540186052
United States
Environmental Protection
Agency
Office of Emergency and
Remedial Response
Washington DC 20460
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
Superfund
vvEPA
'HEALTH EFFECTS ASSESSMENT
FOR GLYCOL ETHERS
Do not remove. This document
should be retained in the EPA
Region 5 Library Collection.
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EPA/540/1-86-052
September 1984
HEALTH EFFECTS ASSESSMENT
FOR GLYCOL ETHERS
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
U.S. Environments! Protection Agency
Region 5,! ;'vr-
77 West J2>:--
Chicago, 1L C,, , . , """'
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DISCLAIMER
The Information in this report has been funded wholly or In part by the
United States Environmental Protection Agency under Contract No. 68-03-3112
to Syracuse Research Corporation. It has been subject to the Agency's peer
and administrative review, and it has been approved for publication as an
EPA document. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with glycol
ethers. All estimates of acceptable Intakes and carcinogenic potency
presented 1n this document should be considered as preliminary and reflect
limited resources allocated to this project. Pertinent toxicologic and
environmental data were located through on-line literature searches of the
Chemical Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data
bases. The basic literature searched supporting this document is current up
to September, 1984. Secondary sources of information have also been relied
upon in the preparation of this report and represent large-scale health
assessment efforts that entail extensive peer and Agency review.
The intent in these assessments is to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited in
scope tending to generate conservative (I.e., protective) estimates. Never-
theless, the interim values presented reflect the relative degree of hazard
associated with exposure or risk to the chemical(s) addressed.
Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer is not the endpoint of concern).
The first, the AIS or acceptable Intake subchronic, 1s an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval (I.e., for an interval that
does not constitute a significant portion of the Hfespan). This type of
exposure estimate has not been extensively used or rigorously defined, as
previous risk assessment efforts have been primarily directed towards
exposures from toxicants in ambient air or water where lifetime exposure is
assumed. Animal data used for AIS estimates generally Include exposures
with durations of 30-90 days. Subchronic human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
The AIC, acceptable intake chronic, Is similar in concept to the ADI
(acceptable daily intake). It is an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
.significant portion of the lifespan [see U.S. EPA (1980) for a discussion of
this concept]. The AIC is route specific and estimates acceptable exposure
for a given route with the Implicit assumption that exposure by other routes
1s Insignificant.
Composite scores (CSs) for noncarcinogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development 1s explained in U.S. EPA (1983).
For compounds for which there is sufficient evidence of carcinogeniclty,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980). Since cancer 1s a
process that is not characterized by a threshold, any exposure contributes
an increment of risk. Consequently, derivation of AIS and AIC values would
be inappropriate. For carcinogens, qa*s have been computed based on oral
and inhalation data if available.
111
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ABSTRACT
In order to place the risk assessment evaluation in proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
For the purpose of this document, the glycol ethanes were divided into
three subclass1f1cat1ons. The first classification is the low molecular
weight ethylene glycol ethers, 2-methoxyethanol and 2-ethoxyethanol. These
compounds appear to have similar toxic effects when tested in laboratory
animals. Of the two, 2-methoxyethanol appears to be more toxic. Data were
not sufficient to derive an oral AIS or AIC for 2-methoxyethanol because
NOELs for fetotoxidty had not been defined by the available studies. A CS
of 22 for teratogenidty in mice was calculated for 2-methoxyethanol
administered by gavage during gestation. For 2-ethoxyethanol, an oral AIS
of 32.6 mg/day has been calculated from a teratogenicity study in rats. An
AIC of 25 mg/day is calculated based on a chronic gavage study in rats. The
AIS and AIC calculated for 2-ethoxyethanol may not be protective for
2-methoxyethanol.
An inhalation AIS for 2-methoxyethanol of 4.1 mg/day was calculated
based on a NOEL for fetoxidty in rats. An AIC value of 1.7 mg/day is esti-
mated based on subchronlc Inhalation data. For 2-ethoxyethanol an AIS of
4.8 mg/day and an AIC of 3.5 mg/day are based on teratology and subchronic
inhalation data, respectively. A CS for 2-ethoxy ethanol of 12.7 is
calculated based on fetotoxiclty following Inhalation exposure.
The second subclass of glycol ethers consists of the ethylene glycol
ethers with higher molecular weight. Although there are a large number of
other ethylene glycol ethers, few have been studied in detail. In general,
they seem to be less potent toxins than 2-methoxyethanol and 2-ethoxy-
ethanol. It seems probable that wide variability may exist in the toxic
potencies of members of this subclass. For example, ethylene glycol
dimethyl ether appears to be less toxic than diethylene glycol monomethyl
ether. Data were Insufficient for calculation of an AIS or AIC for ethylene
glycol dimethyl ether. An AIS of 350 mg/day and an AIC of 140 mg/day for
oral exposure have been calculated for diethylene glycol monomethyl ether
from subchronlc and chronic studies, respectively. Data were inadequate for
Inhalation exposure. This AIS and AIC should be protective for diethylene
glycol monomethyl ether, but not necessarily for other members of the
subclass or for the subclass as a whole.
Inhalation data for the subclass other ethylene glycol ethers were
available only for ethylene glycol monobutyl ether. An inhalation AIS of
11.2 mg/day and an AIC of 1.1 mg/day for ethylene glycol monobutyl ether
were calculated from a subchronic study. A CS of 19 was calculated based on
increased mortality in guinea pigs exposed by inhalation. Because it is
likely that great variation exists in the toxic potencies of members of this
subclass, these recommendations should not be applied to other ethylene
glycol ethers or to the subclass as a whole.
iv
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Propylene glycol ethers are the third subclass of glycol ethers. Oral
studies have been performed with propylene glycol monomethyl ether and
propylene glycol monoethyl ether. Both compounds appear to have equivalent
toxic potencies. An oral AIS of 476 mg/day was calculated for propylene
glycol monoethyl ether and of 475 for the monomethyl ether, based on
subchronlc studies. AICs of 48 and 47 mg/day of the respective Isomers for
chronic oral exposure were estimated from these same studies.
Inhalation studies were performed only with propylene glycol monomethyl
ether. An AIS of 342 mg/day was calculated based on a subchronic study in
rats. An AIC of 34.2 mg/day was calculated from the same data. A CS of 10
was calculated based on increased mortality in rats.
Oral studies indicated that propylene glycol monomethyl ether and
propylene glycol monoethyl ether are roughly equivalent in toxic potency.
If this is also true for inhalation exposure, the AIS and AIC calculated for
propylene glycol monomethyl ether should be protective for propylene glycol
monoethyl ether as well. Subchronlc Inhalation studies, however, indicate
that dipropylene glycol monomethyl ether may be more toxic than the mono-
propylene glycol ethers investigated. Therefore, the AIS and AIC calculated
for propylene glycol monomethyl ether may not be protective for other
members of this subclass or for the subclass as a whole.
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ACKNOWLEDGEMENTS
TECHNICAL REVIEW
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
EDITORIAL REVIEW
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
TECHNICAL SUPPORT SERVICES
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112.
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1.
2.2.
ORAL
2.1.1. 2-Methoxyethanol and 2-Ethoxyethanol . . . .
2.1.2. Other Ethylene Glycol Ethers
2.1.3. Propylene Glycol Ethers
INHALATION
2.2.1. 2-Methoxyethanol and 2-Ethyoxyethanol ...
2.2.2. Other Ethylene Glycol Ethers
2.2.3. 'Propylene Glycol Ethers
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.
3.2.
3.3.
3.4.
SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . . ,
3.3.1. Oral
3.3.2. Inhalation ,
TOXICANT INTERACTIONS
CARCINOGENICITY ,
4.1.
4.2.
4.3.
4.4.
HUMAN DATA
BIOASSAYS
OTHER RELEVANT DATA ,
WEIGHT OF EVIDENCE .
REGULATORY STANDARDS AND CRITERIA
Page
1
5
. . . 5
. . . 5
. . . 5
. . . 6
. . . 6
. . . 6
. . . 7
. . . 7
. . . 8
. . . 8
. . . 8
14
, , , 21
. . . 21
. . . 27
. . . 27
. . . 29
. . . 33
. . . 42
44
. . . 44
. . . 44
. . . 44
. . . 45
. . . 47
V11
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TABLE OF CONTENTS (cent.)
RISK
6.1.
6.2.
6.3.
ASSESSMENT .
ACCEPTABLE INTAKE SUBCHRONIC (AIS) .
6.1.1. Oral
6.1.2. Inhalation
ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1. Oral
6.2.2. Inhalation
CARCINOGENIC POTENCY (q-,*)
6.3.1. Oral
6.3.2. Inhalation
REFERENCES
Page
49
49
49
53
57
57
58
59
59
59
60
APPENDIX: Summary Table for Glycol Ethers ............... 76
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LIST OF TABLES
No. Title Page
1-1 Selected Physical and Chemical Properties of a
Few Glycol Ethers ...................... 2
3-1 Subchronic Oral Studies with 2-Methoxyethanol and
2-Ethoxyethanol ....................... 9
3-2 Subchronic Oral Studies with Other Ethylene Glycol Ethers . . 12
3-3 Subchronic Oral Studies with Propylene Glycol Ethers ..... 15
3-4 Subchronic Inhalation Studies with 2-Methoxyethanol and
2-Ethoxyethanol ....................... 16
3-5 Subchronic Inhalation Studies with Ethylene Glycol
Monobutyl Ether ........................ 19
3-6 Subchronic Inhalation Studies with Propylene Glycol
Ethyl Ethers ......................... 22
3-7 Chronic Oral Studies with 2-Ethoxyethanol ........... 24
3-8 Chronic Oral Studies with Diethylene Glycol Monoethyl Ether. . 26
3-9 Reports of ToxicHy in Humans Chronically Exposed to
2-Ethoxyethanol or 2-Methoxyethanol .............. 28
3-10 Teratogenlcity and Fetotoxicity of Orally-Administered
2-Methoxyethanol and 2-Ethoxyethanol ............. 30
3-11 Teratogenicity and Fetotoxicity of Orally-Administered
Ethylene Glycol Ethers .................... 31
3-12 Teratogenlcity and Fetotoxicity of 2-Methoxyethanol
Administered by Inhalation .................. 34
3-13 Teratogenicity and Fetotoxicity of 2-Ethoxyethanol
Administered by Inhalation .................. 37
3-14 Teratogenlcity and Fetotoxicity of Ethylene Glycol Ethers
Aministered by Inhalation ................... 40
3-15 Teratogenlcity Fetotoxicity of Propylene Glycol Ethers
Administered by Inhalation .................. 41
5-1 Regulatory Standards and Criteria for Glycol Ethers ...... 48
ix
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
BUN Blood urea nitrogen
bw Body weight
CAS Chemical Abstract Service
CNS Chemical Abstract Service
CS Composite score
GI Gastrointestinal
LOAEL Lowest-observed-adverse-effect level
MCV Mean corpuscular volume
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
ppm Parts per million
pvc Packed cell volume
RBC Red blood cell
RV(j Dose-rating value
RVe Effect-rating value
SG Specific gravity
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
WBC White blood cell
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Ethers of glycols with monohydric, dihydMc and polyhydrlc alcohols are
called glycol ethers; however, glycol ethers with dlhydrlc and polyhydrlc
alcohol are commonly classified as glycols. Therefore, only a few ethers of
glycols with monohydrlc alcohols will be discussed here. Selected physical
and chemical properties of a few glycol ethers are shown In Table 1-1.
Pertinent Information pertaining to the fate and transport of the glycol
ethers 1n the atmosphere could not be located In the available literature.
It has been suggested by Graedel (1978) that both singlet oxygen and
hydroxyl radicals 1n the atmosphere may react with aliphatic ethers;
however, the rate constants for these reactions for the listed glycol ethers
are not available. The photochemical reactivities of a few glycol ethers in
the lower atmosphere in the presence of NO (nitrogen oxides) were studied
by Yanagihara et al. (1977). These authors determined that the glycol
ethers have high reactivities in the atmosphere under smog conditions. The
reac- tivlties of the glycol ethers ranged between xylene and toluene reac-
tivities. Based on this information and the residence times of toluene and
xylene in the atmosphere (Singh et al., 1981), it has been speculated that
the half-life of the glycol ethers In the atmosphere may be <1 day. Because
of their high water solubilities, all the glycol ethers listed in Table 1-1,
with the exception of 2-phenoxyethanol, are probably significantly removed
from air through wet deposition.
Pertinent information regarding the fate and transport of glycol ether
in aquatic media could not be located in the literature. Based on the vapor
pressures and the water solubilities of these compounds, it is unlikely that
volatilization will play an important role in determining the fate of these
chemicals in aquatic media. From the rate constant (~109 M"1 sec"1)
-1-
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TABLE 1-1
Selected Physical and Chemical Properties of a Few Glycol Ethers3
Compound
Ethylene glycol
monomethyl ether or
2-methoxyethanol
Ethylene glycol
monoethyl ether or
2-ethoxyethanol
Ethylene glycol
n-butyl ether or
2-buto'xyethanol
Ethylene glycol
phenyl ether or
2-phenoxyethanol
Propylene glycol
monomethyl ether or
2-methoxy propanol
Dlethylene glycol
methyl ether or
Molecular
Weight CAS Number
76.1 109-86-4
90.1 110-80-5
118.2 111-76-2
138.2 122-99-6
90.1 107-98-2
120.1 111-77-3
Vapor Pressure
at 25°C
(mm Hg)
9.5
5.5
0.88
0.03
12.5
0.25
Water Solubility
at 25°C log Kow b
completely -0.74
mlsclble
completely -0.21
mlsclble
completely 0.85
mlsclble
2.3 ml/100 ml NA
completely NA
mlsclble
comletely -0.79 to -0.93
mlsclble
2-(B-methoxy-
ethoxy) ethanol
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TABLE 1-1 (cont.)
Molecular
Compound Weight
Dlethylene glycol 134.2
ethyl ether or
2-(B-ethoxy-ethoxy)
ethanol
Dlethylene glycol 162.2
n-butyl ether or
2-(B-butoxy-ethoxy)
ethanol
Vapor Pressure
CAS Number at 25°C
(mm Hg)
111-90-0 0.26
112-34-5 0.06
Water Solubility
at 25°C log Kow b
completely NA
mlsclble
completely 0.15-0.40
mlsclble
aSource: Dow Chemical Co., 1981
bOctanol/water partition coefficient values obtained from Konemann, 1981; Verschueren, 1983
NA =- Not available
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values given by Dorfman and Adams (1973), H Is unlikely that reaction of
hydroxyl radicals with the glycol ethers In aquatic media would be a
significant process. The reaction rate constants for the more probable
peroxy radical reactions and direct photochemical reactions are not avail-
able. The available studies Indicate that these compounds may biodegrade 1n
aquatic media (Bridle et a!., 1979; Flncher and Payne, 1962; Oow Chemical
Co., 1981). The mlcroblal degradation rates may be rapid for some compounds
(e.g., ethylene glycolmonomethyl and monoethyl ether) and slow for others
(I.e., propylene glycol monomethyl ether). Data 1n the available literature
are Insufficient to permit assessment of the most probable fate of these
chemicals 1n aquatic media.
Very Uttle Information Is available 1n the literature regarding the
fate of glycol ether 1n soils. Based on the physical properties of these
compounds and the available blodegradatlon studies (Flncher and Payne,
1962), 1t can be speculated that blodegradatlon and leaching may play sig-
nificant roles 1n determining the fate of these chemicals In soils. Their
mobility In soils 1s expected to be maximal 1n sandy soils with low organic
carbon content due to low soil sorptlon characteristics for these soils.
-4-
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
2.1.1. 2-Methoxyethanol and 2-Ethoxyethanol. Miller et al. (1983a, 1984)
administered doses of 1 or 8.7 mmol of 14C- or 13C-2-methoxyethanol
labeled at C. or C- to mature male Fischer 344 rats by gavage. Expired
air and urine and feces were collected for the subsequent 48 hours, at which
time the rats were killed. The percentage of the total dose of radio-
activity recovered was 54.3-63.2% from the urine, 11.8-11.9% from expired
C0?, 0.3-0.4% from exhaled volatHes trapped on activated charcoal and
16.2-21.8% from the whole carcass. Fecal excretion accounted for only
2.6-2.7% of the total dose of radioactivity. Absorption of 2-methoxyethanol
from the GI tract was essentially complete.
Similar results were reported by Foster et al. (1984), who administered
a single 500 mg/kg bw dose of 14C-2-methoxymethanol (labeled methoxy
group) by gavage to rats. After 48 hours, 70% of the dose of radioactivity
was recovered from the urine, 2.7% from exhaled air and 12.5% from the
tissues. Only 1.5% of the dose was recovered from the feces.
Cheever et al. (1984) demonstrated that absorption of 2-ethoxyethanol 1s
nearly complete. These researchers administered a single 230 mg/kg bw dose
of 14C-ethoxyethanol (labeled 1n the ethanol or ethoxy group) to mature
male rats, and collected urine, expired air and feces for up to 96 hours
after treatment. Radioactivity In the urine accounted for 75.6-80.6%, 1n
expired air for 4.8-12.1% and 1n the carcass for 1.8-4.6% of the total dose
administered. Fecal excretion accounted for only 2.7-4.5%.
2.1.2. Other Ethylene Glycol Ethers. Oral administration of dlethylene
glycol monoethyl ether to one human subject was followed by recovery of 68%
'1n the urine as the metabolite (2-ethoxy-ethoxy) acetic add, Indicating
-5-
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extensive absorption from the GI tract (Kamerling et a!., 1977). Details of
the protocol were not reported.
Gadasklna and Rud1 (1976) administered 400 mg of ethylene glycol mono-
vinyl ether/kg bw (species not stated) and recovered ethylene glycol 1n the
urine over the following 24 hours, which they felt represented complete
hydrolysis of 24% of the dose of ethylene glycol monovlnyl ether given.
By studying the metabolism of [14C]-labeled ethylene glycol Isopropyl
ether, Hutson and Pickering (1971) determined that 88% of the compound was
excreted from the body within 24 hours following an oral dose. Urinary
excretion accounted for 73%, while 14% was excreted by the lungs. These
data suggest that absorption following oral administration Is rapid and
complete; however, digestion or m1crob1al breakdown 1n the gut or entero-
hepatlc recirculatlon have not been considered.
2.1.3. Propylene Glycol Ethers. Propylene glycol monomethyl ether also
appears to be extensively absorbed, although the metabolism and excretion
appear to differ from these processes for the low molecular weight ethylene
glycol ethers. Miller et al. (1983a) administered a single gavage dose of
1-14C- and l-13C-propylene glycol monomethyl ether at 1.0 or 8.7 mmol/kg
(90.1 or 780 mg/kg bw)- to mature male Fischer 344 rats. Urine, feces and
expired air were collected for 48 hours. A total of 11.2-24.8% of the total
dose of radioactivity was recovered from the urine, 63.4-66.0% from expired
air and only 0.9-1.5% from the feces. Upon sacrifice, the carcass and skin
were found to contain 7.7-10.9% of the total dose.
2.2. INHALATION
2.2.1. 2-Methyoxyethanol and 2-Ethoxyethanol. Dajani (1969) found that
plasma levels of 2-ethoxyethanol 1n rats Increased nearly linearly with
exposures for 1, 2, 4 and 6 hours to 3317 ppm of glycol monoethyl ether.
-6-
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Extending the exposure time to 8 hours resulted 1n a near doubling of the
plasma levels, Indicating saturation of the metabolic pathways and substan-
tial absorption following Inhalation exposure.
2.2.2. Other Ethylene Glycol Ethers. Carpenter et al. (1956) demon-
strated that butoxyacetlc add 1s a metabolite of ethylene glycol monobutyl
ether 1n several laboratory species and man, and they have developed a
method for estimating the concentration of butoxyacetlc add 1n urine that
may Indicate exposure to ethylene glycol monobutyl ether by any route.
Substantial quantities of butoxyacetlc add were found In the urine of dogs,
monkeys and humans exposed to atmospheres containing 100-385 ppm ethylene
glycol monobutyl ether (duration of exposure not specified).
2.2.3. Propylene Glycol Ethers. Absorption data for the propylene glycol
ethers by the Inhalation route could not be located 1n the available
literature.
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral.
3.1.1.1. 2-METHOXYETHANOL AND 2-ETHOXYETHANOL -- Reports of toxldty
related to subacute oral exposure of animals to 2-methoxyethanol and
2-ethoxyethanol are summarized 1n Table 3-1. Many of the early studies are
reported Incompletely.
2-Methoxyethanol and 2-ethoxyethanol appear to have similar spectra of
toxldty, causing depression of RBC, reduced fertility and testlcular
degeneration (Nagano et al., 1984; Stenger et al., 1971; Lamb et a!., 1984;
Zenlck et al., 1984a,b; Oudlz et al., 1984). Reduced appetite and body
weight were also reported (Smyth et al., 1951; Union Carbide, n.d.). For
2-methoxyethanol the effects on the testls of the rat appeared to occur at a
lower dose (179 mg/kg bw/day) than did effects on the blood cells (357 mg/kg
bw/day) In a 5-week study (Nagano et al., 1984). Chapln et al. (1984)
demonstrated that testlcular effects are a very sensitive endpolnt of
2-methoxyethanol Intoxication 1n the rat. These researchers noted a marked
Increase 1n necrotlc spermatocytes 1n rats within 24 hours of a single 150
mg/kg bw dose. Foster et al. (1983) noted degeneration of primary spermato-
cytes within 24 hours 1n rats treated with 100 mg/kg bw. In 11-day studies
comparing the toxldty of 2-methoxyethanol and 2-ethoxyethanol, a dose of
500 mg/kg bw/day of 2-ethoxyethanol caused the same effect on the testes of
rats as did a dose of 100 mg/kg bw/day of 2-methoxyethanol (Creasy et al.,
1984; Foster et al., 1984). Zenlck et al. (1984a,b) and Oudlz et al. (1984)
demonstrated that the effects of 2-ethoxyethanol on the testes are rever-
sible. Five dally doses of 1872 or 2808 mg/kg bw resulted 1n aspermla by
week 7. Recovery was partial to complete by 14 weeks after treatment.
-8-
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TABLE 3-1
Subchronlc Oral Studies with 2-Nethoxyethanol and 2-Ethoxyethanol
Compound
2-Methoxyethanol
2-Methoxyethanol
2-Methoxyethanol
2-Ethoxyethanol
2-Ethoxyethanol
2-Ethoxyethanol
2-Ethoxyethanol
2-Ethoxyethanol
Species/Strain
mlce/JCL-ICR
hamsters/
Syrian golden
guinea plgs/NR
rats/NR
rats/NR
rats/Wlstar
dogs/beagle
mlce/JCL-ICR
Exposure
0, 62.5, 125. 250. 500. 1000.
2000 mg/kg bw. 5 days /week
for 5 weeks by gavage
0. 62.5, 125. 250, 500
mg/kg bw/day 5 days/week
for 5 weeks by gavage
0. 250, 500 mg/kg bw/day,
5 days/week for 5 weeks
90 days In drinking water
90 days, diet
13 weeks, gavage, 7 days/week;
dosage given as 0, 50, 100,
200, 100/400, 200/800
pi/kg bw/day
13 weeks; gelatin capsule, 7
days/week; dosage given as 0,
50. 100 or 200 pi/kg bw/day
0. 500. 1000. 2000. 4000
mg/kg bw/day. 5 days/week
Dose
(mg/kg bw/day)
44.6. 89.3. 179. 357
714. 1429
44.6. 89.3. 179, 357
179, 357
210*
740a
1890a
125b
625b
0, 46.5. 92.9.
186, 191. 382C
0. 46.5
>92.9
186d
357. 714. 1429. 2857
Response
>179 mg/kg: dose-related testlcular atrophy
>357 mg/kg: dose-related decrease In RBC.
WBC
All treatment groups: dose-related decrease
In relative testlcular weight, no effect on
WBC
Both treated groups: marked reduction In
relative testlcular weight and WBC
No effect
Reduced appetite and growth; altered liver
and kidney weights
Mortality
No adverse effects
Body weight depression
No effects
lestlcular degeneration and reduced hemo-
globin and hematocrlt
No effects
Decreased hematocrlt and hemoglobin
lestlcular and kidney degeneration
>714 mg/kg: dose-related testlcular atrophy
and reduced WBC
Reference
Nagano et al..
1984
Nagano et al.,
1904
Nagano et al. ,
1984
Smyth et al.,
1951
Union Carbide
Corp., n.d.
Stenger et al . ,
1971
Stenger et al . .
1971
Nagano et al. .
1984
2-Ethoxyethanol
for 5 weeks by gavage
mlce/COBS 0. 0.5, 1.0 or 2.OX In
drinking water for 14 weeks
(continuous breeding protocol)
1000. 2000, 4000e
2.OX: reproduction precluded; females had no Lamb et al.
fertile matlngs, male fertility reduced 1984
l.OX: reduced fertility
0 and 0.5X: no effects on fertility
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1ABLE 3-1 (cont.)
Compound
2-Ethoxyethanol
Species/Strain Exposure
rats/Long-Evans 0 or 936 mg/kg bw by gavage
5 days /week for 6 weeks
Dose
(mg/kg bw/day)
669
Response
Reduced rate of body weight gain, decreased
hemoglobin and pcv. decreased sperm count
and motHlty. Increased abnormal sperm
morphology
Reference
Zenlck et al..
1984a.b;
Oudlz et al.,
1984
i Assumption: rats drink 35 ml of water/day and weigh 0.35 kg
i ''Assumption: rats eat food equivalent to SX of their body weight/day
C0oses calculated from SG=0.929; 100/400, 200/800. Lower dose given for 59 days: higher dose given for 32 days.
dDoses calculated from SG^O.929
Assumption: Nice drink 6 ml of water/day and weigh 0.03 kg
NR - Not reported; RBC = red blood cells; WBC -- white blood cells; pcv = packed cell volume; SG =- specific gravity
-------
Hamsters appear to be more sensitive than rats to the effects of
2-methoxyethanol, since effects on the testes were noted at 44.6 mg/kg
bw/day, the lowest level tested In a 5-week study (Nagano et al., 1984).
2-Ethoxyethanol has not been tested 1n hamsters.
In early studies with 2-ethoxyethanol 1n rats a dose of 210 mg/kg bw/day
was associated with no effects (Smyth et al., 1951) and 625 mg/kg bw/day was
associated only with body weight depression (Union Carbide, n.d.). These
early studies failed to observe the effects on the blood cells and testes
characteristic of this chemical. These effects appear to occur at 186 mg/kg
bw/day 1n rats (Stenger et al., 1971), 92.9 mg/kg bw/day 1n dogs (Stenger et
al., 1971) and 714 mg/kg bw/day In mice (Nagano et al., 1984).
It appears that 2-methoxyethanol may also be more toxic than 2-ethoxy-
ethanol to mice as well as rats because testicular atrophy was noted for the
2-methoxyethanol at 179 mg/kg bw/day and for 2-ethoxyethanol at 714 mg/kg
bw/day (Nagano et al., 1984).
3.1.1.2. OTHER ETHYLENE GLYCOL ETHERS Several subchronic studies
of other ethylene and diethylene glycols have been performed and are
summarized 1n Table 3-2. Ethylene glycol dimethyl ether appears to have a
spectrum of activity similar to that of 2-methoxyethanol in that mice dosed
at 179 mg/kg bw/day had reduced testicular weights and reduced WBC counts
(Nagano et al., 1984). Slight testicular atrophy was noted in mice at 357
mg/kg bw/day of ethylene glycol monophenyl ether (Nagano et al., 1979).
Nagano et al. (1984) reported no effects on the testes of mice with ethylene
glycol monopropyl ether or ethylene glycol monobutyl ether at 2000 mg/kg
bw/day or with ethylene glycol monophenyl ether at 1000 mg/kg bw/day when
administered by gavage on 5 days/week for 5 days.
-11-
-------
1ABIE 3-2
Subchronlc Oral Studies with Other Ethylene Glycol Ethers
Compound
Ethylene glycol
monobutyl ether
Ethylene glycol
monobutyl ether
Ethylene glycol
dimethyl ether
Ethylene glycol
monophenyl ether
Dlethylene glycol
monoethyl ether
Dlethylene glycol
monoethyl ether
Dlethylene glycol
monoethyl ether
Dlethylene glycol
monoethyl ether
Species/Strain
rats/NR
mlce/NR
mlce/JCL-ICR
mlce/NR
rats/NR
rats/NR
rats/NR
mlce/NR
Exposure
diet, duration unspecified
gavage,
0, 250.
bw/day.
5 weeks
gavage,
30-day,
90-day.
90-day.
90-day.
5 days /week, 5 weeks
500, 1000 nig/kg
5 days/week for
by gavage
5 days/week, 5 weeks
drinking water3
diet
diet
diet
Dose
(mg/kg bw/day)
15 or 62.5
250
62.5-4000
179, 357, 714
357, 714,
1429
210-490
870
1770
<500b
-2500b
-250
-2500
185-1000
7000-10.000
Response
No adverse effects
Growth depression, Increased liver and
kidney weights
No significant effects on testes or blood
All treated groups: dose-related decrease
In relative testlcular weight and reduced
WBC
Slight testlcular atrophy
Death of 5/5
No effects
Reduced appetite
Reduced growth, microscopic lesions In
kidney, spleen, liver, testes
No effects
Reduced growth and food Intake, slightly
Impaired renal function. Increased kidney
and testes weight
No effects
Reduced hemoglobin, oxalurla
No effects
Reduced hemoglobin, severe kidney damage,
Reference
Carpenter,
et al.. 1956
Nagano et al. ,
1979
Nagano et al..
1984
Nagano el al.,
1979
Smyth and
Carpenter, 1948
Hall et al.,
1966
Gaunt et al..
1968
Gaunt et al. ,
1968
oxalurla
-------
TABLE 3-2 (coot.)
Compound
Species/Strain
Exposure
Dose
(g/kg bw/day)
Response
Reference
Dlethylene glycol ferrets/NR
monoethyl ether
Dlethylene glycol rats/NR
monomethyl ether
Dlethylene glycol rats/NR
nonomethyl ether
Dlethylene glycol rats/NR
, nonobutyl ether
CO
i
Dlethylene glycol rats/NR
monobutyl ether
Dlethylene glycol rats/NR
monobutyl ether
duration and method not
reported*
30-day, drinking water8
110-day, drinking water
30-day, drinking watera
109-day, drinking water3
drinking water study,
duration unspecified3
500-3000
190
1830
~1000C
~3000-5000C
51
94
650
~1000C
3000-5000C
No adverse effects
No effects
Reduced growth
No effects
Hydropic degeneration of kidney tubules
No effects
Reduced appetite
Microscopic lesions In liver, kidney,
spleen, testcs
No effects
Anorexia, starvation, dehydration; death
of 3/9. degeneration of renal cortex
Butterworth
et al., 1976
Smyth and
Carpenter, 1948
Kesten et al..
1939
Smyth and
Carpenter, 1948
Kesten et al.,
1939
Kesten et al.,
1939
aProtocol Incompletely reported
''Assumed: Rats eat food equivalent to 5X of their body weight/day
'Assumed: Rats drink 35 ml of water/day and weigh 0.35 kg
NR -- Not reported
-------
Tyler (1984) reviewed three studies of the subchronlc oral toxlcity of
ethylene glycol monobutyl ether In rats and mice. It appeared that the
threshold for testlcular degeneration In rats was 200 mg/kg bw/day In a
3-month study (Union Carbide Corporation, 1963). In another study with this
compound, 250 mg/kg bw/day resulted 1n depressed growth and Increased Hver
and kidney weights, but no mention was made of effects on the testicles
(Carpenter et al., 1956).
Generally, the dlethylene glycols tend to be less toxic than the
ethylene glycol ethers (Smyth and Carpenter, 1948; Hall et al., 1966;
Butterworth et al., 1976; Browning, 1965; Kesten et al., 1939). Effects
Include reduced growth, lesions In the liver and kidney and reduced blood
hemoglobin concentration (Smyth and Carpenter, 1948; Hall et al., 1966;
Kesten et al., 1939). P1gs may be more sensitive to dlethylene glycol mono-
ethyl ether than rats or mice, however, only 2-3 pigs per treatment group
were tested making these data difficult to Interpret (Gaunt et al., 1968).
3.1.1.3. PROPYLENE GLYCOL ETHERS -- The propylene glycol ethers
appear to be somewhat less toxic than the ethylene glycol ethers (Table
3-3). For both propylene glycol monomethyl and monoethyl ethers, the
threshold for adverse effects appears to be -680-900 mg/kg bw/day (Smyth and
Carpenter, 1948; Rowe et al., 1954).
3.1.2. Inhalation.
3.1.2.1. 2-METHOXYETHANOL AND 2-ETHOXYETHANOL -- Subchronlc studies
of the Inhalation toxlcity of 2-methoxyethanol and 2-ethoxyethanol are
summarized In Table 3-4. Effects of inhalation exposure Include mlcrocytlc
anemia, leukocytopenla with a granulocytlc left shift and microscopic
lesions 1n the testes (Werner et al., 1943a,b; Miller et al., 1982, 1984),
and a profound reduction of fertility (Hanley et al., 1984a; Rao et al.,
-14-
-------
TABLE 3-3
Subchrontc Oral Studies with Propylene Glycol Ethers
Compound Species/Strain
Exposure
Dose
Response
Reference
Ing/kg bw/day)
i
_j
i
Propylene glycol rats/NR
monoethyl ether
Propylene glycol rats/NR
monomethyl ether
Dlpropylene glycol rats/NR
mononethyl ether
30-day drinking water
35-day, gavage dose
5 days/week In olive oil
35 days*
680
2140
947
2847
1090
No adverse effects
Reduced growth, kidney changes
No adverse effects
Increased liver, kidney weights.
congestion and cloudy swelling of
liver and kidney tubular epithelium
No adverse effects
Smyth and
Carpenter,
Rowe et al
1954
Browning,
1948
1965
'Protocol Incompletely reported
NR ~ Not reported
-------
TABLE 3-4
Subchronlc Inhalation Studies with 2-Hethoxyethanol and 2-Ethoxyethanol
Compound
2-Hethoxyethanol
2-Hethoxyethanol
2-Hethoxyethanol
1, 2-Hethoxyethanol
i
2-Hethoxyethanol
2-Hethoxyethanol
Species/Strain
rabblts/NR
rabbi ts/NR
rabbit/New
Zealand White
dogs/NR
rats/NR
rat/
Sprague-Dawley
Exposure Dose
(mgAg bw/day)
30 ppm, 5 days /week for NCa
13 weeksb
0.3, 10 or 30 ppm. 5 days/week NCa
for 13 weeksb
0, 30, 100. 300 ppm. 23.6. 78.7, 236b
6 hours/day, 5 days/week
for 13 weeks
750 ppm, 7 hours/day, 57C
5 days/week for 12 weeks
310 ppm, 7 hours/day, 149d
5 days/week for 5 weeks
0, 30, 100, 300 ppm. 12.4. 41.3, 123. 9d
6 hours/day, 5 days/week
Response
Decreased testlcular size and hlstologlcal
changes
No effects on testes
0-30 ppm: no effect
100 ppm: two females died, cause undeter-
mined
300 ppm: two females and two males died,
cause undetermined; testlcular degeneration,
reduced WBC, RBC, hemoglobin, pcv, platelet
count, reduced thymus and testes weights
Occular and nasal Irritation, mlcrocytlc
anemia, leukopenla, granulocytlc left
shift, urinary Ca oxalate crystals
Hoderate splenic hemostderosls, fatty re-
placement of bone marrow cells, granulo-
cytlc left shift
0-30 ppm: no effect
100 ppm: reduced body weight of females
Reference
Hlller et al.,
1982
Hlller et al.,
1982
Hlller et al.,
1984
Werner et al. ,
1943a
Werner et al.,
1943b
Hlller et al.,
1984
2-Hethoxyethanol
2-Ethoxyethanol
for 13 weeks
rat/ 0. 30. 100. 300 ppm,
Sprague-Dawley 6 hours/day, 5 days/week
for 13 weeks
rats/NR
370 ppm, 7 hours/day,
5 days/week for 5 weeks
12.4. 41.3, 123.9d
211*1
300 ppm: reduced body weight of males and
females, reduced relative weight of thymus
and testes. severe testlcular degeneration,
reduced WBC. RBC. hemoglobin, pcv. platelet
count
0-100 ppm: no effect on fertility
300 ppm: male fertility eliminated; no
effect on female fertility
Hemoslderosts of the spleen, decreased
hepatocytocellular cytoplasmlc density,
granulocytlc left shift
Kanley et al.,
1984a;
Rao et al.,
1983
Werner et al.,
1943b
-------
-------
1983). Additionally, Increased ocular and nasal Irritation were noted
(Barbee et al., 1984). No effects were observed In rats or rabbits exposed
to 2-methoxyethanol at 30 ppm (12.4 and 23.6 mg/kg bw/day, respectively) for
13 weeks (Miller et al., 1984). In dogs, mlcrocytlc anemia and leukocyto-
penla were noted at 57 mg/kg bw/day for 12 weeks (Werner et al., 1943a). In
rats, no effects on reproductive performance were observed at 41.3 mg/kg
bw/day for 13 weeks, but 123.9 mg/kg bw/day eliminated reproduction 1n this
species (Hanley et al., 1984a; Rao et al., 1983). Exposure to 123.9 mg/kg
bw/day for 10 days caused marked reduction 1n testlcular weight and atrophy
of the seminiferous tubules In male rats (Doe et al., 1983).
When exposure 1s by Inhalation, 2-ethoxyethanol appears to have nearly
the same toxic potency as 2-methoxyethanol. Altered hematologlc parameters
and occular and nasal Irritation occurred 1n dogs exposed to 2-methoxy-
ethanol at 57 mg/kg bw/day and 2-ethoxyethanol at 76 mg/kg bw/day (Werner et
al., 1943a). Rabbits exposed to 300 ppm 2-methoxyethanol or 236 mg/kg
bw/day (Miller et al., 1984) and 400 ppm 2-ethoxyethanol or 373 mg/kg bw/day
(Barbee et al., 1984) had altered hematograms and evidence of testlcular
degeneration.
3.1.2.2. OTHER ETHYLENE GLYCOL ETHERS -- Of the higher molecular
weight ethylene glycol ether, experimental data were located only for ethyl-
ene glycol monobutyl ether. These experiments are summarized 1n Table 3-5.
In humans, eye and upper respiratory Irritation occur at 100 ppm (Carpenter
et al., 1956). A concentration of 314 ppm 1s highly lethal to rats and 375
ppm 1s lethal to guinea pigs (Carpenter et al., 1956). Erythrocyte fragil-
ity as an early manifestation of hemolytlc anemia occurs at 77 ppm 1n rats
(Dodd et al., 1983) and at 100 ppm 1n mice (Carpenter et al., 1956).
-18-
-------
TABLE 3-5
Subchronic Inhalation Studies with Ethylcne Glycol Nonobutyl Ether
Species
Exposure
Dose
(mg/kg bw/day)
Response
Reference
Humans 100 or 200 ppm for two 69 or 13Ba
4-hour periods/day sep-
arated by 30-mlnute rest
period for "several ex-
posures"
Rats 203 or 314 ppm. 152 or 235b
7 hours/day. 5 days/week
for 6 weeks
Rats 135 or 320 ppm. 101 or 239ğ
8 hours/day. 5 days/week
for 5 weeks
Rats 250 ppm. 7 hours/day. 187b
5 days/week for 6 weeks
Rats 5. 25 or 77 ppm. 3.2. 16.0. 49.4b
6 hours/day. 5 days/week
for 5 or 13 weeks
Nice 100. 200 or 400 ppm. 168. 336 or 671C
7 hours/day. 5 days/week
for 6. 12 and 18 weeks
Guinea pigs 375 or 500 ppm. 202 or 269d
7 hours/day. 5 days/week
for 6 weeks
>100 ppm: nose, throat, eye Irritation; altered
taste sensation, nausea, urinary excretion of
butoxyacctlc acid
200 ppn: headache
314 ppm: 15/15 died
203 ppm: no deaths. Increased liver weight, RBC
fragility, hcmogloblnurla
Both levels: decreased density of hepatic cyto-
plasm decreased RBC, hemoglobin
Hcmogloblnurla after only three exposures. In-
creased relative liver and kidney weights
5-25 ppm: no effects
77 ppm: transient decrease In rate of body weight
gain In females, decreased RBC In females at 5
but not at 13 weeks
>100 ppm: Increased RBC fragility
>200 ppm: hcmogloblnurla and Increased liver
weight
>375 ppm: Increased mortality, decreased rate of
body weight gain, Increased kidney weight
500 ppm: decreased body weight
Carpenter et al., 1956
Carpenter et al., 1956
Werner et al.. 1943b
Union Carbide
Corporation. 1952
Dodd et al.. 1983
Carpenter et al.. 1956
Carpenter et al., 1956
-------
TABLE 3-5 (cont.)
Species
Exposure
Dose
(mg/kg bw/day)
Response
Reference
Guinea pigs 62. 125 or 250 ppm. 33.4. 67.3 or 135d
7 hours/day. 5 days/week
for 6 weeks
Dogs 415 ppm, 5 hours/day 35.3e
5 days/week for 12 weeks
62-125 ppm: no effects
250 ppm: Increased kidney weight
Respiratory and occular Irritation, decreased RBC
and hemoglobin. Increased BUN
Union Carbide
Corporation, 1952
Werner et al.. 1943a
o
i
aAssumed: humans Inhale 10 m* during the workday and weigh 70 kg; 100X absorption
^Assumed: rats Inhale 0.26 ro'/day and weigh 0.35 kg; 100X absorption
cAssumed: mice Inhale 0.05 mVday and weigh 0.03 kg; 100X absorption
dAssumed: guinea pigs Inhale 0.23 mVday and weigh 0.43 kg; 100X absorption
eAssumed: dogs Inhale 1.5 nVday and weight 12.7 kg; 100X absorption
RBC - Red blood cells; BUN = blood urea nitrogen
-------
Decreased density of hepatic cytoplasm was noted In rats at 101 mg/kg bw/day
(Werner et al., 1943b). A concentration of 125 ppm In guinea pigs was the
highest level at which effects were not observed (Union Carbide Corporation,
1952). Respiratory and occular Irritation, decreased RBC and hemoglobin,
and Increased BUN were noted 1n dogs at 35.3 mg/kg bw/day (Werner et al.,
1943a).
3.1.2.3. PROPYLENE GLYCOL ETHERS Subchronlc Inhalation studies
with the propylene glycol ethers are summarized In Table 3-6. The propylene
glycol ethers appear to be somewhat less toxic than the ethylene glycol
ethers. Effects on reproduction have not been observed for these compounds.
Inhalation exposure 1s most likely to result 1n CNS depression, depressed
rate of body weight gain, liver enlargement and hlstopathologlcal changes In
the Hver (Rowe et al., 1954; MUler et al., 1984). In rats, rabbits and
guinea pigs, no-effect levels of propylene glycol monomethyl ether range
from -1100-1700 mg/kg bw/day (Rowe et al., 1954; Miller et al., 1984).
Monkeys appear to be more sensitive to this compound as Increased liver
weights were elevated at 645 mg/kg bw/day; no effects were observed at 344
mg/kg bw/day (Rowe et al., 1954).
Dlpropylene glycol monomethyl ether appears to be more toxic than
propylene glycol monomethyl ether as changes 1n the cytoplasm of hepatocytes
occur In monkeys at 151-220 mg/kg bw/day (Rowe et al., 1954).
3.2. CHRONIC
3.2.1. Oral.
3.2.1.1. 2-METHOXYETHANOL AND 2-ETHOXYETHANOL Data regarding
chronic oral toxldty were located only for 2-ethyoxyethanol. These
studies, performed with rats and mice, are summarized 1n Table 3-7. Degen-
eration of the seminiferous tubules and slight kidney damage were the only
-21-
-------
TABLE 3-6
Subchronlc Inhalation Studies with Propylcne Glycol Ethyl Ethers
Compound
Species
Exposure
Dose
(mg/kg bw/day)
Response
Reference
Propylene glycol rabbits and 800 ppm, 132 exposures over 186 days NO
monomethyl ether monkeys
rats and 1SOO ppm, 130 exposures over 184 days ND
guinea pigs 3000 ppm, 130 exposures over 184 days
i
ro
ro
I
rats
rats
rats
rats
rats
rats
monkeys
10,000 ppm. 2 hours/day for 84 days 2282a
10,000 ppm, 1 hour/day for 78 days 1141a
10.000 ppm. 0.5 hour/day for 79 days 570a
6000 ppm, 7 hours/day for 81 days 4791a
3000 ppm, 7 hours/day for 141 days
1600 ppm, 7 hours/day for 141 days
2396a
1198a
0. 300, 1000 or 3000 ppm, 6 hours/day 0. 147. 489
5 days/week for 13 weeks 1467a
10.000 ppm. 5 hours/day for 66 days 2457a
monkeys 3000 ppm 7. hours/day for 146 days 1290a
monkeys
1SOO ppm. 7 hours/day for 146 days 645a
No adverse effects Patty, 1963
No adverse effects
Hlld CNS depression
Growth depression. CNS depression. Increased Rowe et al.,
liver, kidney weight 19S4
Slight effect on CNS. no effect on growth,
organ or body weights
No effect on behavior, growth, body or organ
weights, histology
Hales: 4/10 dead; females: 7/10 dead; deep
narcosis with development of tolerance, in-
creased liver weight. Increased kidney weight
males; no hlstologlcal change.
Mild CNS depression; Increased liver weight;
effect on final body weight, histology. BUN.
hematology
No effect on mortality, behavior, growth, organ
weights, BUN, hematology. histology
0-1000 ppm: no effects Miller et al.,
3000 ppm: slightly elevated liver weights, 1984
hepatocellular swelling In females; sedation
Depressed body weight, CNS depression, In- Rowe et al.,
creased liver weight, moderately severe change 1954
In liver and lung histology
Increased liver weights, slight hlstologlcal
changes In lung and liver; no effect on body
weight. BUN.hematology
Increased liver weight, moderate lung changes;
No other effects
monkeys 800 ppm, 7 hours/day for 147 days 344a
No effects
-------
TABLE 3-6 (cont.)
Compound
Species
Exposure
Dose
Response Reference
(mg/kg bu/day)
Propylene glycol
monoroethyl ether
guinea pigs
guinea pigs
rabbits
6000 ppn,
3000 ppn.
6000 ppm,
7 hours/day for BO days
7 hours/day for 130 days
7 hours/day for 80 days
3450*
1725*
9133a
Narked narcosis, depression In growth, slight Roue et al.,
effect on liver histology 1954
No effects
Narcosis, growth depression. Increased lung and
rabbits 3000 ppm, 7 hours/day for 130 days
rabbits 1500 ppm. 7 hours/day for 130 days
rabbits BOO ppm, 7 hours/day for 132 days
rabbits 0. 300, 1000 or 3000 ppm, 6 hours/day
5 days/week for 13 weeks
Dlpropylene glycol rats
monomethyl ether
300-400 mg, 7 hour/day, 5 day/week
for 140 exposures (-28 week)
guinea pigs, 300-400 ppm, 7 hours/day, 5 days/week
for 130 exposures (-26 week)
rabbits 300-400 ppm, 7 hours/day. 5 days/week
for 156 exposures (-31 week)
monkeys 300-400 ppm, 7 hours/day, 5 day/week
for 156 exposures (-31 week)
and liver weights, slight histologlcal changes
In lung, but not liver
4567a Slight increase in liver weight, slight histo-
loglcal changes in lung and liver
2283a Increased liver weight, slight histologlcal
changes In lung and liver of females
1218a No adverse effects
0, ?BO. 932 or 0-1000 ppm: no effects Miller et al.,
2796 3000 ppm: sedation 1984
281-375a Slight transient narcosis during first weeks; Rowe el al..
Increased liver weight; no effect on growth, 1954
other organ wetghts;mortal)iy, hematology (RBC.
UBC differential) or histology (lungs, kidney,
heart, testes)
203-?70a Livers of females showed slight granulation and Rowe et al..
vacuolizatlon of cytoplasm; no effects on mor- 1954
tallty, growth, behavior, organ weights or other
histology
536-7153 Hepatic cytoplasm granulated and vacuolatcd; Rowe et al.,
no effect on mortality, growth, behavior, organ 1954
weights or other histology
151-202a Hepatic cytoplasm granulated and vacuolated; Rowe et al..
no effect on mortality, growth, behavior, hema- 1954
tology, organ weights or other histology
Assumptions: Rats Inhale 0.26 m* air/day and weigh 0.35 kg, absorption - 100X
Monkeys inhale 1.4 ng* air/day and weight of 3.5 kg, absorption = 100*
Guinea pigs Inhale 0.23 mğ air and weight of 0.43 kg. absorption = 100X
Rabbits Inhale 1.6 Ğ' air/day and weight of 1.13 kg. absorption = 100%
ND = Not derived (exposure data were Insufficient); RBC = red blood cells; UBC = white blood cells
-------
TABLE 3-7
Chronic Oral Studies with 2-Ethoxyethanol
Species
Exposure
Dose
{mg/kg,
absorption = 100X bw/day)
Response
Reference
i
IS)
Rats 1.45X In diet for 2 years
Rats 0, 500, 1000 or 2000 Dig/kg bw
5 days/week for 103 weeks
Nice 0. 500. 1000 or 2000 ntg/kg bw
5 days/week for 103 weeks
725*
0. 357. 714 or 1429
0. 357, 714 or 1429
Enlarged edemetous testes with seminiferous tubular Morris
degeneration In 2/3 of the animals et al., 1942
2000 mg/kg: terminated at 17-18 weeks due to high Helnlck, 1984
mortality
1000 mg/kg: reduced survival of males
500-1000 mg/kg: reduced body weights In both sexes;
adrenal enlargement In males
2000 mg/kg: terminated at 17-18 weeks due to high Helnlck, 1984
mortality
1000 mg/kg: decreased testlculaj weights
500 mg/kg: no effects reported
'Estimated assuming rats consume 5X of their body weight per day
-------
lesions reported In a 2-year dietary study In rats at 725 mg/kg bw/day
(Morris et al., 1942). In a 2-year NCI bloassay, high mortality occurred
very early (within 17 weeks) 1n rats treated by gavage at 1429 mg/kg bw/day
(Helnlck, 1984). The dead rats had testlcular degeneration and gastric
ulcers, which was considered to be the Immediate cause of death. Reduced
body weights {both sexes) and adrenal enlargement (males only) were observed
at 357 mg/kg bw/day, the lowest dose tested.
In the NCI bloassay, mice treated by gavage at 1429 mg/kg bw/day also
died early 1n the course of treatment, and had lesions Identical to those of
the rats treated at the same level (Melnlck, 1984). Decreased testlcular
weights were reported at 714 mg/kg bw/day. No lesions or effects were
reported at 357 mg/kg bw/day, but few criteria of toxldty were examined and
hlstopathologlcal examination had not been completed.
3.2.1.2. OTHER ETHYLENE GLYCOL ETHERS -- Chronic oral experiments
have been performed only with dlethylene glycol monoethyl ether. These
studies are summarized 1n Table 3-8. In rats, effects In the kidneys were
most commonly observed (Morris et al., 1942; Hanzllk et al., 1947). Other
effects Included slight Hver damage and Interstitial edema of the testls
(Morris et al., 1942).
In the 3-generat1on drinking water study by Smyth et al. (1964), effects
were not observed at <200 mg/kg bw/day. At 950 mg/kg bw/day, adverse
effects were seen 1n the kidneys, spleen and Intestine. Additionally,
fertility was reduced and calculi were found 1n the bladder.
Mice appeared to be more resistant than rats to dlethylene glycol mono-
ethyl ether because exposure via the drinking water at an Intake of 6900
mg/kg bw/day resulted in "no significant adverse effects" (Hanzllk et al.,
1957).
-25-
-------
TABLE 3-8
Chronic Oral Studies with Dlethylene Glycol Monoethyl Ether
I
IV)
Species/
Sex
Rats/NR
Rats/NR
Hlce/f
Rats/H.F
Exposure
2.16X In diet for 2 years
IX in drinking water for 2
years
5X In diet for 16 months
1.0. 0.2, 0.04 and 0.01X In
drinking water for 3 generations
(each generation maintained for
2 years)
Dose
(mg/kg bw/day)
10BOa
1409b
6900b
950. 200. 40 and
10C
Response
Few oxalate concretions In kidney of one rat, slight
liver damage. Interstitial edema of testes
4/5 survived to 16-31 months; 1/4 had tubular hydropic
degeneration of kidney
"No significant adverse effects*
No effects at < 200 mg/kg. At 950 mg/kg adverse
effects In kidney, spleen and Intestine.
Reduced fertility and bladder calculi
Reference
Morris et al.,
1942
Hanzllk et al.,
1947
Smyth et al.,
1964
Assumption: Rats eat food equivalent to 5X of their bw/day.
bBased on Intake data provided In study
cAuthors' estimate
NR = Not reported
-------
3.2.1.3. PROPYLENE GLYCOL ETHERS Pertinent data regarding the
chronic and toxlclty of the propylene glycol ethers could not be located 1n
the available literature.
3.2.2. Inhalation.
3.2.2.1. 2-METHOXYETHANOL AND 2-ETHOXYETHANOL -- There are relatively
few reports of occupational exposure to 2-methoxyethanol and 2-ethoxy-
ethanol, and these are summarized In Table 3-9. Marlnenko (1966) reported
increased pulse rate and decreased arterial pressure In women occupatlonally
exposed to 600-800 mg 2-ethoxyethanol/m3 during the workday. Atmospheres
containing 61-3960 ppm 2-methoxyethanol have been associated with headaches,
dizziness, CNS depression, cerebral atrophy, personality changes and
aplastic anemia and other severe hematological changes (Zavon, 1963;
Greenburg et al., 1938).
No Investigations of chronic inhalation exposure in animals have been
reported 1n the available literature.
3.2.2.2. OTHER ETHYLENE GLYCOL ETHERS Pertinent data regarding the
chronic Inhalation toxldty of other ethylene glycol ethers could not be
located 1n the available literature.
3.2.2.3. PROPYLENE GLYCOL ETHERS -- Pertinent data regarding the
chronic inhalation toxlclty of other ethylene glycol ethers could not be
located in the available literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
The teratogenic and fetotoxic effects of the glycol ethers have been
tested extensively In laboratory animals. Administration has been by both
the oral and Inhalation routes. As 1n the earlier sections of this chapter,
2-methoxyethanol and 2-ethoxyethanol are grouped together because these
-27-
-------
TABLE 3-9
Reports of Toxlclty In Humans Chronically Exposed to 2-Ethoxyethanol or 2-Methoxyethanol
Compound
Species
Exposure
Response
Reference
CO
I
2-Ethoxyethanol
2-Methoxyethanol
human, 600-800 mg/m3;
female occupational
human 61-3960 ppm
9-10 hour/day,
6 day/week
human NR
Increased pulse rate, decreased
arterial pressure
CNS depression, cerebral atrophy,
anemia, hypocellular bone marrow
Headache, dizziness, stomach
disorders, ocular Irritation,
personality changes, aplastlc
anemia, other hematologlcal
changes
Marlnenko, 1966
Zavon, 1963
Greenberg
et al., 1938
NR - Not reported
-------
compounds have similar effects and relative toxic potencies. The other
higher molecular weight ethylene glycol ethers are considered separately and
the propylene glycol ethers constitute a third class.
3.3.1. Oral.
3.3.1.1. 2-METHOXYETHANOL AND 2-ETHOXYETHANOL -- Teratogen1c1ty and
fetotoxlclty studies of these compounds are summarized 1n Table 3-10.
2-Methoxyethanol was administered by gavage to pregnant mice on days 7-14 of
gestation. A high dose of 1400 mg/kg bw/day resulted In the mortality of
14% of pregnant dams; survivors failed to produce any Utters (Schuler .et
a!., 1984). In another study, doses of 31.25-1000 mg/kg bw/day were
administered on days 7-14 of gestation (Nagano et al., 1981, 1984). Reduced
fetal body weights were observed at doses >125 mg/kg bw/day, but skeletal
teratogenlc abnormalities were observed 1n all treated groups In a dose-re-
lated manner for both Incidence and severity.
2-Ethoxyethanol appears to be a somewhat less potent teratogen and feto-
toxln than 2-methoxyethanol. Schuler et al. (1984) observed a 10% maternal
mortality In mice treated with 2-ethoxyethanol at 3605 mg/kg bw/day; no
litters were produced by survivors. In rats treated by gavage, teratogenlc
skeletal malformations were observed at doses >100 pi/kg bw/day (93.1
mg/kg bw/day) but not at lower doses (Stenger et al., 1971). Fetotoxlclty
(abortions, Increased resorptlons, reduced mean fetal body weight) was not
observed at doses <372 mg/kg bw/day. Both 2-methoxyethanol and 2-ethoxy-
ethanol are teratogenlc at doses lower than those associated with maternal
toxlclty or fetal toxldty.
3.3.1.2. OTHER ETHYLENE GLYCOL ETHERS The fetotoxlclty of higher
molecular weight ethylene glycol ethers was tested In mice. These studies
are summarized 1n Table 3-11. At doses >1000 mg/kg bw/day during gestation,
-29-
-------
TABLE 3-10
Teratogenlclty and Fetotoxlctty of Orally Administered 2-Hethoxyelhanol and 2-Ethoxyethanol
Compound
Species/Strain
Dose/Exposure
Maternal Response
Progeny Response
Reference
2-Nethoxyethanol mice/CD-I
2-Hethoxyethanol mlce/JCL-ICR
i 2-Ethoxyethanol mice/CD-I
2-Ethoxyethanol rats/Mlstar
1400 mg/kg bw/day on days
7-14 of gestation
0. 31.25. 62.5. 125. 250,
500 or 1000 mg/kg bw/day
on days 7-14 of gestation
3605 mg/kg bw/day on days
7-14 of gestation
14X mortality
1000 mg/kg/day: leuckocytopenla
>250 mg/kg/day: reduced rate of
body weight gain
10X mortality
0. 12.5. 25. 50. 100. 200 NR
or 400 wt/kg bw/day on
days 1-21 of gestation
(0. 11.6. 23.3, 46.6,
93.1. 186 or 372
mg/kg bw/day)*
No litters produced
250-1000 mg/kg bw/day: severe mortality
125-250 mg/kg bw/day: reduced fetal
body weight
XJ1.25 mg/kg bw/day: skeletal abnor-
malities, very severe In higher dose
groups
no litters produced
4000 pt/kg bw/day: Increased resorp-
tlons. decreased number of live fetuses
/litter, reduced mean fetal body weight
>100 pt/kg bw/day: Increased Inci-
dence of major skeletal malformations
Schuler et al.,
19B4
Nagano et al.,
1981. 1984
Schuler et al.,
1984
Stenger et al.,
1971
'Calculated from SG=0.931
NR = Not reported
-------
TABLE 3-11
Teratogenlclty and Fetotoxlclty of Orally-Administered Ethylene Glycol Ethers
i
CO
Compound
Ethylene glycol
monobutyl ether
Ethylene glycol
dimethyl ether
Ethylene glycol
dimethyl ether
Ethylene glycol
dimethyl ether
Ethylene glycol
dlethyl ether
Dtethylene glycol
monomethyl ether
Dlethylene glycol
monoethyl ether
Dlethylene glycol
monobutyl ether
Dlethylene glycol
rHmpthvl ether
Species/Strain
mice/CD-I
mlce/NR
mlce/JCL/ICR
mice/CD-I
mice/CD-I
mice/CD-I
mice/CD-I
ralce/CD-1
mice/CD-I
Dose/Exposure
1180 mg/kg bw/day on days
7-14 of gestation
2SO-490 mg/kg bw/day on
days 7-10 of gestation
0, 250. 350 or 490
mg/kg bw/day on days
7-10 of gestation
2000 mg/kg bw/day on days
7-14 of gestation
2955 mg/kg bw/day on days
7-14 of gestation
4000 mg/kg bw/day on days
7-14 of gestation
5500 mg/kg bw/day on days
7-14 of gestation
500 mg/kg bw/day on days
7-14 of gestation
3000 mg/kg bw/day on days
7-14 of aestatlon
Naternal Response
20% mortality
NR
no effects
26% mortality
10% mortality
10% mortality
14X mortality
No mortality
41% mortality
Progeny Response
Reduced percentage of viable litters
>480 mg/kg/day: embryonic death
>350 mg/kg/day: major external and
skeletal malformations
>250 mg/kg/day: growth retardation
and skeletal variation
490 mg/kg/day: Increased fetal death
>350 mg/kg/day: gross CNS and Internal
malformations
>250 mg/kg/day: skeletal malformation,
retarded ossification (fetotoxlclty)
No litters produced
Reduced percentage of viable litters, re-
duced proportion of live births, re-
duced birth weight, rate of body weight
gain and postnatal survival
Reduced percentage of viable litters, re-
duced neonatal survival
Reduced pup birth weight
No efffects
No litters produced
Reference
Schuler et al. ,
1984
HcGregor, 1981
Nagano et al.,
1984
Schuler et al.,
1984
Schuler et al.,
1984
Schuler et al.,
1984
Schuler et al.,
1984
Schuler et al.,
1984
Schuler et al.,
1984
-------
TABLE 3-11 (cont.)
Compound
Species/Strain
Dose/Exposure
Maternal Response
Progeny Response
Reference
Dtethylene glycol mice/CD-I
dtethyl ether
Dlethylene glycol mlce/CD-1
dlbutyl ether
TMethylene mice/CD-I
glycol dimethyl
7* ether
3000 mg/kg bw/day on days No mortality
7-14 of gestation
2000 mg/kg bw/day on days 8X mortality
7-14 of gestation
3500 mg/kg bw/day on days 4X mortality
7-14 of gestation
Slightly Increased number of dead pups Schuler et al.,
at birth, slightly decreased birth 1984
weight
Slightly Increased number of dead pups Schuler et al.,
at birth 1984
No litters produced
Schuler et al..
1984
NR = Not reported
-------
ethylene glycol monobutyl ether, ethylene glycol dimethyl and dlethyl
ethers, dlethylene glycol monomethyl, monoethyl, dimethyl, dlethyl and
dlbutyl ethers resulted 1n varying amounts of maternal mortality (0-41%) and
fetal mortality (Schuler et al., 1984). These studies were performed at
only one dosage level. Dlethylene glycol monobutyl ether resulted 1n no
maternal mortality or apparent effects on fertility at 500 mg/kg bw/day, the
only level tested.
MacGregor (1981) and Nagano et al. (1984) observed teratogenlc effects
with ethylene glycol dimethyl ether 1n fetuses from dams treated on days
7-10 of gestation with >350 mg/kg bw/day. Evidence of fetotoxldty such as
growth retardation, minor skeletal variations and delayed ossification
occurred at 250 mg/kg bw/day.
3.3.1.3. PROPYLENE GLYCOL ETHERS -- Pertinent data regarding the
teratogenlc and fetotoxlc effects of the propylene glycol ethers when admin-
istered orally could not be located 1n the available literature.
3.3.2. Inhalation
3.3.2.1. 2-METHOXYETHANOL AND 2-ETHOXYETHANOL -- Table 3-12 summa-
rizes teratogenlclty and fetotoxldty studies with 2-methoxyethanol 1n rats,
mice and rabbits. The sensitivity of the erythrocyte of rats to 2-methoxy-
ethanol was demonstrated by Hanley et al. (1984a,b). Exposures as low as 3
ppm, 6 hours/day for 10 days of gestation reduced both hematocrH and blood
hemoglobin concentration. In other studies 1n rats, high exposures (100-300
ppm, 6- to 7-hours/day) during days 9-11 of gestation resulted In severe
fetal mortality (Nelson et al., 1984a; Doe et al., 1983; Doe, 1984b).
Teratogenlc malformations were noted at 50 ppm 2-methoxyethanol (Nelson et
al., 1984a; Nelson and Brlghtwell, 1984; Miller et al., 1983b). At 25 ppm,
altered regional brain concentrations of neurochemlcals were observed 1n the
-33-
-------
TABIE 3-12
Teratogenlclty and Fctotoxtctty of 2-Nethoxyethanol Administered By Inhalation
Species/Strain
Dose/Exposure
Maternal Response
Progeny Response
Reference
i
CO
Rats/Fischer-344
Rats/
Sprague-Dawley
Rats/
Sprague-Dawley
Rats/Ftsher-344
Rats/Ulstar
Nice/NR
Mice CF-1
0. 3, 10 or SO ppm.
6 hours/day on days 6-IS
of gestation (0. 1.7, 5.8
or 29 mg/kg bw/day)a
sltght, transient decrease In body
weight gain at SO pom; dose-related
reduction In hematocrlt and hemo-
globin In all treated groups
0, 50. 100 or 200 ppm, NR
7 hours/day on days 7-15
of gestation (0, 33.7.
67 or 135 Ğg/kg bw/day)a
0 or 25 ppm, 7 hours/day no effects
on days 7-13 or 14-20 of
of gestation (0 or 16.9
mg/kg bw/day)a
0, 3. 10 or 50 ppm. NR
6 hours/day on days 6-15
of gestation (0. 1.7.
5.8 or 29 mg/kg bw/day)a
0. 100 or 300 ppm,
6 hours/day on days 6-17
of gestation (0, 57.8 or
173 mg/kg bw/day)a
300 ppm: reduced body weight gain
100 ppm: prolonged gestation
0, 3. 10 or 50 ppm, NR
6 hours/day on days 6-15
of gestation (0. 3.9.
13.0 or 65 mg/kg bw/day)b
0, 10 or 50 ppm.
6 hours/day on days 6-IS
of gestation (0. 13.0 or
65 mg/kg bw/day)D
SO ppm: reduced rate of body weight
gain
0-10 ppm: no effects
50 ppm: slight developmental defects In-
dicated slight fetotoxlclty; no terato-
genlclty at any dose level
0-10 ppm: no effects
100-200 ppm: severe fetal mortality
50 ppm: Increased resorptlons, decreased
fetal body weight. Increased malfor-
mations
no biologically significant effects on
behavior; altered regional brain concen-
trations of neurochcmlcals
50 ppm: "slight fetotoxlc effects'
0-10 ppm: no effects
300 ppm: no live litters produced
100 ppm: reduced total number of pups,
proportion of live pups, reduced weight
gain at day 3; no external malformations
In any group
50 ppm: reduced litter size and unilateral
tcstlcular hypoplasla of male offspring
0-10 ppm: no effects
Hanley et al.,
1984a.b
Nelson et al.,
1984a
Nelson et al.,
1984b; Nelson
and Brlghtwell.
1984
Miller et al..
1983b
Doe et al.,
1983;
Doe, 1984b
Blair, 1982
50 ppm: slight skeletal developmental dc- Hanley et al..
fccts Indicative of fetotoxlclty; no tera- 1984a.b
togenlclty at any dose level
0-10 ppm: no effects
-------
TABLE 3-12 (cont.)
Species/Strain
Dose/Exposure
Maternal Response
Progeny Response
Reference
Rabbits/Now
Zealand White
Rabbits/New
Zealand Unite
0, 3, 10 or SO ppra.
6 hours/day on days 6-18
of gestation (0. 3.3.
11.0 or 55 rag/kg bu/day)c
0. 3. 10 or 50 ppm,
6 hours /day on days 6-18
of gestation (0, 3.3,
11.0 or SS mg/kg bw/day)c
NR
SO ppm: reduced rate of body weight
0-10 ppm: no effects
SO ppm: significant Increase In resorp- Hlller et al.,
tlons and malformations 1983b
0-10 ppm: no effects
SO ppm: increased resorptlons, decreased Hanley et al.,
mean fetal body weights, malformations 1984a,b
Involving organs and skeleton
0-10 ppm: no effects
tn
i
aAssumed: Rats inhale 0.26 mVday and wetgh0.3S kg; 100X absorption
bAssumed: Nice Inhale O.OS mVday and weigh 0.03 kg; 100X absorption
cAssumed: Rabbits Inhale 1.6 mVday and weigh 1.13 kg; 100* absorption
NR = Not reported
-------
offspring of rats exposed 7 hours/day on days 7-13 or 14-20 of gestation,
but no biologically significant effects on behavior were noted (Nelson et
a!., 1984b; Nelson and Brlghtwell, 1984).
In mice, 50 ppm 2-methoxyethanol produced reduced Utter size and other
fetotoxlc effects and testlcular hypoplasla (Blair. 1982; Hanley et al.,
1984a,b). No effects were noted at 10 ppm. Similar findings were reported
for rabbits (Miller et al., 1983b; Hanley et al., 1984a,b).
The teratogenldty and fetotoxldty of 2-ethoxyethanol was tested 1n
rats and rabbits, and these experiments are summarized In Table 3-13.
2-Ethoxyethanol appears to have a fetotoxlc potency In rats slightly less
than that of 2-methoxyethanol. Exposures of 600-1200 ppm during gestation
resulted In death of all Utters and 200 ppm resulted 1n death of 34% of
delivered offspring (Nelson et al., 1981; Hardln et al., 1981; Andrew and
Hardln, 1984; Andrew et al., 1981). Exposure of dams to 100 ppm for 7 days
during gestation resulted 1n altered behavior of offspring (Nelson et al.,
1981, 1984c; Nelson and Brlghtwell, 1984). Retarded skeletal ossification,
an Indicator of slight fetotoxldty, was observed 1n the fetuses of rats
exposed to 50 ppm during 10 days of gestation (Doe, 1984a). Effects were
not noted at 10 ppm.
Rabbits may be somewhat more resistant to the fetotoxlc effects of
2-ethoxyethanol. In one study, exposure to 615 ppm for 19 days of gestation
led to the total resorptlon of all Utters (Hardln et al., 1981; Andrew and
Hardln, 1984). At 160 ppm, Increased fetal resorptlon and teratogenlc
changes were observed. In another study, however, only minor skeletal
changes evident of fetotoxldty were noted In fetuses from rabbits treated
at 175 ppm during 13 days of gestation (Doe, 1984a). No effects were noted
at 50 ppm.
-36-
-------
TABLE 3-13
Teratogenlcity and FetotoxtcUy of 2-Cthoxyethanol Administered by Inhalation
Species/Strain
Dose/Exposure
Maternal Response
Progeny Response
Reference
Rats/
Sprague-Dawley
Rats/
Sprague-Dawley
Rats/
Sprague-Dawley
Rats/Ulstar
Rats/Wlstar or
Sprague-Dawley
Rats/Wtstar or
Sprague-Dawley
900. 1200 ppm, NR
7 hours/day on days 7-13
of gestation (719 or 958
mg/kg bw/day)a
200. 600 ppm. NR
7 hours/day on days 7-13
or 14-20 of gestation
(160. 479 mg/kg bw/day)a
0 or 100 ppm. 7 hours/day
on days 7-13 or 14-20 of
gestation (0 or 80
oig/kg bw/day)a
0, 10. SO or 2SO ppm,
6 hours/day on days 6-15
of gestation (0. 6.8. 34
a
or 171 mg/kg bw/day)
0, 200 or 765 ppro,
7 hours/day on days 1-19
of gestation (0. 160 or
611 mg/kg bw/daya
0. ISO or 650 ppm 3 weeks
before mating, followed
by 0. 200 or 765 ppm on
days 1-19 of gestation;
exposures for 7 hours/day
(IHA-0, 139 or 563
mg/kg bw/day)a
Slightly prolonged gestation
(p^O.OOl)
250 ppm: reduced hemoglobin,
hematocrlt. NCV
0-50 ppm: no effects
750 ppm: reduced rate of body
weight gain
200 ppm: no effects
High dose group: reduced rate of
body weight gain
Low dose group: no effects
No live offspring delivered; dams treated Nelson et al..
on days 7-13 and sacrificed on day 20 con- 1981
talned no live fetuses
600 ppm: complete resorptlon of litters Nelson et al..
200 ppm: 34X of offspring delivered dead 1981
Reduced activity on rotorod (p^O.002) of Nelson et al..
offspring treated on days 7-13. reduced 1981. 19B4c;
performance in avoidance conditioning Nelson and
tests (p-0.004) In offspring treated on Brlghlwell.
days 14-20; altered regional or whole- 1984
brain concentrations of neurochemlcals
250 ppm: decreased mean fetal body weight. Doe. I984a
retarded ossification
50 ppm: slight fetotoxiclty (retarded
ossification)
0-10 ppm: no effects
750 ppm: all Utters totally resorbed Hardln et al..
200 ppm: reduced fetal body weight and 1981; Andrew
crown-rump length; cardiovascular and and Hardln,
skeletal malformations 1984; Andrew
et al.. 1981
High dose group: all litters totally re- Hardin et al.,
sorbcd 1981; Andrew
Low dose group: reduced fetal body weight and Hardln.
and crown-rump length; skleltal ma1 for- 1984; Andrew
nations el al.. 1981
-------
TABLE 3-13 (cont.)
Species/Strain
Dose/Exposure
Maternal Response
Progeny Response
Reference
Rabbits/New
Zealand White
Rabbits/Dutch
0. 160 or 615 ppm.
7 hours/day on days 1-18
of gestation (0. 244 or
936 mg/kg bw/day)b
0. 10. SO or 175 ppre,
6 hours/day on days 6-18
of gestation (0. 13. 65
or 228 mg/kg bw/day)b
615 ppm: severe anorexia, weight
loss, death of 5/29
160 ppm: anorexia, reduced body
weight gain, hepatomegaly
No effects
615 ppm: all litters totally resorbcd
160 ppm: Increased resorptlons, major
visceral and minor skeletal defects
175 ppm: minor skeletal defects (evidence
of fetotoxlclty)
0-50 ppm: no effects
Hard In et al.,
1981; Andrew
and Hardln.
1984
Doe. 1984a
co
i
aAssumed: Rats Inhale 0.26 mVday and weigh 0.35 kg; lOOTt absorption
bAssuroed: Rabbits Inhale 1.6 m*/day and weigh 1.13 kg; 100X absorption
NR - Not reported; NCV - mean corpuscular volume
-------
3.3.2.2. OTHER ETHYLENE GLYCOL ETHERS Teratogenlc effects were not
reported for ethylene glycol monobutyl ether or dlethylene glycol monoethyl
ether (Tyl et al., 1984; Nelson et al., 1984a) (Table 3-14). When tested at
100 ppm dlethylene glycol monoethyl ether, rats showed no evidence of feto-
toxlclty (Nelson et al., 1984a). The fetotoxlcity of ethylene glycol mono-
butyl ether, however, 1s not clearly understood. Nelson et al. (1984a)
reported no tox1colog1cally significant maternal effects and no effects on
the progeny of rats exposed to 200 ppm, 7 hours/day on days 7-15 of
gestation. Tyl et al. (1984), on the other hand, noted a reduced rate of
body weight gain and reduced RBC 1n rats exposed to >100 ppm for 6 hours/day
on days 6-15 of gestation. At 200 ppm, Increased resorptlons were noted and
at 100 ppm, there was retarded skeletal ossification, a sign of feto-
toxldty. No effects were observed In dams or fetuses at 50 ppm. Possibly,
the apparent discrepancies 1n the studies by Nelson et al. (1984a) and Tyl
et al. (1984) may represent differences between strains of rats. Nelson et
al. (1984a) used Sprague-Dawley rats and Tyl et al. (1984) used Fischer 344
rats.
Tyl et al. (1984) produced Increased mortality and spontaneous abortions
1n rabbits exposed to 200 ppm ethylene glycol monobutyl ether during days
6-18 of gestation. Fetal effects Included reduced Implantation, Increased
resorptlons and retarded skeletal ossification. No effects were observed In
either dams or fetuses at 100 ppm.
3.3.2.3. PROPYLENE GLYCOL ETHERS The teratogenldty and feto-
toxldty of propylene glycol monomethyl ether has been Investigated 1n rats
and rabbits (Table 3-15). The fetus of the rabbit appears to be resistant
as no effects on the fetus were observed when dams were exposed to 3000 ppm,
6 hours/day on days 6-18 of gestation (Hanley et al., 1984b,c). This level
-39-
-------
TABLE 3-14
Teratogenlclty and Fetotoxlclty of Ethylcne Glycol Ethers Administered by Inhalation
Compound
Species/Strain
Dose/Exposure
Maternal Response
Progeny Response
Reference
Ethylcne glycol
monobutyl ether
i Ethylene glycol
^ monobutyl ether
Ethylcne glycol
monobutyl ether
rats/
Fisher 344
rats/
Sprague-Dawley
rabbits/New
Zealand White
Dtethylene glycol rats/
monoethyl ether Sprague-Dauley
0. 25. SO. 100 or 200 ppm,
6 hours/day on days 6-15
of gestation (0. 22.4.
44.9. 89.8 or 180
mg/kg bw/day)a
0, 150 or 200 ppm,
7 hours/day on days 7-15
of gestation (0, 157 or
209 mg/kg bw/day)a
0. 25, 50. 100 or 200 ppm.
6 hours/day on days 6-18
of gestation (0, 42.8. 86.
171 or 343 ng/kg bw/day)b
0 or 100 ppm. 7 hours/day
on days 7-15 of gestation
(0 or 119 mg/kg bw/day)a
100 and 200 ppm: clinical signs
of maternal toxlclty. reduced
RBC. reduced rate of body
weight gain
0-50 ppm: no effects
No lexicologically significant
effects
200 ppm: clinical signs of tox-
lclty and Increased and spontan-
eous abortions (NS)
0-100 ppm: no effects
No effects
200 ppm: Increased resorptlons
>100 ppm: retarded skeletal ossifi-
cation
0-50 ppm: no treatment-related effects
No effects
Tyl et al.,
1984
Nelson et al..
1984a
200 ppm: reduced implantation. Increased Tyl et al.,
resorpttons. retarded skeletal osslflca- 1984
tlon
0-100 ppm: no treatment-related effects
No effects
Nelson et al.,
1984a
aAssumed: Rats Inhale 0.26 mVday and weigh 0.35 kg; 100X absorption
^Assumed: Rabbits inhale 1.6 m'/day and weight 1.13 kg; 100% absorption
NS = Not statistically significant
-------
TABLE 3-15
leratogenlclty and Fetotoxtclty of Propylene Glycol Ethers Administered by Inhalation
Compound
Species/Strain
Dose/Exposure
Maternal Response
Progeny Response
Reference
Propylene glycol
monomethyl ether
Propylone glycol
monomethyl ether
Propylene glycol
Monomethyl ether
Rats/
Fischer 344
Rats/Ulstar
Rabbits/New
Zealand White
0. 500, 1500 or 3000 ppm,
6 hours/day on days 6-15
of gestation (0. 342. 1027
or 2053 rag/kg bw/day)a
0. 200 or 600 ppm.
6 hours/day on days 6-17
of gestation (0. 137 or
411 mg/kg bw/day)*
0, 500. 1500 or 3000 ppm.
6 hours/day on days 6-18
of gestation (0. 652. 1957
or 3913 mg/kg bw/day)b
3000 ppm: CNS depression, de-
creased food Intake and rate
of body weight gain
0-1500 ppm: no effect
No effects
3000 ppm: transient CNS depres-
sion, decreased rate of body
weight gain
0-1500 ppm: no effects
3000 ppm: slight fetotoxlclty (delayed
sternebrae ossification)
0-1500 ppm: no effects
No effects
No effects
Hanley et al..
1904b,c
Doe et al.,
1983. 1984b
Hanley et al.,
1984b.c
"Assumed: Rats Inhale 0.26 mVday and weigh 0.35 kg
DAssumcd: Rabbits Inhale 1.6 m*/day and weigh 1.13 kg
-------
caused transient CNS depression and decreased rate of body weight gain In
the dams. In rats, delayed sternebral ossification, a mild fetotoxlc
effect, was observed In fetuses of dams exposed to 3000 ppm for 6 hours/day
on days 6-15 of gestation (Hanley et a!., 1984b,c). The dams exhibited CNS
depression, decreased food Intake and decreased rate of body weight gain.
No effects were observed at concentrations <1500 ppm (Hanley et al.,
1984b,c; Doe et al.. 1983, 1984b).
3.4. TOXICANT INTERACTIONS
Because of the effects of glycol ethers on the CNS, Budden et al. (1979)
Investigated the effects of dlethylene glycol monoethyl ether on hexabarbl-
tone-1nduced sleeping time. Oral administration of 0.7 g dlethylene glycol
monoethyl ether/kg bw to female NMRI mice Increased hexabarbHone-lnduced
sleeping time 100%. Similarly, a single 4-hour exposure to 125 ppm ethylene
glycol monomethyl ether also Increased pentobarbHal sleeping time 1n mice
(Goldberg et al., 1962).
The presence of ethylene glycol 1n dlethylene glycol monoethyl ether as
a contaminant can markedly affect the apparent toxldty to animals. Smyth
et al. (1964) exposed rats for 3 generations (animals were killed after 2
years) to drinking water treated with dlethylene glycol monoethyl ether
containing <0.2% or 29.5% ethylene glycol. The sample containing 29.5%
ethylene glycol was considerably more toxic than the purer grade. The
maximum safe dosage for the less pure sample was -0.01 g/kg/day, but the
maximum safe dose for the more pure sample was 0.20 g/kg/day, Indicating
that ethylene glycol may be several times more toxic than dlethylene glycol
monoethyl ether.
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Nelson et al. (1982, 1984c) tested the Influence of ethanol supplied at
10% in the drinking water to modify the neurobehavloral toxlcity of
2-ethoxyethanol administered prenatally via inhalation to Sprague-Dawley
rats. 2-Ethoxyethanol exposure was at 100 or 200 ppm, 7 hours/day on days
7-13 of gestation or at 200 ppm, 7 hours/day on days 14-20 of gestation.
When administered early in gestation (days 7-13), ethanol appeared to reduce
the effects of 2-ethoxyethanol on neuromotor behavior, as evidenced by
improved performance on the rotorod. Ethanol administered late in gestation
(Days 14-20) appeared to intensify the effects of 2-ethoxyethanol, as
performance In the open field test was reduced.
In a study of the effects of 2-methoxyethanol on the testes of rats,
Foster et al. (1984) administered a 500 mg/kg bw oral dose of 2-methoxy-
ethanol to unpretreated rats or rats pretreated with the alcohol dehydro-
genase Inhibitor pyrazole or pretreated with the aldehyde dehydrogenase
inhibitors disulfiram or pargyline. Rats that were not pretreated had
histopathologlcal alterations in the testes consisting of degeneration of
the primary spermatocytes. Pyrazole, the alcohol dehydrogenase inhibitor,
provided complete protection from the effects of 2-methoxyethanol. No
protection was provided by the aldehyde dehydrogenase inhibitors, disulfiram
or pargyline.
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4. CARCINOGENICITY
4.1. HUMAN DATA
No reports of carclnogenlcHy 1n humans exposed to the glycol ethers
have been located in the available literature.
4.2. BIOASSAYS
No bioassays of the glycol ethers 1n animals have been located 1n the
available literature. An NCI gavage bloassay of ethylene glycol monoethyl
ether 1s currently 1n progress, but results are not yet available (Melnlck,
1984).
4.3. OTHER RELEVANT DATA
The mutagenldty of several glycol ethers has been tested In prokaryote
and eukaryote systems. Results 1n the reverse mutation Salmonella typhl-
murlum assay (2-methoxyethanol: McGregor et al., 1983; McGregor, 1983;
2-ethoxyethanol: NTP, n.d.; Kowalek and Andrews, 1980; dlethylene glycol
monobutyl ether: Thompson et al., 1984; dlethylene glycol dimethyl ether:
McGregor et al., 1983; propylene glycol methyl ether: Klrkland and Varley,
1983a; Mendrala, 1983a; propylene glycol ethyl ether: Dow Chemical Co.,
1982; dlpropylene glycol methyl ether: Mendrala, 1983b, Klrkland and Varley,
1983b; trlpropylene glycol methyl ether: Mendrala, 1982), 1n the Escherlchla
coll reverse mutation assay {Szybalskl, 1958) and 1n a test 1n Schlzosac-
charomyces pombe (Abbondandolo et al., 1980) have been consistently negative.
2-Methoxyethanol (McGregor et al., 1983), ethylene glycol monobutyl
ether (Tyler, 1982), dlethylene glycol monobutyl ether (Thompson et al.,
1984), dlethylene glycol dimethyl ether (McGregor et al., 1983), propylene
glycol methyl ether {Mendrala, 1983c), and dlpropylene glycol methyl ether
(Mendrala, 1983b) were negative 1n the cell culture test for unscheduled DNA
synthesis.
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Results were mixed 1n the SCE test with CHO cells. 2-Ethoxyethanol
produced a positive response (NTP, n.d.) and ethylene glycol monobutyl ether
produced a negative response (Tyler, 1982). Similarly, In chromosomal
aberration tests with CHO cells, 2-ethoxyethanol was positive (NTP, n.d.),
but dlethylene glycol monobutyl ether (Thompson et al., 1984), propylene
glycol monomethyl ether (Klrkland, 1983a) and dlpropylene glycol monomethyl
ether (Klrkland, 1983b) were negative.
In tests for point mutations 1n mouse lymphoma L5178Y cells or CHO
cells, negative results were noted for 2-methoxyethanol (McGregor, 1984) and
ethylene glycol monobutyl ether (Tyler, 1982) and a weak positive result was
obtained for dlethylene glycol butyl ether (Thompson et al., 1984). Neg-
ative results were obtained with 2-methoxyethanol and dlethylene glycol
dimethyl ether 1n tests with rat bone marrow cells (McGregor et al.. 1983).
In the sex-linked recessive lethal test 1n Drosophlla. 2-methoxyethanol
(McGregor et al., 1983) and dlethylene glycol dimethyl ether (McGregor,
n.d.) produced Inconsistent results. Negative results were obtained with
2-ethoxyethanol (NTP, n.d.) and dlethylene glycol monobutyl ether (Thompson
et al., 1984). Weakly positive results were obtained for 2-methoxyethanol
and dlethylene glycol dimethyl ether 1n the dominant lethal test 1n male
rats (McGregor et al., 1983). These chemicals produced strongly positive
results 1n the mouse sperm abnormality test (McGregor et al., 1983).
4.4. WEIGHT OF EVIDENCE
The results of the NCI gavage bloassay of 2-ethoxyethanol 1n rats and
mice are not yet available. Intraperltoneal administration of trlethylene
glycol dlglycldyl ether, a research antlneoplastlc chemical, has been
significantly (p<0.001) associated with Increased Incidence of lung tumors
In A/J mice (Sh1mk1n et al., 1966).
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IARC has not evaluated the risks to humans associated with oral or
Inhalation exposure to the glycol ethers. Applying the criteria proposed by
the Carcinogen Assessment Group of the U.S. EPA for evaluating the overall
weight of evidence for cardnogenldty to humans (Federal Register, 1984),
the glycol ethers are most appropriately designated Group 0 - Not Classified
compounds.
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5. REGULATORY STANDARDS AND CRITERIA
Regulatory standards and criteria for glycol ethers are summarized 1n
Table 5-1. The ACGIH (1980) has set the recommended TWA-TLV for 2-methoxy-
ethanol at 5 ppm (-16 mg/m3) based primarily on the effects on reproduc-
tion 1n male rats (Rao et al., 1982). For 2-ethoxyethanol, the ACGIH (1980)
recommended a TWA-TLV of 5 ppm, reduced from an earlier high of 50 ppm
(based on the analogy of this compound with ethylene glycol ether). The
TWA-TLV for ethylene glycol monobutyl ether was recommended at 25 ppm to
protect workers from the hemolytlc effects of this compound, which have been
demonstrated most dramatically In the rat (Werner et al., 1943b; Carpenter
et al., 1956). A STEL of 75 ppm for this compound was recommended. The
toxlclty of propylene glycol monomethyl ether seems to be somewhat less than
the toxlclty of the ethylene glycol ethers discussed above. To protect
workers from the objectionable odors and ocular Irritation associated with
greater concentrations of propylene glycol monomethyl ether, a TWA-TLV of
100 ppm and a STEL of 150 ppm were recommended. The same criteria were
adopted by the ACGIH (1980) for dlpropylene glycol monomethyl ether, also to
protect workers from objectionable odor which may occur at concentrations
>100 ppm. CNS Impairment 1n humans apparently occurs at concentrations of
-1000 ppm.
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TABLE 5-1
Regulatory Standards and Criteria for Glycol Ethers
Standard or Criterion
Value
Reference
2-Methoxyethanol
TWA-TLV
OSHA standard
2-Ethoxyethanol
TWA-TLV
OSHA standard
Ethylene glycol monobutyl ether
TWA-TLV
STEL
OSHA standard
Propylene glycol monomethyl ether
TWA-TLV
STEL
5 ppm {-16 mg/m3)
25 ppm (-80 mg/m3)
5 ppm (-18 mg/m3)
200 ppm (-740 mg/m3)
25 ppm (-120 mg/m3)
75 ppm (-360 mg/m3)
50 ppm (-240 mg/m3)
100 ppm (-360 mg/m3)
150 ppm (-540 mg/m3)
Dlpropylene glycol monomethyl ether
TWA-TLV
STEL
OSHA standard
100 ppm (-600 mg/m3)
150 ppm (-900 mg/m3)
100 ppm (-600 mg/m3)
ACGIH, 1980
Code of Federal
Regulations, 1981
ACGIH, 1980
Code of Federal
Regulations, 1981
ACGIH, 1980
ACGIH, 1980
Code of Federal
Regulations, 1981
ACGIH, 1980
ACGIH, 1980
ACGIH, 1980
ACGIH, 1980
Code of Federal
Regulations, 1981
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6. RISK ASSESSMENT
Most of the toxldty studies discussed 1n Chapter 3 were early studies
that often used small numbers of experimental animals and Inadequate con-
trols. Moreover, the experimental protocol Including specific dosage levels
was often unclear In the secondary sources from which these studies were
cited. Where sufficient data were available, threshold levels were Identi-
fied.
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.1.1. Oral.
6.1.1.1. 2-METHOXYETHANOL AND 2-ETHOXYETHANOL ~ The subchronlc oral
studies with 2-methoxyethanol and 2-ethoxyethanol were summarized 1n Table
3-1. 2-Methoxyethanol appeared to be somewhat more toxic than 2-ethoxy-
ethanol. Nagano et al. (1984) Investigated the toxiclty of 2-methoxyethanol
1n mice, hamsters and guinea pigs by administering the chemical by gavage
for 5 weeks. Hamsters appeared to be the species most sensitive .to the
effects of 2-methoxyethanol on the testes, since a dose-related decrease In
testlcular weight was observed in all treated groups. The lowest dose
tested was 44.6 mg/kg bw/day. In other studies, Nagano et al. (1984)
observed terata in mice treated with 2-methoxyethanol during gestation at
31.25 mg/kg bw/day (see Table 3-10). Since these studies were not performed
at doses sufficiently low to identify a NOAEL, no AIS can be derived for
2-methoxyethanol.
A CS was calculated for 2-methoxyethanol based on teratogenicity 1n
mice, which occurred at 31.25 mg/kg bw/day in the gavage study by Nagano et
al. (1984). The animal dose was multiplied by the cube root of the body
weight ratio of mice (assumed: 0.03 kg) to that of humans (assumed: 70 kg)
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and by 70 kg to obtain a human MED of 165 mg/day, corresponding to an RVd
of 2.2. The teratogenldty observed was assigned an RVg of 10, and a CS
of 22 was calculated as the product of RVrf and RVg.
2-Ethoxyethanol was also found to be teratogenlc In rats when adminis-
tered during the gestation period at levels >93.1 mg/kg bw/day (Stenger et
a!., 1971} (see Table 3-10). Higher doses reduced fertility. No terato-
genic effects were observed at 11.6, 23.3 or 46.6 mg/kg bw/day. In a
13-week gavage study 1n rats, >186 mg/kg bw/day resulted In testlcular
degeneration and effects on the erythrocyte (Stenger et al., 1971} (see
Table 3-1). No effects were observed at 46.5 or 92.9 mg/kg bw/day.
An oral AIS for 2-ethoxyethanol can be calculated from a no-effect level
In the teratogenldty study in rats by Stenger et al. (1971) because 1t is
clear that all teratogenic no-effect levels are below levels that cause
other toxic effects. The NOEL for teratogenlc effects of 46.6 mg/kg bw/day
is used as the basis for the AIS. An uncertainty factor of 100 is applied,
a factor of 10 to reflect the unknowns in interspecies extrapolation and
another factor of 10 to protect unusually sensitive individuals. The result
is multiplied by 70 kg to result in an AIS for 2-ethoxyethanol of 32.6
mg/day for a 70 kg human.
6.1.K2. OTHER ETHYLENE GLYCOL ETHERS -- The ethylene glycol ethers
other than 2-methoxyethanol and 2-ethoxyethanol can be broadly classified
into two groups. The first group consists of other monoethylene glycol
ethers such as ethylene glycol monobutyl ether, ethylene glycol monophenyl
ether and ethylene glycol dimethyl ether. The second group consists of the
di- and triethylene glycol ethers. In the first category, the toxicity of
ethylene glycol dimethyl ether seems similar to the toxicity of 2-methoxy-
ethanol and 2-ethoxyethanol, although it may be relatively less potent. In
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a 5-week gavage test 1n mice, a dose-related decrease in relative testlcular
weights and reduced RBC was noted at all treatment levels (179-714 mg/kg
bw/day) (Nagano et al., 1984). At >350 mg/kg bw/day during gestation, major
Internal, external and skeletal malformations were produced (McGregor, 1981;
Nagano et al., 1984). Skeletal malformations Indicative of fetotoxldty
were observed at 250 mg/kg bw/day, the lowest dose tested. Studies were not
performed at doses sufficiently low to define no-effect levels of ethylene
glycol dimethyl ether. The data base on the other monoethylene glycol
ethers is insufficient to Identify no-effect levels or to rank their toxic
potency relative to that of ethylene glycol dimethyl ether (see Table 3-2).
Therefore, an oral AIS is not derived for the monoethylene glycol ethers.
The dlethylene glycol ethers appear to be somewhat less toxic than the
monoethylene glycol ethers (see Table 3-2). No-effect levels have been
determined at 490 mg/kg bw/day for dlethylene glycol monoethyl ether (Smyth
and Carpenter, 1948), and at 1000 mg/kg bw/day for dlethylene glycol mono-
methyl ether (Kesten et al., 1939). The toxicity of dlethylene glycol mono-
butyl ether Is not as clear, since 1000 mg/kg bw/day yielded no effects in
one study in rats (Kesten et al., 1939), but 650 mg/kg bw/day led to micro-
scopic lesions in the liver, kidney, spleen and testes of rats in another
study (Smyth and Carpenter, 1948). Organoleptic effects were observed 1n
the latter study at 94 mg/kg bw/day.
Schuler et al. (1984) investigated the fetotoxiclty of several diethyl-
ene glycol ethers in mice. High doses during days 7-14 of gestation were
used which were designed to cause -10% maternal mortality, and in all but
one case resulted in maternal mortality ranging from 4-41%. A spectrum of
effects Indicative of fetotoxldty were reported. However, this is not
surprising considering that testing was in the range of doses associated
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with maternal mortality. Additional testing at lower doses would be
desirable. The NOEL of 500 mg/kg bw/day (Hall et a!., 1966) for diethylene
glycol monoethyl ether, may be used to derive an AIS for this compound.
This Is supported by a NOEL of 490 mg/day from Smyth and Carpenter (1948).
An uncertainty factor of 100 Is applied, a factor of 10 for Interspecies
conversion and another factor of 10 to protect unusually sensitive individ-
uals. Multiplying the result by 70 kg results in an AIS for diethylene
glycol monoethyl ether of 350 mg/day for a 70 kg human.
This AIS should also be protective for diethylene glycol monomethyl
ether. Alternatively, a separate value for diethylene glycol monomethyl
ether could be calculated from the NOEL of 1000 mg/kg (Kesten et al., 1939).
The reporting of this study was Incomplete and the sole other report con-
cerning the subchronlc toxicity of this compound was a study of only 30 days
duration, reported in even less detail. In addition, in a fetotoxicity
evaluation, Schuler et al. (1984) reported 10% maternal mortality following
only 7 days of dosing of rats with 4000 mg/kg. In view of these concerns,
and also considering that the value derived for diethylene glycol monoethyl
ether would only over-estimate the AIS by a factor of 2 if following further
testing the NOEL of 1000 mg/kg is supported, it is suggested that the AIS of
343 mg/day based on diethylene glycol monoethyl ether serve as an interim
value for the monomethyl ether as well.
6.1.1.3. PROPYLENE GLYCOL ETHERS The subchronic oral toxicity of
propylene glycol monomethyl ether and propylene glycol monoethyl ether have
been Investigated In rats (see Table 3-3). Although these studies are only
marginally adequate for risk assessment, it appears that a NOEL for the
former compound is -900 mg/kg bw/day (Rowe et al., 1954) and for the latter
is 680 mg/kg bw/day (Smyth and Carpenter, 1948). An oral AIS for the propy-
lene glycol monoethyl ethers can be calculated from the NOEL of 680 mg/kg
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bw/day for propylene glycol monoethyl ether by applying an uncertainty
factor of 100 (10 for Interspedes conversion and 10 to protect unusually
sensitive Individuals) and multiplying the result by 70 kg. An AIS for the
propylene glycol monoethyl ether of 476 mg/day for a 70 kg human 1s calcu-
lated, which should be protective for the propylene glycol monomethyl ether
as well. An AIS for propylene glycol monomethyl ether may be calculated
from the NOEL of 949 rug/kg by multiplying by 5 days/7 days and applying an
uncertainty factor of 100, results In an AIS of 474.5 mg/day.
6.1.2. Inhalation.
6.1.2.1. 2-HETHOXYETHANOL AND 2-ETHOXYETHANOL The subchronlc
Inhalation toxldty of 2-methoxyethanol has been tested 1n rats, dogs and
rabbits (see Table 3-4). The highest NOEL below which effects were not seen
was 30 ppm 1n rabbits, 6 hours/day, 5 days/week for 13 weeks. This exposure
corresponds to a dose of 23.6 mg/kg bw/day (Miller et al., 1984) (see Table
3-4 for dose conversion procedure). In teratogenlclty and fetotoxlclty
studies (see Table 3-12), developmental defects and "slight fetotoxlc
effects" were observed 1n rats at 50 ppm, 6 hours/day on days 6-15 of gesta-
tion (Hanley et al., 1984a,b; Miller et al., 1983b). This exposure corre-
sponds to a maternal dose of 29.0 mg/kg bw/day, which 1s similar to the NOEL
of 23.6 mg/kg bw/day from the subchronlc Inhalation studies. The NOEL for
fetotoxlclty In the Hanley et al. (1984a,b) and Miller et al. (1983b)
studies 1s 10 ppm (5.8 mg/kg bw/day), 5-fold less than the LOAEL.
In a study of behavioral and neurochemlcal alterations resulting from
prenatal exposure to 2-methoxyethanol, exposure to 25 ppm (16.9 mg/kg
bw/day) led to no biologically significant effects on behavior, but appeared
to result 1n altered regional brain concentrations of neurochemlcals (Nelson
et al., 1984b, Nelson and BMghtwell, 1984). The NOEL for fetotoxlclty of
5.8 mg/kg bw/day from the studies of Hanley et al. (1984a,b) and Miller et
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al. (1983b) 1s therefore chosen with confidence that 1s 1t also a NOEL for
subchronlc toxic effects from which to derive an Inhalation AIS for
2-methoxyethanol. An uncertainty factor of 100 is applied (10 for Inter-
species conversion and 10 to protect unusually sensitive individuals), and
the result, when multiplied by 70 kg, Is 4.1 mg/day for a 70 kg human.
The subchronlc inhalation studies with 2-ethoxyethanol summarized in
Table 3-4 define NOELS which are higher than the LOAEL for fetotoxldty in
rats determined by Doe (1984a). Therefore, the NOEL of 6.8 mg/kg from the
Doe (1984a) study may be used to estimate an AIS with assurance that this
dose is below effect levels for other subchronlc effects. Multiplying by 70
kg and applying an uncertainty factor of 100 results in an AIS of 4.8 mg/day.
The next highest exposure level (50 ppm) which resulted 1n fetotoxicity
may be used to calculate a CS. The animal dose is estimated as 23 mg/kg/
day. Application of the cube root of the ratio of the body weight of rats:
body weight of humans results in a human MED of 409 mg/day and an RVrf of
1.6. Multiplying by an RVg of 8 yields a CS of 12.7.
6.1.2.2. OTHER ETHYLENE 6LYCOL ETHERS -- Of this subclass of com-
pounds, subchronlc Inhalation studies have been performed only with ethylene
glycol monobutyl ether (see Table 3-5). In humans, 100 ppm (69 mg/kg
bw/day) resulted in ocular and respiratory Irritation, altered taste and
nausea (Carpenter et al., 1956). Ethylene glycol monobutyl ether has also
been tested for teratogenldty and fetotoxicity (see Table 3-14). Retarded
skeletal ossification was reported in rats at 100 ppm during gestation (Tyl
et al., 1984). No effects occurred at 50 ppm corresponding to 44.9 mg/kg
bw/day (see Table 3-14 for dose conversions).
A NOEL for guinea pigs of 67.3 mg/kg was defined by Union Carbide
(1952), however, the study was of only 6 weeks duration. Dodd et al. (1983)
defined a NOEL of 16 mg/kg for rats following 13 weeks of exposure. The
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next highest exposure corresponding to either a LOAEL or NOAEL was 49.4
mg/kg. The effects, transient weight depression and depressed red blood
cell counts, are difficult to judge because of lack of detail 1n the report-
Ing. In addition, Werner et al. (1943a) reported a LOAEL of 35.3 mg/kg for
the dog following 12 weeks of exposure. In this study only one dose was
tested. The NOEL of 16 mg/kg In the rat may be used to estimate an AIS.
This dose is below the threshold defined for fetotoxlcity. Multiplying by
70 kg and dividing by an uncertainty factor of 100 results in an AIS of 11.2
mg/day.
The Inhalation toxicity of ethylene glycol monobutyl ether appeared to
be more sensitive in guinea pigs than other laboratory species. A CS was
calculated for increased mortality in guinea pigs exposed to 375 ppm (1812.4
mg/m3), 7 hours/day, 5 days/week for 6 weeks. The Intake, assuming guinea
pigs inhale 0.23 mVday and weigh 0.43 kg, was 202 mg/kg bw/day. Applying
the cube root of the ratio of the body weight of guinea pigs to man and
applying an uncertainty factor of 10 to convert from subchronic exposure to
chronic data results in a human MED of 259 mg/day and an RVd of 1.9.
Increased mortality was assigned an RV of 10, and a CS of 19 was
C
calculated as the product of RV . and RV .
6.1.2.3. PROPYLENE GLYCOL ETHERS Subchronic inhalation studies
suitable for risk assessment were performed with propylene glycol monomethyl
ether in rats, monkeys, guinea pigs and rabbits (see Table 3-6). The
highest NOAEL below which adverse effects were not reported was 10,000 ppm
in rats for 0.5 hours/day over a 79-day period. The corresponding dose was
570 mg/kg bw/day (Rowe et al., 1954) (see Table 3-6 for dose conversion).
However, the daily exposure duration in the study is considered inadequate
for continuous-exposure risk estimates. Of studies with adequate exposure
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duration, Miller et al. (1984) defined the highest NOEL which 1s below other
LOAELS (1000 ppm, 6 hours/day 1n the rat). In fetotoxlcity testing, no
effects were produced in rats exposed during gestation at 1500 ppm (1027
mg/kg bw/day Table 3-15). The NOEL of 489 rag/kg bw/day (estimated from 1000
ppm exposure concentration) (Miller et al., 1984) is chosen for derivation
of an AIS for propylene glycol monomethyl ether with confidence that
protection will also be provided against fetotoxlc effects. An uncertainty
factor of 100 is applied as discussed previously. The resultant AIS, 4.9
mg/kg/day, corresponds to 342 mg/day for a 70 kg human.
Dipropylene glycol monomethyl ether appears to be more toxic than propy-
lene glycol monomethyl ether when given by inhalation because effects on the
liver were observed at doses lower than the NOAEL for propylene glycol mono-
methyl ether (see Table 3-6) (Rowe et al., 1954). Since effects were seen
in rats, guinea pigs, rabbits and monkeys at all levels tested, an AIS for
dipropylene glycol monomethyl ether cannot be derived. Therefore, the AIS
for propylene glycol monomethyl ether Is expected to be protective for that
compound, but not for other members of the class propylene glycol ethers or
for the class as a whole.
Rowe et al. (1954) observed Increased mortality in rats in atmospheres
of 6000 ppm propylene glycol monomethyl ether (22,115 mg/m3), 7 hours/day
for 81 days. The intake associated with this exposure is 4791 mg/kg bw/day,
obtained by expanding to continuous exposure and assuming that rats Inhale
0.26 mVday and weigh 0.35 kg. In calculating a CS, a human MED was cal-
culated from the animal intake by multiplying the dose in rats by the cube
root of the ratio of the body weight of rats (assumed: 0.35 kg) to humans
(assumed: 70 kg) and applying an uncertainty factor of 10 to convert from
subchronlc to chronic data. A human MED of 5735 mg/day, corresponding to an
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RV., of 1, was calculated. Increased mortality was assigned an RV of
d e
10; a CS of 10, the product of RV. and RVg, was obtained.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.2.1. Oral.
6.2.1.1. 2-METHOXYETHANOL AND 2-ETHOXYETHANOL -- Chronic oral toxlc-
1ty studies, performed only with 2-ethoxyethanol, Include a 2-year dietary
study 1n rats (Morris et al., 1942) and a 103-week gavage study 1n rats and
mice (see Table 3-7). In the gavage study (Melnlck, 1984), rats had reduced
body weights (both sexes) and apparent adrenal enlargement (males) at 357
mg/kg bw/day, the lowest dose tested. In the feeding study, estimated doses
of 725 mg/kg bw/day resulted 1n testlcular damage. Using the lowest LOAEL
of 357 mg/kg/day and applying an uncertainty factor of 10 to estimate a
NOAEL results 1n a dose of 35.7 mg/kg/day. This dose level 1s lower than
estimates based on fetotoxldty and hence appropriate for AIC estimation.
Applying an additional uncertainty factor of 100 results 1n an AIC of 25
mg/day.
6.2.1.2. OTHER ETHYLENE GLYCOL ETHERS -- In members of this subclass
of compounds, chronic toxlclty testing was conducted only with dlethylene
glycol monoethyl ether 1n rats and mice (see Table 3-8). Smyth et al.,
(1964) determined a NOEL of 200 mg/kg/day In a chronic, 3-generat1on
drinking water study. In rats, 1080 mg/kg/day was a LOAEL associated with
mild lesions In the liver, kidney and testes of rats, the more sensitive
species (Morris et al., 1942). Applying an uncertainty factor of 100 (10
for Interspecles extrapolation and 10 for 1nter1nd1v1dual variability)
results In an AIC of 140 mg/day for a 70 kg man.
6.2.1.3. PROPYLENE GLYCOL ETHERS Pertinent data regarding the
chronic oral toxldty of the propylene glycol ethers could not be located In
the available literature. An oral AIC can be calculated for propylene
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glycol monoethyl ether, however,-by applying an uncertainty factor of 10 to
the AIS of 476 mg/day. The resulting AIC for propylene glycol monoethyl
ether Is 47.6 mg/day. Applying an additional uncertainty factor of 10 to
the AIS for propylene glycol monomethyl ether results 1n an AIC of 47 mg/day.
6.2.2. Inhalation.
6.2.2.1. 2-METHOXYETHANOL AND 2-ETHOXYETHANOL -- The human case
studies of exposure to 2-methoxyethanol and 2-ethoxyethanol summarized 1n
Table 3-9 do not quantHate exposure and effect sufficiently to allow the
use of these studies In risk assessment. An Inhalation AIC for 2-methoxy-
ethanol can be calculated from the TLV of 5 ppm (-16 mg/m3). Assuming a
human Inhales 10 m3/day on the job, works 5 days/week and absorbs 100% of
the Inhaled dose, an exposure of 114 mg/day 1s obtained. An AIC of 11.4
mg/day 1s calculated by applying an uncertainty factor of 10 to protect
unusually sensitive Individuals. Because this value Is larger than the AIS
for 2-methoxyethanol, 1t 1s not recommended as the AIC. Instead, the AIS
for 2-methoxyethanol can be based on the subchronlc NOEL of 23.6 mg/kg/day
(Miller et al., 1984). Multiplying by 70 and dividing by an uncertainty
factor of 1000 results 1n an AIS of 1.65 mg/day.
Chronic Inhalation data for 2-ethoxyethanol are also lacking. The
Inhalation AIS for 2-ethoxyethanol (4.8 mg/day) was based on concern for
fetotoddty which appeared to be a more sensitive endpolnt than other
subchronlc effects. However, fetotoxldty endpolnts are not relevant to
chronic effects extrapolation unless they occur at doses which appear to be
protective for other chronic endpolnts. Subchronlc Inhalation data define a
LOAEL of 76 mg/kg/day for the dog (other exposures not tested) (Werner et
al., 1943a); a NOAEL of 196 mg/kg/day and a NOEL of 49.9 mg/kg/day for the
rat (Barbee et al., 1984); and a LOAEL of 373 mg/kg/day and NOEL of 93.2
mg/kg/day for the rabbit (Barbee et al., 1984). Of these values the highest
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NOEL which 1s below the dog LOAEL is 49.9 mg/kg/day for the rat. Applying
an uncertainty factor of 1000 (10 for subchronlc duration, 10 for Inter-
species extrapolation and 10 for Interindlvldual variability) results 1n
0.0499 mg/kg/day or an AIC Inhalation estimate of 3.5 mg.day. Additional
toxlcologlcal data for non-rodent species would be useful.
6.2.2.2. OTHER ETHYLENE GLYCOL ETHERS -- Studies of the chronic
Inhalation toxlclty of other propylene glycol ethers could not be located 1n
the available literature. For ethylene glycol monobutyl ether, an
Inhalation AIS of 23.4 mg/day was calculated (see Section 6.1.2.2.). An AIC
of 2.3 mg/day can be calculated by applying an additional uncertainty factor
of 10. This estimate 1s lower than that which could be estimated based on
the TLV (25 ppm) (ACGIH, 1980).
6.2.2.3. PROPYLENE GLYCOL ETHERS Chronic Inhalation data regarding
the propylene glycol ethers are lacking; subchronlc Inhalation data suffi-
cient for use In risk assessment are available only for propylene glycol
monomethyl ether. An AIS of 399 mg/day was estimated. Applying an addi-
tional uncertainty factor of 10 results In an estimated AIC of 40 mg/day.
This value 1s lower than that which could be estimated from the TLV of 360
mg/m3.
Subchronlc Inhalation studies Indicate that dlpropylene glycol mono-
methyl ether may be somewhat more toxic than propylene glycol monomethyl
ether although they were Inadequate for AIS estimation (see Section
6.1.2.3.). The ACGIH (1980) has recommended a TLV for dlpropylene glycol
monomethyl ether of 100 ppm, -360 mg/m3. Using the methodology described
above, an AIC of 429 mg/day may be calculated from the TLV. Because this
value is greater than the AIC for the less toxic propylene glycol monomethyl
ether, no AIC for dlpropylene glycol monomethyl ether 1s recommended.
-------
6.3. CARCINOGENIC POTENCY (q.,*)
6.3.1. Oral. No reports of cancer In humans or laboratory animals
regarding oral exposure to glycol ethers have been located 1n the available
literature; hence, no q,* or unit risks for oral exposure can be calcu-
lated.
6.3.2. Inhalation. No reports of cancer related to Inhalation exposure
of humans or laboratory animals to glycol ethers have been located 1n the
available literature; hence, no q * or unit risks for inhalation exposure
can be calculated.
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Zenick, H., K. Blackburn, E. Hope, D. Oudiz and H. Goeden. 1984b. Evalu-
ating male reproduction toxicity in rodents: A new animal model. Teratog.,
Cardnog., Mutagen. 4(1): 109-128.
-76-
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APPENDIX
Summary Table for Glycol Ethers
2-Hethoxyethanol
Inhalation
AIS
AIC
Oral
Maximum composite score
2-Ethoxyethanol
Inhalation
AIS
AIC
Maximum composite score
Oral
AIS
AIC
Dlethylene Glycol Monoethyl Ether
Oral
AIS
Species
rats
rats
mice
rats
rats
rats
rats
rats
rats
Experimental Dose/Exposure
10 ppm, 6 hours/day on days
6-15 of gestation (5.8 mg/kg
bw/day)
30 ppm, 6 hours/day, 5 days/
week for 13 weeks (23.6 mg/kg)
31.25 mg/kg bw/day by gavage
on days 7-14 of gestation
10 ppm. 6 hours/day, days 6-15
100 ppm. 6 hours/day. 5 days/
week for 13 weeks (49.9 mg/kg)
50 ppm (184.2 mg/ro*). 6 hours/
day. days 6-15 (RVd = 1.6)
46.6 mg/kg bw/day by gavage on
days 1-21 of gestation
500 mg/kg/day by gavage
5 days/week for 103 weeks
500 mg/kg bw/day for 90 days
Acceptable Intake
Effect (AIS & AIC) Reference
fetotoxlc; NOEL 4.1 mg/day Hanley et al..
?984a.b; Miller
et al.. 1983b
NOEL 1.7 mg/day Miller et al.,
1984
teratogenlclty 22 Nagano et al.,
(RVe=10) 1984
fetotoxlc; NOEL 4.8 mg/day Doe. 1984a
NOEL 3.5 mg/day Barbee et al..
1984
fetotoxlclty 12.7 Doe. 1984a
(RVe = 6)
teratogenlc; NOEL 32.6 mg/day Stenger et al.,
19/1
reduced body weight; 25 mg/day Melnlck, 1984
LOAEL
NOEL 350 mg/day Hall et al.. 1966
AIC
In diet
rats 200 mg/kg bw/day by the drinking
water; chronic; 3 generations
NOEL
140 mg/day
Smyth et al.. 1964
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APPENDIX (cent.).
1
1
CD
1
**""> *. ; ĞM f^m-
o'Ğ-Hj. f*
CD < o
f~t ^/> L
;--:-., ;~|
-1 fO
. 3
3
i
!T
O
Ethylene Glycol Monobutyl Ether
Inhalation
AIS
AIC
Maximum composite score
Propylene Glycol Monomethyl Ether
Inhalation
AIS
AIC
Oral
AIS
AIC
Maximum composite score
Propylene Glycol Monoethyl Ether
Oral
AIS
AIC
Species
rats
rats
guinea
pigs
rats
rats
rats
rats
rats
rats
rats
Acceptable Intake
Experimental Dose/Exposure Effect (AIS & AIC) Reference
25 ppm. 6 hours/day, 5 days/ NOEL 11.2 mg/day
week for 13 weeks
25 ppm. 6 hours/day, 5 days/ NOEL 1.1 mg/day
week for 13 weeks
375 ppm (1812.4 mg/mğ). Increased mortality 19
7 hours/day, 5 days/week for
6 weeks (202 mg/kg bw/day)
1.000 ppm for 6 hours/day NOEL 342 mg/day
5 days/week for 13 weeks
1.000 ppm for 6 hours/day NOEL 34.2 mg/day
5 days/week for 13 weeks
949 mg/kg/admlnlstcred by NOEL 474.5 mg/day
gavage 5 days/week over
35 days
949 mg/kg/admlnl stored by NOEL 47.4 mg/day
gavage 5 days/week over
35 days
6000 ppm (22.115 mg/m"). Increased mortality 10
7 hours/day for 81 days (RVe-10)
(479 mg/kg bw/day) (RVd-l)
680 mg/kg bw/day/admlnlstercd In NOEL 476 mg/day
the drinking water for 30 days
680 mg/kg bw/day/admlnlstered in NOEL 47.6 mg/day
the drinking water for 30 days
Dodd et al..
Dodd et al..
Carpenter et
1956
Miller et al
1984
Killer et al
1984
Rowe et al..
Rowe et al.,
Rowe et al..
1983
1983
al..
t
*
1954
1954
1954
Smyth and
Carpenter, 1948
Smyth and
Carpenter. 1948
- Not reported
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