FATTY ACIDS, DETERGENTS AND OTHER SURFACTANTS '
CARCINOGENICITY AND STRUCTURE-ACTIVITY
RELATIONSHIPS. OTHER BIOLOGICAL PROPERTIES.
METABOLISM. ENVIRONMENTAL SIGNIFICANCE.
David Y. Lai, Ph. D.
Yin-tak Woo, Ph. D.,
Joseph C. Arcos, D. Sc., and
Mary F. Argus, Ph. D.
Preparation for the Chemical Hazard
Identification Branch "Current
Awareness" Program
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Table of Contents;
5.2.2.9 - Fatty Acids, Detergents and Other Surfactants
5.2.2.9.1 Introduction
5.2.2.9.2 Physical and Chemical Properties. Biological
Effects
5.2.2.9.2.1 Physical and Chemical Properties
5.2.2.9.2.2 Biological Effects Other Than Carcinogenic
5.2.2.9.3 Carcinogenicity and Its Structure. Activity
Relationships
5.2.2.9.3.1 Fatty Acids
5.2.2.9.3.2 Detergents and Other Surfactants
5.2.2.9.4. Metabolism and Mechanism of Action
5.2.2.9.5 Environmental Significance
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5.2.2.9 Fatty Acids, Detergents and Other Surfactants
5.2.2.9.1 Introduction.
A number of epidemiologic and laboratory studies have associated
increased incidence of gastric carcinomas with the consumption of heated fats
(1-3; see also Section 5.1.1.3.2 in Vol. IIA). However, subsequent studies
(4, 5) failed to provide any convincing evidence for a causal relationship.
The role of dietary fat in the induction of cancer has been critically
reviewed by Arffmann (6) and Cooper (7), and was the subject of a workshop in
1981 sponsored by the U.S. National Cancer Institute (8).
Already during the early studies on skin carcinogenesis it was estab-
lished that certain lipophilic-hydrophilic substances, used as vehicles for
carcinogen administration, can considerably modify the effect of carcinogens
(9). For instance, many polar-nonpolar compounds, in the group of non-ionic
detergents ^e_.£., Tweens and Spans) were shown to be potent promoters of skin
tumorigenesis (9, 10). In connection with these findings, some long-chain
fatty acids, which are present in the molecules of certain Tweens and Spans,
were themselves found to have carcinogenic, cocarcinogenic, and/or tumori-
genesis-promoting properties (11-15). These studies generated concern about
the possible carcinogenicity of certain lipids. Because of the increasing
growth of the synthetic detergent industry and the widespread application of
many of its products (see Section 5.2.2.9.5), the possible carcinogenicity of
lipophilic-hydrophilic (surface active) agents has become a focus of
concern. The toxicological properties and carcinogenic activities of this
interesting group of compounds have been extensively reviewed (16-20).
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5.2.2.9.2 Physical and Chemical Properties.. Biological Effects.
5.2.2.9.2.1 PHYSICAL AND CHEMICAL PROPERTIES.
Fatty acids are saturated or unsaturated straight-chain monocarboxylic
acids, usually with an even number of carbons. Short-chain fatty acids are
miscible with water; fatty acids with 10 or more carbon atoms are, on the
other hand, virtually insoluble in water, but readily soluble in nonpolar sol-
vents. The boiling points and melting points of fatty acids increase with the
chain length. Esterification of the carboxyl group and reaction of the double
bond(s) (if any) are the most important chemical reactions of fatty acids.
The common fatty acids (around 18 carbon atoms) exist mostly in the form of
esters as fats, oils, or waxes in animals and plants. Oxidation of the double
bond(s) in unsaturated fatty acids yields unstable hydroperoxides which
further break down to keto and hydroxy-keto acids.
In order to understand the biological activities of detergents and sur-
face active agents ("surfactants") in general, their physico-chemical proper-
ties must be considered. As shown in Tables I and III, all these agents
contain characteristic water-insoluble (hydrophobic, lipophilic, or non-polar)
groups such as alkyl-, alkylaryl-, or other more complex hydrocarbon moieties
and water-soluble (hydrophilic, lipophobic, or polar) moieties such as
+
-(CH2-CH20)n-, -OH, -SOj"", -COO , or -NR^ in their molecules. For a detailed
discussion of the molecular mechanism of action of surface active agents, see
Sections 3.3.2.1 and 3.3.2.2 in Volume I.
In water/oil or water/air systems, surfactants tend to form oriented
monolayers at interfaces; the hydrophilic portion extends into the aqueous
phase whereas the lipophilic part of the molecule is directed toward the lipid
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TABLE 7 Structural Formulas of Surfactants Tested for Carcinogenic Activity
Hh
(CnHzn+i)^^
Alky I benzene sulfonotes
Tweens and Spans
I R-fatty acids
JT«ens-x,y,z"5to 100
(Spons-x,y,z'0
Cholesterol
?"3 CH,
<>V
Deoxycholic acid
CH,
CI©
Triethano famine
CH,
CHj
Benzethonium chloride
Cetyldimettiylbenzylammonium chloride
(R-CeHs; X-CI)
Cetyltrimethylammonium bromide
(R'H;X'6r)
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Table II. Acute Toxicity of Some Fatty Acids,
Detergents and Other Surfactants
Compound Species and Route
A.
B.
(1)
(2)
(3)
Fatty Acids
Laurie acid
Palmitic acid
Stearic acid
Oleic acid ,
sodium salt
Rat, oral
Mouse, i.v.
Mouse, i.v.
Mouse, i.v.
Mouse, i.v.
LD5Q (mg/kg)
12,000
131
57
23
152
Reference
(21)
(22)
(22)
(22)
(21)
Detergents and Other Surfactants
Anionics
Alkylbenzene sulfonates
Deoxycholic acid
Cationics
Triethanolamine
Benzethonium chloride
Cetyldimethylbenzyl-
ammonium chloride
Cetyltrimethylammonium
bromide
Nonionics
Tween 20
Tween 40
Tween 60
Tween 80
Span 20
Span 40
Span 60
Span 80
Rat, oral
Mouse, oral
Mouse, i.p.
Rat , oral
Mouse, i.p.
Rat , oral
Rat, s.c.
Mouse , oral
Rat , oral
Rat, oral
Mouse, i.p.
Rat, oral
Rat, i.p.
Mouse, oral
Mouse, i.p.
Rat, i.v.
Rat, oral
Rat, i.v.
Rat, i.v.
Rat, oral
Rat , oral
Rat, oral
Rat, oral
2,200
4,600
130
8,680
1,450
665
119
485
234
410
106
> 30,000
3,500
> 30,000
2,400
1,580
> 20,000
1,220
1,790
> 20 (ml)
> 10,000
> 30,000
> 10 (ml)
(23)
(23)
(24)
(25)
(21)
(26)
(27)
(26)
(28)
(21)
(29)
(30)
(30)
(30)
(30)
(21)
(31)
(21)
(31)
(31)
(31)
(31)
(31)
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Table III. Carcinogenicity of Fatty Acids and Derivatives in the Mouse
Compound
Structure
Strain
Principal Organ Affected
and Route
Reference
0
II
A. Saturated [CH0(CHJ -C-R]
j i n
Laurie acid
Isopropyl
myristate
Palmitic acid
Stearic acid
n=10, R=OH
n=12, R=OCH(CH3)2
n=14, R=OH
n=16, R=OH
2-, 9-, or 10- n=16, R=OH (hydroxy group
Hydroxystearic at C-2, C-9, or C-10)
acid
Methyl stearate n=16, R=OCH3
12-Hydroxy-
stearic acid
Methyl 12-
hydroxy-
stearate
4-Keto-
stearic acid
Stearohydrox-
amic acid
n=16, R=OH
(hydroxy group at
C-12)
n=16, R=OCH3
(hydroxy group at
C-12)
n=16, R=OH
(keto group at C-4)
n=16, R=NHOH
Albino No significant effect, topical
Swiss-Webster No significant effect, s.c.
Swiss
No significant effect, topical
Swiss-Webster No significant effect, s.c.
BALB/c, ICR/Ha, No significant effect, s.c.
Swiss-Webster
BALB/c
No significant effect, s.c.
ICR/Ha Local sarcoma, s.c
Swiss-Webster No significant effect, s.c.
Swiss-Webster Local sarcoma, s.c.
Swiss-Webster Local sarcoma, s.c.
BALB/c
BALB/c
Local sarcoma , s.c,
Local sarcoma , s.c,
(11) '
(12)
(32, 33)
(12)
(12, 13)
(12)
(13)
(12)
(12)
(12)
(12)
(12)
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Table III. Carcinogenicity of Fatty Acids and Derivatives in the Mouse
(continued)
Compound
Structure
Strain
Principal Organ Affected
and Route
Reference
0
II
B. Unsaturated [CH (CH ) -R-C-O-R']
^™^~™ J ^11
Oleic acid n=7, R=-CH=CH(CH2)7-, R1 =H
Methyl oleate n=7, R=-CH=CH(CH2)7~, R'=Cl
Methyl 12-oxo- n=5, R=-C-CH=CH-(CH ) -,
trans-10-octa- N
decenoate R'=CHo
Methyl 12-
hydroxy-10-
octadecanoate R'=CH
n=5, R=-CH-CH=CH-(CHJ0-,
I •£ o
OH
Swiss-Webster
ST/a
ST/a
ST/a
ST/a
Methyl 13-
hydroxy-9,11-
octadeca-
dienoate
n=4, R=-CH-CH=CH-CH=CH-(CH ) -, ST/a
R'=CH ™
No significant effect, s.c.
Skin, lymphoid tissue, topical
Skin, lymphoid tissue, topical
No significant effect, oral
Skin, topical
Skin, topical
(12)
(14)
(14, 15)
(14)
(14)
Marginal activity
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phase or the air. This molecular orientation brings about a lowering of
interfacial or surface tension. Another characteristic of surfactants is the
formation of micelles in aqueous solution when their concentration in the
solution exceeds the "critical micelle concentration" (CMC). Owing to these
properties, solutions of surfactants exhibit, to various degrees, the
following functional activities: detergency, emulsifying, wetting, solu-
bilizing, foaming, and dispersing, which are closely related to the balance
between their hydrophilic and lipophilic properties. For more details on the
physico-chemical properties of surfactants the reader is referred to the
following publications (34-37, 38a).
On the basis of their ionizing properties, surfactants may be classified
into anionic, cationic, and non-ionic types. Alkylbenzene sulfonates are
typical anionic surfactants because the electrically charged group of these
molecules, the hydrophilic sulfonate moiety, is anionic. Benzethonium
chloride, cetyldimethylbenzylammonium chloride, and cetyltrimethylammoniuin
bromide are cationic surfactants since the charged moiety of these compounds,
the hydrophilic quaternary ammonium ion, is cationic. The Spans and Tweens,
which do not ionize, are non-ionic surfactants. Chemically, the Spans are
fatty acid esters of the cyclic sorbitol anhydride, sorbitan. The fatty acid
moieties of Span 20, Span 40, Span 60, and Span 80 are lauric acid, palmitic
acid, stearic acid, and oleic acid, respectively. Addition of polyoxyethylene
chains of variable length to the three vicinal tertiary hydroxyl groups of
Spans results in the respective Tweens (Tween 20, Tween 40, Tween 60, and
Tween 80). The Tweens commonly used in carcinogenicity studies contain a
total of about 5-100 ethyleneoxide units. The Spans are lipophilic, due to
the fatty acid moieties. The Tweens are hydrophilic and their hydrosolubility
increases with the number of the hydrophilic ethyleneoxide units.
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The emulsifying properties of surfactants is determined by the balance of
the size and strength of the hydrophilic and lipophilic groups in the mole-
V.
cule, the "hydrophile-lipophile balance" (HLB). A strongly lipophilic emulsi-
fier has a low HLB, usually < 10; a highly hydrophilic emulsifier has a HLB
value usually >10. The HLB values may be determined experimentally or may be
calculated. The HLB values of most polyol fatty acid esters can be calculated
with the formula:
HLB = 20 (1 - -I)
A
where "S" is the saponification number of the ester and "A" the acid number of
the acid. For example, the HLB values for Tween 20, Tween 40, and Tween 60
are 16.7, 15.6, and 14.9, respectively (10, 35).
5.2.2.9.2.2 BIOLOGICAL EFFECTS OTHER THAN CARCINOGENIC
Toxicity. Despite little direct evidence for significant toxic effects
of oxidized fats or fatty acids to humans, heated fats and oxidation products
of certain fatty acids have been reported to retard growth and induce patholo-
gical lesions, anorexia, diarrhea, and death in animals (7; cited in ref.
38b). Administration of methyl linoleate derivatives intragastrically to mice
caused atrophy of the spleen, dilatation of the intestine, histological
changes in the lymphatic system, and leukopenia (39). Severe inflammatory
reaction with leukocyte infiltration and necrosis were observed following
subcutaneous injection of methyl-12-oxo-trans-10-octadecenoate (38b). Among
other lipophilic acids, linoleic acid and palmitic acid were shown to be
potent inhibitors of HeLa cell replication (40). Linoleic acid was also
reported to be highly toxic to lung (41) and cultured liver cells of rats
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(42). Oro and Wretlind (22) have determined the LDcg values for saturated
fatty acids from C2 to Cig by intravenous injection into mice. They found
that stearic acid (C-^g) was the most toxic, with LD5Q of 23 rag/kg body weight,
which was ten times lower than that of its unsaturated analog, oleic acid.
Toxicity decreased with the number of carbon atoms in .the molecule, reaching
the lowest point for caproic acid (C6):> LD5Q = 1,725 mg/kg. With further
decrease in the number of carbon atoms, toxicity increased; the LDcQ for
acetic acid (€2) was found to be 525 mg/kg.
In general, most surfactants are relatively innocuous. The oral LD^Q
values for anionic surfactants in various laboratory animals range between 500
and 5,000 mg/kg; cationic surfactants are slightly more toxic and nonionics
are somewhat less (17) (Table II).
Irritation of tissues, mucous membranes, and skin is among the most
common local effects of surfactants. The degree of irritation depends largely
on their surface active properties which in turn depend on their physico-
chemical characteristics. When tested in animals and humans, many anionic and
nonionic surfactants which are used as household detergents do not induce skin
or eye irritation, or sensitization, even at high concentrations (23, 42).
However, exposure of the skin of mice to certain anionic and cationic surfac-
tants (&_•£•, cetyltrimethylammonium bromide) at a concentration of 10% results
in cellular damage and necrosis. Following multiple applications of 1-2.5% of
the agents, acanthosis and hyperkeratosis were observed (44). Toxic myocar-
dial changes and damage in the mucous membrane of the gastrointestinal tract
have also been reported in animals receiving high doses of anionic surfactants
(20). Alkylbenzene sulfonates with alkyl chains of 10-12 carbon atoms are more
irritating and toxic than those with shorter or longer alkyl chains; linear
and branched chain compounds have similar acute oral toxicities (20). Upon
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parenteral administration, certain anionic and cationic detergents are hemo-
lytic, due primarily to their capability to solubilize and elute phospholipids
from the cell membrane. The concentration required for hemolysis is related
to the content of phospholipids in the membrane of the erythrocytes (18).
Mutagenicity. There is a scarcity of information on the mutagenic
activity of fatty acids and detergents. A 1980 study showed that neither
12-hydroxystearic acid nor the oxidized fractions of deep frying fats are
mutagenic in different Salmonella typhimurium tester strains with or without
metabolic activation (45). Linoleic acid, oleic acid, and methyl oleate were
tested for mutagenicity in the U.S. National Toxicology Program. All three
compounds were negative in the Ames test (46). Tween 60 and Tween 80 did not
induce chromosomal aberrations either in vitro in Chinese hamster cells or in
vivo in mouse bone marrow cells (47, 48). They were also nonmutagenic in the
Ames test and in the silkworm oocyte system (47). Consistent with these
findings, Tween 60, Span 60, alkylbenzene sulfonates, cetyltrimethylammonium
chloride, dicetyldimethylammonium chloride, and cetyldimethylbenzylammonium
chloride (49), as well as benzethonium chloride and cholesterol (50) gave
negative results when tested for mutagenicity in strains TA100 and TA98 of S.
typhimuriun in the presence and absence of S-9 activating mix. Tween 80 was
also not mutagenic in the dominant-lethal test in mice (51) or in the sex-
linked recessive lethal test in Drosophila melanogaster (52). The mutagenic
properties of anionic surfactants have recently been reviewed by Oba (19).
Absence of mutagenicity was reported for alkylbenzene sulfonates or other
anionics assayed in various bacterial and mammalian systems. Tween 60 but not
Tween 80 was found mutagenic in strains H-17 and M-45 of Bacillus subtilis and
strain WP-2 of Escherichia coli (47). Moreover, synergism between Tween 60
and ethyleneimine in inducing chlorophyll mutation in barley plants was
-------
reported (53). Various nmtagenic effects have also been described in cluster
beans treated with triethanolamine (54). Hoshino and Tanooka (55), however,
found triethanolamine itself non-mutagenic to Bacillus subtilis; mutagenic
effect to the bacteria was only observed after reacting with sodium nitrite
under acidic conditions or when the mixture was heated.
Teratogenicity. Studies on chemical teratogenesis during the past few
decades have indicated that teratogenic effects may result from a number of
different mechanisms. Freese et_al. (40) have noted a high correlation
between inhibition of mammalian cell growth and reported teratogenicity of
certain lipophilic organic acids; it is interesting to note that palmitic and
linoleic acid are inhibitors of HeLa cell replication (see above under
"Toxicity"). It remains to be tested if exposure to unusually high levels of
these fatty acids is potentially teratogenic. Linoleic acid was positive in
an in vitro cell surface recognition assay system for potential teratogens
(56). An oxidized linoleic acid sample (which contained about 25% linoleic
acid hydroperoxide), but not purified linoleic acid, induced an elevated
incidence of malformations in the offspring of treated rats (57). The terato-
genic activity of other fatty acids is still unknown.
A considerable number of studies on the teratogenic potential of deter-
gents and other surfactants (anionics in particular) have been carried out in
various animal species by oral, dermal, and subcutaneous administration. The
results show no conclusive evidence of teratogenicity. A Japanese group
headed by Mikami (cited in ref. 19) reported that linear alkylbenzene sulfon-
ates and other commercial detergent formulations based on anionic surfactants
caused increased incidence of malformations in rats and mice. However, their
data were considered to be inadequate and incomplete, and other investigators
failed to confirm their results in other strains of animals. Studies by
-------
Mikani's group as well as others on the teratogenic activity of anionic sur-
factants have been critically reviewed (19, 58). Similarly, there is no
significant evidence fo the teratogenicity of cationic surfactants. Except
for a general increase in the incidence of variations of cervical vertebral
arches in the offspring of mice treated with dicetyldimethylammonium chloride
(50 or 200 mg/kg body weight), ho significant change in the rate of malforma-
tions was observed (59). In rats, a high dose (35.6 mg/kg/day) of benze-
thonium chloride produced delayed ossification; however, the effect was not
regarded to be related to teratogenicity, but to the decrease of fetal growth
secondary to maternal toxicity (60). However, when pregnant mice were admini-
stered cetyltrimethylammonium bromide at an intraperitoneal dose of 10.5 or
35.0 mg/kg (10 or 33% of the LD5Q), a higher incidence of malformed fetuses
was found (29). At the time of this writing, the evidence is conflicting
regarding the teratogenicity of the typical non-ionic surfactants, the
Tweens. Verrett et al. (61) found Tween 60 and Tween 80 not teratogenic in
developing chick embryo. However, in recent studies, Kocher-Becker et al.
(62) observed that Tween 20, which was previously regarded to be an inert
vehicle in teratogenicity assays, produced malformations in mice strikingly
similar to those produced by thalidomide. Pregnant mice were given a single
intraperitoneal injection of Tween 20 on day 9 of gestation; the doses that
caused thaiidomide-1ike malformations were 1.0, 1.7, 2.5, and 3.3 mg/kg body
weight.
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5.2.2.9.3 Carcinogenicity and Its Structure-Activity Relationships.
5.2.2.9.3.1 FATTY ACIDS.
A short-term bioassay for preliminary screening of possible carcino-
genicity of a series of fatty acids was developed by Arffmann (63) [based on
injection of the fatty acids into the tail of the newt (Triton cristatus)].
Epidermal hyperplasia and downgrowths into the dermis, suggestive of carcino-
genic activity, was observed with certain derivatives of methyl oleate and
methyl linoleate (64). The most active compound was methyl 12-oxo-trans-10-
octadecenoate, which is derived from methyl oleate and has an oxo group in the
C^-position relative to the double bond. Moderate activity was found with
derivatives of both methyl oleate and methyl linoleate with an Q^-hydroxy
group, namely, methyl 12-hydroxy-10-octadecenoate and methyl 13-hydroxy-9,ll-
octadecadienoate. The corresponding derivatives having a hydroxy group in the
p-position were inactive. On the basis.of the chemical structures, it
appears that conjugation of double bond(s) with an oxygen-containing group in
the composition may be important for the carcinogenic activity of fatty acid
derivatives.
In studies by application of methyl oleate and two oxo- and hydroxy-
derivatives of its 10-octadecenoate isomer (20% v/v in acetone) to the skin (3
times weekly for 1 year) of ST/a mice all three compounds exhibited low level
of complete carcinogenic activity, but were potent promotors of papillomas,
lymphomas, and malignant skin tumors induced by 7, 12-dimethylbenz[a]anthra-
cene (14, 64, 65). In another experiment, the incidence and number of fore-
stomach papillomas initiated by 4-nitroquinoline-N-oxide were also increased
in ST/a mice given methyl-12-oxo-trans-10-octadecenoate (15 mg/day) in the
diet for 300 days; when administered orally alone, however, methyl-12-oxo-
-------
trans-10-octadecenoate did not induce tumors in the mice (15). Data yielded
by these and other studies on the complete carcinogenicity of fatty acids and
derivatives are given in Table III.
Swern^£jil_. (12) investigated the carcinogenic activity of 11 fatty
acids and their derivatives by repeated subcutaneous injection to female
BALB/c or CFW (Swiss-Webster) mice. Laurie acid, palmitic acid, oleic acid,
stearic acid, methyl stearate, and 2-, 9-, or 10-hydroxystearic acid were
regarded by the authors as noncarcinogenic under the conditions of their
experiment. Methyl 12-hydroxystearate and 12-hydroxystearic acid induced
sarcomas in 8 of 27 and 9 of 28 mice, respectively, and were considered to be
carcinogenic. Stearohydroxamic acid and 4-ketostearic acid, which elicited 3
and 2 sarcomas in 13 and 14 mice, respectively, were regarded to be marginally
carcinogenic toward the subcutaneous tissue of mice. The absence of carcino-
genic activity of stearic acid toward the subcutaneous tissue of mice was
later confirmed by Van Duuren et al. (13); methyl stearate, however, was found
to be weakly carcinogenic (13). Oleic and lauric acid did not induce tumors
when applied to the skin of mice daily, 6 times a week for 31 weeks but
displayed significant promoting effect in skin tumor induction (11).
Interestingly, isopropyl myristate which was reported to cause various
cutaneous lesions, did not significantly increase the tumor incidence in
female Swiss mice (32, 33) or New Zealand rabbits (33) by repeated application
to the skin for the life-span of the animals.
5.2.2.9.3.2 DETERGENTS AND OTHER SURFACTANTS.
Studies on the complete carcinogenicity of these compounds are summarized
in Table IV. Their cocarcinogenic and tumorigenesis-promoting activities will
be extensively discussed in Section 6, Vol. IV.
10
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Table IV. Carcinogenicity of Detergents and Surfactants
Compound'
Species and Strain
Principal Organ Affected
and Route
Reference
A. Non-ionic
Tween 60
Tween 80
Cholesterol
B. Anionic
Alkylbenzene
sulfonates
(ABS)
Mouse, Swiss and
unspecified
Rat, Osborne-Mendel and
Bethesda Black
Rat, Shell and Carworth
Farms E
Mouse, C57, MRC and CBA
Mouse, albino and Swiss
Rat, albino
Rat, Wistar
Rat, Moriyama
Mouse, Swiss
Mouse, C57
Rabbit, unspecified
Skin, topical
Local sarcoma, s.c,
Local sarcoma, s.c.
Local sarcoma, s.c.
Bladder, implantation
No significant effect, oral
No significant effect, oral
No significant effect, oral
No significant effect, topical
No significant effect, s.c.
No significant effect, topical
(10, 66-68)
(69)
(70)
(71-73)
(74-76)
(77)
(78)
(79)
(80)
(80)
(80)
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Table IV. Carcinogenicity of Detergents and Surfactants
(continued)
Compound1
Species and Strain
Principal Organ Affected
and Route
Reference
B. Anionic (cont'd)
Deoxycholic
acid
Rat, unspecified
Mouse, C3H
Mouse, CF-1
Local sarcoma, s.c.
Local sarcoma, s.c.
No significant effect, topical
(cited in ref. 16)
(cited in ref. 16)
(81)
C. Cationic
Triethanol-
amine
Benzethonium
chloride
Rat, albino
Mouse, ICR-JCL
Mouse, CBA x C57
Rat, Fischer 344
Cetyldimethyl- Rat, Osborne-Mendel
benzylammonium Rat, albino
chloride
Cetyltrimethyl- Rat, Sprague-Dawley
ammonium bromide
No significant effect0, topical
Lymphoid tissue, mammary gland,
lung, ovary, oral
No significant effect , topical
Local sarcoma, s.c.
No significant effect, oral
No significant effect, oral
No significant effect, oral
(82)
(55)
(82)
(27)
(83)
(28)
(84)
aSee Table 1 for structure
The duration of the study was only 26 weeks
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Anionics. Because of the evident structural relationship to alkyl-
benzenes, there has been concern about the possible carcinogenicity of
mixtures of alkylbenzene sulfonates averaging twelve carbon atoms (ABS), which
are among 'the strongest surfactants known and the major components of commer-
cial detergent products. However, experiments to date failed to demonstrate
any carcinogenic effect of these compounds. Paynter and Weir (77) conducted a
2-year toxicity study, in which 120 albino rats of both sexes were given
dodecylbenzene sodium sulfonate at levels of 0, 200, 1,000, and 2,000 ppm in
the diet and the authors found no pathological changes in various organs
attributable to the intake of the test substance. Similar studies were per-
formed by Tusing££^l_. (78) in 120 male and 120 female Wistar rats. ABS was
administered either in the diet at levels of 0, 0.1% (1,000 ppm) and 0.5%
(5,000 ppm) or in the drinking water (about 0.05%) for 104 weeks. Gross and
microscopic examination of the tissues revealed no evidence of toxic changes
resulting from the treatment with ABS by either route. Saffiotti et al. (80)
tested ABS for possible carcinogenicity in the skin of mice and rabbits.
Application of ABS twice weekly to the skin of Swiss mice or of rabbits for
110 weeks, at concentrations of 5 or 10%, induced no tumors; no carcinogenic
activity was observed either by subcutaneous injection of ABS into C57 mice
(80). Additional evidence for the absence of carcinogenic activity of ABS has
been provided by other bioassays using rats and mice (cited in ref. 19).
In contrast to the lack of complete carcinogenic activity, there is
evidence for the tumorigenesis-promoting properties of ABS. Takahashi (79)
reported significantly higher incidence of gastric cancers in rats which
received concurrent treatment of 4-nitroquinoline-N-oxide and ABS by gavage
than in those given 4-nitroquinoline-N-oxide alone; no neoplasms of the
glandular stomach or other organs were found in the control group of rats
11
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administered only ABS. ABS also enhanced the incidence of N-niethyl-N1-nitro-
N-nitrosoguanidine-induced gastric tumors in rats when administered simul-
taneously in the drinking water (85).
Deoxycholic acid, a bacterial metabolite of bile acid (cholic acid), has
long been suspected to be a carcinogen, cocarcinogen, or promoter in the
pathogenesis of human colon cancer (cited in ref. 86). While several investi-
%
gators reported its sarcomatogenic activity following subcutaneous injection
into rats and mice, others found it not carcinogenic (rev. in ref. 16).
Painting of deoxycholic acid on the skin of mice induced no tumors (81).
Several experiments seem to support the view that deoxycholic acid or its
metabolites ^e_.j^., 12-ketolithocholic acid) may act as a cocarcinogen or
promoter in colon carcinogenesis (87-92). However, studies in the classic
mouse skin system (93) or in the dimethylhydrazine-induced rat colon cancer
model (86) showed no promoting activity of deoxycholic acid or related agents,
Cationics. The carcinogenic potential of triethanolamine has been inves-
tigated by Hoshino and Tanooka (55). Following feeding to male and female
ICR-JCL mice 0.03 and 0.3% of triethanolamine in the diet, significantly
higher incidences of tumors of the lymphoid tissues were found in the
females. Moreover, malignant tumors of various other tissues were also
produced in higher rates in both sexes of the experimentals than in the
untreated controls. Most tumors appeared after at least 60 weeks of treat-
ment. Kostrodymova et al. (82) conducted a 26-week study in which triethanol-
amine (13%) was administered epicutaneously to albino rats and CBA x C57
mice. However, because of the short duration of administration no conclusion
can be made regarding the carcinogenicity or inactivity of this compound.
12
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Benzethonium chloride, when administered subcutaneously at doses of 0.1,
0.3, 1.0, and 3.0 mg/kg body weight twice weekly for 52 weeks to 200 F344
rats, gave rise to 26 fibrosarcomas at the injection site. Only one injection
site-related tumor was observed in the 200 controls (27). Several struc-
turally-related cationics such as cetyltrimethylammonium chloride, dicetyldi-
methylammonium chloride, and cetyldimethylbenzylammonium chloride were
reported negative in the in vitro transformation of hamster embryo cell bio-
assay (49). Oral administration of cetyldimethylbenzylammonium chloride (28,
83) or cetyltrimethylammonium bromide (84) to rats for 4 to 24 months produced
no carcinogenic effects.
Nonionics. In a series of studies on the tumorigenesis-promoting effects
of Span and Tween surfactants, Setala (10) was the first to observe occasional
papillomas on the skin of mice painted with Tween 60 alone (daily, 6 times a
week for 52 weeks) without prior initiation by hydrocarbon carcinogens.
Subsequently, the complete carcinogenic action of Tween 60 in mouse skin was
observed by various investigators, reporting the induction of malignant
squamous cell carcinomas as well as benign tumors (66-68). The compound was
also shown to induce local fibrosarcomas of moderate malignancy in 5 of 30
rats receiving 1 ml (6%) weekly by subcutaneous injection for 73 weeks (69).
Similarly, repeated subcutaneous injections of 2 ml (6%) Tween 80 twice weekly
for 40 weeks induced local sarcomas in 11 of 17 rats (70). Since large doses
are required to induce tumors, these compounds are regarded as only weakly
carcinogenic. Some authors (66, 68) interpreted the effects as due to a
physical phenomenon (the so-called "solid-state carcinogenesis") rather than
to chemical action. No evidence of carcinogenicity was found
with other Tween and Span surfactants (94, 95). This group
of nonionic hydrophilic lipophilic substances are better known in the cancer
literature for their tumorigenesis-promoting properties.
13
-------
Indeed, as early as 1954, Setala and coworkers (9) observed that Span 20
and Tween 60, when applied topically and repeatedly to the skin of mice
»_
enhanced the carcinogenic action of 7,12-dimethylbenz[a]anthracene. Subse-
quent studies on a series of Tween and Span surfactants established that these
compounds represent a new type of physico-chemically defined promoting agents
for the mouse skin (10, 96, 97). Evidence for the tumorigenesis-promoting
action of various Tweens was also provided by other investigators (66-68,
98). The hydrophilic nature of as well as the fatty acid moiety in these
compounds are key features for their promoting activity. The most potent
promoting agents in the group are Tween 40, Tween 60, and Tween 80, which all
possess high HLB values (15.6, 14.9, and 15.0, respectively) and a relatively
long-chain fatty acid in their molecules. Compounds of the Span type, which
lack the hydrophilic polyoxyethylene moieties and have, therefore, lower HLB
values (1.8-8.6) are only weak promoters. The optimum HLB range for skin
tumor promotion is 11.0-15.6 (10). In order to be effective in tumorigenesis
promotion, it is also essential that they are applied in relatively large
doses and with sufficient frequency (10). The difference between this group
of compounds and croton oil lies mainly in the amount of substance necessary
for tumorigenesis promotion (68). More recently, the cocarcinogenic effects
of Span 20 and several Tweens in gastric carcinogenesis, by oral administra-
tion of N-methyl-N'-nitro-N-nitrosoguanidine or methylnitrosocyanimide, have
also been shown in rats (85, 99, 100).
The carcinogenicity of cholesterol — which may be regarded structurally
as a strongly lipophilic nonionic surfactant — has been a subject of contro-
versy and has been critically discussed by several authors (6, 16, 101,
102). Bioassays of cholesterol in many laboratories failed to induce tumors
in experimental animals (cited in ref. 6). An International Agency for
14
-------
Research on Cancer working group (102) considered the tuiaorigenicity of
cholesterol difficult to evaluate in a number of feeding experiments, because.
of the presence of other components and impurities in the diet. Positive
carcinogenic effects were noted in several experiments involving subcutaneous
injection (je.g_., 71-73) or implantation (74-76) of cholesterol pellets into
mice. However, the effects were variably interpreted (72, 102, 103) and the
carcinogenic action of cholesterol is still unclear. On the other hand, the
compound has been reported to exhibit cocarcinogenic activity with dimethyl-
nitrosamine in the induction of bladder tumors in hamsters (104) as well as
with N-hydroxy-acetylaminofluorene in the induction of liver tumors in mice
(105). The carcinogenic activity of cholesterol has also been dicussed in
Vol. IIA, Section 5.1.1.2.1.
5.2.2.9.4 Metabolism and Mechanism of Action.
In contrast to the well established ft-oxidation pathway of normal fatty
acids, there is a relative paucity of information regarding the metabolism of
the carcinogenic fatty acid derivatives. The metabolism and tissue distribu-
tion studies on methyl 13-hydroxy-9,ll-octadecadienoate in the rat (106, 107)
are rather unique in this regard. On the other hand, several important
reviews on the absorption, metabolic degradation, and excretion of various
detergents and other surfactants are available (18, 31, 108). There is no
evidence for bioactivation which might be responsible for the weak carcino-
genic and promoting effects of these hydrophilic-lipophilic compounds toward
the skin and subcutaneous tissue of rats and mice. Instead, there is over-
whelming support for the hypothesis that the action of these polar-nonpolar
substances is due primarily to their surfactant properties, whereby they
structurally disorganize endoplasmic lipoprotein membranes and affect cellular
15
-------
homeostasis (16). Interference with mitochondrial oxidative phosphorylation
by 12-hydroxystearic acid and its methyl ester is believed to be the mechanism
of carcinogenesis by these fatty acid derivatives (109), due possibly to
disruption of membrane systems and denaturation of functional proteins. Many
surfactants have been shown to alter the intestinal permeability of various
nutrient substances (cited in ref. 84). "Solvent action" which facilitates
the absorption and penetration of other carcinogens through the skin or
gastrointestinal tract is believed to play a major role in tumorigenesis
promotion or cocarcinogenesis (10, 11, 79, 85, 99, 110). The promoting
activity of individual agents, on one hand, and the nature and intensity of
histological changes in the skin (9) and stomach wall (111), on the other
hand, have both been correlated with the hydrophile-lipophile balance (HLB
value) of the compounds.
Interestingly, Rohrschneider and Boutwell (112) noted a structural
similarity between phorbol esters, the active principles of croton oil, and
methyl esters of polyunsaturated fatty acids. The authors speculated that
there might be a receptor site in the cell membrane for natural cellular
regulators which are structurally related to fatty acids — prostaglandins,
for instance. The effect of phorbol esters was interpreted as being mediated
by interaction with the receptor site due to structural similarity with the
natural cellular regulator. The weak carcinogenic and promoting activities of
fatty acid derivatives observed may mimic the action of the phorbol esters.
Like croton oil and other promoting agents, some fatty acids, unsaturated in
particular, and their derivatives, have actually been found to induce mitosis
and stimulate cell division when applied to the mouse skin (10, 113).
Jirgensons (114) has recently studied, by circular dichroism, the effects of
various promoting agents on the conformation of histones, which play an impor-
16
-------
Cant role in gene regulation: the order of conformation-modifying activity of
phorbol esters and Tween 60 (polyoxyethylene sorbitan monostearate) was found
to parallel their promoting activity.
Furthermore, there are observations that Tween and Span surfactants are
inhibitors of DNA repair (115-117), and it has been suggested that the
carcinogenic, cocarcinogenic, and tumorigenesis-promoting activities of these
agents are related to their inhibition of DNA repair replication (115).
However, other studies (116, 117) failed to demonstrate any specificity of
these compounds in the inhibition of DNA synthesis. It is possible that the
effects are due to the general action of these substances to denature
proteins, including DNA repair enzymes, by virtue of their surfactant
properties.
5.2.2.9.5 Environmental Significance.
Fatty acids are normal components of animal fats and plant oils.
Unsaturated fatty acids readily undergo autooxidation to yield hydroperoxides
and various oxygen-containing secondary products including epoxides and
hydroxy compounds. (The carcinogenic action of peroxides and epoxides have
been discussed in Sections 5.2.1.7.3 and 5.2.1.1.5 of Vol. IIIA). Altered
fatty acids may also result from polymerization and other chemical reactions
during heating.
Certain fatty acids occur as the lipophilic moiety of soaps and synthetic
surfactants (e^g_., Tweens and Spans), which are used to formulate a wide
variety of household and industrial cleansing products. In addition, many of
the surfactants are used as food additives as well as co-solvents,
solubilizers, dispersants, and emulsifiers in various industries (37, 118).
17
-------
Because of their relatively low cost and rapid rate of biodegradation, the
anionics are the most widely used. An estimate in 1968 indicated that the
production rate of ABS in the U.S. was then about 540 million Ibs/yr (37).
The cationics (^.J[., benzethonium chloride, cetyldimethylbenzylammonium
chloride) are used principally as disinfectants and germicides, rather than as
detergents. Many of these are used in hospitals and restaurants, as well as
in the pharmaceutical, cosmetics, and toiletries industries (119). Moreover,
a considerable amount of triethanolamine, which may be converted to the
carcinogenic nitrosatiines is often present in cutting fluid formulations
(e.g., 55).
The widespread applications of this group of chemicals, both in the home
and in industry, make it almost certain that there is ubiquitous exposure of
humans either through direct contact with the skin, mucous membranes, or
indirectly by ingestion through food and water. The intake of detergents per
person in the U.S. has been estimated to be 0.3-3.0 mg/day (17).
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25
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Notes Added After Completion of Section 5.2.2.9
The promotion of experimental carcinogenesis by dietary unsaturated fatty
acids has been repeatedly demonstrated in rodents. Sakaguchi e±_al_,' (1)
reported that rats fed a diet containig 5% linoleic acid or 4.7% stearic acid
had significantly higher incidence of colon tumors induced by azoxymethane.
Lipid analysis showed that unsaturated fat diet markedly altered the phos-
phatide fatty acyl composition of colon mucosa and increased the level of
arachidonic acid in the neutral lipid of colon tumors (1). The altered lipid
composition of the mucosa can lead to changes in the fluidity and permeability
of cell membranes. In line with these findings, recent research has shown
that dietary unsaturated fatty acids, as many tumorigenesis-promoting chemi-
cals, inhibit "metabolic cooperation" between Chinese V79 hamster cells (2,
3). Interestingly, no such activity was observed with trans-oleic (elaidic)
acid and with saturated fatty acids, suggesting that the cis-double bond
orientation may be essential for the inhibition of intercellular communication
by fatty acids (3). The excess of arachidonic acid, the precursor of prosta-
glandins, in colon tumors has been suggested to play a role in the promotion
of carcinogenesis by the unsaturated fat diet (1). Ip et al. (4) have demon-
strated that at least part of the promoting effects of polyunsaturated fat on
7,12-dimethylbenz[a]anthracene-induced mammary tumorigenesis in rats is
mediated through increased synthesis of prostaglandins, since the addition of
indomethacin (an inhibitor of prostaglandin synthesis) to the diet completely
abolished the stimulatory effect of linoleic acid on tumorigenesis. On the
other hand, arachidonic acid and unsaturated fatty acids (but not saturated
fatty acids) have been found to activate protein kinase C in human (5) and
mouse (6) tissues to similar extent as the tumorigenesis-promotor phorbol
esters. McPhail et al. (5) proposed that the release of arachidonic acid
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could play the role of a second messenger in the regulation of cellular activ-
ities by the stimulation of protein kinase C. It is interesting that the
potency of unsaturated Cjg fatty acids in activating protein kinase C paral-
lels the number of cis-double bonds, in that f -linolenic acid > linoleic
acid > oleic acid, containing three, two and one double bonds, respectively.
Triethanolamine has been selected for carcinogenesis bioassay by the U.S.
National Toxicology Program; the study on a closely related compound
diethanolamine, has been completed and the histopathology of animal tissues
are being examined at the time of this writing (7). The toxicological proper-
ties 'of a large number of surfactants used in cosmetic formulations has been
assessed by the Cosmetic Ingredient Review expert panel (8-11).
References for Section 5.2.2.9 Update
1. Sakaguchi, M., Hiramatsu, Y., Takada, H., Yamamura, M., Hioki, K.,
Saito, K., and Yamamoto, M.: Cancer Res. 44, 1472 (1984).
2. Aylsworth, C.F., Jone, C., Trosko, J.E., and Welsch, C.W.: Proc. Am.
Assoc. Cancer Res. 24, 109 (1983).
3. Aylsworth, C.F., Jone, C., Trosko, J.E., and Welsch, C.W.: Proc. Am.
Assoc. Cancer Res. 25, 152 (1984).
4. Ip, M.M., Carter, C.A., Milholland, R.J., and Shea, W.K.: Proc. Am.
Assoc. Cancer Res. 24, 97 (1983).
5. McPhail, L.C., Clayton, C.C., and Snyderman, R.: Science 224, 622
(1984).
6.. Leach, K.L., and Blumberg, P.M.: Proc. Am. Assoc. Cancer Res. 25, 147
(1984).
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7. NTP: "National Toxicology Program. Fiscal Year 1984 Annual Plan" (NTP-
84-023). National Toxicology Program, Research Triangle Park, North
Carolina, 1984.
8. Elder, R.L. (ed.): Second Report on the Cosmetic Ingredient Review
Expert Panel. In; J. Am. College Toxicol. _H2), 1-177 (1982).
9. Elder, R.L. (ed.): Third Report on the Cosmetic Ingredient Review
Expert Panel. In; J. Am. College Toxicol. JX4), 1-192 (1982).
10. Elder, R.L. (ed.): Fourth Report on the Cosmetic Ingredient Review
Expert Panel. In; J. Am. College Toxicol. 2(5), 1-178 (1983).
11. Elder, R.L. (ed.): Fifth Report on the Cosmetic Ingredient Review
Expert Panel. In: J. Am. College Toxicol. 2(7), 1-235 (1983).
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"Current Awareness'
Program
Vol. IV.
January 1983
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