. In a dietary
two-generation study in rats with 100-1000 mg/kg bw/day ethanolamine HCl, the no-observed adverse effect level (NOAEL)
for systemic toxicity and for reproductive effects was 300 mg/kg bw/day, and the NOAEL for developmental toxicity was
1000 mg/kg bw/day. The effect of ethanolamine HCl on hepatic choline was investigated in the F0 and F1 parental rats, and it
was concluded that ethanolamine HCl did not affect the hepatic choline metabolism in the rat.
Ethanolamine was mostly negative in Ames tests (≤2000 μg/plate). Ethanolamine (≤500 μg/ml) was negative in a
cell transformation assay. Ethanolamine did not produce chromosomal aberrations in rat liver cells, but did produce a “weak
positive” response in human lymphocytes.
In non-human studies, semi-occlusive application of 30-100% ethanolamine was corrosive to rabbit skin. Irritation
responses ranging from irritating to corrosive were observed with 1-10% ethanolamine, respectively, applied non-occlusively
to rabbit ears and under semi-occlusive patches to rabbit skin. The degree of irritation increased with the concentration
applied. In human studies, a formulation containing 5.9% ethanolamine was a cumulative irritant in a 21-day study, and an
irritant response was reported during the induction phase of patch test of a formulation containing 11.47% ethanolamine.
Ethanolamine did not have a sensitizing effect in a local lymph node assay. In a maximization study with intradermal and
epicutaneous inductions of 0.6 and 10.3% aq. ethanolamine, respectively, in guinea pigs, positive reactions were observed at
challenge. Possible cross-reactions to 5% TEA and 7% DEA were reported. In provocative testing of metalworkers with
dermatitis, a higher reaction to ethanolamine was observed for the patients as compared to control subjects. In a study of
hairdressers and clients, cosensitization to DEA was reported for 38% of the patients that reacted to ethanolamine. In ocular
irritation studies in rabbits, 30% aq. ethanolamine was moderately irritating to rabbit eyes, and undiluted ethanolamine
produced severe injury. A hair preparation containing 5.96% ethanolamine had a maximum average irritation score of
0.7/110 in rinsed and unrinsed eyes. Ethanolamine was classified as a moderate irritant in in vitro studies of ocular irritation
potential.
An aerosol of 0.1 ml/kg of 3.3% ethanolamine solution induced bronchoconstriction in guinea pigs. Ethanolamine-
induced bronchoconstriction may result partly from an agonistic effect of ethanolamine at the histamine-H1 receptor and the
muscarinic receptor.
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PART II: ETHANOLAMIDES
INTRODUCTION
Isostearamide MEA, myristamide MEA, and stearamide MEA were reviewed by the CIR Expert Panel in 1995.42
The Panel concluded that these ingredients are safe for use in rinse-off products. In leave-on products, these ingredients are
safe for use at concentrations that will limit the release of free ethanolamine to 5%, but with a maximum use concentration of
17% for isostearamide, myristamide, and stearamide MEA. These ingredients should not be used in cosmetic products in
which N-nitroso compounds may be formed.
The following 49 ingredients are being considered for inclusion of a re-review of isostearamide MEA, myristamide
MEA, and stearamide MEA:
Acetamide MEA* Azelamide MEA Babassuamide MEA Behenamide MEA C16-22 Acid Amide MEA Cocamide MEA* Cocamide Methyl MEA Cocamidopropyl Betainamide MEA Chloride Deoxyphytantriyl Palmitamide MEA Hexyloxodecanamide MEA Hexyloxodecanamide MEA Phosphate Hydroxyethyl Pantothenamide MEA Hydroxypropyl Bisisostearamide MEA Hydroxypropyl Bislauramide MEA Hydroxypropyl Bispalmitamide MEA Hydroxypropyl Bisstearaminde MEA Hydroxystearamide MEA Isostearamide MEA* Lactamide MEA Lauramide MEA Linoleamide MEA Myristamide MEA* Myristoyl/Palmitoyl/Oxostearmide/Arachamide MEA Oatamide MEA Oleamide MEA Oliveamide MEA
Palm Kernelamide MEA Palmamide MEA Palmitamide MEA Pantothenamide MEA Peanutamide MEA Ricinoleamide MEA Stearamide MEA* Stearamide MEA Stearate Stearamidoethyl Ethanolamine Sunfloweramide MEA Tallowamide MEA Trideceth-2 Carboxamide MEA Undecylenamide MEA Glycol Ethers PEG-2 Cocamide PEG-3 Cocamide PEG-4 Cocamide PEG-5 Cocamide PEG-6 Cocamide PEG-7 Cocamide PEG-9 Cocamide MEA PEG-11 Cocamide PEG-20 Cocamide PEG-20 Cocamide MEA
The ingredients marked with an asterisk (*) also have been reviewed previously by the CIR Expert Panel. In 1993,
the Panel concluded that acetamide MEA is safe as used as a cosmetic ingredient at concentrations not to exceed 7.5% in
leave-on products and is safe in the present practices of use in rinse-off products; cosmetic formulations containing acetamide
MEA should not contain nitrosating agents or significant amounts of free acetamide.43 (Acetamide MEA was reported to be
used at up to 25% in rinse-off products.) This conclusion was reaffirmed in 2008. Cocamide MEA was reviewed in 1999;
the Panel concluded that cocamide MEA is safe as used in rinse-off cosmetic products and safe at concentrations up to 10%
in leave-on products.44 (Cocamide MEA was reported to be used at up to 25%, but the types of products, i.e., rinse-off or
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leave-in, were not specified.) Cocamide MEA should not be used as an ingredient in cosmetic products containing N-
nitrosating agents, or in product formulations intended to be aerosolized.
The structures of the ethanolamides are provided in Table 1b. The ingredients included in this review consist of
ethanolamine and one or more components. The safety of many of these components has been reviewed by the CIR. The
conclusions of the previously reviewed ingredients, and of the components that have been reviewed, are provided in Table
2b.
CHEMISTRY
The ethanolamides consist of covalent, secondary amides, whereby one of the nitrogen substituents is ethanol (or at
least an ethanol residue) and the second is a carbonyl attached substituent. For example, myristamide MEA is a secondary
amide wherein one of the nitrogen substituents is ethanol and the second is a fourteen carbon, carbonyl attached chain (Figure
4). These ingredients are not salts and do not readily dissociate in water. However, amidases, such as fatty acid amide
hydrolase (FAAH) which is known to be present in human skin, could potentially convert these amides to ethanolamine and
the corresponding fatty acids. Secondary amides do tend to react with nitrosating agents to form nitrosamides.
Figure 4. Myristamide MEA
Chemical and physical properties of ethanolamides are summarized in Table 3b.
Method of Manufacture
Ethanolamine reacts with long-chain fatty acid esters in a 1:1 mole ratio to produce a 90+% pure, crystalline
ethanolamide mixture.7
Two different routes of synthesis of ethanolamides are common: direct acylation with free fatty acids and transacyl-
ation using fatty acid esters (often enzymatically).45,46 Ethanolamides can be produced via enzymatic amidification; mono-
acylated ethanolamine can be isolated from the reaction mixture. The reaction is carried out using an equimolar ratio of fatty
acid and ethanolamine. The enzyme is filtered upon completion of the reaction, and the product is dissolved in a mixture of
methanol and chloroform. The solvent is then eliminated by evaporation, and the resulting solid is the amide.
Acetamide MEA Acetamide MEA is prepared by the reaction of acetic acid with ethanolamine. Additional methods of production, involving acetamide and ethylene oxide, ethanolamine and acetyl chloride, have been reported. From The Final Report on the Safety Assessment of Acetamide MEA43
Impurities
Acetamide MEA Analysis of 4 lots of acetamide MEA by gas chromatography-mass spectrometry indicated the presence of 0.0006-0.0029% ethanolamine and 0.0006-0.0030% acetamide. Using high-performance liquid chromatography, N-nitrosodiethanolamine was not detected (limit of detection = 0.0-5 ppm) in acetamide MEA. From The Final Report on the Safety Assessment of Acetamide MEA43
Myristamide MEA The maximum free amine content of myristamide MEA is 1.5%. From the Final Report on Isostearamide DEA & MEA, Myristamide DEA & MEA, and Stearamide DEA & MEA42
Stearamide MEA Stearamide DEA has 0.8% max. free fatty acids (as stearic acid), 0.5-2.0% free amine (as ethanolamine), and 54.0-58.0% total fatty acids (as stearic acid). From the Final Report on Isostearamide DEA & MEA, Myristamide DEA & MEA, and Stearamide DEA & MEA42
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USE
Cosmetic
Most of the ethanolamides are reported to function in cosmetics as hair conditioning agents, skin conditioning
agents, and surfactant – foam boosters; a few are reported to have other uses.8 In 1995, data provided through to FDA VCRP
indicated that isostearamide MEA was used in 1 and stearamide MEA was used in 22 cosmetic formulations.42 Isostear-
amide MEA was reported to be used in leave-on products at concentrations of up to 15% and in rinse-off products at up to
6%, and stearamide MEA was reported to be used at concentrations of up to 25%. Myristamide MEA was not reported to be
used. VCRP data obtained in 2011 indicate that the use of stearamide MEA has decreased, with only 10 reported uses.9
Myristamide MEA has one reported use, and isostearamide MEA does not have any uses reported. Other ethanolamides have
many more reported uses. Cocamide MEA has the highest frequency of use with 1122 reported uses; only 33 of those uses
are in leave-on products. Trideceth-2 carboxamide has 189 reported uses, and acetamide MEA is reported to be used in 148
formulations. The use information for the ethanolamides is summarized in Table 5a.
According to data submitted by industry in response to a recent survey conducted by the Personal Care Products
Council (Council), cocamide MEA is reported to be used at up to 18% in rinse-off formulations and at up to 5% in leave-on
formulations. Stearamide MEA has the highest concentration of use in leave-on formulations at up to 15%. The
ethanolamides that are not reported to be in use, according to VCRP data and the Council survey, are listed in Table 5b.
Monoalkylamines, monoalkanolamines, and their salts are listed by the European Commission in Annex III Part 1:
the list of substances which cosmetic products must not contain, except subject to the restrictions and conditions laid down.12
These ingredients are allowed a maximum secondary amine content of 0.5% in finished product; are not use to be used with
nitrosating agents; must have a minimum purity of 99%; the maximum secondary amine content of 0.5% is allowed for raw
materials; maximum nitrosamine content allowed is 50 µg/kg; and must be kept in nitrite-free containers. Acetamide MEA
and babassuamide MEA are the only ethanolamides listed in this category. All the other ethanolamides, with the exception
of PEG-9 cocamide MEA (which in not an INCI ingredient), are listed in the EU inventory.
TOXICOKINETICS
Published toxicokinetic data were not found.
TOXICOLOGICAL STUDIES
In an acute dermal study in rabbits, the LD50 for cocamide MEA was > 2g/kg, which was the highest dose tested. In oral studies, the LD50 of cocamide MEA was >5 g/kg in rats and >10 g/kg in mice. In a 14-day oral study, the NOAEL of cocamide MEA in rats was >750 mg/kg/day, which was the highest dose tested.
Acute (Single) Dose Toxicity
Dermal
Acetamide MEA No deaths occurred when rabbits were dosed dermally with 20 ml/kg acetamide MEA. From The Final Report on the Safety Assessment of Acetamide MEA43
Cocamide MEA The dermal LD50 of cocamide MEA was >2 g/kg, the highest dose tested, in male and female rabbits. Occlusive
patches were applied to abraded and intact skin for 24 h.47,48
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Oral
Cocamide MEA The acute oral toxicity of cocamide MEA (purity not specified) was evaluated in a number of studies using rats.47-49
In most studies, the highest dose administered was 5 g/kg or 5 ml/kg; the LD50 was greater than this dose. In a study in which
doses of 1-32 g/kg were used, the LD50 was reported to be 7.4 g/kg in rats47,48 In two other rat studies, the oral LD50 of
cocamide MEA was identified as 3.3 g/kg and >3.125 g/kg, respectively.49 In studies in mice, the oral LD50 of cocamide
MEA was >10 g/kg in most studies. However, a value of 3.125 g/kg was reported in one study using mice. (Details were not
provided.)
Acetamide MEA The oral LD50 of acetamide MEA has been reported as 26.95 and as 27.66 g/kg in rats. The acute toxicity of two hair products containing 1.3% acetamide MEA was >16.9 g/kg for one product and >25 ml/kg for the other; these were the highest concen-trations tested. From The Final Report on the Safety Assessment of Acetamide MEA43
Lauramide MEA The oral LD50 of lauramide MEA was >2 g/kg in rats.50
Tallowamide MEA (The following is being provided for read-across use.) The oral LD50 of hydrogenated tallow amide was >5 g/kg bw
in male and female rats; 5 g/kg was the highest dose tested.47
Repeated Dose Toxicity
Dermal
Acetamide MEA In a 13-wk study, a hair product containing 1.3% acetamide MEA, applied as an aq. solution that was diluted to 50% w/v, was not toxic to rabbits. Slight-to-moderate erythema was observed sporadically at the application site from days 44-84 of the study. From The Final Report on the Safety Assessment of Acetamide MEA43
Cocamide MEA Cocamide MEA, 25% in olive oil, was applied to mice twice a day for 1 wk, and the application site was not
covered.49 No dermal reactions were observed. Additional details were not provided.
Stearamide MEA The dermal toxicity of a formulation containing 17.0% stearamide MEA was evaluated in a 4-wk study in rabbits. Two g/kg of a 10% aq. solution of the formulation was applied to intact and abraded skin; no gross or microscopic lesions were observed. In a 13-wk dermal study, a formulation containing 5.27% stearamide MEA was not toxic in rats. From the Final Report on Isostearamide DEA & MEA, Myristamide DEA & MEA, and Stearamide DEA & MEA42
Oral
Cocamide MEA Groups of 10 male and 10 female Wistar rats were dosed by gavage with 0, 70, 250, and 750 mg/kg bw/day coca-
mide MEA in olive oil; the high dose was increased to 1500 mg/kg bw after 14 days.47 The animals were dosed once daily,
5x/wk, for 4 wks. Recovery groups of 5 male and 5 female rats per dose level were included. None of the animals died, and
no significant test-article related gross or microscopic lesions were observed. The NOAEL was >750 mg/kg bw/day.
REPRODUCTIVE AND DEVELOPMENTAL TOXICITY
Data on the reproductive and developmental toxicity of the ethanolamides were not found. Since ethanolamine may
be present as an impurity in the ethanolamides, and since amidases in the skin might convert some of the ethanolamide to
ethanolamine and the corresponding fatty acid, summary data from the reports on ethanolamine and a few “components” of
these dialkanolamides is being provided.
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MEA: In a dietary study, 0-7800 ppm of a composite hair dye and base containing 22% ethanolamine was fed to 60 gravid female rats on days 6-15 of gestation, and the rats were killed on day 19 of gestation. No developmental effects were observed. In another dietary study, 30 male rats were fed 0-7800 ppm of the hair for 8 wks prior to mating with female rats that were being fed a basal diet, while a group of 60 female rats were fed 0-7800 ppm of the test substance for 8 wks prior to mating with male rats being fed a basal diet. No effects on reproduction or fertility were observed. In rabbits, no developmental effects were observed when pregnant females were gavaged on days 6-18 of gestation with 0-19.5 ml/kg/day of the hair day containing 22% ethanolamine.1 Arachis Hypogaea (Peanut) Oil Peanut oil was used as the vehicle in a fertility study in rats. It was administered orally for 28 days prior to mating and for 6 days during mating. No unusual findings were noted in the vehicle group. No unusual finding were observed in a teratogenicity study in which rats were injected with a test article, and peanut oil was used as the vehicle. Treatment-related changes were not observed in a study in which rabbits were dosed intramuscularly with 21% peanut oil on day 8 of gestation. However, in a study of the effects of oil vehicles on early embryonic lethality in mice, it was stated that plant oils proved to be unsuitable carriers of test mutagens in female dominant-lethal studies where the route of administration is via the peritoneal cavity.51 Hydroxystearic Acid The dermal teratogenicity of two formulations containing 7% hydroxystearic acid was evaluated using female rats. No teratogenic effects were observed. (However, dermal irritation was reported.)52 Palm Oil: Crude palm oil was not a reproductive toxicant in a study in which male and female Wistar/NIN inbred weanling rats were fed a diet containing this ingredient (10%) prior to mating. Mean litter sizes were comparable between test and con-trol groups. No significant changes were found in liver or kidney weight in adult animals. Neither untreated palm oil (15%) nor 15% heated palm oil in the diet induced anomalies with respect to fertility and in utero growth when fed to male and female Sprague-Dawley SPF rats prior to mating. In a study investigating the effects of palm oil on sexual maturation and endocrine function, vaginal opening was observed significantly earlier (compared to 5% corn oil control) in weanling rats fed 20% palm oil in the diet. No significant differences were observed in endocrine function.53 Palm Kernel Oil: In the second generation resulting from the mating of adult Mongolian gerbils fed a diet containing 8.75% w/w palm kernel oil, no statistically significant differences were found with respect to the following: frequency of litters, mean litter size, total of newborns, and suckling death. Animals receiving a basal diet served as the control.53
GENOTOXICITY
In Vitro
Acetamide MEA Acetamide MEA was not mutagenic in an Ames test, and acetamide MEA did not induce unscheduled DNA synthesis in primary rat hepatocytes. From The Final Report on the Safety Assessment of Acetamide MEA43
Cocamide MEA In an Ames test, cocamide MEA was mutagenic in Salmonella typhimurium TA100 with metabolic activation; it was not mutagenic with S. typhimurium TA98, TA1535, TA1537, or TA1538, with or without metabolic activation using TA100 without metabolic activation. Cocamide MEA was not mutagenic in a plate incorporation assay. From The Final Report on the Safety Assessment of Cocamide MEA44
The mutagenic potential of cocamide MEA was evaluated in an Ames test using S. typhimurium TA1535, TA1537,
TA1538,TA98, and TA100, with and without metabolic activation.47,48 Cocamide MEA, evaluated at doses of 4-2500
μg/plate, was not mutagenic. The use of controls was not specified.
Lauramide MEA The mutagenic potential of lauramide MEA was evaluated in an Ames test with S. typhimurium TA98, TA100,
TA1535, TA1537, and TA1538 at doses of 33-3333 μg/plate, with and without metabolic activation.54 Doses of 3.3 and 10
μg/plate were tested with TA1537 without metabolic activation, and a dose of 10 μg/plate was tested in strains TA100 with-
out metabolic activation. Negative controls were used and gave expected results. Lauramide MEA was not mutagenic in this
assay.
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IRRITATION AND SENSITIZATION
Irritation
Skin
Non-Human Acetamide MEA
Acetamide MEA was a mild skin irritant in an open-patch Draize test in 12 rabbits. In another study, acetamide MEA (70% active) was not a primary irritant when applied to the intact and abraded skin of rabbits using a 24-h occlusive patch. From The Final Report on the Safety Assessment of Acetamide MEA43
Cocamide MEA The irritancy potential of cocamide MEA in petrolatum was evaluated in a 24-h patch test in guinea pigs, rabbits, and hairless mice. Cocamide MEA was slightly irritating to rabbits, but was not irritating to guinea pigs and hairless mice. From The Final Report on the Safety Assessment of Cocamide MEA44
The irritation potential of cocamide MEA was evaluated in rabbits.49 Cocamide MEA, 25%, was not irritating to
rabbits when applied under an occlusive patch for 24 h. (Additional details were not provided.)
Lauramide MEA In a Draize study, lauramide MEA was not irritating to rabbit skin.50 No details were provided.
Stearamide MEA The primary irritation index of a formulation containing 17.0% stearamide MEA was 1.00/8 in a group of 3 rabbits. From the Final Report on Isostearamide DEA & MEA, Myristamide DEA & MEA, and Stearamide DEA & MEA42
Human Acetamide MEA
In a dermal irritation study using 19 female subjects, a formulation containing 0.5% acetamide MEA did not evoke unacceptable clinical irritation and was comparable to the control product From The Final Report on the Safety Assessment of Acetamide MEA43
Cocamide MEA Cocamide MEA, 50% in petrolatum, was not irritating when a single 24-h patch was applied to the arm of 4 subjects. From The Final Report on the Safety Assessment of Cocamide MEA44
Stearamide MEA In a single-insult occlusive patch test with 19 subjects, a 1% aq. solution of a formulation containing 17% stearamide MEA, 7 subjects had questionable reactions and 3 subjects had mild reactions. In a 21-day, 14-subject, cumulative irritation study in which 0.2 ml of a formulation containing 5.0% stearamide MEA was applied using occlusive patches, slight irritation was observed, with a composite total score of 156/882. From the Final Report on Isostearamide DEA & MEA, Myristamide DEA & MEA, and Stearamide DEA & MEA42
Sensitization
Non-Human Acetamide MEA
Acetamide MEA was not a sensitizer in a maximization study using 10 guinea pigs. Induction included an intradermal injection of 5.0% acetamide MEA in propylene glycol and in Freund’s complete adjuvant and a topical application of 10% acetamide MEA. From The Final Report on the Safety Assessment of Acetamide MEA43
Cocamide MEA Cocamide MEA was not a sensitizer in a guinea pig maximization study. Details were not provided.
Human
Acetamide MEA In a 50-subject study, an aq. solution of 7.5% acetamide MEA did not cause primary irritation or sensitization. In an RIPT of a hair product containing 1.3% acetamide MEA, completed with 111 subjects, 12 subjects had mild reactions during induction and, and 2 of those subjects had mild reactions during challenge. However, the researchers concluded that a hair product containing 1.3% acetamide MEA was not a sensitizer. From The Final Report on the Safety Assessment of Acetamide MEA43
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Stearamide MEA
In a repeated insult patch test (RIPT) using 100 subjects in which 0.1 ml a formulation containing 5.27% stearamide MEA was applied using occlusive patches, the formulation did not produce sensitization. From the Final Report on Isostearamide DEA & MEA, Myristamide DEA & MEA, and Stearamide DEA & MEA42
Ocular Irritation
Non-Human Acetamide MEA
Acetamide MEA (70% minimum activity) was practically non-irritation to the eyes of rabbits, and two hair formulations containing 1.3% acetamide MEA were not irritating to rabbit eyes. From The Final Report on the Safety Assessment of Acetamide MEA43
Lauramide MEA In a Draize ocular irritation study, Lauramide MEA was highly irritating to rabbit eyes.50 Details were not provided.
Stearamide MEA A formulation containing 5.27% stearamide MEA was not irritating to rabbit eyes. Minimal irritation was reported in one study with a formulation containing 17.0% stearamide MEA, while moderate irritation was reported in another.. From the Final Report on Isostearamide DEA & MEA, Myristamide DEA & MEA, and Stearamide DEA & MEA42
SUMMARY
This report assesses the safety of 49 Ethanolamides. This safety assessment originated as a re-review of
isostearamide MEA, myristamide MEA, and stearamide MEA, and was expanded to include additional related ingredients.
Some of these ingredients have been previously reviewed by the CIR, and are included here to create a report on the complete
family of ingredients.
Amidases, such as fatty acid amide hydrolase which is known to be present in human skin, could potentially convert
the ethanolamides to ethanolamine and the corresponding fatty acids. The yield of ethanolamine from metabolism of
ethanolamides in human skin is unknown. Secondary amides do not tend to react with nitrosating agents to form
nitrosamides. Impurity data were available for acetamide, myristamide, and stearamide MEA: acetamide MEA contained up
to 0.0029% ethanolamine, 0.0030% acetamide, and no N-nitrosodiethanolamine; myristamide contained a maximum of 1.5%
ethanolamine; and stearamide MEA contained up to 2.0% free amine (as ethanolamine).
Most of the ethanolamides are reported to function in cosmetics as hair conditioning agents, skin conditioning
agents, and surfactant – foam boosters; a few are reported to have other uses . In 2011, stearamide MEA was reported to
have only 10 uses, myristamide MEA had one, and isostearamide had none. Cocamide MEA has the highest frequency of
use with 1122 reported uses; only 33 of those uses are in leave-on products. Cocamide MEA is reported to be used at up to
18% in rinse-off formulations and at up to 5% in leave-on formulations. Stearamide MEA has the highest concentration of
use in leave-on formulations at up to 15%. In Europe, monoalkylamines, monoalkanolamines, and their salts are on the list
of substances which must not form part of the composition of cosmetic products, except subject to restrictions and conditions
laid down. Acetamide MEA and babassuamide MEA are included in this list. These restrictions include a maximum
secondary amines contaminant content of 0.5% in finished products, a maximum secondary amines content of 0.5% in raw
materials, and a maximum nitrosamine content of 50 µg/kg.
In an acute dermal study in rabbits, the LD50 for cocamide MEA was > 2g/kg and for acetamide MEA, it was >20
ml/kg; these were the highest doses tested. In oral studies, the LD50 of cocamide MEA was >5 g/kg in rats and >10 g/kg in
mice. The oral LD50 values in rats for acetamide and lauramide MEA were 27 g/kg and 2 g/kg, respectively. In a 14-day oral
study, the NOAEL of cocamide DEA in rats was >750 mg/kg/day, the highest dose tested.
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No data on the reproductive and developmental toxicity of ethanolamides were found. Available reproductive and
developmental toxicity data from previous CIR reports on ethanolamine and some of the component ingredients were
summarized, and no significant toxic effects were noted.
Cocamide MEA (≤2500 μg/plate) and lauramide MEA (≤3333 μg/plate) were not mutagenic in Ames test with or
without metabolic activation.
Acetamide MEA was at most a mild skin irritant in rabbits, and in humans, a formulation containing 0.5% acetamide
MEA was not an irritant. Cocamide MEA was, at most, slightly irritating to rabbit skin, and it was not irritating to guinea
pigs and hairless mice. In clinical testing, 50% cocamide MEA in petrolatum was not irritating. A formulation containing
17% stearamide MEA had a primary irritation score of 1/8 in rabbits; 5% stearamide MEA produced slight irritation in a
cumulative irritation study. Acetamide MEA and cocamide MEA were not sensitizers in guinea pigs. In clinical testing, a
solution of 7.5% acetamide MEA, a formulation containing 1.3% acetamide MEA, and a formulation containing 5.27%
stearamide MEA were not sensitizers.
Acetamide MEA (70% minimum activity) was practically non-irritating to rabbit eyes, and formulations containing
1.3% acetamide MEA and 5.27% stearamide MEA were not irritating to rabbit eyes. A formulation containing 17% steara-
mide MEA was a moderate ocular irritant and lauramide MEA was highly irritating to rabbit eyes.
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TABLES
Table 1a. Definition and structures of ethanolamine and ethanolamine-containing ingredients
Ingredient CAS No. Definition Formula/structure MEA and Inorganic Acid Salts
Ethanolamine 141-43-5
Ethanolamine is a primary amine with one ethanol functional group.
Ethanolamine HCl 2002-24-6
Ethanolamine HCl is the ethanolamine salt of hydrochloric acid.
MEA-Sulfite 13427-63-9
MEA-Sulfite is the ethanolamine salt of hydrogen sulfite.
HONH3
HSO3
Organic Acid Salts MEA-Benzoate 4337-66-0 33545-23-2
MEA-Benzoate is the ethanolamine salt of benzoic acid.
MEA-Salicylate 59866-70-5
MEA-Salicylate is the ethanolamine salt of salicylic acid.
MEA-Cocoate 66071-80-5
MEA-Cocoate is the ethanolamine salt of coconut acid.
MEA-Tallowate
MEA-Tallowate is the ethanolamine salt of tallow acid.
MEA-Undecylenate 56532-40-2
MEA-Undecylenate is the ethanolamine salt of undecylenic acid.
MEA-Laureth-6 Carboxylate MEA-Laureth-6
Carboxylate is the ethanolamine salt of laureth-6 carboxylic acid (wherein “-6” represents the number ethylene glycol units, including the carboxylate).
MEA PPG-6 Laureth-7 Carboxylate
MEA PPG-6 Laureth-7 Carboxylate is the ethanolamine salt of PPG-6 laureth-7 carboxylic acid (wherein “-7” represents the number ethylene glycol units, including the carboxylate).
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Table 1a. Definition and structures of ethanolamine and ethanolamine-containing ingredients
Ingredient CAS No. Definition Formula/structure
HONH3
OO
OO
OO
OO
OO
CH3
CH3
CH3
O
CH3
O
CH3
O
CH3
CH3O
O
MEA-PPG-8-Steareth-7 Carboxylate
MEA-PPG-8-Steareth-7 Carboxylate is the ethanolamine salt of PPG-8 steareth-7 carboxylic acid (wherein “-7” represents the number ethylene glycol units, including the carboxylate).
HONH3
OO O O O O O O OCH3
CH3O
CH3
O
CH3O
CH3
O O O
CH3
CH3
CH3
CH3O
O
-Protein Salts MEA-Hydrolyzed Silk MEA-Hydrolyzed Silk is
the monoethanolamine salt of Hydrolyzed Silk. Hydrolyzed silk is the substance obtained by acidic, alkaline, or enzymatic hydrolysis of silk worm cocoon, composed primarily of amino acids, peptides, and proteins.
MEA-Hydrolyzed Collagen MEA- Hydrolyzed Collagen is the monoethanolamine salt of Hydrolyzed Collagen. Hydrolyzed collagen the substance obtained by acidic, alkaline, or enzymatic hydrolysis of collagen, composed primarily of amino acids, peptides, and proteins.
Organic-Substituted Inorganic Salts MEA-Lauryl Sulfate 4722-98-9
MEA-Lauryl Sulfate is the ethanolamine salt of sulfated lauryl alcohol.
MEA-Laureth Sulfate 68184-04-3
MEA-Laureth Sulfate is the ethanolamine salt of sulfated, ethoxylated lauryl alcohol (wherein the number of ethylene glycol units ranges from one to four).
MEA-Dicetearyl Phosphate MEA-Dicetearyl Phosphate is the ethanolamine salt of dicetearyl phosphate.
Alkyl Substituted EthanolaminesMethylethanolamine 109-83-1
Methylethanolamine is a secondary amine with one N-ethanol functional group and one N-methyl group.
Ethyl Ethanolamine 110-73-6
Ethyl Ethanolamine is a secondary amine with one N-ethanol functional group and one N-ethyl group.
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Table 1a. Definition and structures of ethanolamine and ethanolamine-containing ingredients
Ingredient CAS No. Definition Formula/structure Butylethanolamine Butylethanolamine is a
secondary amine with one N-ethanol functional group and one N-butyl group.
Dimethyl MEA 108-01-0
Dimethyl MEA is a tertiary amine with one N-ethanol functional group and two N-methyl groups.
Diethyl Ethanolamine 100-37-8
Diethyl MEA is a tertiary amine with one N-ethanol functional group and two N-ethyl groups.
Dibutyl Ethanolamine 102-81-8
Dibutyl MEA is a tertiary amine with one N-ethanol functional group and two N-butyl groups.
Table 1b. Definition and structures of ethanolamides
Ingredient CAS No. Definition Formula/structure Ethanolamides
Acetamide MEA 142-26-7
Acetamide MEA is the ethanolamide of acetic acid.
Myristamide MEA 109-83-1
Myristamide MEA is the ethanolamide of myristic acid.
Cocamide MEA 68140-00-1
Cocamide MEA is a mixture of ethanolamides of Cocos Nucifera (Coconut) Acid.
Isostearamide MEA 54536-43-5
Isostearamide MEA is the ethanolamide of Isostearic Acid.
one example of an “iso”
Stearamide MEA 111-57-9
Stearamide MEA is the ethanolamide of stearic acid.
Azelamide MEA Azelamide MEA is the ethanolamide of azelaic acid.
Babassuamide MEA 69227-24-3
Babassuamide MEA is a mixture of ethanolamides of the fatty acids derived from Orbignya Oleifera (Babassu) Oil.
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Table 1b. Definition and structures of ethanolamides
Ingredient CAS No. Definition Formula/structure Behenamide MEA 94109-05-4
Behenamide MEA is the ethanolamide of Behenic Acid.
C16-22 Acid Amide MEA
C16-22 Acid Amide MEA is a mixture of ethanolamides of C16-22 fatty acids.
Cocamide Methyl MEA Cocamide Methyl MEA is a mixture of tertiary, N-methyl ethanolamides of the fatty acids derived from Cocos Nucifera (Coconut) Oil.
Cocamidopropyl Betainamide MEA Chloride 164288-56-6
Cocamidopropyl Betainamide MEA Chloride is a mixture of N’-betaine ethanolamides of the fatty acids derived from coconut oil.
Deoxyphytantriyl Palmitamide MEA
Deoxyphytantriyl Palmitamide MEA is a multi-branched, polyol derivative of palmitamide MEA.
N
O
HO OH
CH3H3C
H3C OH CH3 CH3 CH3
Hexyloxodecanamide MEA 884905-11-7
Hexyloxodecanamide MEA is the hexyl substituted derivative of oxodecanamide MEA.
H3C NH
O
OH
O
H3C Hexyloxodecanamide MEA Phosphate 934175-85-6
Hexyloxodecanamide MEA Phosphate is the phosphate salt of Hexyloxodecanamide MEA.
H3C NH
O
OH
O
H3CH3PO4
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Table 1b. Definition and structures of ethanolamides
Ingredient CAS No. Definition Formula/structure Hydroxyethyl Pantothenamide MEA
Hydroxyethyl Pantothenamide MEA is the O-monoethyleneglycol substituted derivative Pantothenamide MEA.
NH
O
OOHN
H
O
OH
H3C CH3HO
Hydroxypropyl Bisisostearamide MEA
Hydroxypropyl Bisisostearamide MEA is a 1,3-disubstituted 2-hydroxypropane compound, wherein each substituent is an N-isostearamide MEA.
one example of an “iso”
N
O
N
HO OH OH
O
CH3
CH3
H3C
CH3
Hydroxypropyl Bislauramide MEA
Hydroxypropyl Bisisostearamide MEA is a 1,3-disubstituted 2-hydroxypropane compound, wherein each substituent is an N-lauramide MEA.
N
O
NH3C
HO OH OH
O
CH3
Hydroxypropyl Bispalmitamide MEA
Hydroxypropyl Bisisostearamide MEA is a 1,3-disubstituted 2-hydroxypropane compound, wherein each substituent is an N-palmitamide MEA.
N
O
N
HO OH OH
O
H3C CH3
Hydroxypropyl Bisstearamide MEA
Hydroxypropyl Bisisostearamide MEA is a 1,3-disubstituted 2-hydroxypropane compound, wherein each substituent is an N-stearamide MEA.
N
O
N
HO OH OH
O
CH3H3C
Hydroxystearamide MEA 106-15-0
Hydroxystearamide MEA is the 12-hydroxy substituted derivative of stearamide MEA.
NH
O
OHH3C
OHLactamide MEA 5422-34-4
Lactamide MEA is the ethanolamide of lactic acid
NH
O
OHH3C
OH
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Table 1b. Definition and structures of ethanolamides
Ingredient CAS No. Definition Formula/structure Lauramide MEA 142-78-9
Lauramide MEA is the ethanolamide of lauric acid
NH
O
OHH3C
Linoleamide MEA 10015-67-5
Linoleamide MEA is the ethanolamide of linoleic acid
NH
O
OHCHCH
CHCHH3C
Myristoyl/Palmitoyl Oxostearamide/Arachamide MEA
Myristoyl/Palmitoyl Oxostearamide/Arachamide MEA is the alkyl substituted derivative of an oxoalkylamide MEA.
NH
O
OH
O
H3C
H3C
mn
wherein m is 14-16 and n is 13-15
Oatamide MEA Oatamide MEA is a mixture of ethanolamides of the fatty acids derived from oat kernel oil.
R NH
O
OH
where RCO- represents the fatty acids derived from Avena Sativa (Oat) Kernel Oil
Oleamide MEA 111-58-0
Oleamide MEA is the ethanolamide of oleic acid.
NH
O
OHCHCH
H3C
Oliveamide MEA Oliveamide MEA is a mixture of ethanolamides of the fatty acids derived from olive oil.
R NH
O
OH
where RCO- represents the fatty acids derived from olive oil
Palm Kernelamide MEA Palm Kernelamide MEA is a mixture of ethanolamides of the fatty acids derived from Elaeis Guineensis (Palm) Kernel Oil.
R NH
O
OH
where RCO- represents the fatty acids derived from palm kernel oil
Palmamide MEA Palmamide MEA is a mixture of ethanolamides of the fatty acids derived from Elaeis Guineensis (Palm) Oil.
R NH
O
OH
where RCO- represents the fatty acids derived from palm oil
Palmitamide MEA 544-31-0
Palmitamide MEA is the ethanolamide of palmitic acid.
NH
O
OHH3C
Pantothenamide MEA Pantothenamide MEA is the O-monoethyleneglycol substituted derivative Pantothenamide MEA.
NH
O
OHNH
O
OH
H3C CH3HO
Peanutamide MEA Peanutamide MEA is a
mixture of ethanolamides of the fatty acids derived from Arachis Hypogaea (Peanut) Oil.
R NH
O
OH
where RCO- represents the fatty acids derived from peanut oil
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Table 1b. Definition and structures of ethanolamides
Ingredient CAS No. Definition Formula/structure Ricinoleamide MEA 106-16-1 75033-33-9
Ricinoleamide MEA is ethanolamide derived from ricinoleic acid.
NH
O
OHCH
CH
OH
H3C
Stearamide MEA-Stearate 14351-40-7
Stearamide MEA-Stearate is ethanoate-amide derived from 2 equivalents of stearic acid.
ONH
O
CH3H3C
O
Stearamidoethyl Ethanolamine 141-21-9
Stearamidoethyl Ethanolamine is the ethylamidoethylamine derived from stearic acid.
NH
NH
O
CH3HO
Sunfloweramide MEA 69227-24-3
Sunfloweramide MEA is a mixture of ethanolamides of the fatty acids derived from Helianthus Annuus (Sunflower) Seed Oil.
R NH
O
OH
where RCO- represents the sunflower seed oil fatty acids
Tallowamide MEA 68440-25-5
Tallowamide MEA is a mixture of ethanolamides of Tallow Acid. R N
H
O
OH
where RCO- represents the fatty acids derived from tallow
Trideceth-2 Carboxamide MEA 107628-04-6
Trideceth-2 Carboxamide MEA is the ethanolamide of Trideceth-2.
HONH
O
OO
CH3
Undecylenamide MEA 20545-92-0 75046-17-2
Undecylenamide MEA is the ethanolamide of undecylenic acid.
NH
O
OHH3C
-Glycol ethers PEG-2 Cocamide 61791-08-0 (generic to all ethoxylated deriviatives of Cocamide MEA)
PEG-2 Cocamide is an ethoxylated derivative of Cocamide MEA, with an average of one ethylene glycol unit.
where RCO- represents the coconut oil fatty acids
PEG-3 Cocamide 61791-08-0 (generic to all ethoxylated deriviatives of Cocamide MEA)
PEG-3 Cocamide is an ethoxylated derivative of Cocamide MEA, with an average of two ethylene glycol units.
where RCO- represents the coconut oil fatty acids
PEG-4 Cocamide 61791-08-0 (generic to all ethoxylated deriviatives of Cocamide MEA)
PEG-4 Cocamide is an ethoxylated derivative of Cocamide MEA, with an average of three ethylene glycol units.
where RCO- represents the coconut oil fatty acids
PEG-5 Cocamide 61791-08-0 (generic to all ethoxylated deriviatives of Cocamide MEA)
PEG-5 Cocamide is an ethoxylated derivative of Cocamide MEA, with an average of four ethylene glycol units.
where RCO- represents the coconut oil fatty acids
PEG-6 Cocamide 61791-08-0 (generic to all ethoxylated deriviatives of Cocamide MEA)
PEG-6 Cocamide is an ethoxylated derivative of Cocamide MEA, with an average of five ethylene glycol units.
where RCO- represents the coconut oil fatty acids
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Table 1b. Definition and structures of ethanolamides
Ingredient CAS No. Definition Formula/structure PEG-7 Cocamide 61791-08-0 (generic to all ethoxylated deriviatives of Cocamide MEA)
PEG-7 Cocamide is an ethoxylated derivative of Cocamide MEA, with an average of six ethylene glycol units.
where RCO- represents the coconut oil fatty acids
PEG-9 Cocamide MEA 61791-08-0 (generic to all ethoxylated deriviatives of Cocamide MEA)
PEG-9 Cocamide MEA is an ethoxylated derivative of Cocamide MEA, with an average of nine ethylene glycol units.
where RCO- represents the coconut oil fatty acids
PEG-11 Cocamide 61791-08-0 (generic to all ethoxylated deriviatives of Cocamide MEA)
PEG-11 Cocamide is an ethoxylated derivative of Cocamide MEA, with an average of ten ethylene glycol units.
where RCO- represents the coconut oil fatty acids
PEG-20 Cocamide 61791-08-0 (generic to all ethoxylated deriviatives of Cocamide MEA)
PEG-20 Cocamide is an ethoxylated derivative of Cocamide MEA, with an average of nineteen ethylene glycol units.
where RCO- represents the coconut oil fatty acids PEG-20 Cocamide MEA 61791-08-0 (generic to all ethoxylated deriviatives of Cocamide MEA)
PEG-20 Cocamide MEA is an ethoxylated derivative of Cocamide MEA, with an average of 20 ethylene glycol units.
where RCO- represents the coconut oil fatty acids
Table 2a. Conclusions of previously reviewed ingredients, as pertaining to the ethanolamine and ethanolamine-containing ingredients
Ingredient Conclusion Reference
PREVIOUSLY REVIEWED INGREDIENTS
Ethanolamine is safe for use in cosmetic formulations designed for discontinuous, brief use followed by thorough rinsing from the surface of the skin, and MEA should only be used in rinse-off products
MEA-Salicylate safe as used when formulated to avoid skin irritation and when formulated to avoid increasing the skin’s sun sensitivity, .or, when increased sun sensitivity would be expected; directions for use include the daily use of sun protection
COMPONENTS
Ammonium Lauryl Sulfate Sodium Lauryl Sulfate
safe in formulations designed for discontinuous, brief use followed by thorough rinsing from the surface of the skin; in products intended for prolonged contact with skin, concentrations should not exceed 1%
55
Benzoic Acid safe as used (currently being reviewed)
Coconut Acid safe as used 56
Hydrolyzed Collagen safe as used 57 Laureths safe as used when formulated to be non-irritating 58 PPG safe as used when formulated to be non-irritating 59 Sodium Laureth Sulfate and related salts of ethoxylated alcohols
safe as used when formulated to be non-irritating 60
Steareths safe as used when formulated to be non-irritating 58
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Table 2b. Conclusions of previously reviewed ingredients, as pertaining to the ethanolamides
Ingredient Conclusion Reference
PREVIOUSLY REVIEWED INGREDIENTS
Isostearamide MEA safe for use in rinse-off products; in leave-on products, safe for use at a concentration that will limit the release of free ethanolamines to 5%, with a maximum use concentration of 17%
42
Myristamide MEA safe for use in rinse-off products; in leave-on products, safe for use at a concentration that will limit the release of free ethanolamines to 5%, with a maximum use concentration of 17%
42
Stearamide MEA safe for use in rinse-off products; in leave-on products, safe for use at a concentration that will limit the release of free ethanolamines to 5%, with a maximum use concentration of 17%
42
Acetamide MEA safe as a cosmetic ingredient at concentrations not to exceed 7.5% in leave-on products; safe in the present practices of use in rinse-off products; products containing acetamide MEA should not contain nitrosating agents or significant amounts of acetamide
43
Cocamide MEA safe as used in rinse-off products; safe at concentrations up to 10% in leave-on products; should not be used as an ingreidnet in products containing N-nitrosating agents, or in product formulations intended to be aerosolized
44
COMPONENTS
Ethanolamine (likely an impurity) to be determined at this meeting
Arachis Hypogaea (Peanut) Oil safe as used 61 Azelaic Acid safe as used 62 Cocamidopropyl Betaine safe as used when formulated to be non-sensitizing 63 Coconut Acid safe as used 56 Elaeis Guineensis (Palm) Kernel Oil Elaeis Guineensis (Palm) Oil
safe as used 53
Helianthus Annuus (Sunflower) Seed Oil safe as used 61 Hydroxystearic Acid safe as used 52 Isostearic Acid safe as used 64 Lactic Acid 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
65
Lauric Acid safe as used 66 Myristic Acid safe as used 66 Oat Kernel Oil safe as used 61 Olea Europaea (Olive) Fruit Oil safe as used 61 Oleic Acid safe as used 66 Orbignya Oleifera (Babassu) Oil safe as used 61 Palmitic Acid safe as used 61 Pantothenic Acid safe as used 67 PEGs safe as used 68 Ricinoleic Acid safe as used 69 Stearic Acid safe as used 66 Trideceth-2 safe as used when formulated to be non-irritating 58
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Table 3a. Physical and chemical properties
Property Value Reference Ethanolamine
Physical Form clear viscous liquid 1 Color colorless 1 Odor ammonia-like 1 Molecular Weight 61.08 1 Specific Gravity 1.0117 (25°C) 1 Viscosity 18.95 (25°C) 1 Refractive Index 1.4542 (20°C) 7 Vapor Pressure 0.48 mm Hg (20°C) 1 pKa 9.5 (25°C0 7 Melting Point 10.3-10.5°C 1 Boiling Point 171°C 1 Water Solubility miscible with water 23 Other Solubility miscible with methanol and acetone
soluble in alcohol, ethanol, chloroform,glycerol, logroin
23 7
log Pow (estimated) -1.31 70 MEA Benzoate
Molecular Weight 165.19 (calculated) 71 pKa 8.0 g/cm3 ( (most basic; 25°C) (calculated) 71 Density 1.119 g/cm3 (20°C) (calculated) 71 Boiling Point 271.8°C (calculated) 71 logP 1.336 (25°C) (calculated) 71
Table 3b. Physical and chemical properties of ethanolamides Property Value Reference
Acetamide MEA
Molecular Weight 103.12 (calculated) 71 pKa 14.56 g/cm3 (most acidic; 25°C)
-0.65 g/cm3 (most basic; 25°C) (calculated) 71
Density 1.115 g/cm3 (25°C) (calculated) 72 Melting Point 63-64°C 73 Boiling Point 195-196°C 72 logP -1.336 (25°C) (calculated) 71
Behenamide MEA
Molecular Weight 383.65 (calculated) 71 pKa 14.49 g/cm3 (most acidic; 25°C)
-0.67 g/cm3 (most basic; 25°C) (calculated) 71
Density 0.896 g/cm3 (20°C) (calculated) 71 Boiling Point 74 logP 8.853 (25°C) (calculated) 71
C16-22 Acid Amide MEA
Molecular Weight 117.19 (calculated) 71 pKa 14.81 g/cm3 (most acidic; 25°C)
9.90 g/cm3 (most basic; 25°C) (calculated) 71
Density 0.875 g/cm3 (20°C) (calculated) 71 Melting Point -2°C 74 Boiling Point 199°C 74 logP 0.467 (25°C) (calculated) 71
Cocamide MEA Melting Point ~72°C 49 Density ~0.894 g/cm3 (80°C) 49 partition Coefficient 3.89 (calculated) 49 Solubility not soluble in water 49
Hexyloxodecanamide MEA Molecular Weight 313.48 (calculated) 71 pKa 12.70 g/cm3 (most acidic; 25°C)
-1.00 g/cm3 (most basic; 25°C) (calculated) 71
Density 0.959 g/cm3 (20°C) (calculated) 71 Boiling Point 484.4°C (calculated) 71 logP 4.335 (25°C) (calculated) 71
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Table 3b. Physical and chemical properties of ethanolamides Property Value Reference
Hydroxystearamide MEA Molecular Weight 343.54 (calculated) 71 pKa 14.49 g/cm3 (most acidic; 25°C)
-0.67 g/cm3 (most basic; 25°C) (calculated) 71
Density 0.954 g/cm3 (20°C) (calculated) 71 Melting Point 106.5-108°C 75 Boiling Point 522.4°C (calculated) 71 logP 4.753 (25°C) (calculated) 71
Lauramide MEA Physical Form solid 48 Molecular Weight 243.39 48 pKa 14.49 g/cm3 (most acidic; 25°C)
-0.67 g/cm3 (most basic; 25°C) (calculated) 71
Density 0.925 g/cm3 (20°C) (calculated) 71 Melting Point 89-91°c 76 Boiling Point 410.7°C (calculated) 71 Water Solubility miscible with water 48 logP 3.758 (25°C) (calculated) 71
Linoleamide MEA Molecular Weight 323.51 (calculated) 71 pKa 14.49 g/cm3 (most acidic; 25°C)
-0.67 g/cm3 (most basic; 25°C) (calculated) 71
Density 0.926 g/cm3 (20°C) (calculated) 71 Boiling Point 499.1°C (calculated) 71 logP 6.003 (25°C) (calculated) 71
Myristamide MEA Molecular Weight 271.44 (calculated) 71 pKa 14.49 g/cm3 (most acidic; 25°C)
-0.67 g/cm3 (most basic; 25°C) (calculated) 71
Density 0.916 g/cm3 (20°C) (calculated) 71 Melting Point 93-94°C 77 Boiling Point 436.3°C (calculated) 71 logP 4.777 (25°C) (calculated) 71
Oleamide MEA Molecular Weight 325.53 (calculated) 71 pKa 14.49 g/cm3 (most acidic; 25°C)
-0.67 g/cm3 (most basic; 25°C) (calculated) 71
Density 0.915 g/cm3 (20°C) (calculated) 71 Melting Point 63-64°C 76 Boiling Point 496.4°C (calculated) 71 logP 6.406 (25°C) (calculated) 71
Palmitamide MEA Molecular Weight 299.49 (calculated) 71 pKa 14.49 g/cm3 (most acidic; 25°C)
-0.67 g/cm3 (most basic; 25°C) (calculated) 71
Density 0.910 g/cm3 (20°C) (calculated) 71 Melting Point 98°C 78 Boiling Point 461.5°C (calculated) 71 logP 5.796 (25°C) (calculated) 71
Ricinoleamide MEA Molecular Weight 341.53 (calculated) 71 pKa 14.49 g/cm3 (most acidic; 25°C)
-0.67 g/cm3 (most basic; 25°C) (calculated) 71
Density 0.965 g/cm3 (20°C) (calculated) 71 Melting Point 58-59°C 75 Boiling Point 536.2°C (calculated) 71 logP 4.592 (25°C) (calculated) 71
Stearmide MEA Molecular Weight 327.55 (calculated) 71 pKa 14.49 g/cm3 (most acidic; 25°C)
-0.67 g/cm3 (most basic; 25°C) (calculated) 71
Density 0.904 g/cm3 (20°C) (calculated) 71 Melting Point 106-108°C 76 Boiling Point 486.0°C (calculated) 71 logP 6.815 (25°C) (calculated) 71
Stearamide MEA-Stearate Molecular Weight 370.61 (calculated) 71 pKa 14.76 g/cm3 (most acidic; 25°C)
8.75 g/cm3 (most basic; 25°C) (calculated) 71
Density 0.917 g/cm3 (20°C) (calculated) 71 Melting Point 92-94°C 79 Boiling Point 543.4°C (calculated) 71
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Table 3b. Physical and chemical properties of ethanolamides Property Value Reference logP 6.161 (25°C) (calculated) 71
Stearamidoethyl Ethanolamine Molecular Weight 594.01 (calculated) 71 pKa 15.32 g/cm3 (most acidic; 25°C)
-0.70 g/cm3 (most basic; 25°C) (calculated) 71
Density 0.892 g/cm3 (20°C) (calculated) 71 Melting Point 94.5-96°C 80 Boiling Point 678.4°C (calculated) 71 logP 15.665 (25°C) (calculated) 71
Undecylenamide MEA Molecular Weight 227.34 (calculated) 71 pKa 14.49 g/cm3 (most acidic; 25°C)
-0.67 g/cm3 (most basic; 25°C) (calculated) 71
Density 0.940 g/cm3 (20°C) (calculated) 71 Melting Point 56-58°C 81 Boiling Point 409.4°C (calculated) 71 logP 2.841 (25°C) (calculated) 71
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Table 4a. Frequency and concentration of use according to duration and type of exposure
# of Uses9 Conc of Use (%)11 # of Uses9 Conc of Use (%)11 # of Uses9 Conc of Use (%)11
Ethanolamine MEA Cocoate MEA-Hydrolyzed Collagen
Totals* 764 0.0002-18 4 NR NR 0.03-0.2
Duration of Use
Leave-On 1 NR NR NR NR 0.1-0.2
Rinse-Off 763 0.0002-18 4 NR NR 0.03-0.06
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 3 NR NR NR NR
Incidental Inhalation-Powder NR NR NR NR NR NR
Dermal Contact 1 0.0002-11 4 NR NR 0.03-0.2
Deodorant (underarm) NR NR NR NR NR NR
Hair - Non-Coloring 13 0.05-6 NR NR NR 0.06
Hair-Coloring 750 3-18 NR NR NR NR
Nail NR NR NR NR NR NR
Mucous Membrane NR 0.02-0.05 4 NR NR NR
Baby Products NR NR NR NR NR NR
MEA-Laureth Sulfate MEA-Lauryl Sulfate MEA-Tallowate Totals* 13 NR 5 5-35 6 NR Duration of Use Leave-On NR NR NR NR NR NR
Rinse Off 13 NR 5 5-35 6 NR
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-Powder NR NR NR NR NR NR
Dermal Contact NR NR 1 NR 6 NR
Deodorant (underarm) NR NR NR NR NR NR
Hair - Non-Coloring 1 NR 4 5 NR NR
Hair-Coloring 12 NR NR 35 NR NR
Nail NR NR NR NR NR NR
Mucous Membrane NR NR NR NR 6 NR
Baby Products NR NR 1 NR NR NR * 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. a Includes deodorants, in that it is not known whether or not the product is a spray. b Includes suntan products, in that it is not known whether or not the reported product is a spray. NR – no reported uses Table 4b. Ingredients not reported to be in use *this table will be created after the Panel finalizes the list of ingredients that will be included in the re-review of ethanolamine Table 4c. Status for use in Europe according to the EC CosIng Database for ethanolamine ingredients Fatty Acid Monoalkylamines, monoalkanolamines,and their salts – listed in Annex III – restrictions12 (maximum secondary amine content of 0.5% in the finished product; do not use with nitrosating systems; minimum purity – 99%; maximum secondary amine content of 5% for raw materials; maximum nitrosamine content of 50 µg/kg; keep in nitrite free containers) Ethanolamine Ethanolamine HCl MEA PPG-6 Laureth-7 Carboxylate MEA-Benzoate MEA-Biotinate MEA-Cocoate MEA-Dicetearyl Phosphate MEA -Hydrolyzed Collagen
MEA -Hydrolyzed Silk MEA -Laureth Sulfate MEA -Laureth-6 Carboxylate MEA -Lauryl Sulfate MEA -Ppg-8-Steareth-7 Carboxylate MEA -Salicylate MEA -Sulfite MEA –Undecylenate
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Table 5a. Frequency and concentration of use according to duration and type of exposure – ethanolamides
# of Uses9 Conc of Use (%)11 # of Uses9 Conc of Use (%)11 # of Uses9 Conc of Use (%)11
Acetamide MEA Cocamide MEA Cocamide Methyl MEA
Totals* 148 0.03-8 1122 0.2-18 NR 5
Duration of Use
Leave-On 64 0.03-8 33 0.5-5 NR NR
Rinse-Off 84 0.06-5 1008 0.2-18 NR 5
Diluted for (Bath) Use NR NR 81 2-6 NR NR
Exposure Type
Eye Area 1 0.5 NR NR NR NR
Incidental Ingestion NR NR NR NR NR NR
Incidental Inhalation-Spray 23a 0.1-2a 3b 0.7-3b NR NR
Incidental Inhalation-Powder NR NR NR NR NR NR
Dermal Contact 25 0.03-8 579 0.2-10 NR NR
Deodorant (underarm) 9 2 NR NR NR NR
Hair - Non-Coloring 121 0.06-5 367 1-15 NR 5
Hair-Coloring 1 NR 173 3-18 NR NR
Nail 1 NR 2 NR NR NR
Mucous Membrane 3 3-4 521 1-10 NR NR
Baby Products NR NR 4 2 NR NR
Cocamidopropyl Betainamide MEA
Chloride Lactamide MEA Lauramide MEA
Totals* 21 1-3 27 0.02-3 87 0.3-4 Duration of Use Leave-On NR NR 21 0.02-2 3 0.5-4
Rinse Off 21 1-3 6 0.2-3 80 0.3-3
Diluted for (Bath) Use NR NR NR 2 4 2
Exposure Type
Eye Area NR NR 1 NR NR NR
Incidental Ingestion NR NR NR NR NR NR
Incidental Inhalation-Spray NR NR 4 0.02-0.2 1 1
Incidental Inhalation-Powder NR NR NR NR NR NR
Dermal Contact 21 1-3 9 2-3 35 0.3-4
Deodorant (underarm) NR NR NR NR NR NR
Hair - Non-Coloring NR NR 17 0.02-3 9 1-3
Hair-Coloring NR NR NR NR 43 3
Nail NR NR 1 NR NR 1
Mucous Membrane 18 1-3 1 2-3 28 1-3
Baby Products NR NR NR NR NR 0.5
Myristamide MEA Myristoyl/Palmitoyl/Oxostearamide
/Arachamide MEA Peanutamide MEA
Totals* 1 0.3-4 4 NR NR 0.3
Duration of Use
Leave-On NR 4 3 NR NR NR
Rinse-Off 1 0.3 1 NR NR 0.3
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-Powder NR NR NR NR NR NR
Dermal Contact 1 0.3-4 4 NR NR 0.3
Deodorant (underarm) NR NR NR NR NR NR
Hair - Non-Coloring NR NR NR NR NR NR
Hair-Coloring NR NR NR NR NR NR
Nail NR NR NR NR NR NR
Mucous Membrane 1 NR NR NR NR NR
Baby Products NR NR NR NR NR NR
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Table 5a. Frequency and concentration of use according to duration and type of exposure – ethanolamides
# of Uses9 Conc of Use (%)11 # of Uses9 Conc of Use (%)11 # of Uses9 Conc of Use (%)11
Ricinoleamide MEA Stearamide MEA Stearamide MEA-Stearate
Totals NR 0.02 10 0.07-17 8 3 Duration of Use Leave-On NR NR 2 2-15 7 3
Rinse Off NR 0.02 8 0.07-6 1 NR
Diluted for (Bath) Use NR NR NR 17 NR NR Exposure Type Eye Area NR NR NR 6-7 2 3
Incidental Ingestion NR NR NR NR NR NR
Incidental Inhalation-Spray NR NR 2a 15a NR NR
Incidental Inhalation-Aerosol NR NR NR NR NR NR
Dermal Contact NR 0.02 3 0.2-17 5 NR
Deodorant (underarm) NR NR 2 15 NR NR
Hair - Non-Coloring NR NR NR 0.07 1 NR
Hair-Coloring NR NR 7 2-6 NR NR
Nail NR NR NR 2 NR NR
Mucous Membrane NR NR NR 17 NR NR
Baby Products NR NR NR NR NR NR Trideceth-2 Carboxamide MEA Undecylenamide MEA
Totals* 189 2-14 3 NR Duration of Use Leave-On NR 2 2 NR
Rinse-Off 189 2-14 1 NR
Diluted for (Bath) Use NR NR NR NR Exposure Type Eye Area NR NR NR NR Incidental Ingestion NR NR NR NR
Incidental Inhalation-Spray NR NR 2 NR
Incidental Inhalation-Powder NR NR NR NR
Dermal Contact 1 NR 2 NR
Deodorant (underarm) NR NR 1 NR
Hair - Non-Coloring 5 2 NR NR
Hair-Coloring 183 4-14 1 NR
Nail NR NR NR NR
Mucous Membrane 1 NR NR NR
Baby Products NR NR NR NR PEG-5 Cocamide PEG-6 Cocamide PEG-9 Cocamide Totals* 40 NS 23 NS 1 NR Duration of Use
Leave-On NR NS 3 NS NR NR
Rinse-Off 40 NS 19 NS 1 NR
Diluted for (Bath) Use NR NS 1 NS NR NR
Exposure Type
Eye Area NR NS NR NS NR NR
Incidental Ingestion NR NS NR NS NR NR
Incidental Inhalation-Spray NR NS NR NS NR NR
Incidental Inhalation-Powder NR NS NR NS NR NR
Dermal Contact 24 NS 14 NS NR NR
Deodorant (underarm) NR NS NR NS NR NR
Hair - Non-Coloring 15 NS 8 NS 1 NR
Hair-Coloring 1 NS 1 NS NR NR
Nail NR NS NR NS NR NR
Mucous Membrane 2 NS 12 NS NR NR
Baby Products NR NS NR NS NR NR * 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. NR – no reported uses NS -These ingredients have not been included in a Council concentration of use survey
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Table 5b. Ethanolamides not reported to be in use Azelamide MEA Babassuamide MEA Behenamide MEA C16-22 Acid Amide MEA Deoxyphytantriyl Palmitamide MEA Hexyloxodecanamide MEA Hydroxyethyl Pantothenamide MEA Hydroxypropyl Bisisostearamide MEA Hydroxypropyl Bislauramide MEA Hydroxypropyl Bispalmitamide MEA Hydroxypropyl Bisstearaminde MEA Hydroxystearamide MEA Isostearamide MEA Linoleamide MEA Oatamide MEA Oleamide MEA
Oliveamide MEA Palm Kernelamide MEA Palmamide MEA Palmitamide MEA Pantothenamide MEA Stearamidoethyl Ethanolamine Sunfloweramide MEA Tallowamide MEA PEG-2 Cocamidea
PEG-3 Cocamidea
PEG-4 Cocamidea
PEG-7 Cocamidea
PEG-11 Cocamidea
PEG-20 Cocamidea
PEG-20 Cocamide MEAa
aThese ingredients have not been included in a Council concentration of use survey
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53. Andersen FA (ed). Final Report on the Safety Assessment of Elaeis Guineensis (Palm) Oil, Elaeis Guineensis (Palm) Kernel Oil, Hydrogenated Palm Oil and Hydrogenated Palm Kernel Oil. Int J Toxicol. 2011;19:(Suppl 2):7-28.
54. Zeiger E, Andersen B, Haworth S, Lawlor T, Mortelmans K, and Speck W. Salmonella mutagencitiy tests: III. Results from the testing of 25 chemicals. Environ Mutagen. 1987;9:(Suppl 9):1-110.
55. Elder RL (ed). Final report on the safety assessment of sodium lauryl sulfate and ammonium lauryl sulfate. J Am Coll Toxicol. 1983;2:(7):127-181.
56. Diamante C, Bergfeld WF, Belsito DV, Klaassen CD, Hill RA, Liebler DC, Marks JG, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Amended Safety Assessment of Cocos Nucifera (Coconut) Oil, Coconut Acid, Hydrogenated Coconut Acid, Hydrogenated Coconut Oil, Ammonium Cocomonoglyceride Sulfate, Butylene Glycol Cocoate, Caprylic/Capric/Coco Glycerides, Cocoglycerides, Coconut Alcohol, Coconut Oil Decyl Esters, Decyl Cocoate, Ethylhexyl Cocoate, Hydrogenated Coco-Glycerides, Isodecyl Cocoate, Lauryl Cocoate, Magnesium Cocoate, Methyl Cocoate, Octyldodecyl Cocoate, Pentaerythrityl Cocoate, Potassium Cocoate, Potassium Hydrogenated Cocoate, Sodium Cocoate, Sodium Cocomonoglyceride Sulfate, Sodium Hydrogenated Cocoate, and Tridecyl Cocoate. 2008. Available from the CIR, 1101 17th Street, NW, Ste 412, Washington DC 20036. http://cir-safety.org.
57. Elder RL (ed). Final report on the safety assessment of hydrolyzed collagen. J Am Coll Toxicol. 1985;4:(5):199-221.
58. Fiume MM, Heldreth BA, Bergfeld WF, Belsito DV, Klaassen CD, Liebler DC, Hill RA, Marks JG, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. CIR Expert Panel final amended report on alkyl PEG ethers as used in cosmetics. 2010. Available from the CIR, 1101 17th Street, NW, Ste 412, Washington DC 20036. http://cir-safety.org.
59. Fiume MM, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks A, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Final amended report of the Cosmetic Ingredient Review Expert Panel. Safety assessment of propylene glycol, tripropylene glycol, and PPGs as used in cosmetics. 2010. Available from the CIR, 1101 17th Street, NW, Ste 412, Washington DC 20036. http://cir-safety.org.
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60. Robinson VC, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Final report of the amended safety assessment of sodium laureth sulfate and related salts of sulfated ethoxylated alcohols. Int J Toxicol. 2010;29:(Supple 3):151S-161S.
61. Burnett CL, Fiume MM, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks A, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Final report of the CIR Expert Panel on the safety of plant-derived fatty acid oils and used in cosmetics. 2011. Available from the CIR, 1101 17th Street, NW, Ste 412, Washington DC 20036. http://cir-safety.org.
62. Fiume MM, Heldreth BA, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks JG, Shanks RC, Slaga TJ, Snyder PW, and Andersen FA. Final report of the safety assessment on dicarboxlic acids and their salts and esters of dicarboxylic acids as used in cosmetics. 2010. Available from the CIR, 1101 17th Street, NW, Ste 412, Washington DC 20036. http://cir-safety.org.
63. Burnett CL, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks JG, Shanks RC, Slaga TJ, Snyder PW, and Andersen FA. Final report of the safety assessment of cocamidopropyl betaine. 2010. Available from the CIR, 1101 17th Street, NW, Ste 412, Washington DC 20036. http://cir-safety.org.
64. Elder RL (ed). Final report on the safety assessment of isostearic acid. J Am Coll Toxicol. 1986;2:(7):61-74.
65. Andersen FA (ed). Final report on the safety assessment of glycolic acid, ammonium, calcium, potassium, and sodium glycolates, methyl, ethyl, propyl, and butyl glycolates, and lactic acid, ammonium, calcium, potassium, sodium, and TEA-lactates, methyl, ethyl, isoprpyl, and butyl lactates, and lauryl, myristyl, and cetyl lactates. Int J Toxicol. 1998;17:(Suppl 1):1-241.
66. Elder RL (ed). Final report on the safety assessment of oleic acid, lauric acid, palmitic acid, myristic acid, and stearic acid. J Am Coll Toxicol. 1987;6:(3):321-401.
67. Elder RL (ed). Final report on the safety assessment of panthenol and pantothenic acid. J Am Coll Toxicol. 1987;6:(1):139-162.
68. Andersen FA (ed). Final Report of the CIR Expert Panel - Amended Safety Assessment of Triethylene Glycol and Polyethylene Glycols (PEGs)-4, -6, -7, -8, -9, -10, -12, -14, -16, -18, -20, -32, -33, -40, -45, -55, -60, -75, -80, -90, -100, -135, -150, -180, -200, -220, -240, -350, -400, -450, -500, -800, -2M, -5M, -7M, -9M, -14M, -20M, -23M, -25M, -45M, -65M, -90M, -115M, -160M and -180M and any PEGs 4 as used in Cosmetics. 6-29-2010. Available from the CIR, 1101 17th Street, NW, Ste 412, Washington DC 20036. http://cir-safety.org.
69. Andersen FA (ed). Final Report on the Safety Assessment of Ricinus Communis (Castor) Seed Oil, Hydrogenated Castor Oil, Glyceryl Ricinoleate, Glyceryl Ricinoleate SE, Ricinoleic Acid, Potassium Ricinoleate, Sodium Ricinoleate, Zinc Ricinoleate, Cetyl Ricinoleate, Ethyl Ricinoleate, Glycol Ricinoleate, Isopropyl Ricinoleate, Methyl Ricinoleate, and Octyldodecyl Ricinoleate. Int J Toxicol. 2011;26:(Suppl 3):31-77.
70. Inchem. Ethanolamine. http://www.inchem.org/documents/icsc/icsc/eics0152.htm. 2004. Date Accessed 2-8-2011.
71. ACD/Labs. Advanced Chemistry Development (ACD/Labs) Software. 2011. (9.02):
72. Wenker H. Synthesis of 2-oxazolines and 2-thiazolines from N-acyl-2-aminoethanols. Journal of the American Chemical Society. 1935;57:1079-1080.
73. Effenberger F and Bessey E. Transacylations with acyl derivatives of 4-pyridone. Chemische Berichte. 1980;113:(6):2100-2109.
74. Syracuse Research Corporation. PhysProp data.
75. Rowe RG and Flower G Jr. Antistatic plastics. 1956. (US 2773852):
76. Morales-Sanfrutos J, Megia-Fernandez A, Hernandez-Mateo F, Giron-Gonzalez MD, Salto-Gonzalez R, and Santoyo-Gonzalez F. Alkyl sulfonyl derivatized PAMAM-G2 dendrimers as nonviral gene delivery vectors with improved transfection efficiencies. Organic and Biomolecular Chemistry. 2011;9:(3):851-864.
77. Kimura C, Kashiwaya K, Murai K, and Suzuki S. Preparation and surface active properties of sodium 2-(N-alkanoylamino)ethyl sulfates. Yukagaku. 1983;32:(11):692-694.
78. Roe ET, Miles TD, and Swern D. Fatty acid amides. V. Preparation of N-(2-acetoxyethyl) amides of aliphatic acid. Journal of the American Chemical Society. 1952;74:3442-3443.
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79. Butler RN, Thornton JD, and O'Regan CB. Rapid synthesis and interconversions of fatty 4,5-dihydroimidazoles and fatty 1,4,5,6-tetrahydropyrimidines. Thermal cyclizations of fatty amides involving phenyl phosphorodiamidate. Journal of the Chemical Society. 1983;9:197-200.
80. Bergman CA and Hansen EC. Ampholytic compositions for wet treatment of textiles. 1959. (US 2877178):
81. Guan L-P, Zhao D-H, Xiu J-H, Sui X, Piao H-R, and Quan Z-S. Synthesis and anticonvulsant activity of N-(2-hydroxyethyl)amide derivatives. Archiv der Pharmazie. 2009;342:(1):34-40.
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Data
TO:
FROM:
DATE:
‘Products CouncilCommitted to Safety,Quality & Innovation
F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (CIR)
John Bailey, Ph.D.Industry Liaison to the CW Expert Panel
July 5, 2011
SUBJECT: Concentration of Use by FDA Product Category: Ethanolamine and EthanolamineContaining Ingredients
Concentration of Use by FDA Product Category: Ethanolamine, Diethanolamine and Triethanolamine(this table has already been provided)
Concentration of Use by FDA Product Category: MEA Salts
Concentration of Use by FDA Product Category: MEA Ingredients Alkyl and Alkenyl Amides
11011 7th Street, N.W., Suite 300 Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.personalcarecouncil.org
Personal Care
Memorandum
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CIR Panel Book Page 54
Concentration of Use by FDA Product CategoryEthanolamine, Diethanolaniine and Triethanolamine
Ingredient Product Category Concentration ofUse
Ethanolamine Hair conditioners 4%
Ethanolamine Hair straighteners 3%
Ethanolamine Permanent waves 4-6%
Ethanolamine Shampoos (noncoloring) 0.05%
Ethanolamine Hair dyes and colors (all types requiring caution statement and 3-13%patch testing)
Ethariolamine Hair color sprays (aerosol) 3%
Ethanolamine Hair bleaches 4-18%
Ethanolamine Bath soaps and detergents 0.02-0.05%
Ethanolamine Shaving cream (aerosol, brushless and lather) 0.0002%
Ethanolamine Skin cleansine (cold creams, cleansine lotions. liouids and ads 0.5-11%
Diethanolamine Shampoos (noncoloring) 0.03-0.3%
Diethanolamine Tonics, dressings and other hair grooming aids 0.008%
Diethanolamine Bath soaps and detergents 0.009%
Diethanolamine Shaving cream (aerosol, brushless and lather) 0.06%
Diethanolamine Moisturizin creams, lotions and nowders 0.06%
Triethanolamine Baby lotions, oils, powders and creams 0.2-2%
Triethanolamine Bubble baths 0.4-0.7%
Triethanolamine Other bath preparations 1-2%
Triethanolamine Eyebrow pencil 1-3%
Triethanolamine Eyeliner 0.3-3%
Triethanolamine Eye shadow 0.4-3%
Triethanolamine Eye lotion 0.2-3%
Triethanolamine Eye makeup remover 0.4-0.6%
Triethanolamine Mascara 0.7-4%
Triethanolamine Other eye makeup preparations 0.8-3%
Triethanolamine Colognes and toilet waters 0.001-1%
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Triethanolamine Perfumes 0.05-0.4%
Triethanolamine Hair conditioners 0.0003-0.3%
Triethanolamine Hair sprays (aerosol fixatives) 0.05-2%
Triethanolamine Hair straighteners 3%
Triethanolamine Permanent waves 0.01%
Triethanolamine Shampoos (noncoloring) 0.0003-6%
Triethanolamine Tonics, dressings and other hair grooming aids 0.0003-3%
Triethanolamine Other hair preparations (noncoloring) 0.5-3%
Triethanolamine Hair dyes and colors (all types requiring caution statement and 2-13%patch testing)
Triethanolamine Hair tints 1%
Triethanolamine Hair rinses (coloring) 5%
Triethanolamine Other hair coloring preparations 3%
Triethanolamine Blushers (all types) 0.0002-3%
Triethanolamine Face powders 0.06%
Triethanolamine Foundations 1-2%
Triethanolamine Leg and body paints 6%
Triethanolamine Lipstick 0.2-1%
Triethanolamine Makeup bases 1-3%
Triethanolamine Other makeup preparations 0.7-2%
Triethanolamine Basecoats and undercoats (manicuring preparations) 3%
Triethanolamine Cuticle softeners 0.5-2%
Triethanolamine Nail creams and lotions 0.2-1%
Triethanolamine Other manicuring preparations 0.5-2%
Triethanolamine Bath soaps and detergents 0.5-19%
Triethanolamine Deodorants (underarm) 0.1-0.4%
Triethanolamine Feminine hygiene deodorants 0.1%
Triethanolamine Other personal cleanliness products 0.2-3%
Triethanolamine Aftershave lotions 0.5-2%
Triethanolamine Beard softeners 0.7%
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Triethanolamine Preshave lotions (all types) 0.3%
Triethanolamine Shaving cream (aerosol, brushless and lather) 3-10%
Triethanolamine Other shaving preparations 0.3-6%
Triethanolamine Skin cleansing (cold creams, cleansing lotions, liquids and pads) 0.1-11%
Triethanolamine Depilatories 0.8%
Triethanolamine Face and neck creams, lotions and powders 0.4-6%
Triethanolamine Face and neck sprays 0.07-1%
Triethanolamine Body and hand creams, lotions and powders 0.3-3%
Triethanolamine Body and hand sprays 0.2-0.4%
Triethanolamine Foot powders and sprays 0.4-1%
Triethanolamine Moisturizing creams, lotions and powders 0.2-3%
Triethanolamine Night creams, lotions and powders 0.3-5%
Triethanolamine Paste masks (mud packs) 1-3%
Triethanolamine ---fl- Skin fresheners 2%
Triethanolamine Other skin care preparations1 0.4-2%, 7%
Triethanolamine Suntan gels, creams and liquids 2%
Triethanolamine Indoor tanning preparations 0.3-2%
7% in a rinse-off skin care preparationInformation collected in 2010
Table prepared October 13, 2010Updated November 8, 2010 (Triethanolamine: lowered minimum for Mascara to 0.7; increased maximum
Moisturizing to 3%)
Page 3 of 3
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Concentration of Use By FDA Product Category - MEA SaltsEthanolamine HCI MEA-Laureth SulfateMEA-Sulfite MEA-Lauryl SulfateMEA PPG-6 Laureth-7 Carboxylate, MEA-Dicetearyl PhosphateMEA-Cocoate Dibutyl EthariolamineMEA-Laureth-6 Carboxylate Diethyl EthanolamineMEA-PPG-8-Steareth-7 Carboxylate Dimethyl MEAMEA-Undecylenate Ethyl EthanolamirieMEA-Tallowate MethylethanolamineMEA-Benzoate Butylethanolamine,MEA-Salicylate Stearamidoethyl Ethanolamine PhosphateMEA-Hydrolyzed Silk Lysophosphatidylethanolamine*MEA-Hydrolyzed Collagen
Ingredient Product Category Concentrationof Use
MEA-Hydrolyzed Collagen Hair conditioners 0M6%
MEA-Hydrolyzed Collagen Skin cleansing (cold creams, cleansing 006%lotions, liquids and pads)
MEA-Hydrolyzed Collagen Face and neck creams, lotions and powders 0.1%
MEA-Hydrolyzed Collagen Moisturizing creams, lotions and powders 0.2%
MEA-Hydrolyzed Collagen Night creams, lotions and powders 0.2%
MEA-Hydrolyzed Collagen Paste masks and mud packs 0.03%
MEA-Lauryl Sulfate Shampoos 5%
MEA-Lauryl Sulfate Hair dyes and colors (all types requiring 35%caution statement and patch test)
*Ingredients found in the title of the table but not found in the table were included in theconcentration of use survey, but no uses were reported.
Information collected in 2011Table prepared July 5, 2011
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Concentration of Use by FDA Product
Acetamide MEAMyristamide MBACocamide MEAIsostearamide MEAStearamide MEAAzelamide MEABabassuamide MEABehenamide MEAC 16-22 Acid Amide MEACocamide Methyl MBACocamidopropyl Betainamide MBA ChlorideDeoxyphytantriyl Palmitamide MEAHexyloxodecanamide MBA PhosphateHydroxyethyl Pantothenamide MEAHydroxypropyl Bisisostearamide MEAHydroxypropyl B islauramide MBAHydroxypropyl Bispalmitamide MBAHydroxypropyl Bisstearamide MBAHydroxystearamide MEALactamide MEALauramide MEA
Category - MEA Ingredients Alkyl and AlkenylAmides
Linoleamide MEAMyristoyllPalmitoyl Oxostearamide/ArachamideMEAOatamide MEAOleamide MEAOliveamide MBAPalm Kernelamide MBAPalmamide MBAPalmitamide MBAPantothenamide MBAPeanutamide MBARicinoleamide MEAStearamide MEA-StearateStearamidoethyl EthanolamineSunfloweramide MBATallowamide MBATrideceth-2 Carboxamide MBAUndecylenamide MBAHexyloxodecanamide MBAPEG-9 Cocamide MEA*
Ingredient Product Category Concentration ofUse
Acetamide MBA Eye lotion 0.5%
Acetamide MBA Hair conditioners 0.3-3%
Acetamide MBA Hair sprays (aerosol fixatives) 0.1-0.4%
Acetamide MEA Shampoos (noncoloring) 2-3%
Acetamide MBA Tonics, dressings and other hair grooming aids 0.3-5%
Acetamide MBA Other hair preparations (noncoloring) 0.06-1%
Acetamide MEA Bath soaps and detergents 3-4%
Acetamide MBA Deodorants (underarm) 2%
Acetamide MBA Skin cleansing (cold creams, cleansing lotions, 0.06-8%liquids and pads)
Acetamide MBA Face and neck creams, lotions and powders 0.1%
Acetamide MBA Moisturizing creams, lotions and powders 0.2%
Acetamide MBA Night creams, lotions and powders 0.2-1%
Acetamide MBA Paste masks and mud packs 0.03%
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Myristamide MEA Skin cleansing (cold creams, cleansing lotions, 0.3%liquids and pads)
Myristamide MEA Body and hand creams, lotions and powders 4%
Cocamide MEA Baby shampoos 2%
Cocamide MEA Bubble baths 2-6%
Cocamide MEA Other bath preparations 6%
Cocamide MEA Other fragrance preparations1 3%
Cocamide MEA Hair conditioners 0.3-2%
Cocamide MEA Shampoos (noncoloring) 1-15%
Cocamide MEA Tonics, dressings and other hair grooming aids 0.5%
Cocamide MEA Hair dyes and colors (all types requiring caution 3-18%statement and patch test)
Cocamide MEA Hair rinses (coloring) 3%
Cocamide MEA Hair shampoos (coloring) 3%
Cocamide MEA Bath soaps and detergents 1-7%
Cocamide MEA Other personal cleanliness products2 0.2-10%
Cocamide MEA Shaving cream (aerosol, brushless and lather) 0.2-2% V
Cocamide MEA Skin cleansing (cold creams, cleansing lotions, 0.3-8%liquids and pads)
Cocamide MEA Body and hand creams, lotions and powders 3%
Cocamide MEA Foot powders and sprays 1%
Cocamide MEA Moisturizing creams, lotions and powders 0.7%
Cocamide MEA Other skin care preparations 3-5%
Cocamide MEA Other suntan preparations 0.7%
Stearamide MEA Other bath preparations 17%
Stearamide MEA Eye liner 6%
Stearamide MEA Eye shadow 7%
Stearamide MEA Hair conditioners 0.07%
Stearamide MEA Hair dyes and colors (all types requiring caution 2-6%statement and patch test)
Cocamide MEA Aftershave lotions 1%
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Lactamide MBA Hair conditioners 0.2-3%
Stearamide MEA Blushers (all types) 5%
Stearamide MEA Cuticle softeners 2%
Stearamide MEA Deodorants (underarm) 15%
Stearamide MEA Skin cleansing (cold creams, cleansing lotions, 0.2%liquids and pads)
Cocade Methyl MBA bhampoos (noncoloring)
Cocamidopropyl Betainamide Bath soaps and detergents 3%MBA
Cocamidopropyl Betainamide Other personal cleanliness products 1%MEA
Cocamidopropyl Betainamide Skin cleansing (cold creams, cleansing lotions, 1%MBA liquids and pads)
Lactamide MEA Bubble baths 2%
Lactamide MEA Other bath preparations 2%
Lactamide MBA Other fragrance preparations3 2%
Lactamide MEA Hair sprays (aerosol fixatives) 0.02-0.2%
Lactamide MBA Shampoos (noncoloring) 0.5%
Lactamide MBA Tonics, dressings and other hair grooming aids 0.3-0.5%
Lactamide MBA Other hair preparations (noncoloring) 0.3%
Lactamide MBA Bath soaps and detergents 3%
Lactamide MBA Body and hand creams, lotions and powders 2%
Lactamide MBA Paste masks and mud packs 2%
Lauramide MEA Other baby products 0.5%
Lauramide MBA Bubble baths 2%
Lauramide MBA Other bath preparations 2%
Lauramide MEA Other fragrance preparations 1%
Lauramide MBA Shampoos (noncoloring) 1-3%
Lauramide MBA Hair dyes and colors (all types requiring caution 3%statement and patch test)
Lauramide MEA Nail creams and lotions 1%
Lauramide MBA Bath soaps and detergents 1%
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Lauramide MEA Other personal cleanliness products 1-3%
Lauramide MEA Skin cleansing (cold creams, cleansing lotions, 0.3-2%liquids and pads)
Lauramide MEA Body and hand creams, lotions and powders 1-4%
Lauramide MEA Foot powders and sprays 1%
Peanutamide MEA Paste masks and mud packs 0.3%
Ricinoleamide MEA Other personal cleanliness products4 0.02%
Stearamide MEA-Stearate Mascara 3%
Trideceth-2 Carboximide MEA Hair conditioners 2%
Trideceth-2 Carboximide MEA Hair straighteners 2%
Trideceth-2 Carboximide MEA Shampoos (noncoloring) 2%
Trideceth-2 Carboximide MEA Tonics, dressings and other hair grooming aids 2% s.
Trideceth-2 Carboximide MEA Hair dyes and colors (all types requiring caution 14%statement and patch test)
Trideceth-2 Carboximide MEA Hair bleaches 4%*Ingredients included in the title of the table but not found in the table were included in the survey, but no uses werereported.13% in a rinse-off preparation202% in foot scrub; 0.9% in a liquid hand soap; 2-10% in shower/body washes2% in a rinse-off preparation0.02% in a liquid hand soap
Information collected in 2011Table prepared July 5, 2011
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JOURNAL OF THE AMERICAN COLLEGE OF TOXICOLOGY Volume 2, Number 7, 1983 Mary Ann Liebert, Inc., Publishers
8
Final Report on the Safety Assessment of
Triethanolamine, Diethanolamine, and Monoethanolamine
Triethanolamine (TEA), Diethanolamine (DEA), and Monoethanolamine (MEA) are amino alcohols used in cosmetic formulations as emulsifiers, thickeners, wetting agents, detergents, and alkalizing agents. The nitrosation of the etha- nolamines may result in the formation of N-nitrosodiethanolamine (NDELA) which is carcinogenic in laboratory animals.
In single-dose oral toxicity for rats, TEA was practically nontoxic to slightly toxic, and DEA and MEA were slightly toxic. long-term oral ingestion of the ethanolamines by rats and guinea pigs produced lesions limited mainly to the liver and kidney. long-term cutaneous applications to animals of the ethanol- amines also produced evidence of hepatic and renal damage. TEA and DEA showed little potential for rabbit skin irritation in acute and subchronic skin irritation tests. MEA was corrosive to rabbit skin at a 30% concentration in a single semioccluded patch application and at a > 10% concentration in 10 open applications over a period of 14 days.
The ethanolamines were nonmutagenic in the Ames test and TEA is also nonmutagenic to Bacillus subtilis. TEA did not cause DNA-damage inducible repair in an unscheduled DNA synthesis test. TEA had no carcinogenic or cocarcinogenic activity when dermally applied to mice for 18 months.
Clinical skin testing of TEA and cosmetic products containing TEA and DEA showed mild skin irritation in concentrations above 5%. There was very little skin sensitization. There was no phototoxicity or photosensitization reac- tions with products containing up to 20.04% TEA. A formulation containing 11.47% MEA and a formulation containing 1.6% DEA and 5.9% MEA were irritating to human skin in patch tests.
The Panel concludes that TEA, DEA, and MEA are safe for use in cosmetic formulations designed for discontinuous, brief use followed by thorough rins- ing from the surface of the skin. In products intended for prolonged contact with the skin, the concentration of ethanolamines should not exceed 5%. MEA should be used only in rinse-off products, TEA and DEA should not be used in products containing N-nitrosating agents.
183
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CIR Panel Book Page 184
184 COSMETIC INGREDIENT .REVIEW
CHEMICAL AND PHYSICAL PROPERTIES
Structure
T riethanolamine (CAS No. 102-71-6) (TEA), Diethanolamine (CAS No. 11 l-42-2) (DEA), and Monoethanolamine (CAS No. 141-43-5) (MEA) are amino alco-
hols. They are produced by aminating ethylene oxide with ammonia. The re- placement with ethanol groups of three, two, or one hydrogen of ammonia results in TEA, DEA, or MEA, respectively. The chemical formulas of the ethanol- amines are as follows:
Triethanolamine N
Diethanolamine H-N/CH2C"20"
'C"2CH20"
H Monoethanolamine k
H' -CH2CH20"
Properties
TEA, DEA, and MEA are clear, colorless, viscous liquids with ammoniacal odors. They are hygroscopic and are strong bases. The ethanolamines are soluble in water, alcohol, and chloroform, and are insoluble in benzene, ether, and petroleum distillates. (l-61 Chemical and physical properties of TEA, DEA, and MEA are presented in Table 1. A sampling of the variety of values available in the literature is given for several chemical and physical properties. This variation may reflect the use of different grades of chemicals.
Reactivity
TEA, DEA, and MEA are reactive and are bifunctional, combining the proper- ties of alcohols and amines. The ethanolamines will react at room temperature with fatty acids to form ethanolamine soaps, and DEA and MEA will react at temperatures between 140° and 160°C with fatty acids to form ethanolamides. The reaction of ethanolamine and sulfuric acid produces sulfates, and DEA and MEA may react, under anhydrous conditions, with carbon dioxide to form car- bamates.‘1-3)
The ethanolamines can act as antioxidants in the autoxidation of fats of both animal and vegetable origin. TEA and DEA have stronger antioxidant effects than MEA (I) TEA is an antioxidant as measured by the Tetrahymena photodynamic assay. (8)
TEA and DEA can react with nitrite or oxides of nitrogen to form N-nitro- sodiethanolamine (NDELA). As yet, MEA has not been found to form a stable nitrosamine.‘9,10’ MEA can react with an aldehyde to form DEA, and then can be
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 185
ASSESSMENT: TEA, DEA, AND MEA 185
TABLE 1. Chemical and Physical Properties.
Property TEA DEA MEA Ref.
149.19 105.14 61.08 6
1.1242
1 .0179
1 .0117
1.0881
1.0919
1.092
1.0985
1.1255
1.124
1.126
1.0693
0.9998
0.9844
3,s 6
6
2
5
6
6
1
4
5
1013
590.5 18.95
65.7
380
351.9
53.85 5.03
24
360
335.4
277-279
335,
decomposes
17.9
20-21.2
21.2
21.57
decomposes
268.8
268.0
171 l-3
170.8 6
172.2 4
170.5 5
28.0 10.3 l-3
28.0 10.5 4
28.0 10.5 5
28.0 10.3 6
534 660 825 l-3
<O.Ol
0.01 0.01
0.48 5
0.4 l-3
1.4852
10.5
1.4747
1.4753
11.0
1.4544
1.4539
12.05
Molecular weight
Specific gravity
2014 T
20120 T
2514 “C
3014 “C
30/20 T
30120 T
4014 T
6014 “C
not specified
not specified
not specified
Viscosity fcps)
2OT
25’C
30 “C
30 “C
6OT
not specified
Boiling Point (“C)
760 mm Hg
760 mm Hg
not specified
not specified
Melting Point FC)
Heat of Vaporization (joules/g)
760 mm Hg
Vapor Pressure (mm H@
2OT
not specified
Refractive Index
20 T
2OT
30 oc
30 T
pH of a 0.1 N aqueous solution
nitrosated to form NDELA.(9) The optimum pH for nitrosamine formation is variously reported to be between 1 and 6, and the reaction rate decreases as the pH increases. (9-12) Neutral solutions require 100,000 times as much nitrite as strong acid solutions in order to form the same amount of nitrosamine.(‘“*‘2) However, in the presence of catalysts such as chloral or an aldehyde, nitrosation reactions may occur up to a pH of 11. (9) The rate of NDELA formation in the pH range 4-9 is four to six times greater in the presence of formaldehyde than in its absence.(13) Higher temperatures and longer reactions times increase the yield of
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CIR Panel Book Page 186
186 COSMETIC INGREDIENT REVIEW
nitrosamine.‘“) Nitrosation reactions and salt formation reactions compete in aqueous solutions. (lo) The nitrosation by nitrites of DEA in an oil-in-water e’mul- sion to NDELA can be inhibited by ascorbic acid or sodium bisulfite or much less effectively inhibited by potassium sorbate incorporated into the aqueous phase or can be inhibited by ascorbyl palmitate incorporated into the oil phase.(14)
Methods of Manufacture and Impurities
The ethanolamines are commercially produced by aminating ethylene oxide with ammonia. The reaction temperature can be adjusted to produce mostly TEA or MEA.(‘-‘,“) The product is purified by distillation. A “low freeze grade” prod- uct can be prepared by adding up to 15% water.(1-3)
TEA contains small amounts of DEA and MEA, and DEA contains small amounts of TEA and MEA. MEA contains a small amount of DEA.(‘-‘s’~) TEA used in cosmetics may contain a maximum of 0.5% water, 0.05% sulfated ash, and 15 ppm iron.“‘)
Analytical Methods
Qualitative and quantitative determinations of the ethanolamines are made by calorimetric procedures, (16,18-21) titrimetric methods,(16s20,22-28) thin-layer chromatography,(29-32) gas chromatography,(23-25.33-39) gravimetric analysis,(39) thermogravimetric analysis,(40) the Kjeldahl method, and the Van Slyke pro- cedure.(41) Positive identification of the ethanolamines can be made by com- parison with published infrared spectra. (39042*43) UV absorbance spectra are available for TEA and MEA.(44)
Jones et al.(33) used gas chromatography to determine the amount of TEA in a simulated vanishing cream and shampoo. They did a preliminary separation into classes of compounds and were then able to recover between 96% and 101% of the TEA added to the cosmetic formulations.
USE
Purpose in Cosmetics
Ethanolamine soaps, formed from the reaction at room temperature of TEA, DEA, or MEA and fatty acids, and ethanolamides, formed from the reaction at elevated temperatures of DEA and MEA and fatty acids, are used in cosmetic for- mulations as emulsifiers, thickeners, wetting agents, detergents, and alkalizing agents.(1-3*45)
Scope and Extent of Use in Cosmetics
Product types and the number of product formulations containing TEA, DEA, or MEA reported voluntarily to the Food and Drug Administration (FDA) in 1981 are presented in Table 2. Table 2 does not include products containing TEA- lauryl sulfate or TEA-coca-hydrolyzed animal protein. These two ingredients have been reviewed by the Cosmetic Ingredient Review (CIR) Expert Panel in
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 187
TAB
LE
2.
Pro
duc
t Fo
rmul
atio
n
Da
ta.
Pro
duc
t c
ate
go
ry
Tota
l no
. o
f
form
ula
tions
in
ca
teg
ory
Tota
l no
.
co
nta
inin
g
ing
red
ient
No
. p
rod
uct
form
ula
tions
w
ithin
e
ac
h c
onc
ent
ratio
n ra
nge
08
Unr
ep
ort
ed
co
nce
ntra
tion
>50
>25-
50
>10-
25
>5-1
0 >
l-5
>o.
1-l
so.1
Trie
tha
no
lam
ine
Bab
y sh
am
po
os
Bab
y lo
tions
, o
ils,
po
wd
ers
,
an
d c
rea
ms
Oth
er
ba
by
pro
duc
ts
Bath
o
ils,
tab
lets
, a
nd
sa
lts
Bub
ble
b
ath
s
Oth
er
ba
th p
rep
ara
tions
Eye
bro
w
pe
nc
il
Eye
line
r
Eye
sh
ad
ow
Eye
lo
tion
Eye
ma
keup
re
mo
ver
Ma
sca
ra
Oth
er
eye
ma
keup
p
rep
ara
tions
Co
log
nes
an
d t
oile
t w
ate
rs
Perfu
me
s
Sac
hets
Oth
er
fra
gra
nce
p
rep
ara
tions
Ha
ir c
on
diti
one
rs
Ha
ir sp
rays
(a
ero
sol
fixa
tive
s)
Perm
ane
nt
wa
ves
Ha
ir rin
ses
(no
nc
olo
ring
)
Ha
ir sh
am
po
os
(no
nc
olo
ring
)
Toni
cs,
d
ress
ing
s,
an
d o
the
r
ha
ir g
roo
min
g
aid
s
Wa
ve
sets
Oth
er
ha
ir p
rep
ara
tions
(no
nc
olo
ring
)
35
56
4
15
1
237
1
475
5
132
5
145
6
396
60
2582
15
7
13
1
ai
3
397
141
230
36
1120
12
657
5
119
40
191
40
478
10
265
3
474
3
is8
1
909
36.
290
24
- ia
0 44
-
177
1 a
- - - - - - - -
- - - - - - - - - - - - - -
- 1 - - - - - - - - 1 - -
- - - - 4 - 5 - - 1 1 -
- 1 - 2 - 10
- - - - - 5 1 -
-
2
- -
1
17
73 2
94
14
-
1
17
14 2 1 3
16
1 2 - -
2 5 5
34
al
- 32
22 5 4
23
26 6 2
- - 13
10
41 6
- 3 - - 3 3 1 1 - 7 - - 1 1 - 4 -
* s z z 3 ;;I
P E
P fi
3 F
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 18
8
TAB
LE
2.
(Co
ntin
ue
d.)
Pro
duc
t c
ate
go
ry
Tota
l no
. o
f
form
ula
tions
in
ca
teg
ory
Tota
l no
. N
o.
pro
duc
t fo
rmul
atio
ns
with
in
ea
ch
co
nce
ntra
tion
rang
e (
9)
co
nta
inin
g
Unr
ep
ort
ed
ing
red
ient
c
onc
ent
ratio
n >5
0 >2
5-50
>1
0-25
>5
-10
>I-5
>O
.I-1
so.1
Trie
tha
no
lam
ine
(C
ont
’d.)
Ha
ir d
yes
an
d c
olo
rs
(all
typ
es
req
uiri
ng
c
aut
ion
sta
tem
ent
a
nd
pa
tch
test
)
Ha
ir rin
ses
(co
lorin
g)
Oth
er
ha
ir c
olo
ring
p
rep
ara
tions
Blus
he
rs
(all
typ
es)
Fac
e p
ow
de
rs
Ma
keu
p
foun
da
tions
Lip
stic
k
Ma
keu
p
ba
ses
Roug
es
Ma
keu
p
fixa
tive
s
Oth
er
ma
keup
p
rep
ara
tions
(no
t e
ye)
Cut
icle
so
fte
ners
Na
il c
rea
ms
an
d l
otio
ns
Na
il p
olis
h
an
d e
na
me
l re
mo
ver
Oth
er
ma
nic
urin
g
pre
pa
ratio
ns
Bath
so
ap
s a
nd
de
terg
ent
s
De
od
ora
nts
(un
de
rarm
)
Oth
er
pe
rso
na
l c
lea
nlin
ess
pro
duc
ts
ail
40
76
1
49
a
al9
65
555
14
740
211
3319
17
a31
27
3
211
11
22
2
530
20
32
9
25
6
41
1
50
2
148
a
239
2
227
7 -
1 1
1 2
2
-
- - -
1 - -
- -
- -
- -
- 40
-
- 1
a
- _
-
- 32
28
3 -
71
139
- -
- 14
90
la1
- 4
6 2
- -
4 15
2
- 6
- 3
3 -
1 -
1 -
1
4 -
4 -
- -
2
- - 5 11 1 3 1 1 1 1 - -
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 18
9
282 4
22 2
1 la
-
3 -
56
5
3 6
2
69 1
131
- 13
-
105
276
16
- 1
- 1
2 -
115 34 1 2
-
1
21
15 6
248
24
48
6
16
2
3 -
11
7
6 -
40
6
31
- 3
- 41
-
Aft
ers
have
lo
tions
Bea
rd
soft
ene
rs
Sha
vin
g
cre
am
(a
ero
sol,
bru
shle
ss,
an
d l
ath
er)
Oth
er
sha
vin
g
pre
pa
ratio
n
pro
duc
ts
Skin
c
lea
nsin
g
pre
pa
ratio
ns
(co
ld c
rea
ms,
lo
tions
, liq
uid
s,
an
d p
ad
s)
De
pila
torie
s
Fac
e,
bo
dy,
a
nd
ha
nd
ski
n
ca
re
pre
pa
ratio
ns
(exc
lud
ing
sha
vin
g
pre
pa
ratio
ns)
Foo
t p
ow
de
rs
an
d s
pra
ys
Ho
rmo
ne
skin
c
are
pre
pa
ratio
ns
Mo
istu
rizin
g
skin
-ca
re
pre
pa
ratio
ns
Nig
ht
skin
c
are
pre
pa
ratio
ns
Past
e
ma
sks
(mud
p
ac
ks)
Skin
lig
hte
ners
Skin
fr
esh
ene
rs
Wrin
kle
sm
oo
the
rs
(re
mo
vers
)
Oth
er
skin
c
are
pre
pa
ratio
ns
Sunt
an
ge
ls,
cre
am
s,
an
d l
iqu
ids
Ind
oo
r ta
nnin
g
pre
pa
ratio
ns
Oth
er
sunt
an
pre
pa
ratio
ns
114
64
-
29
11
680
214
32
1
- - -
403 1 3
2 a3
2 17
10
- -
-
747
388
219
aa
171
19
44
5
260
19
38
7
349
69
164
47
15
3
28
10
- - -
- - - 1
-
1981
TO
TALS
27
57
2 2
a 20
40
90
8 16
50
127
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 19
0
TAB
LE
2.
(Co
ntin
ue
d.)
Tota
l no
. o
f To
tal
no.
NO
. p
rod
uct
form
ula
tions
w
ithin
e
ac
h c
onc
ent
ratio
n ra
nge
(%
)
form
ula
tions
c
ont
ain
ing
U
nre
po
rte
d
Pro
duc
t c
ate
go
ry
in c
ate
go
ry
ing
red
ient
c
onc
ent
ratio
n >5
0 >2
5-50
>l
O-2
5 >5
-10
>l-5
>o
. I-l
10
.1
Die
tha
no
lam
ine
Bub
ble
b
ath
s 47
5 4
- -
- -
- -
- 4
Perm
ane
nt
wa
ves
474
1 -
- -
- -
1 -
- H
air
dye
s a
nd
co
lors
(a
ll ty
pe
s
req
uiri
ng
c
aut
ion
sta
tem
ent
an
d p
atc
h te
st)
ail
12
- -
- -
12
- -
Na
il b
ase
co
ats
a
nd
und
erc
oa
ts
44
1 -
- -
1 -
-
1981
TO
TALS
la
-
- -
14
- 4
Mo
no
eth
an
ola
min
e
Ma
sca
ra
397
1 -
- -
- 1
-
Ha
ir c
on
diti
on
ers
47
8 2
- -
- -
- -
2 -
Ha
ir st
raig
hte
ners
64
2
- -
- -
2 -
-
Perm
ane
nt
wa
ves
474
13
- -
- -
2 9
2 -
Ha
ir d
yes
an
d c
olo
rs
(all
typ
es
req
uiri
ng
c
aut
ion
sta
tem
ent
an
d p
atc
h te
st)
a11
25
-
- -
- 9
7 9
-
Ha
ir sh
am
po
os
(co
lorin
g)
16
1 -
- -
- -
- 1
-
Ha
ir b
lea
ch
es
111
2 -
- -
- -
2 -
-
Oth
er
pe
rso
na
l c
lea
nlin
ess
pro
duc
ts
227
3 -
- -
2 -
1 Sh
avi
ng
c
rea
m
(ae
roso
l,
bru
shle
ss,
an
d l
ath
er)
11
4 1
- -
- -
- 1
- M
oist
uriz
ing
sk
in
ca
re
pre
pa
ratio
ns
747
1 -
- -
- -
1 -
1981
TO
TALS
51
-
- -
- 11
22
17
1
Da
ta f
rom
Re
f. 48
.
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 19
1
ASSESSMENT: TEA, DEA, AND MEA 191
other documents.(46.47) Voluntary filing of product formulation data by cosmetic manufacturers, packagers, and distributors conforms to the prescribed format of preset concentration ranges and product types as described in the Code of Federal Regulations (21 CFR, Part 720.4). Some cosmetic ingredients are supplied by the manufacturer at less than 100% concentration and, therefore, the value reported by the cosmetic formulator or manufacturer may not necessarily reflect the actual concentration of the finished product; the concentration in such a case would be a fraction of that reported to the FDA. The fact that data are submitted only within the framework of preset concentration ranges also provides the op- portunity for overestimation of the actual concentration of an ingredient in a par- ticular product. An entry at the lowest end of a concentration range is considered the same as one entered at the highest end of that range, thus introducing the possibility of a two- to lo-fold error in the assumed ingredient concentration.
In 1981, TEA, DEA, and MEA were reported to be ingredients of 2757, 18, and 51 cosmetic products, respectively. The majority of these products con- tained TEA, DEA, or MEA in a concentration of less than or equal to 5°/0.‘4s)
Surfaces to Which Commonly Applied
Cosmetic products containing ethanolamines may be applied to or come in contact with skin, eyes, hair, nails, mucous membranes, and respiratory epithelium. Small amounts may be ingested from lipstick (Table 2).14*l
Frequency and Duration of Application
Product formulations containing ethanolamines may be applied as many as several times a day and may remain in contact with the skin for variable periods of time following each application. Daily or occasional use may extend over many years (Table 2).(48)
Potential Interactions with Other Cosmetic Ingredients
N-nitrosating agents, present as intentional ingredients or as contaminants of cosmetics, may react with the ethanolamines to form N-nitrosodiethanolamine (NDELA). NDELA has been found in cosmetic raw materials. Ninety-nine samples of 17 materials were evaluated and NDELA was detected in concentrations of greater than 1000 ppb, 501-l 000 ppb, 101-500 ppb, and 50-l 00 ppb in 6, 3,6, and 6 samples, respectively. NDELA was found in trace levels in nine samples and was not detected in 69 samples. (13*49) NDELA has also been detected in a variety of cosmetic products. (50-60) An on-going study by the FDA has provided NDELA analysis for 335 off-the-shelf cosmetic formulations. The FDA data are presented in Table 3. NDELA was detected in 110 of a total of 252 products con- taining TEA and in 25 of a total of 64 products not containing TEA. However, products with no TEA may have contained DEA or MEA. These findings suggest the possibility that TEA may lead to the formation of NDELA in some cosmetics.
Bronaugh et al.(61,62) investigated the percutaneous absorption of N DELA through excised human skin. NDELA was dissolved in water, propylene glycol, and isopropyl myristate, and the permeability constants were 5.5 x 10m6, 3.2 x
10m6, and 1.1 x 10m3 cm/h, respectively. The permeability of NDELA through ex-
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 192
192 COSMETIC INGREDIENT REVIEW
TABLE 3. Association of NDELA with TEA in Cosmetics
Analyzed by the FDA.
Cosmetic product samples NDELA No NDELA
reported to contain detected detected
TEA 110 142
No TEA 25 39
Incomplete or no Ingredient information 5 14
-
(Total) 140 (Total) 195
Data from Refs. 51-55.
cised human skin was greatly increased when applied from sufficiently lipoidal formulations. The major route of elimination after oral and topical administration of NDELA to rats was the urine. (63) NDELA was applied to the skin of monkeys and pigs and, afterwards, was detected in their urine.(64) NDELA was detected in rat urine following epicutaneous and intratracheal administration of NDELA and following percutaneous administration of DEA and oral administration of nitrite in drinking water. (“) After application of an NDELA-contaminated cosmetic. NDELA was detected in human urine.‘66’
NDELA, in concentrations of 5-15 mg/plate, was mutagenic to Salmonella typhimurium strains TA1535 and TAlOO in the presence of hamster liver S-9 but not in the presence of rat liver S-9. (67) NDELA is carcinogenic to rats after oral administration’68-70) and to hamsters after subcutaneous injections, skin painting, and oral cavity swabbing. (71.72) Although no epidemiological data were available, the international Agency for Research on Cancer(73) has suggested that “NDELA should be regarded for all practical purposes as if it were carcinogenic to humans.”
Nitrites have been found in cosmetic raw materials.(L3.49.74) TEA and DEA can be nitrosated to NDELA with 2-bromo-2-nitropropane-1,3-diol (BNPD), an anti- microbial agent used in cosmetics. (75-77) A report on the safety assessment of BNPD recommended against its usage in cosmetics where its actions with amines or amides could result in the formation of nitrosamines or nitrosamides.‘75) Ong et al.(78) discovered that NDELA could be formed from the peroxidation and subsequent nitrosation of DEA. They found that peroxides could result from the autoxidation of compounds such as polysorbate 20 and that the addition of an- tioxidants prevented this. Under the same experimental conditions, TEA and MEA did not yield NDELA.
Noncosmetic Uses
The ethanolamines are used in the manufacture of emulsifiers and dispersing agents for textile specialties, agricultural chemicals, waxes, mineral and vegetable oils, paraffin, polishes, cutting oils, petroleum demulsifiers, and ce- ment additives. They are intermediates for resins, plasticizers, and rubber chemicals. They are used as lubricants in the textile industry, as humectants and
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 193
ASSESSMENT: TEA, DEA, AND MEA 193
softening agents for hides, as alkalizing agents and surfactants in phar- maceuticals, as absorbents for acid gases, and in organic syntheses.(5’6)
TEA, at a concentration not exceeding 2 ppm, and MEA, at a concentration not exceeding 0.3 ppm, may be used in flume water for washing sugar beets prior to slicing (21 CFR 173.315). TEA, DEA, and MEA, at no specific concentration limits, may be components of articles intended for use in producing, manufactur- ing, packing, processing, preparing, treating, packaging, transporting, or holding food(79) except that TEA and DEA may not exceed 5% by weight of rubber ar- ticles intended for repeated use. (‘O) TEA and DEA may be used as adjuvants for pesticide chemicals and are exempt from the requirement of tolerances(81) except that DEA maleic hydrazide may not be sold in the United States.(82)
GENERAL BIOLOGY
Antimicrobial Effects
TEA, DEA, ‘and MEA inhibit the growth of a wide variety of microorganisms. The concentration of ethanolamine required to inhibit growth varies with genus and species.(s,63-s7) DEA and MEA have some antimycotic activity when applied on the skin of guinea pigs.(88-90’
Effects on Chick Embryo
The incubation of chicken eggs with 0.03% MEA for 18 h increases the number of eggs with visible blastodisks, increases the synthesis of proteins, fats, and carbohydrates, and increases the number of hatching chicks.r9’)
Effects on Enzymatic Activity
Effects on Enzymes Involved in Lipid Biosynthesis
TEA, DEA, and MEA affect the biosynthesis of lipids. Reactions of particular interest in mammals are those involved in the synthesis of the phosphoglycerides, phosphatidylethanolamine (PE), phosphatidylcholine (lecithin) (PC), and phos- phatidylserine (PS):‘92’
Ethanolamine + ATP ethanolamine kinase
> phosphoethanolamine + ADP
phos hoethanolamine cyti ylyltransferase *8
CTP + phosphoethanolamine - CDP-ethanolamine + PPi
phosphoethanolamine
transferase
CDP-ethanolamine + diacylglycerol -
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 194
194 COSMETIC INGREDIENT REVIEW
phosphatidylethanolamine + CMP
Phosphatidylethanolamine + serine - \
phosphatidylserine + ethanolamine
choline kinase Choline + ATP > phosphocholine + ADP
phosphocholine cytidylytransferase
Phosphocholine + CTP > CDP-choline + PPi
phosphocholine transferase
CDP-choline + diacylglycerol phosphatidylcholice + CMP
The administration of MEA at a dose of 60 mg/kg/day for 30 consecutive days to albino rats with experimentally-induced coarction of the aorta resulted in elevated levels of PE, PS, and PC in the rat myocardium. Metabolic changes pro- duced by MEA action may have inhibited the development of cardiac insufficiency in these animals.‘93’ Hale et al.(94’ grew chicken embryo fibroblasts in standard media with 40 mg/ml of choline in delipidated media without choline, and in delipidated media without choline and with 40 mglml of MEA. The PE content of the cells was increased in both delipidated media and hexose transport was slowed in the MEA supplemented medium. The authors suggested that some property of MEA other than its accompanying increase in PE must be responsible for the drop in hexose transport in these cells. Upreti(9s) injected intraperitoneally approximately 168 mglkg of MEA into male albino mice every day for four days. Mice were sacrificed at 6, 12, 24, 48, and 96 h. At all times from 12 to 96 h, the liver ethanol kinase levels of the treated mice were significantly higher than con- trol mouse liver levels.
Barbee and Hartung(96) investigated the effect of the administration of DEA on the in vivo incorporation of MEA and choline into rat liver and kidney. They found that the administration of 250 mg/kg of labeled DEA in a single injection to male albino rats did not change the amount of injected labelled MEA and choline incorporated into liver or kidney. However, when labelled DEA was ad- ministered to male albino rats at a dose of 320 mg/kg/day in drinking water for up to three weeks, the results were different. Rats were sacrificed at 0, 1, 2, and 3 weeks, and the amounts of injected labeled MEA and choline incorporated in the liver and in the kidney were lower at 1, 2, and 3 weeks than at time 0. MEA and choline phospholipid derivatives were synthesized faster and in greater amounts, and were catabolized faster than DEA phospholipid derivatives. This may favor accumulation of DEA-containing phospholipids during chronic exposure. These researchers also investigated the effects of DEA on mitochondrial function in the male albino rat.(97) Administration of neutralized DEA at doses of 490 mglkglday for three days or of 160 mglkglday for one week in drinking water produced alterations of hepatic mitochondrial function. Barbee and Hartung hypothesize
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 195
ASSESSMENT: TEA, DEA, AND MEA 195
that DEA phospholipids are formed and incorporated into mitochondrial mem- branes with subsequent disruption of mitochondrial metabolism.
The activity of glucosyltransferase, isolated from Streptococcus mutans
culture supernatant solutions, was stimulated by TEA at a concentration of 50 mM and a pH of 6.5. (98) Glucosyltransferase catalyzes the formation of glucocerebro- side, a sphingolipid, from ceramide and UDP-D-glucose.(92)
Effects on Other Enzymes
MEA inhibits the action of purified acetylcholinesterase from bovine erythro- cytes. (99) Acetylcholinesterase catalyzes the reaction of acetylcholine and water to acetic acid and choline. This enzyme functions in the activity of the nervous system .(92)
DEA administered intraperitoneally or orally may affect directly or indirectly the serum enzyme levels, isozyme patterns, and concentrations of some amino acids and urea in the male rat liver and kidney. These changes were observed concomitant with or just after organ damage was histologically detectable.(‘OO~‘O” Subchronic DEA administration in drinking water increased male rat hepatic mitochondrial ATPase and altered mitrochondrial structure and function.(97)
MEA stimulates the activity of purified aspartate transaminase from porcine heart(lo2) and intraperitioneal or intravenous administration of MEA decreases aspartate transaminase activity in rabbit kidney and heart.“03) The reversible reaction of L-aspartate and a-ketoglutarate to oxaloacetate and L-glutamate is catalyzed by aspartate transaminase.(92) Kotogyan et al.(‘04) found that the in- travenous administration of MEA to rabbits for seven days increased the level of aspartate and glutamate in the kidneys and decreased the levels in the brain.
The intraperitoneal or intravenous administration of MEA to rabbits decreased the activity of alanine transaminase in the kidney and the heart.“03) Alanine trans-
-aminase is the enzyme involved in the reversible reaction that converts L-alanine and a-ketoglutarate to pyruvate and L-glutamate.(“)
lntraperitoneal administration of MEA to rats inhibited alcohol dehydroge- nase. Ostroviskii and Bankovskii”“’ suggested that this was the reason for the hepatic accumulation of endogenous ethanol and taurine.
Peroxidase activity and number of organic peroxide molecules in the blood, liver, and homogenate of chick embryos were decreased when chicken eggs were incubated with MEA.‘9’) Peroxidase acts in reactions in which hydrogen peroxide is an electron acceptor.
MEA can inactivate and partially dissociate P-galactosidase from Escherichia co/i (‘O’) Beta-galactosidase catalyzes the formation of D-glucose and D-galactose from lactose and water.‘921
Effects on Hormones
MEA can affect the metabolism of catechol amines. The conversion of in- terest is as follows:
L-tyrosi ne - dihydroxyphenylalanine (DOPA) - dopamine - norepinephrine - epinephrine
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 196
196 COSMETIC INGREDIENT REVIEW
Epinephrine and norepinephrine are hormones secreted by the adrenal medulla. They act in the regulation of heart rate and blood pressure. Epinephrine also activates glycogen breakdown to glucose in the liver and in muscle through its stimulation of adenylate cyclase. (92) lntraperitoneal injection of MEA into rats at 10 mglkg increased norepinephrine and decreased epinephrine in the heart. A 25 mglkg injection of MEA had the opposite effect. At the higher MEA dose, after three days the heart norepinephrine concentration remained altered and the DOPA concentration increased. (lo’) A 25 mg/kg intraperitoneal injection of MEA increased mouse heart muscle content of epinephrine and DOPA and decreased the content of norepinephrine.(108) Goncharenko et al.(109) found in- creased dopamine concentrations in rats following injection of MEA. DOPA decreased or remained unchanged.
Okano(llo) reported that the in vitro conversion of proparathyroid hormone formed in the parathyroid gland to parathyroid hormone was strongly inhibited by the action of MEA. Parathyroid hormone is involved in the metabolism of calcium and phosphorus by the body.
Effects on Protein, Nucleic Acids, and Other Cellular Substances
Subchronic oral administration of MEA to castrated rams increased serum albumin concentrations and total protein concentrations.‘“”
The administration of MEA to rabbits, either intraperitoneally or intrave- nously, increased RNA concentrations in the kidney, heart, and brain, decreased DNA concentrations in the heart and brain, and had no effect on total nitrogen or protein in any of the three tissues.(‘O’)
lntraperitoneal administration of MEA to rats increased glycogen, ATP, and ascorbic acid concentrations in the liver, kidney, brain, and heart.(‘12)
Effects on Liver Structure
Grice et al.(loo) assessed morphological damage to rat liver and kidney four and 24 h after intraperitoneal injection of DEA at 100 and 500 mglkg. At both times, after both doses and in both organs, cytoplasmic vacuolization was observed. In addition, mitochondria of the hepatocytes were swollen and less dense than in the control animals, and after 24 h, liver nuclei were more deeply basophilic than normal. At both times at the high dose of DEA, there was some renal tubular degeneration and some cells were necrotic. Barbee and Hartungt9’) found that the mitochondria from rats treated with 3 mglkglday of DEA for two weeks in their drinking water were consistently spherical and also appeared larger than mitochondria from control animals. Korsud et al.C1O1) administered 100 to 6400 mg/kg of DEA orally to rats. They discovered that liver and kidney weights and damage to the liver and kidney increased as dose increased. They confirmed the observations of Grice et al.(‘OO) except that they found no mor- phological differences in mitochondria from control and treated rats.
Effects on the Heart
MEA, administered to rats with experimentally-induced coarction of the aorta, at doses from 5 to 50 mglkg enhanced myocardial contractility. Thirty-day
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 197
ASSESSMENT: TEA, DEA, AND MEA 197
administration of MEA in a dose of 10 mglkg stimulated and 60 mg/kg of MEA in- hibited the development of myocardial hypertrophy.rg3) Increasing doses of MEA from 9.6 x 1 O-’ M to 1.2 x 1 Ow5 M increased the atrial rate and force of contrac- tion in the isolated rabbit atria.(‘13)
Effects on the Bovine Rhodopsin Chromophore
MEA bleached the visual pigment, rhodopsin, from water-washed bovine retinal rod chromophores, which are responsible for vision in dim light.“14)
ABSORPTION, METABOLISM, STORAGE, AND EXCRETION
MEA is the only naturally occurring ethanolamine in mammals and is ex- creted in the urine.“‘) Much of the available scientific literature on the metabolism of the ethanolamines is concerned with the effect on phospholipid biosynthesis of the intraperitoneal and intracerebral or in vitro administration of MEA to intact mammals or mammalian tissue, respectively. Ansell and Spanner(“‘) have performed a respresentative experiment. Labeled MEA was administered in- traperitoneally to adult female rats, the rats were sacrificed, and incorporation of MEA into phospholipids was traced in the liver, the blood, and the brain. They discovered that MEA was converted to phosphatidylethanolamine (PE) in all the tissues. However, the step-wise methylation of PE that converts it to phospha- tidylcholine (PC), which occurs rapidly in the liver and less rapidly in ex- trahepatic tissues, did not occur at all in the brain. Morin”“’ found that labelled MEA was incorporated into PE and also into PC in isolated human peripheral arteries. This suggests that the enzyme system for transmethylation of PE to PC may be active in human arteries. Researchers have found labeled respiratory car- bon dioxide after intraperitoneal administration of labeled MEA to rats.(“” Fur- ther sources are available that corroborate these findings on the effect of MEA on lipid biosynthesis in mammals.~‘05~11sJ-140)
In vitro administration of MEA had no effect on the incorporation of labeled phosphate into phospholipids in swine coronary and pulmonary arteries”4” or in rabbit or human endometria. (14*) However, in both cases TEA did inhibit the incorporation of labeled phosphate into phospholipids.
Babior(‘43) labeled purified MEA from an unspecified source and demon- strated a coenzyme-B12-dependent ethanolamine deaminase mediated conver- sion of MEA to acetaldehyde and ammonia. Ostrovskii and Bankovskii”“’ ad- ministered MEA intraperitoneally to rats and observed an increase in blood urea and brain glutamine. They suggested that ethanolamine was an ammonia source. Sprinson and Weliky (1441 labeled MEA and administered it in feed to rats. They detected labeled acetate in the urine of the rats. They suggested that MEA is phosphorylated by ATP in vivo, converted to acetaldehyde, ammonia, and in- organic phosphate and then the acetaldehyde is oxidized to acetate. These researchers hypothesize that the removal of phosphorylated MEA by its conver- sion to acetate may exert a regulatory effect on PE biosynthesis.
Labeled MEA was administered to dogs. The route of administration was unspecified. After 24 h, the total blood radioactivity as a percentage of dose was
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 198
198 COSMETIC INGREDIENT REVIEW
1.69%. There was a persistence of low levels of radioactivity in dog whole blood samples; the half-life was 19 days. Excretion in urine of radioactivity as a percent- age of dose was 11 'Yo.(~~')
ANIMAL TOXICOLOGY
Oral Studies
Acute Toxicity
The acute oral toxicity of TEA, DEA, MEA, and a hair preparation containing DEA and MEA has been studied in guinea pigs(146-‘4g’ and in rats.(‘49-‘59) The animals were administered the material by gavage, and then were observed for 14 days. Table 4 presents data from the experiments. The LD50 values for rats of TEA, DEA, and MEA ranged from 4.19 g/kg to 11.26 g/kg, 0.71 ml/kg to 2.83 g/kg, and 1.72 g/kg to 2.74 g/kg, respectively. The LD50 values for DEA and MEA are quite similar and are lower than the LD50 values for TEA. In the Hodge and Sterner(‘60) classification of single-dose oral toxicity for rats, TEA, DEA, and MEA would be classified as practically nontoxic to slightly toxic, slightly toxic, and slightly toxic, respectively.
Oral Corrosivity
A study was conducted on rabbits to determine the oral tissue corrosivity potential of a hair preparation containing 1.6% DEA, 5.9% MEA, and 3.2% sodium borate.““” The undiluted test material at a dose of 0.229 g/kg (0.210 ml/kg) was placed on the posterior tongue surface of four rabbits and they were allowed to swallow. Two rabbits were sacrificed at 24 h and two at 96 h. Gross and microscopic examinations of the tongue, adjacent pharyngeal structures, larynx, esophagus extending to the cardiac incisure, and stomach revealed no observable abnormalities. The hair preparation was not an irritant and was not corrosive in these tests.
Subchronic and Chronic Toxicity
Long-term oral toxicity of TEA, DEA, MEA or a composite of hair dyes and bases has been studied in guinea pigs,(‘49) in rats~‘49~‘55~‘56~‘6z~‘6s~ and in dogs.(‘66) Table 5 presents data from the experiments. Considerably less data are available for DEA and MEA than for TEA. However, it does appear that DEA is the most toxic ethanolamine. Workers at the Mellon Institute (‘54) have suggested that this may be because MEA has a normal function in the lipid metabolism of the body and DEA is structurally similar enough to MEA to act in competition with it and interfere in lipid metabolism. TEA may be so sufficiently unlike MEA that it does not act in competition and therefore is less toxic than DEA.
Acute Toxicity
Dermal Studies
than Undiluted TEAS, 91.8% and 88.1% active and both containing slightly more 6% of DEA, were each applied to the intact skin of three rabbits and to the
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 199
TAB
LE
4.
Ac
ute
O
ral
Toxi
city
.
Ma
teria
l te
ste
d
Co
w.
of
ma
teria
l te
ste
d (
%)
an
d v
eh
icle
Do
se
of
No
. a
nd
sp
ec
ies
eth
an
ola
min
ea
o
f a
nim
al
LD50
C
om
me
nts
Ref.
TEA
, VV+
Perc
ent
20
in
wa
ter;
100
4.0; 5.0, 6.3 g/k
g
2 ra
ts
at
ea
ch
do
se
leve
l
TEA
, VV+
Perc
ent
TEA
, 70
.6%
(DEA
, 8.
6%;
MEA
, 1.
7%)
TEA
, 91
.8%
(DEA
, 6.
5%)
TEA
, 88
.1%
(DEA
, 6.
1%)
TEA
, C
om
me
rcia
l
or
hig
h
pu
rity
gra
de
In
gum
a
rab
ic
solu
tion
25
in
wa
ter
100
0.6-7.0
g/k
g
2.6-
7.4
ml/
kg
TEA
3.64
-14.
00
ml/
kg
100
3.64-10.00
ml/
kg
100
1 .O
-26.
0 g
/kg
TEA
, C
om
me
rcia
l 10
0
gra
de
1.0-12.0
g/k
g
2-3
(un
spe
cifi
ed
) g
uin
ea
pig
s a
t e
ac
h d
ose
le
vel
10
rats
a
t e
ac
h o
f 4
do
se
leve
ls
10
rats
a
t e
ac
h o
f 5
do
se
leve
ls
10
rats
a
t e
ac
h o
f 4
do
se
leve
ls
10
gui
ne
a
pig
s a
t LD
50
an
d a
t 1
g <
LD
50
est
ima
ted
fro
m
sing
le
fee
din
gs
10
rats
a
t LD
50
an
d a
t
1 g
<
LD50
e
stim
ate
d
from
sin
gle
fe
ed
ing
s
4.03
m
l/kg
(4.19
g/k
g)
7.11
m
l/kg
5.39 m
l/kg
8 slk
g
012,
11
2, 2
12 d
ea
ths,
mo
de
rate
liv
er
an
d
kid
ne
y d
am
ag
e a
t a
ll
do
se
leve
ls.
All
surv
ive
d
0.6
an
d
1.4
g/k
g;
No
ne
surv
ive
d
7.0
g/k
g.
150
146
No
u
nu
sua
l o
bse
rva
tions
. 15
1
Slig
ht
to
mo
de
rate
d
eg
ree
s
of
hem
orrh
ag
ic
rhin
itis
in
rats
d
ose
d
at
~7.1
4
ml/
kg.
Slig
ht
to
mo
de
rate
d
eg
ree
s
of
hem
orrh
ag
ic
rhin
itis
in
rats
do
sed
a
t ~7
.14
ml/
kg.
Gro
ss
pa
tho
log
y c
on
fine
d
to
inte
stin
al
tra
ct.
Befo
re
de
ath
, d
iarr
he
a
an
d
pro
stra
tion
ob
serv
ed
in
mo
st
an
ima
ls.
Som
e
we
re
pa
raly
zed
in
the
ir h
ind
qua
rte
rs.
Gro
ss
pa
tho
log
y c
on
fine
d
to
inte
stin
al
tra
ct.
Befo
re
de
ath
, d
iarr
he
a
an
d
pro
stra
tion
ob
serv
ed
in
mo
st
an
ima
ls.
152
152
149
149
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 20
0
TAB
LE
4.
(Co
ntin
ue
d.)
Ma
teria
l te
ste
d
CO
W.
-of
ma
teria
l
test
ed
(%
)
an
d v
eh
icle
Do
se
of
eth
ano
/am
ine
a
No
. a
nd
sp
ec
ies
of
an
ima
l LD
50
Co
mm
ent
s Re
f.
TEA
, h
igh
p
urit
y
gra
de
TEA
in
wa
ter
TEA
, p
rod
uce
d
from
19
39-l
960
20
in w
ate
r/l0
0
DEA
, 99
+ Pe
rce
nt
DEA
DEA
DEA
DEA
, p
rod
uce
d
from
19
39-1
949
100
in
gum
a
rab
ic
solu
tion
in w
ate
r
100
100
20
in w
ate
r
I .0
-l 2.
0 g
lkg
10
ra
ts
at
LD50
a
nd
at
1 g
<
LD50
e
stim
ate
d
from
sin
gle
fe
ed
ing
s
6 m
ale
ra
ts
at
ea
ch
do
se
leve
l
rats
0.6-
5.0
g/k
g
2-3
(un
spe
cifi
ed
) g
uin
ea
pig
s a
t e
ac
h d
ose
le
vel
6 m
ale
ra
ts
at
ea
ch
do
se
leve
l
5 fe
ma
le
rats
a
t e
ac
h
do
se
leve
l
5 fe
ma
le
rats
a
t e
ac
h
do
se
leve
l
90-l
20
(un
spe
cifi
ed
) ra
ts
9 d
ke
9.11
g
/kg
8.54
-9.8
5
ml/
kg
or
7.3-
l 1.
26
glk
g
1 .a
2 g
/kg
0.80
m
l/kg
0.71
ml/
kg
1.41
-2.8
3
g/k
g
Gro
ss
pa
tho
log
y c
on
fine
d
to
inte
stin
al
tra
ct.
Befo
re
de
ath
, d
iarr
he
a
an
d
pro
stra
tion
ob
serv
ed
in
mo
st
an
ima
ls.
All
surv
ive
d
6.0
an
d
1 .O
g/k
g;
No
ne
surv
ive
d
3.0
g/k
g.
149
156
154,
155
147
156
157
158
154
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 20
1
MEA
, 99
+ Pe
rce
nt
in g
um
ara
bic
0.
64-l
.4 g
/kg
2.
3 (u
nsp
ec
ifie
d)
gui
ne
a
All
surv
ive
d
0.6
g/k
g;
No
ne
148
solu
tion
pig
s a
t e
ac
h d
ose
le
vel
surv
ive
d
7.0
g/k
g.
MEA
in
wa
ter
6 m
ale
ra
ts
at
ea
ch
do
se
2.74
g
/kg
15
6
leve
l
MEA
m
ale
ra
ts
I .9
7 g
/kg
15
9
MEA
fe
ma
le
rats
1.
72
g/k
g
159
MEA
, p
rod
uce
d
20
in w
ate
r 90
-l 20
(u
nsp
ec
ifie
d)
rats
2.
14-2
.74
154
from
19
39-l
949
g/k
g
____
____
____
____
____
____
____
____
____
____
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
---
__
_---
--
Ha
ir p
rep
ara
tion
10
0 8.
72-l
7.4
g/k
g
10
rats
a
t e
ac
h o
f 4
do
se
14.1
g
/kg
A
nim
als
rec
eiv
ing
b 1
3.8
dkg
16
7
(DEA
, 1.
6%;
(8.0
0-l
6.0
leve
ls
(12.
9 m
l/k@
o
f p
rod
uct
ha
d s
igns
o
f
MEA
, 5.
9%;
ml/
kg)
of
for
un
di-
me
lan
uria
, d
iarr
he
a,
sod
ium
b
ora
te,
un
dilu
ted
lu
ted
pre
p
po
lyu
ria,
an
d d
isco
lora
tion
3.2%
) p
rep
ara
tion
p
ara
tion
of
sto
ma
ch,
in
test
ina
l
muc
osa
, a
nd
ga
stro
inte
s-
tina
l c
ont
ent
s.
aA
dju
ste
d
for
co
nce
ntra
tion
test
ed
a
nd
ma
teria
l a
ctiv
ity,
wh
en
kn
ow
n.
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 20
2
TAB
LE
5.
Sub
ch
ron
ic
an
d
Ch
ron
ic
Toxi
city
.
Ma
teria
l te
ste
d
Do
se
an
d v
eh
icle
Le
ngth
o
f st
udy
No
. a
nd
sp
ec
ies
of
an
ima
ls Re
sults
Re
f.
TEA
O
-2.6
1 g
/kg
/da
y
in f
oo
d
90
da
ys
10
rats
at
ea
ch
d
ose
le
vel
TEA
, 88
.5%
O
-l .O
glk
gld
ay
(DEA
, 6%
) in
fo
od
TEA
, c
om
me
rcia
l
or
hig
h
pu
rity
gra
de
0.2-
l .g
g/k
g/d
ay
in f
oo
d
91
da
ys
60,
120
da
ys
20
rats
o
f e
ac
h
sex
at
ea
ch
of
4 d
ose
le
vels
8 ra
ts
of
ea
ch
do
se
leve
l fo
r
ea
ch
tim
e
No
e
ffe
cts
o
bse
rve
d
at
~0.0
8 g
/kg
/da
y.
De
cre
ase
d
we
igh
t g
ain
at
1.27
g
/kg
/da
y.
He
avy
liv
ers
a
nd
kid
ne
ys
pro
duc
ed
w
he
n
do
se
wa
s ~0
.17
g/k
g/d
ay.
Ma
jor
pa
tho
log
y
of
sma
ll in
test
ine
, ki
dn
ey,
liv
er,
or
lun
g
rare
at
~0.7
3 g
/kg
/da
y. M
ost
m
ajo
r p
a-
tho
log
y o
bse
rve
d
wa
s fa
tty
de
ge
nera
tion
of
the
liv
er.
Som
e
de
ath
s a
t ~0
.73
g/k
g/d
ay.
Inc
rea
sed
w
eig
ht
ga
in
in f
em
ale
ra
ts
rec
eiv
ing
0.25
g
/kg
/da
y.
Inc
rea
sed
fe
ed
co
nsum
ptio
n
in f
em
ale
ra
ts
rec
eiv
ing
0.
5 g
/kg
/da
y.
No
sign
ific
an
t d
iffe
renc
es
note
d i
n o
rga
n to
bo
dy
we
igh
t ra
tios.
N
o
gro
ss
or
hist
op
ath
olo
gic
ind
ica
tion
s o
f a
tre
atm
ent
re
late
d
eff
ec
t.
No
sig
nifi
ca
nt
hem
ato
log
ic
eff
ec
ts.
Perip
he
ral
op
tic
ne
rve
s sh
ow
ed
sc
att
ere
d
de
-
ge
nera
tion
in t
he
mye
lin
of
ind
ivid
ua
l fib
ers
at
all
do
ses
for
bo
th
60
an
d
120
da
ys.
Live
r
cha
nge
s w
ere
o
bse
rve
d
at
~0.4
g
/kg
/da
y
for
60
or
120
da
ys.
Kid
ne
y c
hang
es
we
re
ob
serv
ed
a
t 0.
2 to
0.2
25
g/k
g/d
ay
for
120
da
ys a
nd
at
0.4-
0.45
g
/kg
/da
y fo
r 60
o
r
120
da
ys.
Kid
ne
y d
am
ag
e w
as
ob
serv
ed
a
t
~0.8
g
/kg
/da
y fo
r 60
o
r 12
0 d
ays
. N
o
kid
ne
y d
am
ag
e w
as
seve
re
eno
ugh
to
inte
rfe
re
with
o
rga
n fu
nctio
n.
154,
156
163
149
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 20
3
TEA
, c
om
me
rcia
l
or
hig
h
pu
rity
gra
de
0.2-
l .8
g
/kg
/da
y
in f
oo
d
TEA
, c
om
me
rcia
l 0.
2-l
.6 g
/kg
/da
y
or
hig
h
pu
rity
by
pip
ett
e
gra
de
5
da
ys/w
ee
k
TEA
, c
om
me
rcia
l
or
hig
h
pu
rity
gra
de
TEA
, 99
%
0.2-
l .6
g/k
g/d
ay
by
pip
ett
e
5 d
ays
/we
ek
1.4
mg
ll in
drin
kin
g
wa
ter;
TEA
in
drin
kin
g
wa
ter
an
d 6
.5%
TEA
so
lutio
n
ap
plie
d
to
skin
ca
ud
ally
fo
r 1
h
5 d
ays
/we
ek;
TEA
in
drin
kin
g
wa
ter
an
d
13%
TEA
so
lutio
n
ap
plie
d
to
skin
ca
ud
ally
fo
r 1
h
120
da
ys a
nd
the
n,
-3
mo
nths
w
ith-
out
TE
A
60,
120
do
ses
120
do
ses
an
d
the
n,
-3
mo
nths
w
ith-
out
TE
A
6 m
ont
hs
8 ra
ts
at
ea
t h
do
se
leve
l
8 g
uin
ea
p
igs
at
ea
ch
do
se
leve
l fo
r e
ac
h
num
be
r o
f
do
ses
8 g
uin
ea
p
igs
at
ea
ch
do
se
leve
l
10
rats
in
ea
ch
ww
Kid
ne
y re
ge
nera
tion
wa
s o
bse
rve
d
aft
er
org
an
da
ma
ge
.
149
Perip
he
ral
op
tic
ne
rve
s sh
ow
ed
sc
att
ere
d
de
ge
nera
tion
in t
he
mye
lin
of
ind
ivid
ua
l
fibe
rs
at
all
do
ses
for
bo
th
60
an
d
120
da
ys.
Live
r a
nd
kid
ne
y d
am
ag
e w
as
ob
serv
ed
a
t
~0.8
g
/kg
/da
y.
No
ki
dn
ey
or
live
r d
am
ag
e
wa
s se
vere
e
noug
h to
in
terf
ere
w
ith
org
an
func
tion.
149
Live
r a
nd
kid
ne
y re
ge
nera
tion
wa
s o
bse
rve
d
aft
er
org
an
da
ma
ge
.
149
No
to
xic
e
ffe
ct
ob
serv
ed
fro
m
6.5
pe
rce
nt
top
ica
l TE
A
an
d
1.4
mg
/l T
EA
in d
rinki
ng
wa
ter.
Cha
nge
s o
bse
rve
d
aft
er
1 m
ont
h in
the
fu
nctio
ns
of
the
liv
er
an
d c
ent
ral
ne
rvo
us
syst
em
in
an
ima
ls re
ce
ivin
g
13%
top
ica
l TE
A
an
d 1
.4
mg
/l T
EA
in
drin
kin
g
wa
ter.
Inc
rea
se
see
n in
nu
mb
er
of
seg
-
me
nte
d
ne
utro
ph
ils
aft
er
3 m
ont
hs
an
d
inc
rea
se
see
n in
nu
mb
er
of
lym
ph
oc
yte
s
aft
er
4 m
ont
hs.
165
* E
El
r z . . ;;1
P
0 3 : 3 F
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 20
4
TABL
E 5.
(C
ont
inue
d.)
Ma
teria
l te
ste
d
Do
se
an
d v
eh
icle
5 d
ays
/we
ek.
DEA
, n
eut
raliz
ed
1
.o,
2.0,
3.
0
salt
(lab
ele
d)
m M
/kg
/da
y
ora
lly
Leng
th
of
stud
y
11
da
ys
(5th
-
15th
d
ay
aft
er
birt
h)
No
. a
nd
sp
ec
ies
of
an
ima
ls
Ne
ona
tal
rats
Resu
lts
No
c
hang
es
ob
serv
ed
in
he
art
o
r b
rain
.
Mo
de
rate
c
lou
dy
swe
llin
g
see
n in
ki
dn
ey
pro
xim
al
tub
ule
. Pe
ripo
rta
l c
lou
dy
swe
llin
g
an
d v
ac
uo
liza
tion
se
en
in
live
r. Sw
olle
n
he
pa
tic
mito
cho
ndria
o
bse
rve
d.
Ma
ny
de
ath
s o
bse
rve
d.
The
re
wa
s liv
er
an
d
kid
ne
y d
am
ag
e a
nd
a p
ron
oun
ce
d
norm
oc
ytic
an
em
ia
with
ou
t b
one
m
arr
ow
d
ep
letio
n
or
ob
vio
us
inc
rea
se
in
num
be
r o
r re
ticul
oc
yte
s.
Ref.
162
DEA
, n
eut
raliz
ed
4
mg
/ml
in
drin
kin
g
wa
ter
7 w
ee
ks
Ma
le
rats
16
4
DEA
O
-O.6
8 g
/kg
/da
y
in f
oo
d
90
da
ys
10
rats
a
t e
ac
h
do
se
leve
l
No
e
ffe
cts
o
bse
rve
d
at
~0.0
20
glk
gld
ay.
H
ea
vy
live
rs
an
d k
idn
eys
p
rod
uce
d
at
r0.0
90
g/k
g!
da
y. M
ajo
r p
ath
olo
gy
of
sma
ll in
test
ine
,
kid
ne
y,
live
r, o
r lu
ng
o
bse
rve
d
at
~0.1
7
g/k
g/d
ay.
M
ajo
r p
ath
olo
gy
inc
lud
ed
c
lou
dy
swe
llin
g
an
d d
eg
ene
ratio
n o
f ki
dn
ey
tub
ule
s
an
d l
ive
r fa
tty
de
ge
nera
tion.
So
me
a
nim
als
die
d
at
0.17
a
nd
0.3
5 g
lkg
lda
y a
nd
all
die
d
at
leve
ls
gre
ate
r th
an
tha
t.
154,
156
____
____
__--
____
-__-
---
---_
____
____
__-_
____
____
____
____
____
____
----
----
----
----
----
----
----
----
----
----
----
----
----
----
--
---
MEA
O
-2.6
7 g
/kg
/da
y 90
d
ays
10
ra
ts
at
ea
ch
N
o
eff
ec
ts
ob
serv
ed
a
t ~0
.32
glk
gld
ay.
H
ea
vy
154,
156
in f
oo
d
do
se
leve
l liv
ers
a
nd
kid
ne
ys
pro
duc
ed
a
t ~0
.64
dke
/
da
y. S
om
e
de
ath
s a
nd
ma
jor
pa
tho
log
y a
t
b 1
.28
g/k
g/d
ay.
__
____
____
____
____
__--
----
----
----
----
----
----
----
----
----
----
--
____
____
____
____
____
____
____
____
____
____
----
----
----
----
----
Co
mp
osit
e
ha
ir o
-O.0
975
g/k
g/d
ay
2 ye
ars
12
b
ea
gle
do
gs
No
to
xic
e
ffe
cts
o
bse
rve
d.
166
%
of
co
mp
osit
e
in
at
ea
ch
of
z d
yes
an
d b
ase
s ;;
(MEA
, 22
fo
od
3
do
se
leve
ls.
5 p
erc
ent
)
%
<
;;;
s
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 20
5
ASSESSMENT: TEA, DEA, AND MEA 205
abraded skin of three rabbits. The test was a 24 h closed patch test and the TEAS were applied to yield a rabbit exposure of 2 g/kg of actual TEA. The 88.1% TEA elicited mild erythema and no edema at 24 h and the skin returned to normal by Day 6. The 91.8% TEA produced moderate erythema and no edema at 24 h and the treated sites were normal by Day 10. The animals were observed for 14 days. All rabbits gained weight and none died.(16*’
Subchronic and Chronic Toxicity
Kindsvatter(‘4g) applied commercial and high purity grades of TEA each to the shaved skin of 10 guinea pigs. The test was a closed patch continuous ex- posure test in which 8 g/kg was applied daily for five days a week to guinea pigs. Deaths occurred at from 2 to 17 applications. No guinea pigs survived 17 applica- tions. Adrenal, pulmonary, hepatic, and renal damage was observed.
Kostrodymova et al. (16s) applied TEA caudally to rats for 1 h, five days per week, for six months. No toxic effects were observed with a 6.5% solution of TEA. A 13% solution of TEA did effect changes in the liver and central nervous system function. The toxic effect of TEA was not increased when rats were given 1.4 mg/l of TEA in their drinking water in addition to the dermal application of the 13% solution of TEA.
The percutaneous application of MEA to rats at a dose of 4 mglkglday resulted in nonspecific histological changes in the heart and lung. Hepatoxic manifestations included fatty degeneration of the liver parenchyma and subse- quent focal necrosis.(169)
Groups of 16 rabbits had a cosmetic formulation containing 14% TEA stearate and 1% methycellulose, applied to one of two clipped sites on their backs that were alternated weekly, at doses of 1 and 3 ml/kg five times per week for 13 weeks. Mild to moderate skin irritation which cleared within 72 h was observed and this was followed by moderate to heavy skin scaling. No toxic effects were seen in any rabbits. The control rabbits received 3 mg/ml of 1% methylcellulose in water. The low dose group had significantly lower kidney weights and the high dose group gained less weight and had significantly greater kidney weights than the control rabbits.(ls3)
Burnett et aI. applied three hair dyes containing O.lO%-0.15% TEA, 1.500% TEA, or 2.0% DEA to the backs of groups of 12 rabbits for 13 weeks. The doses were 1 mg/kg twice weekly and two clipped sites were alternated. The skin of half the rabbits was abraded. The dye was placed on the skin, the rabbits were restrained for 1 h, then shampooed, rinsed and dried. Control rabbits were treated identically except that no dye was applied to their skin. No systemic tox- icity was observed and there was no histomorphologic evidence of toxicity in the treated rabbits after 13 weeks.
Primary Skin Irritation
Rabbits were used in primary skin irritation studies for TEA,(“‘*“*) DEA,(‘73.‘74) and MEA (“So”) Data from these experiments are presented in Table 6. These data suggest that MEA is irritating to rabbit skin, and that TEA and DEA are much less irritating to rabbit skin than MEA.
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 206
TABL
E 6.
Pr
ima
ry
Skin
Ir
rita
tion
.
Ma
teria
l te
ste
d
Co
nce
ntra
tion
w
Me
tho
d
TEA
, 99
+ p
erc
ent
10
0 10
0.1
m
l o
pe
n a
pp
lica
tion
s to
the
e
ar
ove
r 14
da
ys.
10
24-h
our
se
mio
cc
lud
ed
pa
tch
ap
plic
atio
ns
to t
he
inta
ct
sha
ved
ab
do
me
n.
TEA
, 99
+ p
erc
ent
lo
o
TEA
10
0
3 24
-ho
ur
sem
ioc
clu
de
d
pa
tch
ap
plic
atio
ns
to t
he a
bra
de
d s
ha
ved
a
bd
om
en.
1 24
-ho
ur
oc
clu
de
d
pa
tch
ap
plic
atio
n
to
clip
pe
d
ba
ck.
Er
ythe
ma
(0
to
4),
e
de
ma
(0 t
o 4
),
an
d n
ec
rosis
(0
to
15
) e
valu
-
atio
ns
are
ma
de
at
24
an
d 7
2 ho
urs
an
d
are
ad
de
d a
nd
div
ide
d
by
2 to
yie
ld
a
prim
ary
irr
itatio
n
sco
re
(sc
ale
=
0
to
24).
Tota
l p
oss
ible
sc
ore
fo
r 22
la
bo
rato
ries
wa
s 40
0.
Num
be
r o
f
rab
bits
Re
sults
Re
f.
Un
spe
cifi
ed
Un
spe
cifi
ed
8 .m
ale
/ea
ch
lab
ora
tory
Slig
ht
hyp
ere
mia
a
fte
r
7 a
pp
lica
tion
s.
“Slig
ht
to
mo
de
rate
ly
irrita
ting
,
pro
long
ed
o
r re
pe
ate
d
exp
osu
re
ma
y b
e i
rrita
ting
.”
Mo
de
rate
h
ype
rem
ia,
ed
em
a,
an
d
nec
rosis
. “S
light
to
mo
de
rate
ly
irrita
ting
, p
rolo
nge
d
or
rep
ea
ted
exp
osu
re
ma
y b
e i
rrita
ting
.”
Prim
ary
irr
itatio
n
sco
res
rang
ed
from
0
to
5.5
for
22
lab
ora
torie
s.
Tota
l sc
ore
fo
r a
ll 22
la
bo
rato
ries
wa
s 27
.3.
171
171
172
____
---_
____
____
____
____
____
____
____
____
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 20
7
I P
D
EA,
99 +
p
erc
ent
10
0 10
0.1
m
l o
pe
n a
pp
lica
tion
s to
the
e
ar
Un
spe
cifi
ed
So
me
d
ena
tura
tion
on
ea
r a
fte
r 17
3
ove
r 14
da
ys.
10
24-h
our
se
mio
cc
lud
ed
10
d
ose
s a
nd
on
be
lly
aft
er
2 p
atc
h a
pp
lica
tion
s to
the
sh
ave
d
3 d
ose
s.
“Mo
de
rate
ly
irrita
ting
.”
P D
EA,
99+
pe
rce
nt
10
in w
ate
r a
bd
om
en.
U
nsp
ec
ifie
d
No
irr
itatio
n
ob
serv
ed
. 17
3
DEA
, 99
+ p
erc
ent
50
i
6 Es
sent
iah~
no
irri
tatio
n
of
the
sk
in.
1’74
. 5
Sem
ioc
clu
de
d
pa
tch
ap
plic
atio
ns
to
inta
ct
Prim
ary
/ irr
itatio
n
sco
re
=
0.17
. 0
an
d a
bra
de
d s
ha
ved
sk
in.
Eryt
hem
a
an
d
“No
t a
prim
ary
irr
itant
.”
3
DEA
, 99
+ p
erc
ent
30
e
de
ma
re
ac
tions
a
re e
valu
ate
d
at
24
an
d
6 Es
sen
tially
no
irri
tatio
n
of
the
sk
in.
174
72
h a
nd
va
lue
s a
re a
vera
ge
d t
o y
ield
a
F
Prim
ary
irr
itatio
n
sco
re
=
0.29
. p
rima
ry
irrita
tion
sc
ore
(s
ca
le
=
0 to
8)
. “N
onc
orro
sive
to
ski
n.”
__
____
_ __
____
____
____
____
____
____
____
____
____
__--
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
MEA
, 99
+ p
erc
ent
85
, 10
0 Se
mio
cc
lud
ed
p
atc
h a
pp
lica
tion
s to
in
tac
t 1
Vis
ible
d
est
ruc
tive
a
ltera
tion
of
the
17
6
an
d a
bra
de
d s
ha
ved
sk
in.
Rea
ctio
n tis
sue
a
t th
e
site
o
f a
pp
lica
tion
.
eva
lua
ted
a
t 4
h.
“Co
rrosiv
e.”
MEA
, 99
+ p
erc
ent
30
Se
mio
cc
lud
ed
p
atc
h a
pp
lica
tion
s to
in
tac
t 6
Vis
ible
d
est
ruc
tive
a
ltera
tion
of
the
17
7
an
d a
bra
de
d s
ha
ved
sk
in.
Rea
ctio
n tis
sue
a
t th
e
site
o
f a
pp
lica
tion
a
t
eva
lua
ted
a
t 4
an
d a
t 24
h.
4
h.
Ne
cro
sis
ob
serv
ed
a
t 24
h.
“Co
rrosiv
e
to
skin
.”
MEA
, 99
+ p
erc
ent
l-1
00
10 0
.1
ml
op
en
ap
plic
atio
ns
to t
he
ea
r U
nsp
ec
ifie
d
10
pe
rce
nt
or
hig
he
r w
as
co
rro
sive
17
5
ove
r 14
d
ays
, TO
24-
hour
se
mio
cc
lud
ed
to
the
sk
in,
> 1
%
wa
s e
xtre
me
ly
pa
tch
ap
plic
atio
ns
to t
he
sha
ved
irr
itatin
g
to t
he
skin
a
nd
1%
w
as
ab
do
me
n.
irrita
ting
to
the
sk
in.
“Ext
rwn
eljx
co
rro
sive
to
sk
in.”
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 20
8
208 COSMETIC INGREDIENT REVIEW
Phototoxicity
The phototoxicity of a suntan lotion containing 1% TEA was evaluated by ap- plying the lotion to the stripped ears of six guinea pigs. A known photosensitizer was used as a positive control in four other guinea pigs. Each animal was then ex- posed to ultraviolet (UVA) from two GE F8T5-BL lamps at a distance of 4-6 cm for 2 h. No erythema or edema was observed in any of the guinea pigs treated with suntan lotion. Results of the positive controls are unavailable.“7s’
Skin Sensitization
Pairs of guinea pigs were treated dermally with 5%-100% TEA in water for 6 h with occlusion, and the treated sites were scored for erythema at 24 and 48 h. Since use of undiluted TEA resulted in only one erythemic reaction at 24 h, 100% TEA was used in both induction and challenge procedures in the subsequent sen- sitization test. Twenty guinea pigs received dermal applications of undiluted TEA once per week for three weeks. A challenge patch was applied after 14 days and again seven days later. One erythemic reaction occured in each of three animals during the induction procedure, in two other animals during the first challenge, and in one other animal during the second challenge. All the guinea pigs remained healthy and made normal weight gains during the test. There was no evidence of any skin sensitizing activity of undiluted TEA for guinea pigs.(“‘)
TEA from four different suppliers was evaluated in guinea pig skin sensitiza- tion tests.(180-‘83’ The tests were conducted with 10 control and 20 treated guinea pigs. The induction patches were applied once a week for up to six hours for three weeks. Two weeks later challenge patches were applied to both control and treated guinea pigs. One test was conducted with undiluted TEA at induction and 90% TEA at challenge’181’ and all the other tests were conducted with 50% TEA at induction and 90% TEA at challenge. (180,182*183) None of the animals showed clinicalsymptoms during or after the treatment period and no guinea pigs showed signs of primary irritation of the skin. Challenge reactions were measured with a reflectometer and average readings between control and experimental animals were compared. TEA was not a guinea pig skin sensitizer in these studies.
Patches containing a 25% active TEA solution and 10% and 5% TEA in aqueous solution were applied to the backs of four clipped guinea pigs. No irrita- tion was observed in this preliminary study. Induction patches containing the 25% TEA solution were applied to the backs of 20 clipped guinea pigs for 6 h once per week for three weeks. One week later, a challenge patch containing 25% TEA was applied for 6 h to the clipped backs of the 20 treated and 10 control guinea pigs. Challenge reactions were read at 24 h and at 48 h. No irritation was observed. No positive primary irritation or sensitization responses were observed under the test conditions with the 25 percent active TEA soIution.(184)
Eye Irritation
The eye irritation potential of TEA, DEA, MEA, or cosmetic products contain- ing the ethanolamines has been studied in rabbits(17*~‘72~174~‘77~1~s~1”7) and in rhesus monkeys. (la8) Data from these experiments are presented in Table 7. In high concentrations and with long contact time, TEA, and DEA may be irritating to the rabbit eye and MEA is irritating to the rabbit eye.
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 209
TABL
E 7.
Ey
e
Irrita
tion.
Co
nce
ntra
tion
Ma
teria
l te
ste
d
w
Me
tho
d
No
. a
nd
spe
cie
s
of
an
ima
ls Re
sults
Re
f.
TEA
, 99
+ p
erc
ent
10
0
TEA
, 99
+ p
erc
ent
10
in
wa
ter
ml
of
test
m
ate
rial
inst
ille
d
into
c
on
jun
ctiv
al
sac
of
bo
th
rab
bit
eye
s.
Left
e
ye u
nw
ash
ed
. A
fte
r
30
sec
. e
xpo
sure
, rig
ht
eye
wa
she
d
for
2 m
in
with
ta
p w
ate
r.
TEA
10
0
TEA
, 98
p
erc
ent
10
0
0.00
5,
0.02
m
l o
f te
st m
ate
rial
ap
plie
d
to c
orn
ea
1 c
ent
er
wh
ile
eye
lids
are
retr
ac
ted
. Li
ds
rele
ase
d
aft
er
1 m
in.
Eye
in
jury
sc
ore
d
on
a s
ca
le o
f 0
to
20
po
ints
a
fte
r 18
-24
h.
0.01
, 0.
03,
0.10
m
l o
f te
st
ma
teria
l
ap
plie
d
dire
ctly
to
co
rne
a
an
d
eye
lids
rele
ase
d
imm
ed
iate
ly.
Eye
s
sco
red
a
t d
ays
1,
3,
7,
14
an
d 2
1
by
the
m
eth
od
o
f D
raiz
e,
et
al.“
“’
(sc
ale
=
0
to
110)
.
TEA
10
0 0.
1 m
l o
f te
st
ma
teria
l w
as
pla
ce
d
insid
e
the
lo
we
r e
yelid
. Li
ds
we
re
he
ld t
og
eth
er
for
a f
ew
se
co
nds.
Eye
s w
ere
e
xam
ine
d
at
1,
24,
an
d
72
hour
s a
nd
7 d
ays
aft
er
ap
plic
a-
tion.
Sc
orin
g
wa
s a
cc
ord
ing
to
the
sca
le o
f D
raiz
e
et
al.i
’Prr
(sc
ale
=
0
to
110)
.
Rab
bits
Rab
bits
Rab
bits
6 ra
bb
its
at
ea
ch
do
se
leve
l
6 m
ale
rab
bits
Mo
de
rate
p
ain
an
d s
we
llin
g
in
un
wa
she
d
171
eye
. Sl
ight
c
on
jun
ctiv
al
irrita
tion
w
hic
h
sub
side
d
in 4
8 h.
N
o
irrita
tion
o
bse
rve
d
in t
he
wa
she
d
eye
. “S
light
to
m
od
era
tely
irrita
ting
, no
co
rne
a1
da
ma
ge
lik
ely
.”
Esse
ntia
lly
no i
rrita
tion
o
bse
rve
d
in w
ash
ed
17
1
or
un
wa
she
d
eye
s.
0.00
5 m
l yi
eld
ed
a
sc
ore
o
f ~5
.0,
0.02
m
l 18
5
yie
lde
d
a s
co
re
of
>5.0
. 5.
0 is
the
le
vel
rep
rese
nta
tive
o
f se
vere
in
jury
; n
ec
rosis
visi
ble
a
fte
r st
ain
ing
a
nd
co
verin
g
- 75
%
of
the
su
rfa
ce
o
f th
e c
orn
ea
.
0.01
m
l g
ave
a 0
sc
ore
o
n a
ll d
ays
eye
s 18
7
we
re
exa
min
ed
. 0.
03
ml
ga
ve a
sc
ore
o
f
1 o
n D
ay
1 a
nd
0 t
here
aft
er.
0.10
m
l
yie
lde
d
a s
co
re
of
4 o
n D
ay
1, 2
on
Da
ys
3 a
nd
7,
an
d 0
on
Da
ys
14
an
d 2
1.
The
m
ed
ian
nu
mb
er
of
da
ys f
or
eye
s to
retu
rn
to
no
rma
l w
as
1 fo
r 0.
01
an
d
0.03
m
l a
nd
3 f
or
0.10
m
l.
Eye
irri
tatio
n
sco
res
rang
ed
fro
m
O-1
0 fo
r 17
2
24
lab
ora
torie
s.
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 21
0
TAB
LE
7.
(Co
ntin
ue
d.)
Co
nce
ntra
tion
Ma
teria
l te
ste
d
PM
DEA
, 99
+ p
erc
ent
30
in
wa
ter
DEA
, 99
+ p
erc
ent
50
in
wa
ter
Me
tho
d
ml
of
test
m
ate
rial
wa
s p
lac
ed
into
th
e
co
nju
nc
tiva
l sa
c o
f th
e
rab
bit
eye
an
d a
llow
ed
to
re
ma
in
for
15
sec
. Th
e
eye
wa
s rin
sed
.
No
. a
nd
spe
cie
s
of
an
ima
ls
6 ra
bb
its
6 ra
bb
its
Resu
lts
The
m
ate
rial
wa
s e
sse
ntia
lly
noni
rrita
ting
to t
he e
ye.
“No
nco
rrosiv
e
to e
ye”.
Mo
de
rate
to
se
vere
c
on
jun
ctiv
al
irrita
tion
an
d c
orn
ea
1 in
jury
w
ith
slig
ht
red
de
nin
g
of
the
iri
s w
as
ob
serv
ed
. Th
e
eye
ess
en
tially
h
ea
led
in
7
da
ys.
“Se
vere
Ref.
174
174
DEA
10
0 Ra
bb
its
185
irrita
nr.
0.00
5,
0.02
m
l o
f te
st
ma
teria
l
ap
plie
d
to c
orn
ea
1 c
ent
er
wh
ile
eye
lids
are
re
tra
cte
d.
Lid
s re
lea
sed
aft
er
1 m
in.
Eye
in
jury
sc
ore
d
on
a
sca
le o
f 0
to 2
0 p
oin
ts
aft
er
18 t
o
24
hour
s.
0.00
5 m
l yi
eld
ed
a
sc
ore
o
f ~5
.0,
0.02
yie
lde
d
a s
co
re
of
~5.0
. 5.
0 is
the
le
vel
rep
rese
nta
tive
o
f se
vere
in
jury
; n
ec
rosis
visi
ble
a
fte
r st
ain
ing
a
nd
co
verin
g
- 75
pe
rce
nt
of
the
su
rfa
ce
o
f th
e c
orn
ea
.
____
____
____
____
____
____
____
____
____
____
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
MEA
, 99
+ p
erc
ent
30
in
wa
ter
-0.2
m
l o
f te
st
ma
teria
l w
as
pla
ce
d
6 ra
bb
its
Slig
ht
disc
om
fort
, sli
ght
c
on
jun
ctiv
al
irrita
- 17
7
into
th
e
co
nju
nc
tiva
l sa
c o
f th
e
tion,
a
nd
slig
ht
co
rne
a1
clo
ud
ing
w
hic
h
rab
bit
eye
an
d a
llow
ed
to
re
ma
in
he
ale
d i
n 4
8 ho
urs
wa
s o
bse
rve
d.
for
15
sec
. Th
e
eye
wa
s rin
sed
. “M
od
era
tely
irr
itatin
g.”
MEA
1,
5,10
0 0.
005
ml
of
un
dilu
ted
o
r d
ilute
d
test
Ra
bb
its
1%
solu
tion
yie
lde
d
a s
co
re
I 5.
0;
5 a
nd
18
5
ma
teria
l a
pp
lied
to
co
rne
a1
ce
nte
r 10
0%
solu
tions
yi
eld
ed
sc
ore
s >5
.0.
wh
ile
lids
are
re
tra
cte
d.
Lid
s 5.
0 is
the
le
vel
rep
rese
nta
tive
o
f se
vere
rele
ase
d
aft
er
1 m
in.
Eye
in
jury
in
jury
; n
ec
rosis
vi
sib
le
aft
er
sta
inin
g
an
d
sco
red
o
n a
sc
ale
of
0 to
20
p
oin
ts
co
verin
g
- 75
p
erc
ent
o
f th
e
surf
ac
e
of
aft
er
18
to 2
4 h.
th
e
co
rne
a.
____
____
____
____
____
____
____
____
____
____
----
----
----
----
----
----
----
----
----
----
----
----
----
__
____
____
____
_-__
__--
----
----
--
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 21
1
Sha
mp
oo
(T
EA,
12.6
%)
Ha
ir p
rep
ara
tion
(DEA
, 1.
6%;
MEA
, 5.
9%;
sod
ium
b
ora
te,
3.2%
)
100
of
the
sha
mp
oo
100
of
the
ha
ir
pre
pa
ratio
n
0.1
ml
of
the
sh
am
po
o
wa
s in
still
ed
into
th
e
co
nju
nc
tiva
l sa
c o
f th
e
left
eye
. H
eld
c
lose
d
for
1 se
c.
Aft
er
15
set,
rinse
d
with
50
m
l ta
p
wa
ter.
Eye
s w
ere
e
xam
ine
d
at
24,
48,
an
d 7
2 ho
urs
an
d a
t 4
an
d
7 d
ays
p
ost
-inst
illatio
n.
0.1
ml
of
the
h
air
pre
pa
ratio
n
wa
s
pla
ce
d i
nto
th
e
co
nju
nc
tiva
l sa
c o
f
one
eye
. Th
e
lids
we
re h
eld
to
ge
the
r
for
1 se
c.
Atie
r 30
se
t, th
e
eye
s o
f
3 a
nim
als
we
re
wa
she
d
with
20
m
l
of
de
ion
ize
d
wa
ter.
The
e
yes
we
re
exa
min
ed
a
t 24
, 48
, a
nd
72
hour
s
an
d a
t 4
an
d 7
da
ys a
nd
we
re
sco
red
a
cc
ord
ing
to
the
m
eth
od
o
f
Dra
ize
e
t a
1.r’
“’
(sc
ale
=
0
to
110)
.
6 rh
esu
s Sl
it la
mp
exa
min
atio
ns
at
24
h r
eve
ale
d
188
mo
nke
ys
ed
em
ato
us
co
rne
a
an
d s
light
slo
ughi
ng
of
the
co
rne
a1
ep
ithe
lium
in
the
tre
ate
d
eye
s o
f 2
an
ima
ls.
At
72
h, a
slig
ht
po
sitiv
e
fluo
resc
ein
st
ain
ing
w
as
ob
serv
ed
in t
he e
ye o
f o
ne
mo
nke
y a
nd
at
Da
y 7,
a f
ain
t,
diff
use
p
osit
ive
st
ain
ing
w
as
note
d
in o
ne
mo
nke
y.
9 ra
bb
its
Ma
xim
um
ave
rag
e i
rrita
tion
sc
ore
s fo
r b
oth
19
4
wa
she
d
an
d u
nw
ash
ed
e
yes
wa
s 0.
7.
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 21
2
212 COSMETIC INGREDIENT REVIEW
Vaginal Mucosa Irritation
A spermicidal preparation containing 1.92% TEA was tested for vaginal mucosa irritation using six female rats in the same stage of estrus. A 0.5 ml volume of the ointment was placed inside the vaginas of the rats at a depth of 0.6X1.8 cm daily for three days. On the fourth day, the vaginas were exposed and examined for erythema, exudate, and edema. The researchers classified the sper- micidal preparation as a nonirritant to rat vaginal mucosa.(‘Bg)
Inhalation Studies
Respiratory difficulties and some deaths in male rats resulted from the short- term inhalation of 200 ppm DEA vapor or 1400 ppm DEA aerosols. Inhalation of 25 ppm DEA for 216 continuous hours resulted in increased liver and kidney weights. A workday schedule inhalation of 6 ppm DEA for 13 weeks resulted in growth rate depression, increased lung and kidney weights, and some deaths in male rats.(164)
Weeks et aI. reported that the dominant effects of continuous exposure of dogs, guinea pigs, and rats to 5-6 ppm MEA vapor were skin irritation and lethargy. The inhalation of MEA vapor at concentrations of 12-26 ppm for 90 days did not result in any mortality in dogs or rodents. Some deaths did occur after 25 days in dogs exposed to 102 ppm MEA vapor, and after 24-28 days in rodents exposed to 66-75 ppm MEA vapor. Exposure to 66-l 02 ppm MEA vapor caused behavioral changes and produced pulmonary and hepatic inflammation, hepatic and renal damage, and hematologic changes in dogs and rodents.
Parenteral Studies
The mouse acute intraperitoneal LD50s of TEA and MEA have been reported to be 1.450 and 1.050 g/kg, respectively.‘lgl) Blum et al.(l’*) determined that the mouse acute intraperitoneal LD50 of DEA was 2.3 g/kg. This level of DEA produced hepatic steatosis, cellular degeneration and swollen hepatic mitochondria in the 24 h following the injection. After 24 h, survivors were apparently normal. The livers of mice that survived over 48 h appeared to have returned to normal. Other information can be found in the literature on the intraperitoneal administration of the ethanolamines to mice and rats.(164.‘g5,1g6)
SPECIAL STUDIES
Mutagenesis
The Ames assay has been used to investigate the mutagenic potential of the ethanolamines.(‘g7) TEA, 99 + percent, with or without metabolic activation, was not mutagenic at concentrations of 0.001 to 100 mg/plate to Salmonella typhimurium strains TA98, TAlOO, TA1535, TA1537, and TA1538.““) The Na- tional Toxicology Program (NTP) tested O-3.333 mg/plate of TEA and DEA in their preincubated Salmonella mutagenicity assay in strains TA98, TAlOO, TA1535, and TA1537 with and without metabolic activation and reported both
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 213
ASSESSMENT: TEA, DEA, AND MEA 213
chemicals to be negative. (lgg) Hedenstedt’2”“) tested DEA and MEA with and without metabolic activation by liver preparations from rats induced with a polychlorinated biphenyl mixture in S. typhimurium strains TAl 00 and TA1535. There was no observed increase in the number of mutants per plate with either DEA or MEA.
The mutagenicity of TEA, sodium nitrite, and a mixture of the two, with and without metabolic activation by liver S-9, was tested with Bacillus subtilis. Only the mixture of TEA and sodium nitrite was mutagenic to the bacteria. N-nitro- sodiethanolamine (NDELA) was found in this mixture, but NDELA does not in- duce mutations in B. subtilis without metabolic activation. Some other reaction mixture product must be mutagenic and this product loses its mutagenic activity in the presence of liver enzymes.(*O1’
Fresh primary rat hepatocyte cultures were treated simultaneously with TEA and ‘H-thymidine in an unscheduled DNA synthesis test. DNA repair was quan- titated by microautoradiographic evaluation of the incorporation of 3H-thymidine into nuclear DNA. The concentrations of TEA tested ranged from 10-8-10-1 M and three cultures were tested per concentration. The authors reported that TEA did not appear to cause DNA-damage inducible repair.‘*‘*)
Carcinogenesis
Kostrodymova et aI. used a total of 560 male mice, strain CBA X C67Bi6,
in a series of three experiments to study the possible carcinogenic and cocarcin- ogenic effects of pure TEA, 99+ percent, and industrial TEA, 80+ percent, and the combined effect of TEA and syntanol DC-lo, applied cutaneously. The ex- periments ran for 14-18 months, and they found no evidence of TEA car- cinogenicity or cocarcinogenicity.
Hoshino and Tanooka(*“) fed a diet containg O.Ol%, 0.03%, or 0.3% TEA to groups of 40 ICR-JCL male and 40 ICR-JCL female mice throughout the life-span of the animals. The malignant tumor incidence in females was 2.8%, 27%, and 36%, and in males was 2.9%, 9.1%, and 3.6% for the mice fed diets containing O.O%, 0.03%, and 0.3% TEA, respectively. Treated females showed a much higher incidence of thymic and nonthymic tumors in lymphoid tissues than treated males. The mice fed TEA in their diet survived as long as the control mice.
DEA is currently being tested in an NTP carcinogenesis bioassay program. It is being administered in drinking water to rats and mice.(“‘)
Teratogenesis and Reproduction Studies
Hair dyes containing O.lO%-0.15% TEA, 1.5% TEA, or 2.0% DEA were topically applied to the shaved skin of groups of 20 pregnant rats on Days 1,4, 7, 10, 13, 16, and 19 of gestation. On Day 20, the rats were sacrificed and com- parisons were made with control rats. No significant soft tissue or skeletal changes were noted in the fetuses. The mean number of corpora lutea, implanta- tion sites, live fetuses, resorptions per pregnancy, and number of litters with resorptions were not significantly different in the dye-treated and control rats.(l’O)
A composite hair dye and base containing 22% MEA was given to 60 female rats at concentrations of 0 to 7800 ppm in the diet from Day 6 to 15 of gestation.
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 214
214 COSMETIC INGREDIENT REVIEW
The rats were sacrificed at Day 19 and there was no evidence of any adverse ef- fects on the rats or their pups. No differences were observed in the average number of implantation sites, live pups, early or late resorptions per litter, or females with one or more resorption sites. Thirty male rats were fed diets contain- ing O-7800 ppm composite for eight weeks prior to mating and during mating to 60 female rats on a basal diet. Sixty female rats were fed O-7800 composite- containing diets eight weeks prior to mating through Day 21 of lactation. They were mated with 30 male rats on the basal diet. In both experimental designs, there were no dose-related significant differences in male and female fertility, length of gestation, number of females with resorption sites, live pups per litter, pup body weights, and pup survival. The composite hair dye and base was also administered at a dose of O-19.5 mg/kg/day by gavage to 48 artificially in- seminated female rabbits from Day 6 to 18 of gestation. The rabbits were sacrificed at Day 30. There was no evidence of any teratologic effects. Fetal survival was not adversely affected and no grossly abnormal fetuses or soft tissue defects were seen.(166)
CLINICAL ASSESSMENT OF SAFETY
Dermal Studies
Patch tests can be used to measure skin irritation and sensitization by a chemical substance in human subjects. However, caution should be exercised in the interpretation of patch tests. Patches will elicit positive reactions in cases where the test material is a primary irritant or when the human subject has been sensitized by previous contact with the chemical, either in a past patch or in the course of his daily life. (*03) In addition, patch tests may elicit positive responses because the threshold irritating concentration of a chemical has decreased after repeated exposure of the skin to irritants; this would be a fatigue response. The population from which the subjects are drawn is also important. Certain skin types may be predisposed to react more intensely to chemical insult.(204)
Triethanolamine is the only ethanolamine for which human skin irritation and sensitization data are presented. The results of six patch test experiments with triethanolamine and details of those experiments are presented in Table 8. TEA produced minimal irritation in 1143 “normal” subjects and was more ir- ritating to subjects chosen because they were “hyper reactors” to skin irritants or because they were suffering from eczema.
The cosmetic industry has conducted studies on the skin irritation, sensitiza- tion, and photosensitization of a variety of products containing the ethanolamines. Data from these unpublished experiments are presented in Table 9. There was some evidence of irritation by some products.
Inhalation Studies
MEA inhalation by humans has been reported to cause immediate allergic responses of dyspnea and asthma(205) damage and chronic hepatitis.(‘6g)
and clinical symptoms of acute liver
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 215
TAB
LE
8.
Skin
Irr
itatio
n a
nd
Se
nsiti
zatio
n b
y Tr
ieth
an
ola
min
e.
Ma
teria
l
test
ed
Co
nce
ntra
tion
an
d d
ose
M
eth
od
Num
be
r
of
sub
jec
ts
Resu
lts
Ref.
TEA
, 88
.6%
0.
5 m
l o
f 1%
(DEA
, 6%
) a
ctiv
e T
EA
TEA
5%
TEA
2%
in
wa
ter
TEA
TEA
5 %
in
pe
tro
latu
m
100%
; 10
a
nd
5%
in
eth
ano
l
TEA
5%
, 1%
in
eu
ce
rin
with
wa
ter
24
h s
em
ioc
clu
sive
in
duc
tion
p
atc
hes
we
re
ap
plie
d
on
the
d
ors
al
surf
ac
e
of
the
u
pp
er
arm
3
time
s p
er
we
ek
for
3 w
ee
ks.
14
da
ys
late
r, c
ha
llen
ge
pa
tche
s w
ere
a
pp
lied
to
the
sa
me
site
a
nd
the
o
the
r a
rm
an
d t
hese
we
re
gra
de
d a
t 48
a
nd
96
h o
n a
sca
le o
f O
-6.
Patc
h te
st,
1979
-l 98
0
Patc
h te
sts,
19
74-1
976,
M
ars
eill
e,
Fra
nc
e
Patc
h te
sts
Test
m
ate
rial
ap
plie
d
in a
n a
lum
inu
m
cha
mb
er
co
nta
inin
g
a c
ott
on
disk
onc
e d
aily
fo
r 3
da
ys,
aft
er
light
sca
rific
atio
n
of
the
fo
rea
rm
site
w
ith
a n
ee
dle
. Re
ad
ing
s o
n a
sc
ale
of
O-4
a
t 72
h
30
min
a
fte
r c
ham
be
r
rem
ova
l.
24
h p
atc
h te
sts.
Re
ad
ing
s a
fte
r 24
a
nd
48
h.
64
479
500
100
5-10
(u
nsp
ec
ifie
d)
Ca
uc
asia
n “
hyp
er
rea
cto
rs”
(ga
ve
bris
k in
flam
ma
tory
rea
ctio
n to
24
h
fore
arm
e
xpo
sure
of
5%
aq
ueo
us
sod
ium
la
ury
l
sulfa
te
in a
n
alu
min
um
cha
mb
er.)
22
sub
jec
ts
suff
erin
g
from
d
iffe
rent
typ
es
of
ec
zem
as
No
irr
itatio
n
(0)
in 4
51
ind
uctio
ns.
Mild
irrita
tion
(1
) in
420
a
nd
mo
de
rate
irrita
tion
(2
) in
3 i
nd
uctio
ns
(inc
lud
es
resid
ua
l re
ac
tions
).
188
an
d 6
8 sc
ore
s
of
0 a
nd
1
at
ch
alle
ng
e,
resp
ec
tive
ly.
“No
se
nsiti
zatio
n.“a
9 (2
%)
po
sitiv
e
rea
ctio
ns
for
co
nta
ct
de
rma
titis
ob
serv
ed
. (S
en
sitiz
ing
)
23
(4.6
%)
po
sitiv
e
rea
ctio
ns
for
co
nta
ct
de
rma
titis
ob
serv
ed
. (S
en
sitiz
ing
)
2 p
osit
ive
re
ac
tions
fo
r a
llerg
ic
co
nta
ct
de
rma
titis
we
re
ob
serv
ed
. (S
en
sitiz
ing
)
100%
TE
A
wa
s re
qu
ired
to
p
rod
uce
a
n
irrita
nt
rea
ctio
n o
n n
on
sca
rifie
d
skin
.
10%
TE
A
wa
s a
ma
rke
d
irrita
nt
(2.5
-
4.0)
a
nd
pus
tule
s w
ere
o
bse
rve
d
an
d
5%
TEA
w
as
a s
light
irr
itant
(0
.5-l
.4)
on
sca
rifie
d
skin
.
4 a
nd
3 p
osit
ive
re
ac
tions
to
5%
a
nd
1%
TEA
, re
spe
ctiv
ely
. (Ir
rita
ting
)
214
215
21’6
217
218
219
aC
onc
Iusio
ns
of
the
re
sea
rche
rs
are
in
quo
tatio
ns.
Inte
rpre
tatio
ns
of
the
Ex
pe
rt
Pan
el
are
in
p
are
nthe
ses.
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 21
6
TAB
LE
9.
Skin
Ir
rita
tion
, Se
nsi
tiza
tion
, Ph
oto
toxi
city
, a
nd
Ph
oto
sen
sitiz
atio
n
by
Pro
du
cts
C
on
tain
ing
th
e
Eth
an
ola
min
es.
Ma
teria
l te
ste
d
Co
nce
ntra
tion
an
d d
ose
M
eth
od
Num
be
r
of
sub
jec
ts
Resu
lts
Ref.
Sha
vin
g
pre
pa
ratio
n
100%
2
24-h
our
p
atc
hes
ap
plie
d
10 t
o
14
da
ys
508
46
we
ak
(no
nve
sicu
lar)
(+
) re
ac
tions
to
the
(T
EA,
4.2%
) a
pa
rt o
n th
e
sam
e s
ite.(
z031
Sim
ulta
neo
us
first
c
lose
d
pa
tch,
42
+
a
nd
7 s
tro
ng
clo
sed
p
atc
h o
n b
ac
k a
nd
op
en
pa
tch
(ed
em
ato
us
or
vesic
ula
r)
(+
+)
rea
ctio
ns
on
arm
. Sc
orin
g
sca
le w
as
+
to
to t
he
sec
ond
clo
sed
p
atc
h. 6
7 +
re
ac
tions
+
+
+
.r1
20)
Ad
diti
on
ally
, th
ere
w
as
UV
a
fte
r U
V
(Ha
no
via
Ta
nett
e
Ma
rk
1 la
mp
, e
xpo
sure
o
f th
e
sec
ond
p
atc
h.
360
nm
at
12
in f
or
1 m
in)
exp
osu
re
of
the
se
co
nd
pa
tch.
“N
oni
rrita
ting
.”
(Irr
i-
tatin
g.
Eith
er
mild
ly
pho
toto
xic
o
r U
V
enh
anc
em
ent
o
f a
n i
rrita
tion
re
spo
nse
).a
Sh
avi
ng
p
rep
ara
tion
10
0%
10
24-h
our
in
duc
tion
p
atc
hes
with
24
-ho
ur
260
Betw
ee
n
31
an
d 6
4 +
re
ac
tions
w
ere
(T
EA,
4.2%
) re
cup
era
tive
p
erio
ds
in
be
twe
en
. A
fte
r o
bse
rve
d
to c
lose
d
ind
uctio
n
pa
tche
s 2
to
3 w
ee
ks
rest
, a
48-
hour
c
ha
llen
ge
1
thro
ugh
10.
1,3,
3,4,
a
nd
4 s
tro
ng
+ +
pa
tch
(mo
difi
ca
tion
o
f Re
f. 22
1).
Sim
ul-
rea
ctio
ns
to c
lose
d
ind
uctio
n
60
+
an
d
tane
ous
c
lose
d
pa
tch
on
ba
ck
an
d o
pe
n 2
+
+
rea
ctio
ns
to t
he
clo
sed
c
ha
llen
ge
pa
tch
on
arm
. Sc
orin
g
sca
le w
as
+
to
pa
tch.
Fo
llow
ing
U
V
(Ha
no
via
Ta
nett
e
+
+
+ .
(“O
1 A
dd
itio
na
lly,
the
re
wa
s U
V
Ma
rk
1 la
mp
, 36
0 nm
a
t 12
in
ch
es
for
exp
osu
re
of
ind
uctio
n
pa
tche
s 1,
4,7,
a
nd
1
min
.)
exp
osu
re,
7,6,
1,4,
a
nd
8
+
10,
an
d t
he
ch
alle
ng
e
pa
tch.
re
ac
tions
w
ere
o
bse
rve
d
at
ind
uctio
n
pa
tche
s 1,
4,7,
a
nd
10
, a
nd
the
ch
alle
ng
e
pa
tch,
re
spe
ctiv
ely
. “N
ons
ens
itizi
ng
an
d
nonp
hoto
sens
itizi
ng.”
(Ir
rita
ting
) Sh
avi
ng
p
rep
ara
tion
N
orm
al
use
U
sed
o
n th
e
fac
e f
or
4 w
ee
ks
an
d s
co
red
52
m
ale
N
o
rea
ctio
ns
we
re
ob
serv
ed
. “N
oni
rrita
ting
.”
(TEA
, 4.
2%)
ea
ch
we
ek.
Sun
cre
am
lO
O%
, 24
-ho
ur
oc
clu
sive
in
duc
tion
p
atc
hes
48
1 b
are
ly
pe
rce
ptib
le
(h)
rea
ctio
n;
min
ima
l (T
EA,
3.75
%)
-0.1
m
l a
pp
lied
to
the
u
pp
er
ba
ck
3 tim
es
a
fain
t (li
gh
t p
ink)
un
iform
o
r sp
ott
y w
ee
k fo
r 3
we
eks
. A
fte
r 2
we
eks
re
st,
a
ery
the
ma
a
t in
duc
tion
p
atc
h 2.
“N
o
24-h
our
o
cc
lusiv
e
ch
alle
ng
e
pa
tch
wa
s p
ote
ntia
l fo
r in
du
cin
g
alle
rgic
ap
plie
d
to a
pre
vio
usl
y un
pa
tche
d
site
. se
nsiti
zatio
n.”
Rea
ctio
ns
we
re
sco
red
24
a
nd
48
hour
s
aft
er
pa
tch
rem
ova
l o
n a
sc
ale
of
0 to
4.
222
222
223
186
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 21
7
Sha
vin
g
cre
am
(TEA
, 3.
3%)
100%
Sha
vin
g
cre
am
(TEA
, 3.
3%)
100%
Sha
vin
g
cre
am
(TEA
, 2.
6%)
100%
Ma
sca
ra
form
ula
tion
loo
%,
0.2
n
(TEA
, 2.
1%)
Ma
sca
ra
form
ula
tion
loo
%,
0.2
m
(TEA
, 2.
1%)
Ma
sca
ra
form
ula
tion
100%
(TEA
, 2.
1%)
Ma
sca
ra
form
ula
tion
100%
(TEA
, 2.
1%)
12-h
our
o
cc
lusiv
e
ind
uctio
n
pa
tche
s
ap
plie
d
to t
he
me
dia
l su
rfa
ce
o
f th
e
up
pe
r a
rm
4 tim
es
a w
ee
k fo
r 2
we
eks
an
d s
co
red
a
t p
atc
h re
mo
val
on
a s
ca
le
of
0 to
4.
Aft
er
2 w
ee
ks
rest
, a
24-
hour
oc
clu
sive
c
ha
llen
ge
p
atc
h w
as
ap
plie
d.
Rea
ctio
ns
we
re
sco
red
a
t 24
, 48
, a
nd
72
hour
s.
!3-h
ou
r p
atc
hes
ap
plie
d
to t
he
ba
ck
eve
ry
da
y fo
r 21
d
ays
. Re
ac
tions
w
ere
sc
ore
d
da
ily
on
a s
ca
le o
f 0
to
4.
48-h
our
o
cc
lud
ed
p
atc
h w
as
ap
plie
d
to
the
a
rm
or
ba
ck;
24
-ho
ur
aq
ueo
us
sod
ium
lau
ryl
sulfa
te
oc
clu
de
d
pa
tch
on
arm
o
r
ba
ck,
the
n 5
alte
rna
te
da
y 48
-ho
ur
oc
-
clu
de
d
pa
tche
s o
f th
e
test
m
ate
rial.
Aft
er
a I
O-d
ay
rest
, 5-
10
pe
rce
nt
sod
ium
la
ury
l
sulfa
te
wa
s a
pp
lied
to
ano
the
r te
st
site
for
1 ho
ur
an
d f
ollo
we
d
by
a 4
8-ho
ur
oc
clu
de
d
pa
tch
of
the
te
st
ma
teria
l.
Rea
ctio
ns w
ere
ob
serv
ed
at
pa
tch
rem
ova
l
an
d 2
4 ho
urs
late
r.
54
57
51
15
15
25
25
5,
16,
an
d 1
4 ve
ry
slig
ht
ery
the
ma
(*
),
slig
ht
ery
the
ma
(l)
, a
nd
we
ll d
efin
ed
e
ryth
em
a
(2)
rea
ctio
ns,
resp
ec
tive
ly,
we
re
ob
serv
ed
to t
he
8 in
duc
tion
p
atc
hes.
N
umb
er
of
po
sitiv
e
rea
ctio
ns
inc
rea
sed
w
ith
ea
ch
ind
uctio
n.
No
re
ac
tions
to
the
ch
alle
ng
e
pa
tch.
(Ir
rita
ting
)
104,
36
, 5,
a
nd
2 s
light
e
ryth
em
a
(l),
mo
de
rate
e
ryth
em
a
(2),
se
vere
e
ryth
em
a
(3),
an
d e
de
ma
with
o
r w
itho
ut
ery
the
ma
(4)
rea
ctio
ns,
resp
ec
tive
ly,
we
re
ob
serv
ed
to t
he 8
in
duc
tion
p
atc
hes.
N
umb
er
of
po
sitiv
e
rea
ctio
ns
ge
ne
rally
in
cre
ase
d
with
ea
ch
in
duc
tion
. 6
1 +
a
nd
1 2
+
rea
ctio
ns
we
re
ob
serv
ed
o
n c
ha
llen
ge
a
t 24
ho
urs.
At
48
hour
s,
4 1
+
an
d
1 2+
re
ac
tions
we
re
ob
serv
ed
, a
nd
at
72
hour
s,
2 1
+
rea
ctio
ns
we
re
ob
serv
ed
. (Ir
rita
ting
)
27
slig
ht
ery
the
ma
(1
) a
nd
1 m
od
era
te
ery
the
ma
(2
) re
ac
tions
w
ere
o
bse
rve
d
to
the
8
ind
uctio
n
pa
tche
s.
1 1
+
rea
ctio
n
wa
s o
bse
rve
d
on
ch
alle
ng
e
at
24
hour
s.
(Mild
ly
Irrita
ting
)
7,
42,
2,
an
d 3
que
stio
na
ble
e
ryth
em
a
(*),
ery
the
ma
(l)
, e
ryth
em
a
an
d p
ap
ule
s (2
),
an
d e
ryth
em
a,
pa
pu
les,
ve
scic
les,
a
nd
po
ssib
ly
ed
em
a (
3) r
ea
ctio
ns,
resp
ec
tive
ly,
to t
he
21
pa
tche
s.
(Irrit
atin
g)
5,
54,
an
d 6
*,
1,
an
d 2
re
ac
tions
, re
spe
c-
tive
ly,
to t
he
21
pa
tche
s.
(Irrit
atin
g)
No
re
ac
tions
o
bse
rve
d
to c
ha
llen
ge
. “N
o
sens
itiza
tion.
”
No
re
ac
tions
o
bse
rve
d
to c
ha
llen
ge
. “N
o
sens
itiza
tion.
”
224
225
226
227
227
228
229
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 21
8
Y
co
TAB
LE
9.
(Co
ntin
ue
d.)
Ma
teria
l te
ste
d
Co
nce
ntra
tion
an
d d
ose
M
eth
od
Num
be
r
of
sub
jec
ts
Resu
lts
Ref.
Sunt
an
lotio
n
(TEA
, 1.
0%)
100%
Ma
sca
ra
loo
%,
-0.1
CTE
A,
20.0
4%)
ml/
cm
*
Ma
sca
ra
lOO
%,
-0.1
(TEA
, 2.
8%)
ml/
cm
’
48-h
our
o
cc
lusiv
e
ind
uctio
n
pa
tche
s w
ere
ap
plie
d 3
tim
es
a w
ee
k fo
r a
to
tal
of
10 t
ime
s.
Patc
hes
1,5,
6,
an
d 7
we
re o
n
the
le
ft s
ho
uld
er,
the
oth
ers
o
n th
e r
ight
.
The
sit
es
we
re s
co
red
24
to 4
8 ho
urs
aft
er
pa
tch
rem
ova
l. A
fte
r 8
da
ys r
est
, a
ch
alle
ng
e p
atc
h w
as
ap
plie
d t
o a
virg
in
ba
ck
site
an
d s
co
red
24
hour
s a
fte
r
pa
tch
rem
ova
l. Th
e
skin
sit
es
wh
ere
pa
tche
s 1,
4,7,
a
nd
10
an
d t
he c
ha
llen
ge
pa
tch
ha
d b
ee
n w
ere
exp
ose
d t
o U
V
light
(H
an
ovi
a
Tane
tte
M
ark
I
Lam
p)
at
a
dist
anc
e o
f 12
in
ch
es
for
1 m
in
an
d
sco
red
48
hour
s la
ter.
26 f
em
ale
5 tim
es/
we
ek
for
3 w
ee
ks,
du
plic
ate
24-h
our
o
cc
lusiv
e
ind
uctio
n
pa
tche
s
ap
plie
d
to t
he
ba
ck.
The
n,
one
sit
e
an
d
a c
ont
rol
site
(n
o t
est
p
rod
uct)
irr
ad
iate
d
with
3
time
s th
e
ind
ivid
ua
l’s
“min
ima
l
ery
the
ma
d
ose
” (M
ED)
usin
g
a. X
eno
n 26
fe
ma
le
arc
so
lar
simul
ato
r (2
90-4
00
nm).
48
hour
s la
ter,
bo
th
site
s.w
ere
re
ad
.
The
re
wa
s a
lo
-da
y re
st
an
d t
hen,
du
plic
ate
c
ha
llen
ge
p
atc
hes
we
re
ap
plie
d
23
at
fre
sh
site
s.
24
hour
s la
ter
one
sit
e
an
d a
co
ntro
l sit
e
exp
ose
d
to
3 m
in.
of
irra
dia
tion
fro
m
the
so
lar
simul
ato
r
(Sc
hott
W
345
filte
r).
Site
s g
rad
ed
at
15,
_ 24
, 48
, a
nd
72
hour
s a
fte
r lig
ht
exp
osu
re.
No
re
ac
tions
ob
serv
ed
. “N
ot
a p
hoto
-
toxi
ca
nt.”
230
2 sli
ght
re
ac
tions
up
on
c
ha
llen
ge
to
te
st
pro
duc
t a
lon
e.
On
e
do
ubtf
ul
an
d o
ne
ery
the
ma
re
ac
tion
be
fore
irr
ad
iatio
n.
“No
sens
itiza
tion.
” (Ir
rita
tion
)
No
re
ac
tions
o
bse
rve
d.
“No
t p
hoto
toxi
c
or
ph
oto
alle
rge
nic
.”
231
232
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 21
9
Skin
lo
tion
1 O
O%
,
(TEA
, 0.
83%
) -0
.2
ml
Skin
lo
tion
lO
O%
,
(TEA
, 0.
83%
) -0
.2
ml
Skin
lo
tion
1 O
O%
,
(TEA
, 0.
83%
) -0
.2
ml
Skin
lo
tion
1 OO%
,
(TEA
, 0.
83%
) -0
.2
ml
r Site
s o
n b
oth
fo
rea
rms
we
re t
ap
e-s
trip
pe
d
seve
ral
time
s.
Dup
lica
te
24-h
our
o
cc
lu-
sive
p
atc
hes
ap
plie
d
to e
ac
h f
ore
arm
.
The
n,
one
sit
e
irra
dia
ted
w
ith
UV
lig
ht
for
15
min
. a
t a
dist
anc
e
of
- 10
c
m
(-4,
400
CW
lcm
’ U
VA
).
Site
s sc
ore
d
aft
er
pa
tch
rem
ova
l, a
fte
r irr
ad
iatio
n,
an
d 2
4 a
nd
48
hour
s a
fte
r irr
ad
iatio
n.
Exa
min
ed
fo
r ta
nnin
g
aft
er
1 w
ee
k.
_ Sc
ore
d
on
a s
ca
le o
f O
-4.
24-h
our
o
cc
lusiv
e
ind
uctio
n
pa
tche
s w
ere
ap
plie
d
3 tim
es
a w
ee
k to
bo
th
fore
arm
s
for
a t
ota
l o
f 10
tim
es.
A
t th
e
en
d o
f
24
hour
s th
e
site
s w
ere
sc
ore
d
an
d
1 sit
e
wa
s irr
ad
iate
d
with
no
nery
thro
ge
nic
U
V
rad
iatio
n
for
15
min
. a
t a
dist
anc
e
of
10 c
m
(-4,
400
pW
lcm
’ U
VA
) a
nd
the
n
sco
red
a
ga
in.
Aft
er
10 t
o
14 d
ays
re
st,
ch
alle
ng
e
pa
tche
s w
ere
a
pp
lied
to
vi
rgin
ad
jac
ent
sit
es.
24
ho
urs
late
r, th
e
site
s
we
re
sco
red
, 1
site
w
as
irra
dia
ted
a
nd
sco
red
. Th
e
ch
alle
ng
e
site
s w
ere
a
lso
rea
d 4
8 a
nd
72
hour
s la
ter.
Sco
red
o
n a
sca
le o
f O
-4.
10
10
30
30
On
e
sub
jec
t h
ad
min
ima
l e
ryth
em
a
(*)
at
233
bo
th
site
s a
t a
ll re
ad
ing
s e
xce
pt
for
the
irra
dia
ted
sit
e
at
the
24
-ho
ur
be
fore
a
nd
aft
er
irra
dia
tion
re
ad
ing
s.
Ano
the
r su
bje
ct
ha
d m
inim
al
ery
the
ma
(*
) a
t th
e
irra
dia
ted
site
a
t th
e
72-h
our
re
ad
ing
. N
o
tann
ing
wa
s o
bse
rve
d.
“No
t p
hoto
toxi
c.”
(Ir
rita
ting
)
On
e
sub
jec
t h
ad
min
ima
l e
ryth
em
a
(*)
at
234
bo
th
site
s a
t a
ll re
ad
ing
s.
Ano
the
r su
bje
ct
ha
d m
inim
al
ery
the
ma
(*
) a
t th
e
irra
dia
ted
site
a
t th
e 4
8-
an
d 7
2-ho
ur
rea
din
gs.
N
o
tann
ing
w
as
ob
serv
ed
. “N
ot
pho
toto
xic
.”
(Irrit
atin
g)
Am
ong
30
0 in
duc
tion
re
ad
ing
s fo
r th
e
235
no
nirr
ad
iate
d
site
s,
the
re
we
re
13
min
ima
l
ery
the
ma
(*
) a
nd
2 e
ryth
em
a
(1)
rea
din
gs.
The
re
wa
s 1
min
ima
l e
ryth
em
a
(*)
ch
alle
ng
e
rea
din
g
at
48
hour
s.
Am
ong
600
ind
uctio
n
rea
din
gs
for
the
irr
ad
iate
d
site
s,
the
re
we
re 8
an
d 9
m
inim
al
ery
the
ma
(A)
rea
din
gs
be
fore
a
nd
aft
er
irra
dia
tion
,
resp
ec
tive
ly,
an
d 4
ery
the
ma
(1
) re
ad
ing
s
aft
er
irra
dia
tion
. Th
ere
w
as
1 m
inim
al
ery
the
ma
(*
) re
ad
ing
a
fte
r irr
ad
iatio
n
at
24
hour
s.
“Do
es
not
ind
uc
e
ph
oto
alle
rgy
or
co
nta
ct
alle
rgy.
” (Ir
rita
ting
)
Am
ong
30
0 in
duc
tion
re
ad
ing
s fo
r th
e
236
no
nirr
ad
iate
d
site
s,
the
re
we
re
15
min
ima
l
ery
the
ma
(*
) a
nd
3 e
ryth
em
a
(1)
rea
din
gs.
The
re
we
re
2 m
inim
al
ery
the
ma
( l )
ch
alle
ng
e
rea
din
gs,
o
ne
at
24
an
d o
ne
at
48
hour
s.
Am
ong
60
0 in
duc
tion
s fo
r th
e
irra
dia
ted
sit
es,
th
ere
w
ere
7
an
d
10
min
ima
l e
ryth
em
a
(*)
rea
din
gs
be
fore
an
d a
fte
r irr
ad
iatio
n,
resp
ec
tive
ly,
an
d
5 e
ryth
em
a
(1)
rea
din
gs
aft
er
irra
dia
tion
.
The
re
wa
s o
ne
ery
the
ma
re
ad
ing
(1
) a
fte
r
irra
dia
tion
a
t 24
ho
urs.
“D
oe
s no
t in
du
ce
ph
oto
alle
rgy
or
co
nta
ct
alle
rgy.
” (Ir
rita
ting
)
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 22
0
TAB
LE
9.
(Co
nti
nu
ed.)
# 0
Ma
teria
l te
ste
d
Co
nce
ntra
tion
an
d d
ose
M
eth
od
Num
be
r
of
sub
jec
ts
Resu
lts
Ref.
Sha
vin
g
cre
am
(TEA
, 2.
1%)
Sha
vin
g
cre
am
(TEA
, 2.
4%)
100%
100%
10
48-
to
72-h
our
o
cc
lusiv
e
ind
uctio
n
pa
tch
ap
plic
atio
ns
to t
he
sam
e
site
,
rea
din
gs
be
fore
th
e
ap
plic
atio
n
of
the
suc
ce
ed
ing
p
atc
h, f
ollo
we
d
by
a r
est
pe
riod
o
f a
bo
ut
3 w
ee
ks
an
d t
hen
a f
ina
l
ch
alle
ng
e
pa
tch
on
a f
resh
sit
e.
Mo
difi
ed
Dra
ize
te
st.(
‘93’
Sha
vin
g
cre
am
(TEA
, 2.
1%)
100%
9 a
-ho
ur
“se
mi-o
pe
n”
ind
uctio
n
ap
plic
atio
ns,
sco
red
48
to
72
ho
urs
late
r ju
st
be
fore
ap
plic
atio
n
of
the
ne
xt
pa
tch,
a
2-w
ee
k
rest
fo
llow
ed
b
y c
ha
llen
ge
p
atc
hes
sco
red
at
48
an
d 9
6 ho
urs
aft
er
ap
plic
atio
n.
Ch
alle
ng
e
pa
tche
s w
ere
a
pp
lied
to
the
orig
ina
l a
nd
to
virg
in
site
s.
Rea
ctio
ns
we
re
sco
red
o
n a
sc
ale
of
O-6
.
104
Am
ong
10
40
ind
uctio
n
rea
din
gs,
th
ere
w
ere
23
7
172
f re
ad
ing
s,
11
(1)
rea
din
gs
an
d o
ne
(3)
rea
din
g.
The
re
we
re
16
(?) c
ha
llen
ge
rea
din
gs.
(Ir
rita
ting
)
76
76
Am
ong
68
4 in
duc
tion
re
ad
ing
s th
ere
w
ere
23
8
231,
83
, a
nd
1
rea
ctio
n o
f (1
) (s
light
ery
the
ma
),
(2)
(ma
rke
d
ery
the
ma
) a
nd
(3)
(ery
the
ma
a
nd
pa
pu
les)
, re
spe
ctiv
ely
.
The
re
we
re
28
(l),
4 (2
),
an
d 3
(E)
(e
ryth
em
a
an
d p
oss
ibly
a
lso
ed
em
a)
rea
ctio
ns
upo
n
ch
alle
ng
e
at
the
o
rigin
al
site
a
nd
23
(1)
rea
ctio
ns
at
the
vi
rgin
sit
e
am
ong
30
4
ch
alle
ng
e
rea
din
gs.
“M
od
era
tely
irr
itatin
g
follo
win
g
initi
al
an
d r
ep
ea
ted
ap
plic
atio
n.
Ve
ry
little
c
um
ula
tive
irr
itatio
n.
No
evi
de
nc
e
of
sens
itiza
tion.
” (S
en
sitiz
ing
)
Am
ong
68
4 in
duc
tion
re
ad
ing
s th
ere
w
ere
23
8
222
an
d
101
rea
ctio
ns
of
(1)
an
d (
2),
resp
ec
-
tive
ly.
Am
ong
30
4 c
ha
llen
ge
re
ad
ing
s
the
re
we
re
33,
13,
an
d 2
re
ac
tions
o
f
(l),
(2),
an
d (
E),
resp
ec
tive
ly,
at
the
o
rigin
al
site
a
nd
20,
2,
a
nd
1
rea
ctio
ns
of
(l),
(2)
an
d
(E),
re
spe
ctiv
ely
, a
t th
e
virg
in
site
. “M
od
er-
ate
ly
irrita
ting
fo
llow
ing
in
itia
l a
nd
rep
ea
ted
ap
plic
atio
n.
Ve
ry
little
c
um
ula
tive
irrita
tion.
N
o
evi
de
nc
e
of
sens
itiza
tion.
”
(Se
nsit
izin
g)
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 22
1
Sha
vin
g
cre
am
10
0%
(TEA
, 2.
1%)
0.5
ml
Sha
vin
g
cre
am
(TEA
, 2.
1%)
100%
)
0.5
ml
9 24
-ho
ur
“se
mi-o
pe
n”
pa
tch
ind
uctio
n
ap
plic
atio
ns
sco
red
48
to
72
ho
urs
late
r
just
b
efo
re
ap
plic
atio
n
of
the
ne
xt
pa
tch
a 2
-we
ek
rest
fo
llow
ed
b
y c
ha
llen
ge
pa
tche
s sc
ore
d
at
48
an
d 9
6 ho
urs
aft
er
ap
plic
atio
n.
Ch
alle
ng
e
pa
tche
s w
ere
ap
plie
d
to
orig
ina
l a
nd
virg
in
site
s.
Rea
ctio
ns
we
re
sco
red
o
n a
sc
ale
of
O-6
.
63
63
Am
ong
56
7 in
duc
tion
re
ad
ing
s,
the
re
we
re
239
106,
4,
2,
a
nd
4
rea
ctio
ns
of
1, 2
, 3
an
d 4
(ery
the
ma
, e
de
ma
, a
nd
pa
pu
les)
, re
spe
c-
tive
ly.
Am
ong
25
2 c
ha
llen
ge
re
ad
ing
s
the
re
we
re
28,
6,
1, 9
, a
nd
1
rea
ctio
ns
of
1, 2
, 3,
4,
a
nd
6
(str
ong
re
ac
tion
spre
ad
ing
be
yon
d
test
sit
e),
re
spe
ctiv
ely
, a
t th
e
orig
-
ina
l sit
e
an
d 9
, 4,
a
nd
2
rea
ctio
ns
of
1,
2,
an
d 3
, re
spe
ctiv
ely
, a
t th
e
virg
in
site
. Sl
ight
irrita
tion
re
sulte
d
from
in
itia
l a
pp
lica
tion
an
d i
nc
rea
ses
in
irrita
tion
w
ere
o
bse
rve
d
follo
win
g
rep
ea
ted
ap
plic
atio
n.
Seve
ral
mo
de
rate
ly
stro
ng
rea
ctio
ns
we
re
ob
serv
ed
wh
en
c
ha
llen
ge
sit
es
we
re
sco
red
a
t
48
hour
s b
ut
in a
ll c
ase
s,
the
re
wa
s m
ark
ed
rem
issio
n
of
rea
ctio
n se
verit
y w
he
n
sco
red
at
96
hour
. “P
roa
bly
sk
in
fatig
ue.”
A
mo
ng
567
ind
uctio
n
rea
din
gs,
th
ere
w
ere
23
9
144,
20
, 8,
a
nd
12
re
ac
tions
o
f 1,
2,
3,
an
d 4
, re
spe
ctiv
ely
. A
mo
ng
252
ch
alle
ng
e
rea
din
gs,
th
ere
w
ere
42
, 8,
5,
19
, a
nd
1
rea
ctio
ns
of
1, 2
, 3,
4,
a
nd
6,
resp
ec
tive
ly,
at
the
o
rigin
al
site
a
nd
19
, 8,
a
nd
2
rea
ctio
ns
of
1,
2,
an
d 4
, re
spe
ctiv
ely
, a
t
the
vi
rgin
sit
e.
Slig
ht
irrita
tion
re
sulte
d
from
in
itia
l a
pp
lica
tion
a
nd
in
cre
ase
s in
irrita
tion
w
ere
o
bse
rve
d
follo
win
g
rep
ea
ted
ap
plic
atio
n.
Seve
ral
mo
de
rate
ly
stro
ng
rea
ctio
ns
we
re
ob
serv
ed
w
he
n
ch
alle
ng
e
site
s w
ere
sc
ore
d
at
48
hour
s b
ut
in
all
ca
ses,
th
ere
w
as
ma
rke
d
rem
issio
n
of
rea
ctio
n se
verit
y w
he
n
sco
red
a
t 96
ho
urs.
“Pro
ba
bly
sk
in
fatig
ue.”
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 22
2
TABL
E‘9.
(C
on
tinu
ed
.) Co
nce
ntra
tion
Num
be
r
Ma
teria
l te
ste
d
an
d d
ose
M
eth
od
o
f su
bje
cts
Re
sults
Re
f.
Sha
vin
g
cre
am
1 O
O%
,
(TEA
, 2.
1%)
0.5
ml
Sha
vin
g
cre
am
(TEA
, 2.
1%)
Sha
vin
g
cre
am
(TEA
, 2.
6%)
Sha
vin
g
cre
am
(TEA
, 2.
1%)
Sha
vin
g
cre
am
(TEA
, 2.
1%)
Sha
vin
g
cre
am
(TEA
, 1.
9%)
100%
100%
100%
100%
100%
Eve
rv
oth
er
da
v fo
r a
to
tal
of
20
da
vs
(ld
op
en-
pa
tch
ap
plic
atio
ns)
a
1 i
n.
squa
re
of
ga
uze
w
as
dip
pe
d
in s
am
ple
an
d a
pp
lied
to
the
su
bje
cts
’ a
rm
(the
sam
e
site
w
as
use
d
ea
ch
tim
e).
24
ho
urs
aft
er
ap
plic
atio
n
the
sit
es
we
re
sco
red
.
A
lo-d
ay
rest
w
as
follo
we
d
by
a c
ha
l-
leng
e
op
en
pa
tch
wh
ich
w
as
ob
serv
ed
24
an
d 4
8 ho
urs
late
r. Re
ac
tions
w
ere
sco
red
o
n a
sc
ale
of
+ 1
to
+4
.
60
60
60
60
60
63
Am
ong
56
7 in
duc
tion
re
ad
ing
s,
the
re
we
re
239
131,
23
, 2,
a
nd
14
re
ac
tions
o
f 1,
2,
3,
an
d 4
, re
spe
ctiv
ely
. A
mo
ng
252
ch
alle
ng
e
rea
din
gs,
th
ere
w
ere
34
, 16
, 6,
18
, a
nd
1
rea
ctio
ns
of
1, 2
, 3,
4,
a
nd
6
resp
ec
tive
ly,
an
d
19,
5,
1, a
nd
1
rea
ctio
ns
of
1, 2
, 3,
an
d 4
, re
spe
ctiv
ely
, a
t th
e v
irgin
sit
e.
Slig
ht
irrita
tion
re
sulte
d
from
in
itia
l
ap
plic
atio
n
an
d i
nc
rea
ses
in
irrita
tion
we
re
ob
serv
ed
fo
llow
ing
re
pe
ate
d a
pp
li-
ca
tion.
Se
vera
l m
od
era
tely
st
rong
re
ac
tions
we
re
ob
serv
ed
w
he
n
ch
alle
ng
e
site
s w
ere
sco
red
a
t 48
ho
urs
but
in
all
ca
ses,
th
ere
wa
s m
ark
ed
re
miss
ion
o
f re
ac
tion
seve
rity
wh
en
sc
ore
d
at
96
hour
s.
“Pro
ba
bly
sk
in
fatig
ue.”
Am
ong
60
0 in
duc
tion
a
nd
12
0 c
ha
llen
ge
24
0
rea
din
gs,
th
ere
w
ere
no
re
ac
tions
. “S
hort
-
live
d
ac
ute
irr
itatio
n,
no s
ens
itiza
tion.
”
Am
ong
60
0 in
duc
tion
re
ad
ing
s th
ere
w
ere
24
0
5 (1
+)
(mild
e
ryth
em
a)
rea
ctio
ns.
The
re
we
re
no c
ha
llen
ge
re
ac
tions
. “S
ho
rt-li
ved
ac
ute
irri
tatio
n,
no s
ens
itiza
tion.
”
Am
ong
60
0 in
duc
tion
re
ad
ing
s th
ere
w
ere
24
0
5 (1
+)
rea
ctio
ns.
The
re
we
re
no c
ha
llen
ge
rea
ctio
ns.
“Sh
ort
-live
d
ac
ute
irri
tatio
n,
no
sens
itiza
tion.
”
Am
ong
60
0 in
duc
tion
re
ad
ing
s,
the
re
we
re
240
3 (1
+)
rea
ctio
ns.
The
re
we
re
no c
ha
llen
ge
rea
ctio
ns.
“Sh
ort
-live
d
ac
ute
irri
tatio
n,
no
sens
itiza
tion.
”
Am
ong
60
0 in
duc
tion
re
ad
ing
s,
the
re
wa
s 24
0
1 (1
+)
rea
ctio
n.
The
re
we
re
no c
ha
llen
ge
rea
ctio
ns.
“Sh
ort
-live
d
ac
ute
irri
tatio
n,
no
sens
itiza
tion.
”
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 22
3
Sha
vin
g
cre
am
(TEA
, 2.
3%)
Suns
cre
en
pro
duc
t
(TEA
, 0.
45%
)
Suns
cre
en
pro
duc
t
(TEA
, 0.
45%
)
Suns
cre
en
pro
duc
t
(TEA
, 0.
45%
)
Sha
vin
g
cre
am
(TEA
, 2.
4%)
Sha
vin
g
cre
am
(TEA
, 2.
1 %
)
100%
1 OO
%,
-0.2
g
1 O
O%
,
-0.2
g
lOO
%,
-0.2
g
10
24-h
our
o
cc
lusiv
e
pa
tch
ap
plic
atio
ns
with
24
- to
48-
hour
re
st
pe
riod
s in
be
twe
en
. Si
tes
sco
red
ju
st
prio
r to
ne
xt
pa
tch
ap
plic
atio
n.
An
1 l-
to
1 S-
da
y re
st
follo
we
d
by
a 2
4-ho
ur
ch
alle
ng
e
pa
tch
on
a v
irgin
sit
e.
Site
s sc
ore
d
at
24
an
d
48
hour
s a
fte
r a
pp
lica
tion
, Sc
ore
d
on
a
sca
le o
f O
-4.
Fore
arm
s w
ere
ta
pe
-str
ipp
ed
to
re
mo
ve
co
rnifi
ed
e
pith
eliu
m.
24-h
our
o
cc
lusiv
e
pa
tch
ap
plic
atio
ns
to
bo
th
arm
s,
pa
tche
s
rem
ove
d,
site
s sc
ore
d,
an
d o
ne
site
sub
jec
ted
to
15
m
inut
es
of
UV
lig
ht
(-
4,40
0 ~W
lcm
’ U
VA
) a
t a
dist
anc
e
of
10
cm
an
d r
est
ore
d.
Ad
diti
on
al
rea
din
gs
we
re
ma
de
48
an
d 9
6 ho
urs
aft
er
ap
plic
atio
n.
Sco
red
o
n a
sc
ale
of
O-4
.
10
24-h
our
o
cc
lusiv
e
pa
tch
+pp
lica
tion
s
to
bo
th
arm
s w
ith
24-
to M
I-ho
ur
rest
pe
riod
s in
b
etw
ee
n.
Site
s sc
ore
d
at
pa
tch
rem
ova
l a
nd
the
n irr
ad
iate
d
for
15
min
at
a d
ista
nce
o
f 10
c
m
(-4,
400
pW
/cm
*
UV
A)
an
d r
e-s
co
red
. A
n 1
l-. t
o
1 S-
da
y
rest
p
erio
d,
24-h
our
c
ha
llen
ge
s to
.virg
in
site
s,
pa
tche
s re
mo
ved
a
nd
site
ssc
ore
d,
irra
dia
ted
, sc
ore
d
ag
ain
an
d s
co
red
24
an
d 4
8 ho
urs
late
r. Sc
ore
d
on
a s
ca
le o
f
o-4
.
lOO
%,
-0.1
ml/
cm
2 10
48
- to
72
-ho
ur
no
no
cc
lusiv
e
ind
uctio
n
r p
atc
h a
oo
lica
tion
s.
Site
s sc
ore
d
at
pa
tch
. . 1
rem
ova
l. 10
th
pa
tch
also
sc
ore
d
24
hour
s
late
r, 1
l-da
y re
st
pe
riod
, fo
llow
ed
b
y a
48-h
our
c
ha
llen
ge
p
atc
h to
a v
irgin
sit
e.
Ch
alle
ng
e
site
sc
ore
d
at
pa
tch
rem
ova
l
an
d 2
4 ho
urs
late
r.
lOO
%,
-0.1
ml/
cm
’
60
52
10
26
100
100
Am
ong
60
0 in
duc
tion
re
ad
ing
s th
ere
w
ere
24
0
2 (1
+)
rea
ctio
ns.
The
re
we
re
no c
ha
llen
ge
rea
ctio
ns.
“Sh
ort
-live
d
ac
ute
irri
tatio
n,
no
sens
itiza
tion.
”
Am
ong
52
0 in
duc
tion
re
ad
ing
s,
the
re
we
re
7 &
(m
inim
al
ery
the
ma
) sc
ore
s.
Am
ong
104
ch
alle
ng
e
rea
din
gs,
th
ere
w
ere
2
*
sco
res.
“N
o
irrita
tion
o
r se
nsiti
zatio
n.”
241
The
re
wa
s 1
f re
ac
tion
at
24
hour
s a
nd
24
1
1 *
rea
ctio
n a
t a
noth
er
site
a
fte
r irr
ad
iatio
n
at
24
hour
s.
“No
p
hoto
toxi
c
resp
ons
e.”
Am
ong
26
0 in
duc
tion
re
ad
ing
s o
f th
e
no
n-
241
irra
dia
ted
sit
e,
the
re
we
re
5 *
sco
res.
Am
ong
78
c
ha
llen
ge
re
ad
ing
s,
the
re
we
re
3 *
sco
res.
A
mo
ng
520
ind
uctio
n
rea
din
gs
of
the
irr
ad
iate
d
site
th
ere
w
ere
5
* sc
ure
s
be
fore
a
nd
5 l
sco
res
aft
er
irra
dia
tion
.
Am
ong
10
4 c
ha
llen
ge
re
ad
ing
s,
the
re
we
re
2 +
Z sc
ore
s.
“No
p
ho
toa
llerg
ic
resp
ons
e.”
Am
ong
11
00
ind
uctio
n
rea
din
gs,
th
ere
w
ere
24
2
2 (d
oub
tful
re
ac
tion,
ve
ry
mild
e
ryth
em
a,
ba
rely
e
xce
ed
ing
th
at
of
the
un
tre
ate
d
skin
) re
ac
tions
. Th
ere
w
ere
no
ch
alle
ng
e
rea
ctio
ns.
“No
irr
itatio
n
or
sens
itiza
tion.
”
Am
ong
11
00
ind
uctio
n
an
d 2
00
ch
alle
ng
e
242
rea
din
gs,
th
ere
w
ere
no
re
ac
tions
. “N
o
irrita
tion
o
r se
nsiti
zatio
n.”
w
W
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 22
4
TAB
LE
9.
(Co
ntin
ued
.)
Ma
teria
l te
ste
d
Co
nce
ntra
tion
an
d d
ose
M
eth
od
N
umb
er
of
sub
jec
ts
Resu
lts
Ref.
Dye
less
Ba
se
Form
u-
latio
n
(DEA
, 2%
),
no
n-c
om
me
rcia
l
pro
duc
t
Sha
ve
ge
l lO
O%
, -0
.1
(DEA
, 2.
7%)
ml/
cm
*
Dye
less
Ba
se
Form
u-
latio
n
(MEA
,
11.4
7%),
n
on
-
co
mm
erc
ial
pro
duc
t
Ha
ir p
rep
ara
tion
(DEA
, 1.
6%;
MEA
, 5.
9%;
sod
ium
b
ora
te,
3.2%
)
Ha
ir p
rep
ara
tion
(DEA
, 1.
6%;
MEA
, 5.
9%;
sod
ium
b
ora
te,
3.2%
)
0.3
ml,
10%
in
dist
ille
d
wa
ter
0.3
ml,
5%
in
25%
a
lco
ho
l
-0.2
m
l,
100%
0.3
ml,
100%
24-h
our
se
mio
cc
clu
sive
p
atc
hes
ap
plie
d
to
up
pe
r a
rm
3 tim
es
a w
ee
k fo
r 3
we
eks
.
Sco
red
24
to
48
hour
s a
fte
r p
atc
h
rem
ova
l. C
ha
llen
ge
p
atc
hes
on
the
sa
me
site
a
nd
a v
irgin
sit
e
aft
er
15 t
o
17
da
ys.
Ch
alle
ng
es
sco
red
a
t 24
a
nd
72
hour
s
aft
er
pa
tch
rem
ova
l o
n a
sc
ale
of
0 to
5.
10
48-
to
72-h
our
n
on
oc
clu
sive
in
duc
tion
pa
tch
ap
plic
atio
ns.
Si
tes
sco
red
a
t p
atc
h
rem
ova
l. 10
th
pa
tch
also
sc
ore
d
24
hour
s
late
r, 1
l-da
y re
st
pe
riod
, fo
llow
ed
b
y a
48-h
our
c
ha
llen
ge
p
atc
h to
a v
irgin
sit
e.
Ch
alle
ng
e
site
sc
ore
d
at
pa
tch
rem
ova
l
an
d 2
4 ho
urs
late
r.
165
100
24-h
our
se
mio
cc
lusiv
e
pa
tche
s a
pp
lied
to
16
5
up
pe
r a
rm
3 tim
es
a w
ee
k fo
r 3
we
eks
.
Sco
red
24
to
48
hour
s a
fte
r p
atc
h
rem
ova
l. C
ha
llen
ge
p
atc
hes
on
the
sa
me
site
a
nd
a v
irgin
sit
e
aft
er
15 t
o
17
da
ys.
Ch
alle
ng
es
sco
red
a
t 24
a
nd
72
hour
s
aft
er
pa
tch
rem
ova
l o
n a
sc
ale
of
0 to
5.
23-h
our
p
atc
hes
ap
plie
d
to t
he
ba
ck
eve
ry
12
fem
ale
da
y fo
r 21
d
ays
. Re
ac
tions
w
ere
sc
ore
d
da
ily
on
a s
ca
le o
f 0
to
7.
48-h
our
o
cc
lud
ed
p
atc
h o
n th
e
fore
arm
;
5 48
-ho
ur
oc
clu
de
d
ind
uctio
n
pa
tche
s,
a
lo-d
ay
rest
, th
en
a 4
8-ho
ur
oc
clu
de
d
ch
alle
ng
e
pa
tch.
Re
ac
tions
sc
ore
d
at
pa
tch
rem
ova
l a
nd
24
hour
s la
ter
on
a
sca
le o
f 0
to
3.
25
No
re
ac
tions
o
bse
rve
d.
“No
c
ont
ac
t
sens
itiza
tion.
”
Am
ong
11
00
ind
uctio
n
rea
din
gs,
th
ere
w
ere
2 (d
oub
tful
re
ac
tion,
ve
ry
mild
e
ryth
em
a,
ba
rely
e
xce
ed
ing
th
at
of
the
un
tre
ate
d
skin
) re
ac
tions
. Th
ere
w
ere
no
ch
alle
ng
e
rea
ctio
ns.
“No
irr
itatio
n
or
sens
itiza
tion.
”
19,
1,
1, a
nd
1
sco
res
of
mild
e
ryth
em
a
(l),
de
finite
p
ap
ula
r re
spo
nse
(2
),
de
finite
ed
em
a (
3),
an
d d
efin
ite
ed
em
a a
nd
pa
pu
les
(4),
re
spe
ctiv
ely
, d
urin
g
ind
uctio
n.
No
re
ac
tions
o
bse
rve
d
at
ch
alle
ng
e.
“No
co
nta
ct
sens
itiza
tion.
” (Ir
rita
ting
)
4,3,
a
nd
225
sc
ore
s o
f m
inim
al
ery
the
ma
,
ba
rely
p
erc
ep
tible
(l)
, d
efin
ite
ery
the
ma
,
rea
dily
vi
sib
le
(2),
e
ryth
em
a
an
d p
ap
ule
s
(3).
“Ex
pe
rime
nta
l c
um
ula
tive
irr
itant
.”
Test
m
ate
rial
wa
s irr
itatin
g
dur
ing
a
pre
-te
st.
No
re
ac
tions
o
bse
rve
d
dur
ing
th
e
ind
uc
-
tion
an
d c
ha
llen
ge
p
roc
ed
ure
s.
“No
co
nta
ct
sens
itiza
tion.
”
243
242
243
244
245
aC
onc
Iusio
ns
of
the
re
sea
rche
rs
are
in
quo
tatio
ns.
Inte
rpre
tatio
ns
of
the
Ex
pe
rt
Pan
el
are
in
pa
rent
hese
s.
Dis
tribu
ted
for C
omm
ent O
nly
-- D
o N
ot C
ite o
r Quo
te
CIR
Pan
el B
ook
Pag
e 22
5
ASSESSMENT: TEA, DEA, AND MEA 225
An eight-year-old female developed a nasal allergic reaction to a detergent containing TEA. The prick test was positive for 10-'-l Om4 M TEA and not for any of the other ingredients in the product. Sneezing was relieved after removal of the detergent from the clothes by extensive washing and recurred upon re-exposure.(206’
Potential hazards from inhalation of TEA and DEA are probably minimized by their low vapor pressures.(“)
Occupational Exposure
Information on vascular, neurologic, and hepatic disorders and respiratory and skin allergies of people who come in contact with the ethanolamines in their work environment can be found in the literature.(207-2’3)
SUMMARY
TEA, DEA, and MEA are amino alcohols and as such, are chemically bifunc- tional, combining the properties of alcohols and amines. The pHs of 0.1 N aqueous solutions of TEA, DEA, and MEA are 10.5, 11 .O, and 12.05, respectively. Ethanolamine soaps and ethanolamides are used in cosmetic formulations as emulsifiers, thickeners, wetting agents, detergents, and alkalizing agents. In 1981, TEA, DEA, and MEA were reported to be ingredients of 2757, 18, and 51 cosmetic products, respectively. Most products contained TEA, DEA, and MEA in concentrations less than or equal to 5%. The nitrosation of the ethanolamines may result in the formation of N-nitrosodiethanolamine (NDELA) which is car- cinogenic in laboratory animals. Traces of NDELA (below 5 ppm) have been found in a variety of cosmetic products.
The LD50 values for rats of TEA, DEA, and MEA ranged from 4.19 g/kg to 11.26 g/kg, 0.71 ml/kg to 2.83 g/kg, and 1.72 g/kg to 2.74 g/kg, respectively. In single-dose oral toxicity for rats, TEA is practically nontoxic to slightly toxic, and DEA and MEA are slightly toxic. Long-term oral ingestion of the ethanolamines by rats and guinea pigs produced lesions limited mainly to the liver and kidney. Long-term cutaneous applications to animals of the ethanolamines also produced evidence of hepatic and renal damage. TEA and DEA showed little potential for rabbit skin irritation in acute and subchronic skin irritation tests. MEA was cor- rosive to rabbit skin at a 30% concentration in a single semioccluded patch ap- plication and at a greater than 10% concentration in 10 open applications over a period of 14 days. A lotion containing 1% TEA was not phototoxic to guinea pigs, and TEA was not a guinea pig skin sensitizer. With long contact time TEA, DEA, and MEA are irritating to the rabbit eye at concentrations of loo%, 50%, and 5%,
respectively. The ethanolamines have been shown to be nonmutagenic in the Ames test
and TEA is also nonmutagenic to Bacillus subtilis. TEA did not cause DNA- damage inducible repair in an unscheduled DNA synthesis test.
TEA had no carcinogenic or cocarcinogenic activity when dermally applied to mice for 18 months. There was a higher incidence of malignant lymphoid tumors in female mice fed diets containing TEA for their whole lifespan than in male mice on the same diet or in control mice.
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 226
226 COSMETIC INGREDIENT REVIEW
Clinical skin testing of TEA and cosmetic products containing TEA and DEA showed mild skin irritation in concentrations above 5%. There was very little skin sensitization. There was no phototoxicity and photosensitization reactions with products containing up to 20.04% TEA. A dyeless base formulation containing 11.47% MEA and a hair preparation containing 1.6% DEA and 5.9% MEA were irritating to human skin in patch tests.
COMMENTS
In the presence of N-nitrosating agents, TEA and DEA may give rise to N-nitro- sodiethanolamine, a known animal carcinogen.
TEA and DEA are mild skin and eye irritants and irritation increases with in- creasing ingredient concentration.
Animal studies with MEA indicate that it is both a skin and eye irritant and clinical studies with formulations containing MEA indicate that it is a human skin irritant. The longer MEA stays in contact with the skin the greater the likelihood of irritation. MEA is primarily used in rinse-off hair products.
CONCLUSION
The Panel concludes that TEA, DEA, and MEA are safe for use in cosmetic for- mulations 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 ethanolamines should not exceed 5%. MEA should be used only in rinse-off products. TEA and DEA should not be used in products containing N-nitrosating agents.
ACKNOWLEDGMENT
Ms. Karen Brandt, Scientific Analyst and writer, prepared the literature review and technical analysis used by the Expert Panel in developing this report.
REFERENCES
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CTFA. (2-S-19). Cosmetic Ingredient Chemical Description on Triethanolamine.*
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Diethanolamine.*
3. CTFA. (May 6, 1981). Submission of data by CTFA. (2-s-17). Cosmetic Ingredient Chemical Description on
Ethanolamine.*
4. GREENBERG, L.A. and LESTER, D. (1954). Handbook of Cosmetic Materials. New York, NY: Interscience
Publishers.
*Available on request: Administrator, Cosmetic Ingredient Review, 1110 Vermont Ave., N.W., Suite 810,
Washington, DC 20005.
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 227
ASSESSMENT: TEA, DEA, AND MEA 227
2. HAWLEY, G.G. (ed.). (1971). The Condensed Chemical Dictionary, 8th ed. USA: Van Nostrand Reinhold
co.
y 6. KAMALYAN, G.V. and ARAKSYAN, S.M. (1956). Effect of di- and triethanolamine on the autoxidation of
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+. EPSTEIN, S.S., SAPOROSCHETZ, E.B., and HUTNER, S.H. (1967). Toxicity of antioxidants to Tetrahymena
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- monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine.’
&ll. LIJINSKY, W., KEEFER, L., CONRAD, E., and VAN DE BOGART, R. (1972). Nitrosation of tertiary amines
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+4. KABACOFF, B.L., LECHNIR, R.J., VIELHUBER, S.F. and DOUGLASS, M.L. (1981). Formation and inhibi- tion of N-nitrosodiethanolamine in an anionic oil-water emulsion. Am. Chem. SOC. Symp. Ser. 174,
149-l 56.
l/i5. WAKELIN, J. (1938). Chemical notes on the ethanolamines. Textile Colorist 60, 373-5. -l6. JAPAN COSMETIC INDUSTRY ASSOCIATION (JCIA). (1967). (Translated in 1979). /apanese Standards of
Cosmetic Ingredients. Tokyo, Japan: Yakuji Nippo, Ltd.
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Fragrance Association.
vc18. LEKHAN, A.S., SOLONSKAYA, N.T., EREMINIA, Z.I., and SALO, D.P. (1972). Methods for controlling tri-
ethanolaminobentonite and boric acid ointment, prepared from a triethanolaminobentonite-based water-
soluble emulsion. Farm. Zh. (Kiev) 27, 61-5.
L/ 19. TAWA, R. and HIROSE, S. (1979). Indirect microdetermination of primary and secondary amines by cop-
per (I&catalyzed oxidation of pyrocatechol violet. Chem. Pharm. Bull. 27, 2515-7.
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macopeial Convention, Inc.
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Konf. Khim.-Anal. Pribalt. Resp. 6. SSR, (Tezisy Dokl.), 1st. 125-8.
-22. BESADA, A., and GAWARGIOUS, Y.A. (1974). lodometric submicrodetermination of 2-amino alcohols by
an amplification method. Talanta 21, 1247-52.
-23. DOW CHEMICAL COMPANY. (May 10, 1977). Submission of data by CTFA. (2-5-19). Analytical Method
No. 87719a: Triethanolamine 85.’
---24. DOW CHEMICAL COMPANY. (May 10, 1977). Submission of data by CTFA. (2-5-18). Analytical Method
No. 2llOOa: Diethanolamine.’ -_ 25. DOW CHEMICAL COMPANY. (Jan. 23, 1979). Submission of data by CTFA. (2-5-17). Analytical Method
No. 55894a: Monoethanolamine.*
- 26. ESTRIN, N.F. (ed.). (1971). CTFA Standards: Methods. Washington, DC: Cosmetic, Toiletry and Fragrance
Association.
-27. NATIONAL FORMULARY BOARD. (1975). The National Formulary, 14th ed. Washington, DC: American
Pharmaceutical Association.
i/is. NEUMANN, F.W. (1970). Improved accuracy and precision for assay of triethanolamine. Cosmet. J. 2,
57-64.
9. LITEANU, C. and NASCU, H. (1974). Optimization of separations by thin-layer chromatography on silica
gel. I. Separation of some ethanolamines in several polycomponent solvent systems. Rev. Roum. Chim.
19,1941-7.
&O. PETRONIO, B.M. and RUSSO, M.V. (1980). Separation of aliphatic and aromatic amines by thin-layer
chromatography using silica gel plates. Chromatographia 13, 623-5.
1/ 31. RAPAPORT, L.I., KOFMAN, S.H., and GORTSEVA, L.V. (1976). Determination of microquantities of
mono-, di- and triethanolamines by thin-layer chromatography. Gig. Sanit. 59-61.
L/32. STARILOVA, S.V., NEMTSEV, V.A., and DEDKOV, Y.M. (1980). Thin-layer chromatographic determina-
tion of diamines and ethanolamines. Khim. Prom-St., Ser.: Metody. Anal. Kontrolya Kach. Prod. Khim.
Prom-sti. 3, 15-7.
fl JONES, J.H., NEWBURGER, S.H., CHAMPION, M.H., KOTTEMANN, C.M., and GROSS F.C. (1968). Gas
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 228
228 COSMETIC INGREDIENT REVIEW
chromatography in cosmetic analysis: a progress report. Proc. Joint Conf. Cosmet. Sci. 75-89. Toilet
Goods Assoc., Inc., Washington, DC.
1/ 34. LANGVARDT, P.W. and MELCHER, R.C. (1980). Determination of ethanol- and isopropanolamines in air
at parts-per-billion levels. Anal. Chem. 52, 669-71.
~35. O’CONNELL, A.W. (1977). Analysis of coconut oil-diethanolamine condensates by gas chromatography.
Anal. Chem. 49, 835-8.
36 I/ ‘.
PIEKOS, R., KOBYLCZYK, K., and CRZYBOWSKI, J. (1975). Quantitative gas chromatographic determina-
tron of ethanolamines as trimethylsilyl derivatives. Anal. Chem. 47, 1157-g.
37. RAMSEY, I.D., LEE, T.D., OSSELTON, M.D., and MOFFAT, A.C. (1980). Gas-liquid chromatographic
retention indexes of 296 nondrug substances on SE-30 or OV-1 likely to be encountered in toxicological
analyses. j. Chromatogr. 184, 185-206.
~38. SAHA, H.C., JAIN, S.K., and DUA, R.K. (1977). A rapid and powerful method for the direct gas
chromatographic analysis of alkanolamines: application to ethanolamines. Chromatographia 10, 368-71.
39. SENZEL, A.J. (1977). Newburger’s Manual of Cosmetic Analysis, 2nd ed. Washington, DC: Assoc. of Of-
ficial Analytical Chemists.
y40. LORANT, B. (1977). Thermogravimetric determination of basic and intermediary substances in cosmetics.
Seifen. Oele. Fette. Wachse. 103, 393-6.
- 41. ESTRIN, N.F. (ed.). (1974). CTFA Standards: Methods. Washington, DC: Cosmetic, Toiletry and Fragrance
Association.
-42. ESTRIN, N.F. (ed.). (1971). CTFA Standards: Spectra. Washington, DC: Cosmetic, Toiletry and Fragrance
Association.
- 43. WEAST, R.C. (ed.). (1978). CRC Handbook of Chemistry and Physics, 5th ed. West Palm Beach, FL: CRC
Press.
44. CTFA. (May 17, 1982). Submission of data by CTFA. UV absorbance data for TEA and MEA.*
/45. MARTIN, C.W. (1974). Alkanolamines in skin lotions. Cosmet. Perfum. 89, 29-31.
- 46. CIR. (1982). Final Report on the safety assessment of TEA-lauryl sulfate. J. Am. College Toxicol. 1,
143-67.’
-47. CIR. (1983). Tentative report on the safety assessment of potassium-coca-hydrolyzed animal protein and
TEA-coca-hydrolyzed animal protein.*
h-48. FOOD AND DRUG ADMINISTRATION (FDA). (1981). Cosmetic product formulation data. Ingredients
J.
used in each product category. Computer printout. Washington, DC. ,
49 CTFA (Apnl 15, 1982). Final report on Midwest Research Institute program for development of analytical
methods for NDELA using HPLC-TEA, determination of “Nitrites,” determination of NDELA by a non-TEA
method.*
~50. FAN, T.Y., GOFF, U., SONG, L., FINE, D.H., ARSENAULT, G.P., and BIEMANN, K. (1977). N-Nitro-
sodiethanolamine in cosmetics, lotions and shampoos. Food Cosmet. Toxicol. 15, 423-30.
- 51. FDA. (June 30, 1978). Division of Cosmetics Technology, Food and Drug Administration Progress Report
on the Analysis of Cosmetic Products and Raw Materials for N-Nitrosodiethanolamine. Washington, DC.
&2. FDA. (Sept. 30, 1978). Division of Cosmetics Technology, Food and Drug Administration Progress Repon
on the Analysis of Cosmetic Products and Raw Materials for N-Nitrosodiethanolamine. Washington, DC.
-. 53. FDA. (March 31, 1980). Division of Cosmetics Technology, Food and Drug Administration Progress
Report on the Analysis of Cosmetic Products and Raw Materials for N-Nitrosodiethanolamine.
Washington, DC.
-‘- 54. FDA. (June 30, 1980). Division of Cosmetics Technology, Food and Drug Administration Progress Report
on the Analysis of Cosmetic Products and Raw Materials for N-Nitrosodiethanolamine. Washington, DC.
~55. HO, J.L., WISNESKI, H.H., and YATES, R.L. (1981). High pressure liquid chromatographic-thermal energy
determination of N-nitrosodiethanolamine in cosmetics. J. Assoc. Off, Anal. Chem. 64, 800-4.
/ 56. KLEIN, D., GIRARD, A.-M., DE SMEDT, J., FELLION, Y., and DEBRY, G. (1981). Analyse de la
J.
nitrosodiethanolamine dam les produits de l’industrie cosmetique. Food Cosmet. Toxicol. 19, 233-5.
57 MIZUISHI, K., TAKEUCHI, M., YOSHIHARA, T., and HARADA, H. (1981). Determination of N-nitro-
sodiethanolamine in shampoos and creams. Tokyo-toritsu Eisei Kenkyusho Kenkyu Nempo 32-1, 104-6.
/58. ROLLMANN, B., LOMBART, P., RONDELET, J., and MERCIER, M. (1981). Determination of N-nitroso- diethanolamine in cosmetics by gas chromatography with electron capture detection. J. Chromatogr. 206,
J .
158-83.
59 TELLING, GM. and DUNNETT, PC. (1981). The determination of N-nitrosodiethanolamine (NDELA) at trace levels in shampoos and skin creams by a simple, rapid calorimetric method. Int. J. Cosmet. Sci. 3,
241-8.
/ 60. TUNICK, M., VEALE, H.S., and HARRINGTON, G.W. (1982). Qualitative determination of N-nitro-
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 229
ASSESSMENT: TEA, DEA, AND MEA 229
L, 61.
lp2,
ti3.
~ 64.
65.
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/--
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_ 188. CTFA. (March 22, 1976). Submission of data by CTFA. (2-S-61). CIR safety data test summary, primate eye
test of shampoo containing 12.6 percent triethanolamine.’
yl89. KASSEM, A.A., ABD EL-BARY, A., ABDEL AZIZ, M.T., and NOUR, S.A. (1976). Evaluation of certain sper-
micidal formulations. Bull. Fat. Pharm., Cairo Univ. 14, 155-67.
t/l90. WEEKS, M.H., DOWNING, T.O., MUSSELMAN, N.P., CARSON, T.R., and GROFF, W.A. (1960). The ef-
fects of continuous exposure of animals to ethanolamine vapor. Am. Indus. Hyg. Assoc. J. 21, 374-81,
bl91. LUKEVICS, E., GUTBERGA, S., LIBERTS, L., KIMENIS, A., and VORONKOV, M.G. (1969). Structure-
activity relations for aminoalkoxysilanes. Latv. Psr Zinat. Akad. Vestis 8, 60-3.
&l-92. BLUM K., HUIZENGA, C.G., RYBACK, R.S., JOHNSON, D.K., and GELLER, I. (1972). Toxicity of
diethanolamine in mice. Toxicol. Appl. Pharmacol. 22, 175-85.
-193. DRAIZE, J.H., WOODWARD, G., and CALVERY, H.O. (1944). Methods for the study of irritation and tox-
icity of substances applied topically to the skin and mucous membranes. J. Pharmacol. Exp. Ther. 82,
377-90.
w. STILLMEADOW. (Feb. 28, 1980). Submission of data by CTFA. (2-5-4). Project No. 1558-80, Rabbit eye ir-
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 234
COSMETIC INGREDIENT REVIEW
ritation, solutioh NML-2-30B.* /ig5. FOSTER, Jr., G.L. (1971). Acute and subacute toxicologic responses to tiiethanolamine in the rat. Dlss.
J’
Abstr. Int. B 1972, 32, 6549.
196. NISHIJIMA, T. (1970). Pharmacological studies of monoethanolamine. Showa lgakkai Zasshi 30, 687-94.
-197. AMES, B.N., MCCANN, J., and YAMASAKI, E. (1975). Methods for detecting carcinogens and mutagens with the Salmonella/mammalian-microsome mut@enicity test. Mutat. Res. 31, 347-64.
498. CTFA. (1980). Submission of data by CTFA. (2-5-30). CIR safety data test summary, Ames t&t with
triethanolamine.’ _ 199. NATIONAL TOXICOLOGY PROGRAM (NTP). (Dec. 1980). Annual Plan for Fiscal Year 1981.
(NTP-80-62).
v-200. HEDENSTEDT, A. (1#‘8). Mutagenicity screening of industrial chemicals: seven aliphatic amines and one
amide tested in the Sd/fnonella/microsomal assay. Mutat. Res. 53, 198-9.
&--201. HOSHINO, H. and TANOOKA, H. (1978). Carcinogenicity of triethanolamifie in mice and its mutagen-
icity after reaction with sodium nitrite in bacteria. Cancer Res. 38, 3918-21,
-702. CTFA. (1979). Subniission of data by CTFA. (2-5-31). CIR safety data test summary unscheduled DNA syn-
thesis with triethanolamine.*
203. SCHWARTZ, L. and PECK, S.M. (1944). The patch test in contact dermatitis. Public Health Report 59,
546-57.
204. KLIGMAN, A.M. (1978). Cutaheous toxicology: an oVerrle\vfrom the underside. Curr. Probl. Dermatol. 7,
l-25. t
p205. KABE, J. (1971). Bronchial asthma and asthma-like dysptiea caused by inhalation of simple chemicals.
Japn. J. Allergol. 20, 444-50.
b 206. HERMAN, J.J. (1982), Intractable sneezing due to IgE mediated triethanolamine sensitivity. J. Allergy Clin.
Immunol. 69, 158.
~207. MADORSKII, V.A. and VORONIN, A.K. (1968). Vascular and neurologic changes in people working with
cooling liquids containing sodium nitrite and triethanolamine. Kazan. Med. Zh. 1, 79-8. /208. PAUSTOVSKAYA, V.V., KRASNYUK, E.P., ONIKIENKO, F.A., and VASILYUK, L.M. (1977). Effect ofwork-
ing conditions on the health of people working with inhibitors of the atmospheric corrosion of metal.
Vrach. Delo 4, 121-4.
1/ 209. SELISSKII, G.D., OBUKHOVA, A.S., ANTON’EV, A., SOMOV, B.A., SHAPARENKO, M.V., and
ALCHANGYAN, L.V. (1978). Prophylaxis of occupational dermatoses caused by inhibitors of atmospheric
metal corrosion. Vestn. Dermatol. Venerol. 9, 36-9. (/ 210. SIDORENKO, E.N., BUSLENKO, A.I., BAIDA, N.A., KOtlNtSEVA, P.V., IVANOVA, S.I., DIACHENKO,
E.I., MUKHTAROVA, N.D., and TITENKOV, I.K. (1980). Allergic diseases in workers of rubber produc-
tion. Vrach. Delo 12, 14-6.
V- 211. SIDOROV, K.K. and TIMOFEEVSKAYA, L.A. (1979). Data for substantiation of the maximum possible con-
centrationof monoethanolamine in the working environment. Gig. Tr. Prof. Zabol. 9, 55.
/ 212. TSYRKUNOV, L.P. (1975). Skin diseases in workers contacting with inhibitors of the atmospheric corro-
sion’of metals. Vestn. Dermatol. Venerol. 3, 62-5.
L/ 213. VENEDIKTOVA, K.P., ANTON’EV, A.A., and TUMARKIN, B.M. (1977). Occupational dermatitis and
eczema of finishing-shop textile workers and problems of prophylaxis. Zdravookhr Kaz. 1, 28-31,
A14. CTFA. (May 16, 1974). Submission of data by CTFA. (2-5-56). Human sensitization tests oftriethanolamine
(7406-4) .*
715. NORTH AMERICAN CONTACT DERMATITIS GROUP (NACDG). (Dec. 4, 1980). Standard screening tray
1979 vs. 1980. Summary.
)R16. CALAS, E., CASTELAIN, P.Y., and PIRIOU, A. (1978). Epidemiology of contact dermatitis in Marseilles.
Ann. Dermatol. Venereol. 105, 345-7.
Y 217. FISHER, A.A., PASCHER, F., and KANOF, N.B. (1971). Allergic contact dermatitis due to ingredients of vehicles. A “vehicle tray for patch testing. Arch. Dermatol. 104, 286-90.
w.218. FROSCH, P.J. and KLIGMAN, A.M. (1976). The chamber-scarification test for irritancy. Contact Dermatitis 2, 314-24.
v 219. SUURMOND, D. (1966). Patch test reactions to phenergan cream, promethazine and tri-ethanolamine.
Dermatologica 133, 503-6.
220. WILKINSON, D;>., FREGERT, S., MAGNUSSON, B., BANDMANN, H.J., CALNAN, C.D., CRONIN, E.,
HJORTH, N., MAlBACH, H.J., MALTEN, K.E., MENEGHlNl, C.L., and PIRILA, V. (1970). Terminology of contact dermatitis. Acta Dermatov. 50, 287-92.
221. SHELANSKI, H.A. and SHELANSKI, M.V. (1953). A new technique of human patch tests, Proc. Sci. Sect.
Toil. Goods Assoc. 19, 46-9.
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CIR Panel Book Page 235
ASSESSMENT: TEA, DEA, AND MEA 235
- 222. CTFA. (1977). Submission of data by CTFA. (2-S-9). CIR safety data test summary, human patch test of
shaving preparation containing triethanolamine.*
---223. CTFA. (1978). Submission of data by CTFA. (2-5-10). CIR safety data test summary,human patch test of
shaving preparation containing triethanolamine.’
-224. CTFA. (July 1978). Submission of data by CTFA. (2-S-12). CIR safety data test summary, human patch test
of a shave cream containing triethanolamine.*
-225. CTFA. (July 1978). Submission of data by CTFA. (2-5-14). CIR safety data test summary, human patch test
of a shave cream containing triethanolamine.*
-226. CTFA. (Sept. 1974). Submission of data by CTFA. (2-5-13). CIR safety data test summary, human patch test
of a shave cream containing triethanolamine.*
327. FOOD AND DRUG RESEARCH LABORATORIES (FDRL). (Oct. 27, 1976). Submission of data by CTFA.
(2-5-2). Final Report, Clinical safety evaluation of a group of products.*
- 228. IVY RESEARCH LABORATORIES (IRL). (Sept. 15, 1976). Submission of data by CTFA. (2-5-l). Report on
appraisal of sensitizing potential of four products by maximization testing, Ivy Prot. No. 3368.*
----229. IRL. (Oct. 18, 1976). Submission of data by CTFA. (2-5-3). Report on appraisal of sensitizing potential of
four products by maximization testing, protocol No. 3379.’
,230. CTFA. (Oct. 8, 1976). Submission of data by CTFA. (2-s-16). CIR safety data test summary, human patch
test of a suntan lotion containing triethanolamine.*
-231. CTFA. (January 28 to March 21, 1980). Submission of data by CTFA. CIR safety data test summary, human
patch test of mascara containing TEA.*
-232. CTFA. (Sept. 17, 1979). Submission of data by CTFA. CIR safety data test summary, human patch test of
mascara containing TEA.*
a33. FDRL. (Dec. 2, 1981). Submission of data by CTFA. Final Report, Clinical safety evaluation of sample:
854-90A R-2.*
-234. FDRL. (Dec. 2, 1981). Submission of data by CTFA. Final Report, Clinical safety evaluation of sample:
859-72L R-l .*
=?Z35. FDRL. (Dec. 2, 1981). Submission of data by CTFA. Final Report, Clinical safety evaluation of sample:
85490A R-2.*
-236. FDRL. (Dec. 2, 1981). Submission of data by CTFA. Final Report, Clinical safety evaluation of sample:
859-72L R-l .*
~237. CTFA. (Jan. 11, 1971). Submission of data by CTFA. Sensitization studies on products containing
triethanolamine (TEA), products OM-02-N.’
w.238. HTR. (April 26, 1972). Submission of data by CTFA. Sensitization studies on products containing trietha-
nolamine (TEA), product A(1429-152 EHH-60) and B(1429-152 RR-302).*
.... 239. HTR. (Feb. 22, 1973). Submission of data by CTFA. Sensitization studies on products containing
triethanolamine (TEA), products A (EXL-2062, RH-757), B(SR-300, 2103E), and C(SR-347 1506-169).*
m.240. INSTITUTE FOR APPLIED PHARMACEUTICAL RESEARCH (IAPR). (March 27, 1975). Submission of data
by CTFA. Sensitization studies on products containing triethanolamine (TEA), products A (RH-836), B
(RH-757), C (SR-407), D (EHH-259), E (RLH-146) and F (ECH-190-l).*
e.,.241, FDRL. (July 31, 1981). Submission of data by CTFA. Sensitization studies on products containing
triethanolamine (TEA), sunscreen formulation SP 104-L-3-A.*
-242. CTFA. (Jan. 13, 1981). Submission of data by CTFA. Sensitization study on products containing
triethanolamine (TEA), products No. 76 and No. 78, and diethanolamine (DEA), product No. 80.’
~~~243. HTR. (July 7, 1981). Submission of data by CTFA. (2-5-63). Repeated insult patch test, 81-0242-74.’
I-‘-’ 244. HTR. (March 17, 1980). Submission of data by CTFA,, (2-5-8). The study of cumulative irritant properties of
a series of test materials, 8@0192r74.*
45. IRL. (March 31, 1980). Submission of data by CTFA. (2-5-7). The appraisal of the contact-sensitizing poten-
tial of four (4) materials by means of the maximization study, Ivy Research protocol: No. 4308/01.*
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 236
ETHANOLAMINE 1 05A - Hair Conditioner 13ETHANOLAMINE 1 05C - Hair Straighteners 750ETHANOLAMINE 6 05D - Permanent WavesETHANOLAMINE 2 05F - Shampoos (non-coloring)ETHANOLAMINE 1 05G - Tonics, Dressings, and Other Hair Grooming AidsETHANOLAMINE 1 05H - Wave SetsETHANOLAMINE 1 05I - Other Hair PreparationsETHANOLAMINE 710 06A - Hair Dyes and Colors (all types requiring caution statements and patch tests)ETHANOLAMINE 22 06B - Hair TintsETHANOLAMINE 1 06D - Hair Shampoos (coloring)ETHANOLAMINE 4 06F - Hair Lighteners with ColorETHANOLAMINE 6 06G - Hair Bleaches 1ETHANOLAMINE 7 06H - Other Hair Coloring Preparation 763ETHANOLAMINE 1 12A - Cleansing 764
ACETAMIDE MEA 1 03G - Other Eye Makeup Preparations 25ACETAMIDE MEA 40 05A - Hair Conditioner 121ACETAMIDE MEA 14 05B - Hair Spray (aerosol fixatives) 23ACETAMIDE MEA 2 05E - Rinses (non-coloring)ACETAMIDE MEA 32 05F - Shampoos (non-coloring)ACETAMIDE MEA 21 05G - Tonics, Dressings, and Other Hair Grooming AidsACETAMIDE MEA 2 05H - Wave SetsACETAMIDE MEA 10 05I - Other Hair PreparationsACETAMIDE MEA 1 06A - Hair Dyes and Colors (all types requiring caution statements and patch tests)ACETAMIDE MEA 1 08F - Nail Polish and Enamel RemoversACETAMIDE MEA 3 10A - Bath Soaps and DetergentsACETAMIDE MEA 9 10B - Deodorants (underarm)ACETAMIDE MEA 4 12A - CleansingACETAMIDE MEA 4 12D - Body and Hand (exc shave)ACETAMIDE MEA 2 12F - Moisturizing 64ACETAMIDE MEA 1 12G - Night 84ACETAMIDE MEA 1 12J - Other Skin Care Preps 148
COCAMIDE MEA 2 01A - Baby ShampoosCOCAMIDE MEA 2 01C - Other Baby Products 579COCAMIDE MEA 6 02A - Bath Oils, Tablets, and Salts 521COCAMIDE MEA 59 02B - Bubble BathsCOCAMIDE MEA 16 02D - Other Bath PreparationsCOCAMIDE MEA 2 04E - Other Fragrance PreparationCOCAMIDE MEA 7 05A - Hair Conditioner 367COCAMIDE MEA 1 05E - Rinses (non-coloring)COCAMIDE MEA 346 05F - Shampoos (non-coloring)COCAMIDE MEA 4 05G - Tonics, Dressings, and Other Hair Grooming AidsCOCAMIDE MEA 7 05I - Other Hair PreparationsCOCAMIDE MEA 167 06A - Hair Dyes and Colors (all types requiring caution statements and patch tests)COCAMIDE MEA 3 06D - Hair Shampoos (coloring) 173COCAMIDE MEA 2 06F - Hair Lighteners with ColorCOCAMIDE MEA 1 06G - Hair BleachesCOCAMIDE MEA 2 08G - Other Manicuring PreparationsCOCAMIDE MEA 223 10A - Bath Soaps and DetergentsCOCAMIDE MEA 1 10C - DouchesCOCAMIDE MEA 216 10E - Other Personal Cleanliness ProductsCOCAMIDE MEA 2 11E - Shaving CreamCOCAMIDE MEA 37 12A - CleansingCOCAMIDE MEA 6 12D - Body and Hand (exc shave) 33COCAMIDE MEA 3 12F - Moisturizing 1,008COCAMIDE MEA 6 12J - Other Skin Care Preps 81COCAMIDE MEA 1 13C - Other Suntan Preparations 1,122
COCAMIDOPROPYL BE 14 10A - Bath Soaps and DetergentsCOCAMIDOPROPYL BE 4 10E - Other Personal Cleanliness ProductsCOCAMIDOPROPYL BE 3 12A - Cleansing 21
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DIMETHYL MEA 1 03G - Other Eye Makeup PreparationsDIMETHYL MEA 5 12C - Face and Neck (exc shave)DIMETHYL MEA 1 12D - Body and Hand (exc shave)DIMETHYL MEA 1 12G - NightDIMETHYL MEA 2 12I - Skin Fresheners 10
LACTAMIDE MEA 1 03G - Other Eye Makeup PreparationsLACTAMIDE MEA 2 05A - Hair Conditioner 17LACTAMIDE MEA 4 05B - Hair Spray (aerosol fixatives)LACTAMIDE MEA 1 05F - Shampoos (non-coloring)LACTAMIDE MEA 10 05G - Tonics, Dressings, and Other Hair Grooming AidsLACTAMIDE MEA 1 08F - Nail Polish and Enamel RemoversLACTAMIDE MEA 1 10E - Other Personal Cleanliness Products 9LACTAMIDE MEA 2 12D - Body and Hand (exc shave) 21LACTAMIDE MEA 4 12F - Moisturizing 6LACTAMIDE MEA 1 12H - Paste Masks (mud packs) 27
LAURAMIDE MEA 2 02B - Bubble Baths 28LAURAMIDE MEA 2 02D - Other Bath PreparationsLAURAMIDE MEA 1 04E - Other Fragrance Preparation 35LAURAMIDE MEA 1 05E - Rinses (non-coloring)LAURAMIDE MEA 8 05F - Shampoos (non-coloring)LAURAMIDE MEA 41 06A - Hair Dyes and Colors (all types requiring caution statements and patch tests)LAURAMIDE MEA 2 06D - Hair Shampoos (coloring)LAURAMIDE MEA 14 10A - Bath Soaps and DetergentsLAURAMIDE MEA 10 10E - Other Personal Cleanliness ProductsLAURAMIDE MEA 4 12A - CleansingLAURAMIDE MEA 2 12J - Other Skin Care Preps 87
MEA-COCOATE 4 10E - Other Personal Cleanliness Products
MEA-LAURETH SULFAT 1 05F - Shampoos (non-coloring)MEA-LAURETH SULFAT 11 06A - Hair Dyes and Colors (all types requiring caution statements and patch tests)MEA-LAURETH SULFAT 1 06H - Other Hair Coloring Preparation
MEA-LAURYL SULFATE 1 01A - Baby ShampoosMEA-LAURYL SULFATE 3 05F - Shampoos (non-coloring)MEA-LAURYL SULFATE 1 10A - Bath Soaps and Detergents
MEA-TALLOWATE 6 10E - Other Personal Cleanliness Products
MYRISTAMIDE MEA 1 10A - Bath Soaps and Detergents
MYRISTOYL/PALMITOY 1 12A - CleansingMYRISTOYL/PALMITOY 3 12F - Moisturizing
PEG-9 COCAMIDE MEA 1 05A - Hair Conditioner
STEARAMIDE MEA 5 06A - Hair Dyes and Colors (all types requiring caution statements and patch tests)STEARAMIDE MEA 2 06F - Hair Lighteners with ColorSTEARAMIDE MEA 2 10B - Deodorants (underarm)STEARAMIDE MEA 1 12A - Cleansing 10
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CIR Panel Book Page 238
STEARAMIDE MEA-STE 2 03F - MascaraSTEARAMIDE MEA-STE 1 05A - Hair ConditionerSTEARAMIDE MEA-STE 1 12A - CleansingSTEARAMIDE MEA-STE 4 12F - Moisturizing 8
TRIDECETH-2 CARBOXA 5 05I - Other Hair PreparationsTRIDECETH-2 CARBOXA 130 06A - Hair Dyes and Colors (all types requiring caution statements and patch tests)TRIDECETH-2 CARBOXA 53 06H - Other Hair Coloring Preparation 183TRIDECETH-2 CARBOXA 1 10E - Other Personal Cleanliness Products 189
UNDECYLENEAMIDE M 1 06H - Other Hair Coloring PreparationUNDECYLENEAMIDE M 1 10B - Deodorants (underarm)UNDECYLENEAMIDE M 1 12E - Foot Powders and Sprays
PEG-5 COCAMIDE 15 05F - Shampoos (non-coloring)PEG-5 COCAMIDE 2 10A - Bath Soaps and Detergents 24PEG-5 COCAMIDE 19 10E - Other Personal Cleanliness ProductsPEG-5 COCAMIDE 3 12A - Cleansing 40PEG-5 COCAMINE 1 06B - Hair Tints
PEG-6 COCAMIDE 1 02B - Bubble BathsPEG-6 COCAMIDE 6 05F - Shampoos (non-coloring)PEG-6 COCAMIDE 2 05I - Other Hair PreparationsPEG-6 COCAMIDE 1 06D - Hair Shampoos (coloring)PEG-6 COCAMIDE 11 10A - Bath Soaps and DetergentsPEG-6 COCAMIDE 1 12A - Cleansing 23PEG-6 COCAMIDE 1 12D - Body and Hand (exc shave)
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CIR Panel Book Page 239