PHENOLS AND PHENOLIC COMPOUNDS
CARCINOGENICITY AND STRUCTURE-ACTIVITY
RELATIONSHIPS. OTHER BIOLOGICAL PROPERTIES.
METABOLISM. ENVIRONMENTAL SIGNIFICANCE.
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;
5.2.2.4 Ethylene Glycol, Diethylene Glycol, Dioxane and
Related Compounds
5.2.2.4.1 Introduction
5.2.2.4.2 Physicochemical Properties and Biological Effects
5.2.2.4.2.1 Physical and Chemical Properties
5.2.2.4.2.2 Biological Effects Other Than Carcinogenic
5.2.2.4.3 Carcinogenicity and Structure-Activity Relationships
5.2.2.4.4 Metabolism and Mechanism of Action
5.2.2.4.5 Environmental Significance
References
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5.2.2.4 Ethylene Glycol, Diethylene Glycol, Dioxane and Related Compounds.
5.2.2.4.1 Introduction.
Glycols are organic compounds characterized by two hydroxyl groups linked
to separate carbon atoms in an aliphatic chain. Simple glycols have the
general formula, GnH2n^OH^2* Polygiycols* GnH2n° ^OH^2' are adducts of simple
glycols with intervening ether linkage(s) in the hydrocarbon chain. Replace-
ment of one or both hydroxyls with alkoxy groups yields glycol ethers.
jv-Dioxane, a cyclic ether, is generally considered to be a derivative of
ethylene or diethylene glycol. Many of these chemicals have been extensively
used as solvents for numerous industrial, pharmaceutical and consumer
products, as anti-freeze fluids, as surfactants, as fixatives in cosmetic
products, as dessicants, and as reaction media in chemical synthesis.
The concern over the potential carcinogenicity of glycol and related
compounds arose in 1946 when Fitzhugh and Nelson (1) demonstrated that rats
fed diets containing high concentrations of diethylene glycol developed
bladder tumors; in all but one case, rats that bore tumors also had bladder
stones (calculi). Subsequent studies by Weil J2£_al/ (2, 3) casted doubt on
the carcinogenieity of diethylene glycol proper. In fact, experiments
designed to determine the effect of implanted calcium oxalate stones on
bladder carcinogenesis led the authors to conclude that diethylene glycol is
not a primary carcinogen and that diethylene glycol-induced bladder tumori-
geuesis is most likely the result of mechanical irritation by the bladder
stones. However, the carcinogenieity of diethylene glycol cannot be
completely discredited. In a 1968 study, a Russian investigator (4) reported
that mice exposed to vapor containing low concentrations of diethylene glycol
developed mammary tumors. Further studies of this class of compounds are
needed in view of their extensive use.
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p-Dioxane was first reported to be carcinogenic in rats by Argus et al.
(5) in 1965. This finding has been confirmed in subsequent studies (6) and by
other investigators (7, 8). In addition, mice and guinea pigs are also
susceptible to the hepatocarcinogenic action of this widely used industrial
[ text-figure]
solvent. Two related compounds, 2,3-dichloro-p_-dioxane and diiaethoxane, also
display carcinogneic activity. The dioxanes appear to represent a new
oncogenic structural type and it is likely that other active agents may be
found among their derivatives and analogs.
This section focuses on the carcinogenicity of glycols, dioxanes and
related compounds and their possible mechanism of action. Mutagenicity and
developmental toxicity are also discussed in some detail.
./ .
5»2.2.4.2 Physicocheraical Properties and Biological Effects.
5.2.2.4.2.1 PHYSICAL AND CHEMICAL PROPERTIES.
THe physical and chemical properties of various glycols, glycol ethers,
glycol ether acetates and _p_-dioxane have been reviewed by Rowe (9, 10) in 1963
and by Brown et al. (11) in 1980. The physical properties of some glycols and
related compounds are summarized in Table I. Simple glycols with low
molecular weight are odorless and colorless, freeze below 0°C, have low
volatility, are very hygroscopic and ciiscible in all proportions with water,
and have excellent solvent properties. Glycols undergo reactions common to
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(
•o ci
2,3-Dichloro
p-dioxane
CH
.0
0-C-CH
il
0
Dimethoxane
Text-Figure
-------
Table I. Physical Properties of Glycols and Related Compounds*
Compound
Ethylene glycol
monomethyl ether
dimethyl ether
monoethyl ether
Propylene glycol
3-Chloro-l , 2-
m.p.
(°C)
-13
-85
-71
-70
-60 '
—
b.p.
(°C)
197.6
124.2
85.1
134.7
187.2
213
Vapor Pressure
(mm Hg)
0.06 at 20°C
9.7 at 25°C
59 at 20°C
5.3 at 25°C
0.13 at 25°C
0.03 at 25°C
Specific Gravity
1.1155 (20/20°C)
0.963 (25/25°C)
0.869 (20/20°C)
0.928 (25/25°C)
1.038 (20/20°C)
1.3204 (20/4°C)
Solubility in
Water
miscible
miscible
miscible
niscible
miscible
miscibled
propanediol
2-Ethyl-l,3-
hexanediol
Diethylene
glycol
|Triethylene
" glycol
j>-Dioxane
Dimethoxane0
-40 244.2 < 0.01 at 20°C 0.9422 (20/20°C) 4.2 gm/100 ml
-8.0 245
at 20°C
< 0.01 at 20°C 1.1184 (20/20°C) miscible
-4.3 287.4 0.001 at 20°C 1.1254 (20/20°C) miscible
11.8 101.3 37 at 25°C
< -25 86
(at 10 mm Hg)
1.0356 (20/20°C) miscible
1.055-1.070
(25/25°C)
miscible
Summarized from data compiled by C.H. Hine, J.K. Kodama, J.S. Wellington, M.K. Dunlap
and H.H. Anderson [A.M.A. Arch. Ind. Hlth. 14, 250 (1956)]; V.K. Rowe, _In_ "Patty's
Industrial Hygiene and Toxicology" (D.W. Fassett and D.D. Irish, eds.) 2nd edn., Vol.
II, Interscience, New York, 1963, p. 1497; E.S. Brown, C.F. Hauser, B.C. Ream, and
R.V. Berthold [Kirk-Othmer's Encycloped. Chem. Tech. (3rd edn.) 11, 933 (1980)]; G.H.
Riesser [Kirk-Othmer's Encycloped. Chem. Tech. (3rd edn) _5_, 848 (1979)]; International
Agency for Research on Cancer [IARC Monog. 15, 177 (1977)].
Also known as glycerol X -monochlorohydrin;
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alcohols; they form esters, acetals, ethers and similar reaction products.
Ethylene glycol may be dehydrated to yield diethylene glycol, which gives rise
to p-dioxane following intramolecular cyclization. ^-Dioxane and glycol
ethers have similar physicochemical properties as glycols but are considerably
more volatile. Chlorinated derivatives of simple glycols are expected to be
more reactive than Che parent glycols themselves, if the chlorine atom and
hydroxyl group are on adjacent carbon atoms. 3-Chloro-l,2-propanediol
(-dioxane (18), and glycol derivatives (11) have since been
published. Representative acute LDcn data of glycols and related compounds
are summarized in Table II. As the data in the Table indicate, unsubstituted
glycols (especially propylene glycol) have very low acute toxicity. Alkyl
ether derivatives of glycols (glycol ethers) are considerably more toxic than
their parent compounds. Chlorination may have an even more pronounced effect
in enhancing the acute toxicity of glycol and related compounds (compare
propylene glycol vs 3-chloro-l,2-propanediol; p-dioxane vs trans-2,3-dichloro-
p-dioxane). A 1980 study by Woo et al. (19) showed that the enhancement of
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Table II. Acute Toxicity of Glycols and Related Compounds
Compound
Ethylene glycol
Ethyl ene glycol mono-
methyl ether
Ethyl glycol mono-
ethyl ether
Propylene glycol
3-Chloro-l ,2-propanediol
2-Ethyl-l , 3-hexanediol
Diethylene glycol
Diethylene glycol
dimethyl ether
Triethylene glycol
p-Dioxane
trans-2,3-Dichloro-
p-dioxane
Species & Route
Rat, oral
Rabbit, topical
Pat, oral
Rabbit, topical
Rat, oral
Rabbit, topical
Rat, oral
Rabbit, topical
Rat, oral
Rat, oral
Rat, oral
Rabbit, topical
Rat, oral
Rat, oral
Rabbit, topical
Rat, oral
Rat, i.p.
Rat, oral
Rat, i.p.
Rabbit, topical
LD50
7.4 ml/kg
20 ml/kg
2.46 g/kg
1.34 ml/kg
3.0 g/kg
3.5 ml/kg
34.6 ml /kg
20 ml/kg
0.15 g/kg
2.71 g/kg
28.3 ml/kg
11.9 ml /kg
5 g/kg
28.2 nil/kg
20 ml/kg
5.17 g/kg
5.3 g/kg
1.41 ml /kg
0.435 g/kg
0.44 ml/kg
Reference
(11)
(11)
(11)
(11)
(11)
(11)
(ID
(11)
(19)
(20)
(11)
(ID
(ID
(11)
(11)
(21)
(22)
(23)
(24)
(23)
-------
toxicity of p-dioxane by chlorination is stereoselective and that a stereo-
isomer of 2,3,5,6-tetrachloro-jv-dioxane is 1,000 times more toxic than its
parent compound.
*
Ethylene glycol, diethylene glycol and _p_-dioxane are known to have caused
many cases of human poisoning (9, 10, 15, 18, 25) due to intentional, acci-
dental or incidental misuses of these solvents. The principal toxic actions
are: severe depression of the central nervous system, damage of the kidney,
the brain and the liver. Judging from the cases in which the amount ingested
could be approximated, the lethal dose of ethylene and diethylene glycol for
humans is estimated to be 1.4 ml/kg (9) and 1.0 ml/kg (2), resepctively. In
addition to being relatively more toxic than glycols, a number of glycol
ethers have been shown to exert reproductive and developmental toxicity toward
animals. In 1942, Morris et al. (26) reported that ethylene glycol monoethyl
ether caused testicular enlargement, edema and tubular atrophy in rats. Since
1971, at least five glycol ethers and ether acetates (monomethyl ether, mono-
methyl ether acetate, nonoethyl ether and monoethyl ether acetate of ethylene
glycol and diethylene glycol dimethyl ether) have been demonstrated to cause
testicular atrophy, male sterility or abnormal sperm head morphology in mice,
rats, rabbits or dogs (27-29). The U.S. National Institute for Occupational
Safety and Health has recently selected 15 glycols and glycol ethers for
testing for reproductive toxicity to elucidate possible structure-activity
relationships. Besides glycol ethers, 3-chloro-l,2-propanediol (glycerol
o^-monochlorohydrin) also causes testicular atrophy in rats (30).
Mutagenicity. A number of glycols and glycol derivatives have been
tested for mutagenicity in a variety of test organisms. With the exception of
chlorinated derivatives, compounds of this chemical class are generally inac-
tive in microbial and mammalian assays but may display some activity in cer-
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tain plants. In the Ames Salmonella test, ethylene glycol (31, 32) and its
mono- and dimethyl ether derivatives (29, 33), propylene glycol (32, 34, 35),
diethylene glycol (27, 32) and _p_-dioxane (33, 36, 37) have all been consis-
tently shown to be inactive. In fact, some of the compounds mentioned above
are routinely used as solvents in mutagenicity testing of other chemicals.
Only jn-dioxane displays weak mutagenic activity in one study but its activity
in another is questionable (36). As may be expectable from its chemical
properties, 3-chloro-l;2-propanediol (glycerol c<-nionochlorohydrin) is muta-
genic, inducing base-pair substitution in Salmonella typhimurium TA1535 both
with and without metabolic activation. Esterification of the compound with
fatty acids significantly reduces its nutagenicity (38).
In other mutagenicity tests, ethylene glycol, its monomethyl ether, and
_p_-xlioxane are nonmutagenic in the yeast Schizosaccharomyces pombe and in V79
Chinese hamster cells (39). No chromosome aberrations were observed in Swiss
C.F.L.P. mice which received ethylene glycol orally and intraperitoneally
(40). Preliminary communications by McGregor e± al_. (29) and by National
Toxicology Program (27) indicate that ethylene glycol monomethyl ether and
.diethylene glycol dimethyl ether are both inactive in inducing unscheduled DNA
synthesis, are devoid of clastogenic potential in rat bone marrow cells, and
have marginal activity in Drosophila sex-linked recessive lethal test.
Although both compounds display activity in the rat dominant lethal assay, the
activity is attributed to the antifertility effects rather than to dominant
lethal mutations. Ethylene glycol monoethyl ether is inactive in both the rat
dominant lethal and the Drosophila sex-linked recessive lethal assays (27).
In contrast to mammalian and inicrobial organisms, there is some evidence that
ethylene glycol and _p_-dioxane may be mutagenic in certain higher plants.
Bhattacharyya, 3ose and Kandu (cited in ref. 41) reported that ethylene glycol
-------
is nutagenic in rice plants and reduces germination of seeds. Alain et al.
(42) showed that treatment of wheat seeds with ethylene glycol induces chromo-
*.
some aberrations in both mi to tic and meiotic cells of the resulting plants.
Hohl (43) demonstrated that _p_-dioxane causes chromosomal abnormalities in the
root cells of Vicia faba and Allium cepa; its activity is similar to that of
urethan.
Teratogenicity. The potential teratogenicity of ethylene glycol, di-
ethylene glycol, propyiene glycol, 1,3-propanediol and several butanediol
isomers has been tested by Gebhart (44) using chick embryo. Only 1,3-propan-
diol is teratogenic, inducing micromelia; interestingly, its isomer, propyiene
glycol, is inactive. The lack of teratogenicity of propyiene glycol has been
confirmed in the rat (45). In contrast to glycols, two methyl ether deriva-
tives of ethylene glycol have been shown to be active teratogens. Stenger et
al. (46) reported that ethylene glycol monomethyl ether induces skeletal
abnormalities in the rat, but not in the mouse and the rabbit. A 1981 study
by Nagano ^_£jil_. (47) showed that the compound is also teratogenic in strain
ICR mice. A significant increase in the incidence of skeletal malformations
was observed in the fetuses of mice given daily oral dose of 31.25 mg/kg on
days 7-14 of gestation. At the dose of 250 mg/kg, all fetuses examined had
skeletal malformations. Uemura (48) demonstrated that ethylene glycol
dimethyl ether is also teratogenic in mice inducing skeletal abnormalities as
well as surface deformities such as external brain, palpebral potency, caudal
defect, peritoneal hernia and cleft palate. The doses administered ranged
from 250-490 ng/kg. Teratology assays conducted in the U.S. National
Toxicology Program show that monone thy1 ether, monoethyl ether and monoethyl
ether acetate derivatives of ethylene glycol increase fetal malformations in
animals exposed by inhalational or dermal route (28). As mentioned under
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Toxic Effects section, the U.S. National Institute for Occupational Safety and
Health has expressed concern over the potential developmental toxicity of
glycol ethers as a chemical class (27). A monobutyl ether derivative of
propylene glycol has been tested in CD rats up to a daily oral dose of 87.5
mg/kg on days 6-15 of gestation; the compound caused minor embryotoxicity and
is not considered teratogenic ('49). There is no information available on the
teratogenicity of j>-dioxane. A 1964 study by Franceschini (50) showed that
p-dioxane, like thalidomide, affects the growth of tibial buds of cultured
7-day-old chick embryo; whether this activity is indicative of potential
teratogenicity remains to be investigated.
5.2.2.4.3 Carcinogenicity and Structure-Activity Relationships.
Nine glycols and related compounds have been tested for carcinogenicity;
the results of these studies are summarized in Table III. The data available .
indicate that most glycols have little or no carcinogenic activity. There is
some suggestive evidence that 3-chloro-l,2-propanediol (
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Table III. Carcinogenic!ty of Clycols and Related Compounds
Compound
Ethylene glycol
(1,2-ethanediol)
Propylene glycol
( 1 , 2-propanediol )
3-Chloro-l , 2-propanediol
(glycerol -mono-
chlorohydrin)
2-Ethyl-l , 3-hexanedlol
Diethylene glycol
Triethylene glycol
p-Dioxane
2 , 3-Dichloro-p-dioxane
Dime thoxane
Species & Strain
Rat, Sprague-Dawley
Rat, F344
Mouse, Swiss
Rat, Charles River CD
Rabbit, New Zealand
Mouse, ICR/Ha
Rat, Charles River CD
Mouse, Swiss
Rat, —
Rabbit, New Zealand
Mouse, —
Rat, Osborne-Mendel
Rat, CFN
Rat, Osborne-Mendel
Mouse, Swiss-Webster
Mouse, B6C3F.
Rat, Wistar
Rat, Charles-River CD,
Sherman or Osborne-
Mendel
Rat, Wistar
Guinea pig
Mouse, ICR/Ha
Mouse, ICR/Ha
Mouse, ICR/Ha
Rat, Wistar
Route
oral
s .c .
topical
oral
topical
topical or s.c.
oral
topical
oral
topical
inhala tion
oral
oral
oral
topical
oral
oral
oral
inhala tion
oral
topical
s.c.
i .p.
oral
Principal Organs
Affected
None
None
None
None
None
None
o
None (inconclusive)
None
None
None
Mammary gland
Urinary bladder
None
None
None
Liver
Liver
Liver, nasal cavity
None
Liver
Skin (?)c
Local sarcoma
None
Liver
Reference
(51)
(52)
(53)
(54)
(55)
(13)
(30)
(53)
(Lehman, cited in ref. 9)
(55)
(A)
(1)
(2, 3)
(1)
(56)
(8)
(5)
(6-8)
(57)
(58)
(13)
(13)
(13)
(59)
a. ,,,...., .
With concomitant formation of bladder stones (calculi).
cSkin papilloma in 2/50 mice.
Also known as 2,6-dime thyl-m-dioxan-4-ol acetate.
-------
mammary gland) were observed toward the end of the experiment but the distri-
bution of the tumors was such that it was impossible to correlate incidence
with treatment. None of the tumors were associated with the occurrence of
calculi. Ethylene glycol has also been tested in the rat by subcutaneous
route at maximum tolerated dose; no evidence of carcinogenicity was found
(52). Ethylene glycol and its monoethyl ether derivative are being tested for
carcinogenicity in the U.S. National Toxicology Program at the time of this
wri ting.
Propylene glycol has consistently been found to be noncarcinogenic by
oral or topical route in 3 species of animals (see Table III). In the oral
study, rats were fed diets containing up to 50,000 ppm propylene glycol for 2
years with no untoward effects. This level is equivalent to daily consumption
of 2.5 g/kg body weight (54). 3-Chloro-l,2-propanediol, a chlorinated deriva-
tive of propylene glycol, is also noncarcinogenic when tested by topical
application or subcutaneous injection to ICR/Ha mice (13). When tested by
oral administration at the maximum tolerated dose, the compound induced para-
thyroid adenomas in 3/26 male rats. The increase in tumor incidence was not
s
s-tatistically significant. However, because of possible incomplete reporting
of the data, this study was considered inconclusive (30). 2-Ethyl-l,3-hexane-
diol, an insect repellent, is also inactive by topical or oral route (see
Table III).
Diethylene glycol was first reported to be carcinogenic in Osborne-Mendel
rats by Fitzhugh and Nelson (1) in 1946. Groups of 12 nale rats were fed
diets containing 1, 2, or 4% diethylene glycol for up to 2 years. Six rats of
the 2% group and five of the 4% group developed bladder tumors. With one
exception, the rats that bore tumors also had bladder stones. The signifi-
cance of diethylene glycol as a bladder carcinogen was doubted by Weil et al.
8 -
-------
(2, 3), who found only one bladder tumor among 155 CFN rats treated with
diethylene glycol. Instead, they found that a number of rats, that were never
fed diethylene glycol, developed bladder tumors after receiving surgical
implantation of either calcium oxalate stones or glass beads in the bladder.
They concluded that diethylene glycol is not a primary carcinogen and that the
induction of bladder tumors by the compound is probably the result of
mechanical irritation by the bladder calculi. The formation of bladder
calculi is now believed to be involved in bladder carcinogenesis in rodents by
a number of chemicals (60). A 1968 Russian study (4) reported that diethylene
glycol also fails to induce any bladder tumor in mice after long-term
intragastric administration. However, chronic (6-7 months) inhalational
exposure to low concentrations of diethylene glycol (4-5 ug/1) caused malig-
nant mammary gland tumors in 9 of 16 mice and one lympholeukosarcoma in the
cervix 2.5-11 months after the end of treatment. No tumors were found in 20
control mice.
Triethylene glycol was also tested in the study of Fitzhugh and Nelson
(1). No adverse effects were observed in rats fed diets containing 1, 2, or
4% of the compound for 2 years. These doses are equivalent to daily intake of
3-4 g/kg body weight. In a study designed to test the carcinogenicity of
7,12-dimethylbenz[a]anthracene, triethylene glycol was used as the vehicle.
The glycol alone induced planocellular cancer in one and papillotnas in four of
the 80 mice (Shemyakina, cited in ref. 16); the significance of this finding
is questionable, however, due to the lack of proper control gz^^£/.
_p_-Dioxane was first reported to be carcinogenic in rats by Argus et al.
(5). Six of the 26 male Wistar rats that received drinking water containing
1% _p_-dioxane (equivalent to daily intake of 300 rag) for up to 63 weeks
developed hepatomas. In addition, one rat bore a transitional cell carcinoma
-------
in the kidney pelvis and one rat had leukemia. No tumors were found in nine
control rats. A subsequent experiment by Hoch-Ligeti £_£.£!/ (6) showed that
_p_-dioxane is also carcinogenic toward the nasal cavity of the rat. Six out of
120 Charles River CD rats fed _p_-dioxane in drinking water at levels of
0.75-1.8% developed squamous cell carcinomas in the nasal cavity. Spontaneous
tumors at this tissue localization occur extremely rarely in laboratory
animals. Four rats with nasal carcinoma also bore hepatocellular carci-
nomas. The hepatic and nasal carcinogenicity of _p_-dioxane has been confirmed
by Kociba _e_t _al_. (7) and by U.S. National Cancer Institute (8). In the study
of Kociba ^e£^l_. (7), liver tumors were found in 12 and nasal carcinomas in 2
out of 66 Sherman rats that received 1% £-dioxane in drinking water. In rats
receiving lower doses of £-dioxane (0.1% or 0.01%), no treatment-related tumor
induction was noted. In the National Cancer Institute study (b), in which
Osborne-Mendel rats were given .0.5 or 1.0% £-dioxane in the drinking water,
significant increase in the incidences of squamous cell carcinoma of the nasal
turbinates (males: controls 0/33, low dose 12/33, high dose 16/34; females:
controls 0/34, low dose 10/35, high dose 8/35) and hepatocellular adenomas
(females: controls 0/31, low dose 10/33, high dose 11/32) were noted. The
totality of-these results clearly indicate the carcinogenicity of j3-dioxane at
high dose. It appears that Osborne-Mendel and Charles River CD rats are more
susceptible to nasal carcinogenesis while Wistar and Sherman rats are more
susceptible to hepatocarcinogenesis by _p_-dioxane. j>-Dioxane has also been
tested in rats by inhalational route, no significant carcinogenic effects were
observed in rats exposed to vapor containing 111 ppm j>-dioxane, 7 hours/day, 5
days/week for 2 years (57).
In addition to rats, _p_-dioxane has been shown to be hepatocarcinogenic in
the guinea pig and the mouse. Hoch-Ligeti and Argus (58) showed that of the
10
-------
22 male guinea pigs that received drinking water containing 0.5-2% _p_-dioxane,
two had carcinoma of the gall bladder and three had hepatomas. No liver
tumors were found in 10 untreated control animals after 28 months. The
results of a U.S. National Cancer Institute bioassay (8) show significant
increase in the incidence of hepatocellular carcinomas in B6C3F. mice
(males: controls 2/49, low dose 18/50, high dose 24/47; females: controls
0/50, low dose 12/48, high dose 28/37) fed 0.5 or 1.0% jv-dioxane in the
drinking water. When tested by topical route in Swiss-Webster mice, King et
al. (56) initially reported that _p_-dioxane was inactive as a complete
carcinogen but highly potent as a tumorigenesis promoter, displaying an
activity comparable to that of croton oil. However, a subsequent report (King
_e_t jil.,. 1974, cited in ref. 18), referring to later studies stated that the
promoting activity of jv-dioxane is substantially less than that noted in the
initial study.
In contrast to p-dioxane, trans-2,3-dichloro-p-dioxane displays some
complete or tumor-initiating activity toward the skin. The details of these
studies have been discussed in the Haloether section (Section 5.2.1.1.2, Vol.
Ill A). Dimethoxane (2,6-dimethyl-m-dioxan-4-ol acetate), an m^dioxane deri-
vative, has also been tested by Hoch-Ligeti _e_t _al_. (59). Administered orally,
the compound induced hepatomas in 8 of 25 Wistar rats and tumors of kidney,
skin, subcutaneous and lymphoid tissues, and leukemia in 5 other rats. The
demonstration of carcinogenic!ty of this ^-dioxane derivative, together with
that of _p-dioxane, indicates that the dioxanes ui*»y represent a new structural
type of chemical carcinogens.
11
-------
5.2.2.4.4 Metabolism and Mechanism of Action.
The metabolism of ethylene glycol has been studied for decades (e.g., 15,
61-64). The metabolites include glycolaldehyde (HOl^CCHO), glycolic acid
(HOH2CCOOH), glyoxylic acid (OHCCOOH), oxalic acid (HOOCCOOH), carbon dioxide,
glycine, malate and possibly glyoxal (OHCCHO). The major urinary metabolites
are glycolic and oxalic acids along with the unchanged parent compound. Renal
and cerebral damage produced by ethylene glycol has been generally attributed
to the deposition of oxalate crystals in these tissues. A number of metabolic
intermediates are known to be more toxic than ethylene glycol in the rat;
these are, in decreasing order of toxicity: glyoxylate > glycolaldehyde >
glycolate > ethylene glycol (64). With the exception of glyoxal, none of
these metabolites appear to have been shown to be genotoxic. Glyoxal, a
1,2-dicarbonyl compound, has been shown to be mutagenic in the Ames test (65);
however, its role as an ethylene glycol metabolite is still debatable (63).
As mentioned in Section 5.2.2.4.2.2, ethylene glycol is mutagenic in certain
higher plants; the-.raechanism of its mutagenic action is not known. Ethylene
glycol has been reported to inhibit RNA synthesis in Neurospora crassa conidia
(41), cause s trucJtur-a-1—changes of ribosomes in Escherichia coli_.(J&-6i). and .
increase DNA polymerase activity possibly by denaturing DNA primer (67);
whether these activities may contribute to genotoxic activity, if any, of
ethylene glycol remains to be elucidated.
Relatively little information is available on the metabolism of di-
ethylene glycol. In the rat, oxalate has oeen detected in the urine or blood
after oral dosing (1, 9, 15). Compared to ethylene glycol, diethylene glycol
is considerably less effective in producing oxalate, and most of the compound
is excreted unchanged (15). A 1977 study by Woo £££!_• (68) showed that di-
ethylene glycol may be metabolized to _p_-dioxane-2-one (see Fig. 1) in the
12
-------
rat. Under similar conditions, ethylene glycol, diglycolic acid and oxalic
acid did not give rise to this metabolite. Wiley et_ al. (69) were unable to
.demonstrate the presence of oxalate in the urine of rabbits and dogs given
large oral doses of diethylene glycol indicating significant species dif-
ference in the metabolism. The mechanism of bladder carcinogenesis by di-
i
ethylene glycol has generally been attributed to mechanical irritation by
oxalate bladder stones (see Section 5.2.2.4.3). However, it is important to
point out that ethylene glycol, a better producer of oxalate, has thus far not
been shown to induce bladder tumors. Furthermore, the demonstration of
mammary carcinogenic!ty of diethylene glycol suggests that other mechanisms
may also be involved. In this respect, it is interesting to note that di-
ethylene glycol and _p_-dioxane are metabolically closely related (see Fig. 1);
whether they may have a common mechanism of action needs further investiga-
tion.
The metabolism and mechanism of action of jv-dioxane have been extensively
studied. The major urinary metabolite in the rat has been independently
identified as ^-hydroxyethoxyacetic acid (compound III in Fig. 1) and
£-dioxane-2-one (compound IV in Fig. 1) by Braun and Young (70) and by Woo et
al. (68), respectively. The two compounds are actually readily-interconvert-
ible depending on the pH of the solution. It is believed that hydroxyacids of
this type have a narked tendency to form lac tone except under alkaline condi-
tions (71). The possible metabolic pathways proposed by Woo £_£ jil_. (68) are
depicted in Fig. 1. These include: (a) hydrolysis of _p-dioxane (I) to
diethylene glycol (II), followed by oxidation of one of the hydroxyl group to
form A-hydroxyethoxyacetic acid (III) and its lactonic form, _p_-dioxane-2-one
(IV), (b) direct conversion via a possible ketoperoxyl radical intermediate
similar to the reaction scheme proposed by Lorentzen et al. (72) for the
13
-------
(c)/
/
_ JQ) _ HOH2C CH2_OH
0" \ ^^
(I) X
\
\
\
HOH2C COOH
(b)
N
(ni)
Fig. 1. Proposed metabolic pathways of p-dioxane.
-------
conversion of benzo[a]pyrene to benzo[a]pyrene diones and (c) ctf-hydroxyla-
tion, followed by oxidation of the hemiacetal or hydroxyaldehyde interme-
diate. Pathway (a) is supported by the observation that IV may be detected as
an urinary' metabolite of rats given II; however, the absence of II in the
urine of rats given £-dioxane suggests either very rapid conversion of II to
IV or other mechanisms. It is interesting to note that the activating
metabolism of a number of cyclic nitrosamines has been shown to occur via ring
o<-hydroxylation (see Section 5.2.1.2.4.1 in Vol. Ill A). The toxicological
.implication of _p_-dioxane neltabolisn depicted above is still not understood and
is probably dependent on the shift of equilibrium between III and IV under
physiological conditions. Considering III as the sole metabolite, Young et
al. (73) proposed that j>_-dioxane is mainly detoxified by the above pathway and
_tha.C .toxic,, .effects of jj-dioxane are manifested only after the saturation of
metabolic capacity. Woo et ^1_. (22), however, showed that IV is more toxic
than _p_-dioxane_.and that there is an apparent correlation between the
metabolism and toxicity of j)-dioxane in rats pretreated with enzyme inducers
such as polychlorinated biphenyls or 3-methylcholanthrene. A number of lac-
tones, mostly o< ,A -unsatiirated, are known to be carcinogenic (see Section
5.2.1.1.6 in Vol. Ill A). The mechanism of carcinogenic action of _p_-dioxane
is not known. In vitro (74) and in vivo (37) binding studies indicate that
jv-dioxane does not bind covalently to DNA to any significant extent.
jv-Dioxane is also ineffective in inducing unscheduled DNA synthesis in primary
rat hepatocytes (37). TH--», it appears that jv-dioxane may exert its carcino-
genic action by some epigenetic mechanisms, the nature of which remains to be
elucidated.
14
-------
5.2.2.4.5 Environmental Significance.
Glycols, glycpl ethers, dioxanes, and related compounds have numerous
commercial applications. Exposure may occur to workers as well as. to
consumers. Ethylene glycol is the most extensively used simple glycol.
Worldwide production of this compound in 1978 exceeded 6 million metric
tons. About 40% of this amount is used in nonvolatile antifreeze for automo-
biles, 35% in the manufacture of polyester fibers and the remaining as de-
icing agent, heat-transfer fluid, drying agent, motor oil additive, and in
many other product applications (11). Residue of ethylene glycol may be found
in pharmaceutical products, medical devices or food samples sterilized by
ethylene oxide (75). Propylene glycol has an annual production volume of
about 0.38 million metric tons in United States alone; it is extensively used
in the food and pharmaceutical industries as solvent, humectant (for tobacco),
preservative, emollient (for cosmetics and Pharmaceuticals), in the manufac-
ture of plasticizers for food wraps, as lubricant or antifreeze for food
machinery or refrigeration units (11). Residue of propylene glycol has also
been detected in potato starch that had been fumigated with propylene oxide
/
(76). The—use of diethyl'ene glycol appears to be mainly confined to indus-
trial applications following the "elixir of sulfanilamide" tragedy in 1937
when more than 100 deaths occurred as a result of ingestion of the solvent
(77). The higher homolog, triethylene glycol,/is used industrially (11) as
well as in fragrances (16). A number of alkyl ether derivatives of glycols
are also widely pi\-ent ift a variety of consumer products such as paints,
inks, soaps, degreasing agents, cosmetics, etc. (27). The National Institute
for Occupation Safety and Health estimates that 10,000 to 2,000,000 workers in
United States are exposed occupationally to each of at least 14 glycols,
glycol ethers and glycol ether acetates (cited in ref. 27). Epidemiologic
15
-------
studies of possible health effects of such exposure are lacking. A 1971
Russian study (78) reported that hematologic disorders occurred more often in
V
90 workers occupationally exposed to diethylene glycol in the aromatic hydro-
carbon industry than in those exposed only to aromatic hydrocarbons. No
increase in tumor induction was observed in workers exposed for 1-9 years;
however, no firm conclusion regarding carcinogenicity should be made from this
study because of the short duration of follow-up time.
_p_-Dioxane is a commonly used industrial and laboratory solvent; its
annual produc tion"ifi United Spates alone exceeded 7.4 million kg in 1973. It
has been used as a stabilizer for trichloroethylene, as a solvent for cellu-
lose, resins, oils, waxes, dyes, adhesives, cosmetics, Pharmaceuticals, rubber
chemicals and surface coatings (79). In the laboratory, it is employed as a
solvent in chemi-calTynthesis, liquid scintillation counting fluid and in the
preparation of tissues for histological studies. The threshold limit value
(TLV) recommended by the American Conference of Governmental and Industrial
o
Hygienist (80) in 1980 is 25 ppm (90 mg/m air); a lower limit of 1 ppm has
been proposed by the National Institute for Occupational Safety and Health
(18). Human - exposure~"to £-di ox ane is not confined to occupational settings.
In a 10-city survey, jv-dioxane (0.01 iig/1) has been detected in the drinking
water of one (Lawrence, MA) of these cities (81). Marzulli £££l_. (82) have
demonstrated that _p_-dioxane may penetrate skin with relative ease; it has been
estimated that 60 ug _p_-dioxane would be expected to be absorbed with one
applicative, of a suntan lotion containing 600 ppm _p_-dioxane. Two epidemio-
logic studies of workers exposed to p-dioxane have been conducted. In a
German study of 74 current, previous and retired employees of a dioxane-
manufacturing plant, Thiess £t_^l_« (83) reported that no significant health
hazards were identified. There were two cancer deaths (a lanellar epithelial
16
-------
f
\l
carcinoma of the lumbar region and a nyelofibrotic leukemia); however, the
incidence was not significantly different from that expected from a control
\
population. As a group, the workers were potentially exposed for an average
of 24.9 years; the estimated (under simulated conditions) concentration of
£-dioxane in the workplace air ranged from 0.01 to 13.3 ppm. In another study
of 165 employees who worked in a, dioxane plant in Texas, Buffler et al. (84)
found no significant difference between observed cancer deaths and that
o
expected in a control population. The authors noted, however, that the mean
duration of exposure to dioxane for this cohort is less than 5 years and that
the exposure of only 41% of this group occurred early enough to satisfy a
latency criterion of 10 years.
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17
-------
.
8. NCI: "Bioassay of 1,4-Dioxane for Possible Carcinogenic!ty," NCI
/ !
Technical Report No. 80, National Cancer Institute, Be thesda, Maryland,
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9. Rowe, V.K.: Glycols. In "Patty's Industrial Hygiene and Toxicology"
i, i
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(1978).
i |
16. Opdyke, D.L.J.: Food Cosraet. Toxicol. 17, 913 (1979).- , "" - '~
17. Maibach, H.I., and Marzulli, F.N.: Toxicologic Perspectives of Chemicals
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to Dioxane," DHEW Publ. No. 77-226, National Institute for Occupational
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18
-------
19. Hlne, C.H., Kodama, J.K., Wellington, J.S., Dunlap, M.K., and Anderson,
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v
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Triangle Park, North Carolina, April, 1982.
28. NTP: NTP Technical Bulletin No. 8, National Toxicology Program, Research
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29. McGregor," D.B., Willins, M.J., McDonald, P., Holmstrom, M., McDonald, D.,
and Neimeier, R.: Bis(2-me thoxye thyl)e ther and 2-Me thoxye thanol:
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30. Weisburger, E.K., Ulland, B.M., Nam, J.-m., Gart, J.J., and Weisburger,
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19
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Sci. U.S.A. _72, 5135 (1975).
32. Pfeiffer, E.H., and Dunkelberg, H.: Food Cosmet. Toxicol. 18, 115
(1980).
33. Maron, D., Katzenellenbogen, J., and Ames, B.N.: Mutat. Res. 88, 343
(1981).
34. Stolzenberg,. S.J., and Hine, C.H.: J. Toxicol. Environ. Health 5, 1149
(1979).
35. Florin, I., Rutberg, L., Curvall, M., and Enzell, C.R.: Toxicology 15,
219 (1980).
36. NTP: NTP Technical Bulletin No. 4, National Toxicology Program, Research
Triangle Park, North Carolina, April, 1981.
37. Stott, W.T., Quast, J.F., and Watanabe, P.G.: Toxicol. Appl. Phanaacol.
60, 287 (1981).
38. Silhanova, L., Smid, F., Cerna, M., Davidek, H., and Velisek, J.: Mutat.
Res. 103, 77 (1982).
39. Abbondandolo, A., Bonatti, S., Corsi, C., Corti, G., Fiorio, R.,
Leporini, C., Mazzaccaro, A., Nieri, R., Barale, R., and Loprieno, N.:
Mutat. Res. 79, 141 (1980).
40. Conan, L, Foucault, B., Siou, G., Chaigneau, M., and Le Moan, G.: Ann.-
Falsif. Expert. Chim. 72, 141 (1979).
41. Chaudhuri, R.K.: Experientia 34, 735 (1978).
42. Alam, S., Khan, M.R., and Banu, K.: Bengladesh J. Agric. Sci. _8_, 63
(1981).
43. Hohl, K.: Experientia 3, 109 (1947).
44. Gebhart, D.O.E.: Teratology 1, 153 (1968).
20
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45. Mackler, B., Grace, R., Tippit, D.F., Leraire, R.J., Shepard, T.H., and
Kelley, V.C.: Teratology 12, 291 (1975).
46. Stenger, E.G., Aeppli, L., Mueller, D., Peheim, E., and Thomann, P.:
Arzneim.-Forsch. 21, 880 (1971).
47. Nagano, K., Nakayama, E., Oobayashi, H., Yamada, T., Adachi, H.,
Nishizawa, T., Ozawa, H., Nakaichi, M., Okuda, H., Minami, K., and
Yamazaki, K.: Toxicology 20, 335 (1981).
48. Uemura, K.: Nippon Sanka Fujinka Gakkai Zasshl 32, 113 (1980).
49. Unger, T.M., Kliethermes, J., Van Goethem, D., and Short, R.D.:
"Teratology and Postnatal Studies in Rats of the Propylene Glycol Butyl
Ether and Isooctyl Esters of 2,4-Dichlorophenoxyacetic Acid." NTIS Publ.
No. PB 81-191,141, U.S. National Technical Information Service,
Springfield, Virginia, 1981.
50. Franceschini, M.: La Sperimentale 114, 1 (1964).
51. Blood, F.R.: Food Cosmet. Toxicol. 3, 229 (1965).
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53. Stenback, F., and Shubik, P.: Toxicol. Appl. Pharmacol. 30, 7 (1974).
54. Gaunt, I.F., Carpanini, F.M.B., Grasso, P., and Lansdown, A.B.C.: Food
Cosmet. Toxicol. 10, 151 (1972).
55. Stenback, F.: Acta Pharmacol. Toxicol. 41, 417 (1977).
56. King, M.E., Shefner, A.M., and Bates, R.R.: Environ. Health Persp. 5,
163 (1973).
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P.J.: Toxicol. Appl. Pharmacol. 30, 287 (1974).
58. Hoch-Ligeti, C., and Argus, M.F.: Effect of Carcinogens in the Lung of
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65. Bjeldanes, L.F., and Chew, H.: Mutat. Res. 67, 367 (1979).
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Biochemistry 14, 3970 (1975).
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22
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76. Steele, L., and Hadziyev, D.: Z. Lebensnittelunters-Forsch. 162, 387
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v
77. Gelling, E.M.K., and Cannon, P.R.: J. Am. Med. Assoc. Ill, 919 (1938).
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Prof. Zabol. 15, 40 (1971).
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20, 255 (1978). .
23
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Notes Added After Completion of Section 5.2.2.4
The concern over glycol ethers as teratogens and reproductive toxins has
continued to attract extensive investigations.. Hardin (1) has recently
reviewed the reproductive toxicity data of 13 glycol ethers and related com-
pounds. The glycol ethers, which have been thus far shown to exhibit clear
reproductive toxicity (testicular atrophy and/or teratogenicity), are mostly
methyl or ethyl ether derivatives of ethylene glycol. Monobutyl or monophenyl
derivative of ethylene glycol failed to cause significant reproductive toxic-
ity suggesting that bulky substituents tend to mitigate the toxicity. Both
monomethyl and dimethyl derivatives of ethylene glycol produce similar spectra
of embryotoxic and teratogenic effects suggesting in vivo metabolism to a
common active form, possibly 2-methoxyacetic acid. The demonstration by
Foster et al. (2) of similarity between the nature and severity of testicular
toxicity obtained with 2-methoxy- and 2-ethoxyacetic acids and their corre-
sponding glycol ethers lends support to the suggestion that 2-alkoxyacetic
acids are the active metabolites of glycol ethers. Further support has been
provided by studies showing lack of reproductive toxicity of propylene glycol
monomethyl ether in rats (3) and the inability of rats to biotransform this
glycol ether to its acetic acid derivative (4). Unlike ethylene glycol mono-
methyl ether, propylene glycol monomethyl ether is mainly metabolized via
0-demethylation to propylene glycol, which has a low degree of toxicity. The
final results of a study on genetic effects of monomethyl and dimethyl deriva-
tives of ethylene glycol (2-methoxyethanol and bis-2-methyoxyethyl ether) in
rats by McGregor et_ jiJL (5) have been published. Both comopunds were negative
in the Ames test, unscheduled DNA synthesis (UDS) and chromosome aberrations
assays but showed some (albeit weak) mutagenic activity in dominant lethal
test and strong antifertility effects. The possible molecular mechanism of
-------
teratogenesis by glycol ethers and other teratogens has been studied by Welsch
(6). Like a number of other potent teratogens, several glycol ethers have
been shown, by "metabolic cooperation" experiments, to inhibit intercellular
communication. Cell-to-cell transfer, through gap junction, of regulatory
growth factors is believed to be involved in the control of cell differentia-
tion and proliferation. A number of "epigenetic" carcinogens and potent
tumorigenesis promoters have also been shown to inhibit intercellular communi-
cation (7); it remains to be tested whether glycol ethers may have similar
properties.
References for Section 5.2.2.4 Update
1. Hardin, B.D.: Toxicology 27, 91 (1983).
2. Foster, P.M.D., Creasy, D.M., Foster, J.R., Thomas, L.V., Cook, M.W.,
and Gangolli, S.D.: Toxicol. Appl. Pharmacol. 69, 385 (1983).
3. Doe, J.E., Samuels, D.M., Tinston, D.J., and de Silva Wickramaratne,
G.A.: Toxicol. Appl. Pharmacol. 69, 43 (1983).
4. Miller, R.R., Herman, E.A., Langvardt, P.W., McKenna, M.J., and Schwetz,
B.A.: Toxicologist 3, 82 (1983).
5. McGregor, D.B., Willins, M.J., McDonald, P., Holmstrom, M., McDonald,
D., and Niemeier, R.W.: Toxicol. Appl. Pharmacol. 70, 303 (1983).
6. Welsch, F.: Mechanisms of Teratogenesis. ln_ "CUT Activities," Vol. 3,
No. 7, Chemical Industry Institute of Toxicology, Research Triangle
Park, North Carolina, 1983.
7. Boreiko, C.J.: Intercellular Communication and Tumor Promotion. In
"CUT Activities," Vol. 4, No. 3, Chemical Industry Institute of
Toxicology, Research Triangle Park, North Carolina, 1984.
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