X Ml
TECHNICAL REPORT DATA
(fttate rttd Instructions on int revene before completing)
1. REPORT NO.
EPA/6QQ/8-88/038
2.
3. RECIPIENTS ACCESSION NO.
PB88-180252/AS
4. TITLE AND SUBTITLE
Health Effects Assessment for Ethylene Glycol
6. REPORT DATE
6. PERFORMING ORGANIZATION CODE
7. AUTMOR(S)
i. PERFORMING ORGANIZATION REPORT NO
9. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CON TRACT/OR ANT NO.
12 SPONSORING AGENCY NAME AND ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
13. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
is SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 12991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. 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 systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfD$ or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD 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. For compounds for which there is sufficient evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
7.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.IDENTIFIERS/OPEN ENDED TERMS C. COSATI Field Group
8. DISTRIBUTION STATEMENT
Public
19. SECURITY CLASS (This Report)
JJnclasslfied
21. NO. OF PAGES
20. SECURITY CLASS (This page/
Unclassified
22. PRICE
EPA F*n* 2220-1 (R*v. 4-77) PREVIOUS COITION is OMOLCTC
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EPA/600/8-88/038
July, 1987
HEALTH EFFECTS ASSESSMENT
FOR ETHYLENE GLYCOL
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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DISCLAIMER
This document has been reviewed \n accordance with the U.S.
Environmental Protection Agency's peer and 'administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with ethylene
glycol. All estimates of acceptable Intakes and carcinogenic potency
presented In this document should be considered as preliminary and reflect
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-Hne literature searches of the
TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The basic
literature searched supporting this document Is current up to May, 1986.
Secondary sources of Information have also been relied upon 1n the
preparation of this report and represent large-scale health assessment
efforts that entail extensive peer and Agency review.
The Intent In these assessments 1s to suggest acceptable exposure levels
for noncardnogens and risk cancer potency estimates for carcinogens
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.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemical(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, Is
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 1n ambient air or water where lifetime
exposure Is assumed. Animal data used for RFD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD§i) and oral (RfD$o)
exposures.
The RfD (formerly AIC) Is similar In concept and addresses chronic
exposure. It Is an estltiiote of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the Hfespan [see U.S. EPA (1980) for a discussion of this concept]. The
RfD 1s route-specific and estimates acceptable exposure for either oral
(RfDn.) or Inhalation (RfDj) with the Implicit assumption that exposure
by other routes Is Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development 1s explained In U.S.
EPA (1984).
111
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For compounds for which there Is sufficient evidence of cardnogenldty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980). Since cancer Is a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, 1f appro-
priate, based on oral and Inhalation data If available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n 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.
Orally administered ethylene glycol at high doses produces severe
effects on the kidneys and results 1n Increased mortality. In addition,
high doses of ethylene glycol produce fetotoxldty which appears to be the
critical effect for short-term exposure. A NOEL for fetotoxldty In the rat
of 200 mg/kg/day was established by Maronpot et al. (1983). From these data
an RfD$Q of 1*0 mg/day was derived. An RfOg of HO mg/day was derived
from a NOAEL of 200 mg/kg/day In rats (DePass, 1986a). A CS of 10 was
associated with Increased mortality at 1% In the diet In the same 2-year
study 1n rats. However, higher CSs are suggested based on occular effects
following Inhalation exposure. However, these effects at low exposure
levels are only supported by one study.
The critical effect of Inhalation exposure to ethylene glycol appears to
be Inflammation In the lungs, which was observed 1n several species of
laboratory animals (Coon et al., 1970). Deficiencies In this study combined
with lack of supporting data precluded calculation of an RfO$i or an
RfDj.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati. OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents In this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and K1m Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
5.
6.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral
3.3.2. Inhalation
3.4. TOXICANT INTERACTIONS
CARCINOGENICITY
4.1. HUMAN DATA
4.2. BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
4.3. OTHER RELEVANT DATA
4.4. WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfOs)
6.1.1. Oral (RfDso)
6.1.2. Inhalation (RfDSI)
Paqe
. . . 1
. . . 3
. . . 3
. . . 3
. . . 5
5
. . . 5
6
7
. . . 7
. . . 9
. . . 9
. . . 9
. . . 13
14
15
. . . 15
15
. . . 15
15
. . . 15
16
17
. . . 18
18
. . . 18
. . . 21
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TABLE OF CONTENTS
Page
6.2. REFERENCE DOSE (RfD) 22
6.2.1. Oral (RfD0) 22
6.2.2. Inhalation (RfDj) 25
6.3. CARCINOGENIC POTENCY (q-|*) 25
6.3.1. Oral 25
6.3.2. Inhalation 27
7. REFERENCES 27
APPENDIX: Summary Table for Ethylene Glycol Using the Rat 33
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LIST OF ABBREVIATIONS
bw Body weight
CAS Chemical Abstract Service
CS Composite score
EEG Electroencephalogram
EKG Electrocardiogram
PEL Frank effect level
Koc Soil sorptlon coefficient standardized
with respect to organic carbon
LD-|o Dose letnal to 10* of recipients
(and all other subscripted dose levels)
LD2Q Dose lethal to 20% of recipients
LOAEL Lowest-observed-adverse-effect level
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
ppm Parts per million
RBC Red blood cells
RfD Reference dose
RfDj Inhalation reference dose
RfDg Oral reference dose
RfD$ Subchronlc reference dose
RfD$i Subchronlc Inhalation reference dose
RfD$Q Subchronlc oral reference dose
RVd Dose-rating value
RVe Effect-rating value
w/v Weight per volume
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected chemical and physical properties and environmental fate of
ethylene glycol are presented In Table 1-1.
In the atmosphere, ethylene glycol should exist mostly In the vapor
phase and Is expected to react with photochemlcally generated HO radical.
Based on an estimated rate constant of 6.252xlO-2 cmVmolecule-sec at
25°C and an ambient HO radical concentration of S.OxlO5 molecules/cm3,
the hydroxyl reaction half-life has been estimated to be 1.60 days (U.S.
EPA, 1986a). Considering the complete solubility of ethylene glycol In
water, removal from the atmosphere by dissolution Into clouds and wet
deposition may also be significant (NLM, 1986). In water, ethylene glycol
will readily blodegrade under aerobic and anaerobic conditions (NLM, 1986).
River die-away tests with four river waters Indicated 100X degradation In 3
to >14 days (Evans and David, 1974). Adsorption to suspended solids and
sediments and bloaccumulatlon In aquatic organisms should not be significant
(NLM, 1986). The half-life of ethylene glycol 1n soil could not be located
1n the available literature, although the fact that H Is highly biodegrad-
able In water suggests that 1t will blodegrade In soil. Based on an esti-
mated K value of 4, this compound should be highly mobile In soil (Swann
et al., (1983); however, rapid degradation would limit the extent of leach-
Ing. In groundwater, rapid blodegradatlon Is expected (NLM, 1986).
OlOSh -1- 01/12/87
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TABLE 1-1
Selected Chemical and Physical Properties and
Environmental Fate of Ethylene Glycol
Property
Value
Reference
CAS number:
Chemical class:
Molecular weight:
Vapor pressure at 20°C:
Water solubility:
Log octanol/water
partition coefficient:
Bloconcentratlon factor:
Soil adsorption
coefficient:
Half-lives In
Air:
Water:
Soil:
107-21-1
aliphatic dlol
62.07
0.06 mm Hg
completely mlsdble
-1.36
0.05 (estimated)
4 (estimated)
1.60 days (estimated)
several days
NA
NLM, 1986
NLM, 1986
Hansch and Leo, 1985
Lyman et al., 1982
Lyman et al., 1982
Lyman et al., "!982
Evans and David, 1974
NA = Not available
0105h
-2-
10/24/86
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2. ABSORPTION FACTORS IN HUNAN AND EXPERIMENTAL ANIMALS
2.1. ORAL
NLM (1986) briefly reported an excerpt from the foreign literature 1n
which an Investigator drank 100 ml of water containing an unspecified
amount of ethylene glycol and collected his urine. Within 24 hours of
1ngest1on, 24-31% of the ethylene glycol was excreted In an unchanged form
In the urine. Urinary oxalic acid was elevated above background levels for
8-12 days. These data suggest that humans absorb a minimum of 24-31% of an
unspecified oral dose of ethylene glycol 1n drinking water and that absorp-
tion from the gastrointestinal tract Is rapid. Regardless of route, follow-
ing absorption ethylene glycol 1s metabolized primarily as follows:
ethylene glycol -» glycoladehyde •» glycollc acid -» glycoxyllc add
GlycoxyHc add Is metabolized through a number of pathways, but predomi-
nantly to C0_ and water via formic add (Rowe and Wolf, 1982).
2.2. INHALATION
Wills et al. (1974) exposed 20 male volunteers to aerosolized ethylene
glycol at a wide range of atmospheric concentrations averaging -30 mg/m3,
20-22 hours/day for 30 days. Ten unexposed male volunteers were maintained
as controls. Droplet size was monitored at unspecified Intervals during the
exposure period and was determined with a calibrated microscope to be
1-5 y In diameter, larger than that usually associated with penetration
past the bronchial and bronchlolar passages to the alveoli (Henzel and
McClellan, 1980). Serum and urinary levels of unchanged ethylene glycol
were monitored as Indicators of absorption. Concentrations of ethylene
glycol 1n serum and urine varied widely 1n both control and exposed groups,
0105h -3- 03/10/87
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but there appeared to be no readily discernible differences between values
from the two groups. The Investigators concluded that there was "Uttle
evidence of the absorption of Important quantities of ethylene glycol."
Marshall and Cheng (1983) exposed rats by nose only to 14C-ethylene
glycol vapor at 32 mg/m3 for 30 minutes or to an aerosol formed by conden-
sation on Inert particles at 184 mg/m3 for 17 minutes. The Investigators
estimated that ~60X of the Inhaled material was deposited, primarily In the
nasal cavity; the data substantiating this estimate were not provided In the
abstract. Absorption and distribution from the site of deposition appeared
to be rapid, since 75-80% of the Initial body burden was distributed
throughout the body on sacrifice Immediately after exposure.
0105h -4- 03/10/87
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3. TOXICITY IN HUMAN AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
Rowe and Wolf (1982) have summarized the clinical symptoms of ethylene
glycol tox1c1ty following acute exposure. They separate clinical signs Into
three stages: central nervous system effects occurring from 30 minutes to
12 hours following exposure; cardlopulmonary effects stage lasting from
12-36 hours following exposure; and the final stage of renal failure
occurring 1f the patient survives the first two stages. Included within the
central nervous system stage are ocular signs Including optic atrophy.
Acute ethylene glycol toxldty has been effectively treated 1n animals with
ethanol or alcohol dehydrogenase Inhibitors.
3.1.1. Oral. Groups of 10 male and 10 female Fischer 344/N rats and 10
male and 10 female B6C3F1 mice were fed diets containing 0, 0.32, 0.63,
1.25, 2.5 or 5.0% (0, 3200, 6300, 12,500, 25,000 or 50,000 ppm) of ethylene
glycol for 13 weeks (Melnlck, 1984). The endpolnts evaluated Included
mortality, body and organ weights, serum and urine analyses and hlstopatho-
loglcal effects. In rats, the mortality rate was 40% 1n males Ingesting
5.0%. Decreased body weight gain, Increased kidney-to-body weight ratios,
Increased serum urea nitrogen levels and renal hlstopathology were observed
1n the male rats Ingesting 2.5 or 5.0%. High-dose males also had crystal
deposits In the brain. Increased kidney-to-body weight ratio was observed
In female rats Ingesting 2.5 or 5.0%, but was accompanied by adverse hlsto-
loglcal changes only In females Ingesting 5.0%. Among groups of mice, only
the males at 2.5 and 5.0% had adverse effects, which consisted of renal
cytoplasmlc vacuollzatlon and centMlobular hepatic degeneration. No
adverse effects were observed 1n males at <1.25% or 1n females at any
dietary concentration. Helnlck (1984) concluded that the NOEL for renal
0105h -5- 03/10/87
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toxldty 1n male rats Is 1.2554 of dietary ethylene glycol, which corre-
sponded to a dose of 0.6-1.0 g/kg/day. The dietary level of 1.25% was also
a NOAEL for male mice.
3.1.2. Inhalation. Twenty mice and 10 rats were exposed to an average
concentration of 398 mg/m3 of ethylene glycol for 8 hours/day, 5 days/week
for up to 16 weeks (WHey et al., 1936). Selected animals were sacrificed
at Intervals starting with week 7 of exposure. Endpolnts evaluated Included
mortality rate, body weight and histology of liver, kidney, testes, brain,
lung, pancreas, spleen, adrenals, stomach, Intestines and lymph nodes.
Although three mice and one rat died during the experiment, cause of death
was not reported and no pathological changes that could be attributed to
ethylene glycol treatment were reported. Mice gained weight during the
experiment, but rats did not. Controls were not evaluated 1n this
experiment.
Groups of male and female Sprague-Oawley and Long-Evans rats (n=15),
male and female Princeton-derived guinea pigs (n=15), male New Zealand
albino rabbits (n=3), male squirrel monkeys (n=3) and male beagle dogs (n=2)
were exposed continuously to 12 mg/m3 ethylene glycol for 90 days (Coon et
al., 1970). Unexposed control groups were maintained. The endpolnts
evaluated Included mortality rate, hematology, histology of heart, lung,
liver, klaney and spleen and enzyme levels In the blood, liver and kidneys.
In addition, the histology of brain, spinal cord and adrenals In monkeys and
dogs and of the thyroid 1n dogs was evaluated. Deaths occurred 1n 1/15
rats, 3/15 guinea pigs and 1/3 rabbits; cause of death was not reported.
Pulmonary Inflammation was observed 1n treated groups of all species to a
greater degree than 1n controls. Ocular Irritation and edema, resulting 1n
eye closure, was observed In the rabbits. Corneal opacity, which resulted
0105h -6- 03/10/87
-------
1n blindness, developed In two of the rats. In both species, the ocular
lesions developed within 8 days of the start of treatment. No other effects'
were reported by Coon et al. (1970).
In another experiment, similar groups of rats, guinea pigs, rabbits,
dogs and monkeys were exposed to 10 or 57 mg/m3 for 8 hours/day, 5 days/
week for 6 weeks (Coon et al., 1970). Unexposed controls were maintained.
Death did not occur at either exposure level. Two rabbits at 10 mg/m3 had
mild, unilateral conjunctivitis, but these signs were not observed at 57
mg/m3 and were attributed to accidental trauma rather than to the chemi-
cal. On hlstopathologlcal examination, mild splenic congestion was observed
1n dogs at 10 but not 57 mg/m3. M1ld liver changes were observed In some
rats and guinea pigs at both levels of exposure and In monkeys at 57
mg/m3, but these changes were not attributed to exposure to ethylene
glycol. Nonspecific Inflammatory changes In the lungs and hearts of all
species were reported at 57 but not 10 mg/m3. These changes may have been
associated with treatment.
3.2. CHRONIC
3.2.1. Oral. Groups of 16 male and 16 female Sprague-Oawley rats were
fed diets containing 0, 0.1, 0.2, 0.5, 1.0 or 4.0% (0, 1000, 2000, 5000,
10,000 or 40,000 ppm) of ethylene glycol for 2 years (Blood, 1965). The
endpolnts evaluated Included mortality, food and water consumption, body and
organ weights, hematology and histology. Accelerated mortality was observed
In the male rats Ingesting 1.0 or 4.0% and In the female rats Ingesting 4.0%
ethylene glycol. In addition, the rats 1n these three groups had decreased
growth rates, Increased water consumption, protelnurla before death and
renal calculi 1n >68% of the males and >93% of the females. An Increased
Incidence of cytoplasmlc crystal deposition 1n renal tubular epithelium
occurred In 4/10 males evaluated at the 0.5% dose level and 1n 5/15 female
0105h -7- 03/10/87
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rats evaluated at the 1.0% dose level. No other adverse effects were
reported and Blood (1965) concluded that the NOEL 1n rats 1s 0.2% of dietary
ethylene glycol.
Groups of 130 male and 130 female Fischer 344 rats and groups of 80 male
and 80 female CD-I mice were fed diets containing ethylene glycol 1n amounts
such that the rats and mice Ingested 0, 0.04, 0.2 or 1.0 g of ethylene
glycol/kg of body weight each day for 2 years (DePass et al., 1986a). The
endpolnts evaluated Included mortality rate, body and organ weights, food
and water consumption, clinical chemistry, hematology, urine analysis and
histology of major organs. The high-dose male rats had statistically
significant Increases In mortality rate, neutrophll count, water Intake,
kidney weight, urine volume and blood urea nitrogen levels and a statisti-
cally significant decrease 1n body weight, RBC count and hematocrlt and
hemoglobin levels. Also observed In the high-dose male rats were chronic
nephritis Including tubular 'dilation and protelnosls, glomerular shrinkage,
tubular cell hyperplasla and Interstitial nephritis. Increased kidney
weights unaccompanied by any other renal changes were observed 1n the
high-dose female rats. M1ld fatty changes In the liver were reported 1n
female rats Ingesting 1.0 or 0.2 g of ethylene glycol/kg bw/day. Adverse
effects were not observed at any other dose level 1n the rats or at any dose
level In the mice.
Blood et al. (1962) fed a diet containing ethylene glycol at 0.2% to two
male rhesus monkeys and a diet containing 0.5% to one female rhesus monkey
for 3 years. Rad1ograph1c examinations of the urinary tract at 3-month
Intervals revealed no evidence of calcification or calculi formation.
H1stopatholog1cal examinations of major organs and tissues revealed no
lesions 1n one male or the female monkey. The other male monkey had become
obese, weighing twice as much as his companion, and mild lesions In the
0105h -8- 03/10/87
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kidney tubules and scattered foci of sclerotic Bowman's capsules. The
Investigators did not associate these findings with exposure to ethylene
glycol and concluded that no toxic effects were seen In this experiment.
3.2.2. Inhalation. Pertinent data regarding the toxldty of chronic
Inhalation of ethylene glycol could not be located In the available
literature.
3.3. TERATOGEMICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. The teratogenlc and .reproductive effects of orally admin-
istered ethylene glycol 1n rats and mice have been evaluated using five
different experimental designs (Maronpot et al., 1983; Schuler et al., 1984;
Lamb et al., 1985; Price et al., 1985; DePass et al., 1986b). In the
Maronpot et al. (1983) study, groups of 20 pregnant Fisher 344 rats were
exposed to dietary ethylene glycol at "concentrations based upon established
food consumption and body weight gain data to produce dosage goals of 1.0,
0.2 and 0.04 g/kg." The rats received treated food on days 6-15 of gesta-
tion. The dams were killed on day 21 of gestation, and the pups were
examined. The endpolnts evaluated Included maternal body weight, fetal
length and body weight, number of Implantations, Utter size and Incidence
of major malformations. The only effects were Increased prelmplantatlon
loss and Increased Incidence of poorly ossified and unosslfled vertebral
centra 1n the high-dose group. Only the skeletal changes were statistically
significant.
In the Schuler et al. (1984) study that was designed to screen chemicals
for their potential to cause reproductive toxldty 1n pregnant females, 50
pregnant CD-I mice were treated by gavage on days 7-14 of gestation with
11,090 mg/kg/day of ethylene glycol, approximately the LD,Q for mice.
0105h -9- 03/10/87
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Fifty pregnant CD-I mice constituted the control group. The endpolnts
evaluated Included pup survival in utero measured by the ratio of live
Utters/pregnant survivors, pup perinatal and postnatal survival measured by
the ratio of the number of live pups/Utter and the number of dead pups/
Utter and the percent of pups surviving 2.5 days postpartum, and pup body
weight measured at birth and at 2.5 days of age. Compound-related deaths
occurred 1n five treated mice. Statistically significant adverse effects
were observed In each of the six parameters measured 1n this study. Schuler
et al. (1984) concluded that ethylene glycol belongs 1n the group of
chemicals given a high priority for further testing because of the drastic
reduction 1n viable Utters observed at dose levels equal to or below the
maternal LDpg.
In the Lamb et al. (1985) experiment, which followed the Continuous
Breeding Protocol designed by the NTP to assess fertility, groups of 20 male
and 20 female 6-week-old COBS CrlfCOl, (ICR)BR outbred albino mice were
provided drinking water containing 0, 0.25, 0.5 or l.OX ethylene glycol
(w/v) for 14 weeks. The Gulatl et al. (1984) report summarizes the same
study. The mice In each group were housed 1n pairs and allowed to breed
continuously for 14 weeks, during which time Utters were evaluated and
discarded. After 14 weeks, the males and females 1n the FQ generation
were separated and the Utters born to the control group and the high-dose
group during the next 3 weeks were allowed to survive as the F, genera-
tion. Exposure of the F, generation to 0 or 1.0% ethylene glycol 1n the
drinking water continued uninterrupted for 70*10 days after birth, at which
time the F. generation was mated and the reproductive performance evalu-
ated by examining the F? pups. The endpolnts evaluated Included maternal
and fetal body weight, water consumption, number of litters/fertile pair,
number of live pups/Utter, proportion of pups born alive and skeletal
0105h -10- 03/10/87
-------
changes 1n the offspring. A statistically significant decrease 1n the
number of Utters/fertile pair, 1n the mean number of live pups/Utter and
1n the mean live pup weight was observed In the offspring of the F_ gener-
ation of high-dose mice. Although the fertility of the F, generation and
the number of live pups/Utter and the live pup weight of the f? genera-
tion were decreased, the decrease was not statistically significant. Gross,
but not hlstologlcal, alterations were observed In the cranial and axial
skeletons of F_ pups treated with 1% ethylene glycol in the drinking
water. Skeletal changes were not present 1n F_ control pups. Lamb et al.
(1985) reported that cleft lip occurred 1n "at least six pups from three
treated Utters" of the F? generation and concluded that exposure to
drinking water contaminated with 1.0% ethylene glycol, equivalent to >1600
mg/kg/day, resulted 1n adverse effects on reproduction.
In a 3-generat1on reproductive study (DePass et al., 1986b), groups of
20 female and 10 male Fischer 344 rats were treated with -1000, 200 or 40
mg/kg/day of dietary ethylene glycol. Two untreated diet control groups
were Included to estimate the variation between two groups handled In like
manner. The Utter size of each dam was culled to 10, 1f necessary, on
postpartum day 4. Twenty females and 10 males were randomly selected for
mating from the F and the F» generations In each treatment group at
-100 days of age. The endpolnts evaluated Included adult and pup body
weights, food consumption, male and female fertility Indices, gestation
Index, gestation survival Index, days from first mating to Utter, and
survival Indices at 0, 4, 14 and 21 days.
H1stopatholog1cal evaluation of liver, kidneys, lungs, heart, adrenal
thyroids, trachea, accessory sex glands, adipose tissue, lymph nodes, pitui-
tary, thymus, testes and epldldymls or uterus and ovaries were performed on
0105h -11- 03/10/87
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five males and five females randomly selected from each dosage level of the
F- parents and the F~ wean!1:ngs.
In addition, males from the F2 generation were removed from diets
containing ethylene glycol at 155 days of age and mated with groups of 15
untreated female rats each week for 3 weeks In a study, of dominant lethal
effects. On day 12 of gestation, the females were killed, the uteri and
ovaries examined and the number of live and dead fetuses tabulated. A group
of 15 male rats that had been maintained on the control diets was Injected
Intraperltoneally with tMethylenemelamlne (0.5 g/kg) and served as a
positive control group. No statistically significant effects were observed
at any dose level 1n the 3-generat1on reproductive study.
Slight Increases In the dominant lethal mutation Index were observed 1n
high-dose rats for the week-2 mating and In low-dose rats for the week-3
mating. The Investigators concluded that these elevations were probably
random occurrences rather than effects of treatment because they did not
occur 1n a dose-related manner. Positive controls responded appropriately.
In the Price et al. (1985) study designed to evaluate teratogenlclty,
groups of at least 20 pregnant CD rats and 20 pregnant CD-I mice were treat-
ed by gavage on days 6-15 of gestation with 0, 1250, 2500 or 5000 mg/kg/day
of ethylene glycol (rats) or 0, 750, 1500 or 3000 mg/kg/day (mice). End-
points evaluated Included maternal toxldty, the number of Implantation
sites/Utter, the number of live fetuses/Utter, percentages of postlmplan-
tatlon (resorbed + dead fetuses) losses/litter, the number of Utters with
postlmplantatlon losses at one or more sites, the number of males/Utter,
live fetuses malformed/litter and Utters with one or more malformed live
fetuses. The percentage of Utters with one or more malformed live fetuses
was significantly Increased In a dose-related manner (p<0.01; Fisher Exact
0105h -12- 03/10/87
-------
Probability Test) In both rats and mice at all dose levels tested. In
addition, there was a dose-related Increase 1n the postlmplantatlon losses/
Utter 1n both species, reaching statistical significance only In high-dose
rats. Maternal body weight gain during treatment was significantly
decreased 1n a dose-related manner at all dose levels 1n the rats and at the
two higher dose levels 1n the mice.
3.3.2. Inhalation. Groups of 25 timed pregnant CO rats and CD-I mice
were exposed to a resplrable aerosol of ethylene glycol at concentrations of
0, 60, 400 or 1000 ppm (0, 150, 1000, 2500 mg/m3) for 6 hours/day on days
6-15 of gestation (Tyl, 1985). The rats and mice were killed on day 21 and
day 18 of gestation, respectively. The endpolnts evaluated Included
maternal body, liver, kidney and gravid uterine weights; the number of
corpora lutea, resorptlons, dead fetuses and live fetuses/Utter; and the
fetal weight, sex and number of visceral and skeletal malformations. In the
rats, ethylene glycol exposure was associated with a significant Increase 1n
maternal liver weight at 1000 ppm and delayed ossification 1n the zygomatlc
arch, metatarsals and proximal phalanges 1n the hlndllmb of pups at 400 ppm
and 1000 ppm. No effect on pre- or postlmplanatlon loss, the number of live
fetuses/Utter, sex ratio, fetal body weight or the Incidence of fetal
malformations was observed In the rats exposed to ethylene glycol. In the
mice, decreased maternal and fetal body weight was observed at the two
highest dose levels tested. Ethylene glycol exposure was associated with a
significant decrease 1n the number of viable Implants/Utter and a signifi-
cant Increase 1n the number of late resorptlons and dead fetuses at 1000 ppm.
A significant Increase In the number of late resorptlons was observed 1n the
mice exposed to 400 ppm. A significant Increase 1n the Incidence of
external, visceral and skeletal malformations was observed In mice exposed
0105h -13- 03/10/87
-------
to 1000 and 400 ppm. The malformations observed Included cleft palate,
exencephaly, destruction of normal brain architecture, axial skeletal
defects and facial deformities. An Increased Incidence of adverse effects
was not observed In the mice exposed to 60 ppm.
Although the study of Tyl (1985) was designed to evaluate the develop-
mental tox1c1ty of Inhaled ethylene glycol 1n rats and mice, nearly continu-
ous grooming by the rats and mice both In and out of the Inhalation chamber
was observed. The Investigator concluded that a substantial amount of
ethylene glycol was Ingested from the fur. Based on experimentally deter-
mined amounts of ethylene glycol present on the hair coats after 1 exposure,
5 exposures, 10 exposures and at the time of sacrifice of similarly exposed
sentlnal animals of both species, Tyl (1985) determined that rats Ingested
263.43 and 620.1 mg/kg/day and that mice Ingested 385.89 and 909.1 mg/kg/day
at the middle- and high-exposure levels, respectively. The Investigator did
not estimate the Ingested dose at 60 ppm, which was not associated with
adverse effects In either species, but did conclude that 1h this experiment
the Ingested dose was substantially larger than the Inhaled dose.
3.4. TOXIC INTERACTIONS
Metabolism of ethylene glycol, with the subsequent precipitation of
oxalate crystals, can be blocked or slowed down by concurrent Ingestlon or
Infusion of ethyl alcohol (Balazs et a I., 1982). Pyrazole and 4-methylpyra-
zole, which are Inhibitors of alcohol dehydrogenase activity, were effective
1n reducing the mortality of rats treated by gavage with ethylene glycol
from 100 to 0%. The protective effect was observed when the dehydrogenase
Inhibitors were administered 1ntraper1toneally either 4 hours before or
concurrently with the ethylene glycol, but not when administered more than 4
hours after gavage treatment with ethylene glycol (Chou and Richardson,
1978).
0105h -14- 03/10/87
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4. CARCINOGENICITY
4.1. HUMAN DATA
Pertinent data regarding the carclnogenldty of Ingested or Inhaled
ethylene glycol 1n humans could not be located In the available literature.
4.2. BIOASSAYS
4.2.1. Oral. In the DePass et al. (1986a) study described 1n more detail
In Section 3.2.1., groups of 130 male and 130 female Fischer 344 rats and
groups of 80 male and 80 female CD-I mice were exposed to food containing
ethylene glycol 1n amounts such that the rats and mice Ingested 0, 0.04, 0.2
or 1.0 g ethylene glycol/kg body weight dally for 2 years. Ethylene glycol
exposure was not associated with an Increased Incidence of tumors 1n the
rats or the mice. In the Blood (1965) study, also discussed 1n greater
detail In Section 3.2.1., an Increased Incidence of cancer was not reported
1n any of the groups of 16 male and 16 female Sprague-Oawley rats treated
with diets containing 0, 0.1, 0.2, 0.5, 1.0 or 4.0% ethylene glycol for 2
years. However, these studies were not designed primarily as cancer
bloassays and hence did not report control tumor Incidence and other
appropriate details.
The NTP (1986) management status report Indicates that hlstopathologlcal
examinations of mice chronically fed ethylene glycol 1n the diet Is
currently 1n progress.
4.2.2. Inhalation. Pertinent data regarding the cardnogenlcHy of
Inhaled ethylene glycol 1n animals were not located 1n the available data.
4.3. OTHER RELEVANT DATA
Ethylene glycol was not mutagenlc In Salmonella typhlmurlum strains
TA98, TA100, TA1535 or TA1537 with or without metabolic activation (McCann
et al., 1975).
0105h -15- 03/10/87
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An Increased Incidence of polychromatic erythrocytes with Howell-Jolly
bodies, which may Indicate chromosome breakage, were reported In mice
treated orally or Intraperltoneally with ethylene glycol (Conan et al.,
1970). In the same study, an Increased Incidence of chromosome anomalies In
bone marrow cells- of mice treated with ethylene glycol was not observed.
4.4. HEIGHT OF EVIDENCE
IARC has not evaluated the carcinogenic potential of ethylene glycol.
Applying the criteria described In the EPA's proposed guidelines for assess-
ment of carcinogenic risk (U.S. EPA, 1986b), ethylene glycol may be classi-
fied 1n Group D: not classifiable as to human cardnogenlclty. This
category Is for chemicals that show Inadequate evidence of cardnogenlclty
for both humans and animals. This classification may be modified pending
the outcome of the NTP (1986) dietary study using mice currently 1n
progress. Ethylene glycol may also be classified 1n IARC Group 3: cannot
be classified.
0105h -16- 03/10/87
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5. REGULATORY STANDARDS AND CRITERIA
Based on the study of Wills et al. (1974), the ACGIH (1986a,b) has
recommended a celling limit of 50 ppm (-125 mg/m3) for ethylene glycol
vapor and mist to minimize Irritation of the respiratory passages. In the
study by Hills et al. (1974), one group of 20 human males were exposed to a
mean concentration of -30 mg/m3 of ethylene glycol for 20-22 hours/day for
30 days. A group of 14 human males served as controls. The endpolnts
evaluated Included hematology, clinical chemistry, uMnalysls. EKG and EEG
and psychological testing of reaction time with and without discrimination,
visual-motor coordination, perception and mental ability. No adverse
effects were associated with exposure to the mean concentration of 30
mg/m3 (11.8 ppm) of ethylene glycol. Sporadic Increases 1n the concentra-
tion of atmospheric ethylene glycol Indicated that the respiratory system
became Irritated at 140 mg/m3 of ethylene glycol and that the Irritation
became Intolerable at 200 mg/m3 of ethylene glycol.
0105h -17- 10/24/86
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfDc)
d
6.1.1. Oral (RfD--). Based on the subchronlc oral study by Melnlck
(1984), a NOEL was Identified In rats and mice Ingesting diets containing
1.25X ethylene glycol. At 2.5X of the diet, the next higher concentration
tested, male rats had lesloos 1n the kidney and male mice had lesions 1n the
liver and kidney. In both species, the male appears to be more sensitive
than the female to the toxldty of ethylene glycol. Femalie rats had lesions
at 5.0 but not 2.5X of the diet, and female mice had no adverse effects on
diets containing <5.0X. The dietary NOEL of 1.25X 1n male rats Is equiva-
lent to 625 mg/kg/day, assuming rats eat food equivalent to 5% of their body
weight/day.
Developmental toxldty may be a more sensitive endpolnt than subchronlc
toxldty for ethylene glycol. Maronpot et al. (1983) observed fetotoxlclty
manifested as Increased prelmplantatlon embryo loss and retarded vertebral
ossification 1n rats fed a diet that provided 1000 mg/kg/day. No effects
were observed at 200 mg/kg/day, the next lower dose. In mice, reduced
fecundity and evidence of fetotoxlclty were observed with exposure to drink-
Ing water containing IX ethylene glycol (Lamb et al., 1985; Gulatl et al.,
1984). No such effects were observed at 0.5X. The Investigators estimated
that ethylene glycol Intake at the IX level exceeded 1600 mg/kg/day, but did
not estimate compound Intake at the lower dose level. Assuming that mice
weigh 0.03 kg and drink 0.0057 l/day, the 0.5X level corresponds to an
Intake of 950 mg/kg/day.
In a teratogenlclty study using rats and mice, Price et al. (1985)
observed a dose-related Increase In the Incidence of Utters with
0105h -18- 07/09/87
-------
malformations In both species at all doses tested. Rats were treated with
1250, 2500 and 5000 mg/kg/day and mice were treated at 750, 1500 and 3000
mg/kg/day.
Tyl (1985) exposed rats and mice to aerosols of ethylene glycol at
concentrations of 0, 60, 400 or 1000 ppm (0, 150, 1000 or 2500 mg/m3} 6
hours/day on days 6-15 of gestation. Although the study was designed to
evaluate developmental toxlclty of Inhaled ethylene glycol, the Investi-
gators noted nearly continuous grooming during and after exposure and
concluded that a substantial amount of ethylene glycol was Ingested. By
measuring the amounts of ethylene glycol that adhered to the halrcoats of
similarly exposed sentinel rats and mice at 400 and 1000 ppm. Tyl (1985)
estimated that rats Ingested 263.43 and 620.1 mg/kg/day and mice Ingested
385.89 and 909.1 mg/kg/day at 400 and 1000 ppm, respectively. These
atmospheric concentrations were associated with fetotoxldty manifested as
delayed ossification In the rats and an Increased Incidence of fetal malfor-
mations In the mice. Adverse effects were not observed In either species at
60 ppm, but Tyl (1985) did not estimate the dose of ethylene glycol ingested
by rats and mice at this exposure. Tyl (1985) concluded that the Ingested
doses were substantially greater than the Inhaled doses 1n this experiment.
Assuming that the ventHatory volume of a rat Is 0.223 m3/24 hours
(U.S. EPA, 1980), that 50% of the ethylene glycol Inhaled was absorbed ana
that the rat body weight was 0.35 kg, rough estimates of the Inhaled compo-
nent of the dose can be estimated as 79.6 nig/kg for the mid-concentration
group rats (1000 mg/m3). Assuming that the ventllatory volume of a mouse
Is 0.039 m3/24 hours (U.S. EPA, 1980), that 50% of the dose was absorbed
and that the mouse body weight was 0.03 kg, the Inhaled component of the
dose for the 1000 mgym3 exposure group of mice can be estimated as 162.5
0105h -19- 01/12/87
-------
mg/kg/day. The total doses then for the 1000 mg/m3 groups would be 263
mg/kg/day <• 80 mg/kg/day = 343 mg/kg for rats and analagously 549 mg/kg/day
for mice. These doses were associated with both fetotoxldty and maternal
toxlclty In both species. The finding of maternal toxlclty at these dose
levels when compared with the other subchronlc and reproductive studies
strongly suggests that the dose may have been underestimated.
Arraying the data to compare NOELs and LOAELs results In the following
summary:
Subchronlc toxlclty
Rat
male
female
Mouse
male
female
NOEL 625 mg/kg/day
LOAEL 1250 mg/kg/day
NOAEL 1250 mg/kg/day
LOAEL 2500 mg/kg/day
NOEL 625 mg/kg/day
LOAEL 1250 mg/kg/day
NOEL 2500 mg/kg/day
None established
Melnlck, 1984
Melnlck, 1984
Reproductive and Teratology Studies
Rat teratology
fetotoxldty NOEL 200 mg/kg
LOAEL 1000 mg/kg
LOAEL 1250 mg/kg
Mouse teratology
fetotoxldty LOAEL 750 mg/kg
Mouse 3-generatlon
Rat 3-generat1on
NOEL 950 mg/kg
LOAEL 1650 mg/kg
NOEL 1000 mg/kg
LOAEL None
Maronpot et al., 1983
Maronpot et al., 1983
Price et al., 1985
Price et al., 1985
Lamb et al., 1985
DePass et al.. 1986b
0105h
-20-
01/12/87
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The teratology studies appear to show effects at lower doses than the
3-generatlon studies. The study showing a NOEL for fetal effects at a dose
below the LOAELs 1s the Maronpot et al. (1983) teratology study In rats
which defined a NOEL of 200 mg/kg/day.
An RfDso of 2 mg/kg/day or 140 mg/day for a 70 kg human can be derived
by dividing the NOEL of 200 mg/kg/day by an uncertainty factor of 100 to
account for Interspecles extrapolation uncertainty and Intraspedes
variability.
6.1.2. Inhalation (RfD-j). Three subchronlc animal Inhalation studies
are available for consideration In the derivation of an RfDST- Wiley et
al. (1936) observed deaths In rats and mice exposed 8 hours/day, 5 days/week
to 398 mg/m3 for 16 weeks, but this experiment did not define a NOAEL.
Coon et al. (1970) observed deaths and ocular lesions In guinea pigs, rats
and rabbits, and pulmonary Inflammation 1n these species and In dogs and
monkeys continuously exposed to 12 mg/m3 for 90 days. Inflammation In the
heart and lungs was also observed In all the species mentioned above when
exposed to 57 but not 10 mg/m3, 8 hours/day, 5 days/week for 6 weeks (Coon
et al., 1970).
The Coon et al. (1970) study Is limited 1n scope and reporting detail.
It was designed to be a preliminary Investigation. Animal group sizes were
small, no mention was made of evaluations of organ or body weights which
frequently provide the first Indication of adverse effects of a chemical.
Although the authors state In the abstract that there were no chemically-
Induced changes following exposure to 10 and 57 mg/m3 ethylene glycol,
this conclusion Is not clearly supported by the discussion of the results.
0105h -21- 07/09/87
-------
For example, the 10 mg/rn3 group was described as follows:
"H1stopatho1og1c examination revealed mild congestion In the
spleens of both dogs, hepatic fatty changes In 2/8 guinea pigs and
1/8 rats (sex not specified); and focal necrosis In the liver of
1/8 guinea pigs and 1/8 rats. Focal necrosis of the liver was also
seen 1n 1/3 control guinea pigs."
For the 57 mg/m3 group the following summary was provided:
"H1stopatholog1c examinations revealed nonspecific Inflammatory
changes In the. lungs and occasionally the hearts of all species.
The livers of 2 of the 3 monkeys and 1 of the 8 guinea pigs
revealed areas of focal necrosis; these were considered not to be
chemically Induced."
In addition, continuous exposure to 12 mg/m3 ethylene glycol resulted In
moderate to severe eye Irritation In rabbits and rats. Two rats "appeared"
to be blind after 8 days of exposure. Hlstopathologlc examination showed
Inflammatory changes In the lungs of all species. "Occasional" foci of
Inflammatory cells were seen In kidneys from "several" guinea pigs. "These,
however, were not Interpreted as being specific chemically Induced changes."
In addition to the animal studies mentioned above, Wills et al. (1974)
exposed humans almost continuously to -30 mg/m3 for 30 days and observed
no adverse effects. Although this level appears to be a NOAEL 1n humans,
the most sensitive Indication of toxlclty, nonspecific Inflammation of the
thoracic viscera, was of necessity not evaluated, and the experimental
period Is too short for this study to be useful for risk assessment. In
conclusion, the data are deemed Inadequate for quantitative risk assessment.
6.2. REFERENCE DOSE (RfD)
6.2.1. Oral (RfDJ. Two chronic experiments, the DePass et al. (1986a)
study and the Blood (1965) study, can be used to derive an RfDQ for
ethylene glycol. Based on the Blood (1965) study, a NOEL of 100 mg/kg/day
0105h -22- 07/09/87
-------
of ethylene glycol was Identified In rats. The next highest dose tested,
250 mg/kg/day, was Identified as a LOAEL In male rats associated with
Increased Incidences of renal calcification and calculi. An Increased
mortality rate as well as renal toxldty was observed 1n male rats Ingesting
500 mg/kg/day and In female rats Ingesting 1000 mg/kg/day. The DePass et
al. (1986a) study using rats and mice defined a NOAEL at 200 mg/kg/day, a
dose resulting In Increased Incidence of fatty changes In the liver In
female rats. The Incidence of fatty liver changes Increased at the highest
dose tested, 1000 mg/kg/day, which was Identified as a PEL because of the
Increased mortality observed 1n male rats. An RfDn of 2.0 mg/kg/day, or
140 mg/day for a 70 kg human, for ethylene glycol Is derived by dividing the
NOAEL of 200 mg/kg/day by an uncertainty factor of 100 to account for Inter-
species extrapolation and the range of sensitivity to xenoblotlcs within the
human population.
CS values, summarized In Table 6-1, are based on the adverse liver and
kidney effects and the Increased mortality rate observed 1n rats after
chronic Ingestlon of food contaminated with ethylene glycol (DePass et al.,
1986a; Blood, 1965). In addition, the lowest oral dose of ethylene glycol,
750 mg/kg/day, administered to pregnant mice was associated with an
Increased Incidence of malformations and was used as the basis for a CS for
teratogenldty (Price et al., 1985). Because the teratogenlc effects of
oral exposure cannot be clearly separated from the effects due to Inhala-
tion, this study 1s not used In the derivation of a CS. The highest CS Is
10, based on the Increased mortality observed 1n male rats Ingesting food
contaminated with ethylene glycol for 2 years (Blood, 1965).
0105h -23- 07/09/87
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6.2.2. Inhalation (RfD»). There are no available Inhalation data on
the chronic toxldty of ethylene glycol. Subchronlc data are summarized In
Section 6.1.2. Data are deemed Inadequate for quantitative risk assessment.
The effect of concern for short duration continuous Inhalation exposure
appears to be occular Irritation. This effect was not seen In any of the
reports utilizing Intermittent exposure protocols. In addition, Coon et al.
(1970) cited a personal communication from another laboratory which failed
to confirm severe occular effects at a similar exposure level. Conse-
quently, It 1s uncertain whether this report of severe occular Irritation Is
an experimental anomaly or represents a reproducible effect. Coon et al.
(1970) also dte unpublished data suggesting that higher exposure concentra-
tions than those associated with severe eye Irritation In rats and rabbits
In their study were tolerated by humans with no 111 effects. These
potential occular effects would be of concern 1f an accidental release of
ethylene glycol occurred 1n a confined space. Inhalation composite scores
are summarized In Table 6-2.
6.3. CARCINOGENIC POTENCY (q.,*)
6.3.1. Oral. No evidence of cardnogenlclty was observed 1n male or
female Fischer 344 rats or CD-I mice Ingesting 40, 200 or 1000 mg/kg/day of
ethylene glycol for 2 years (DePass et al., 1986a) or In male or female
Sprague-Oawley rats Ingesting up to 4% dietary ethylene glycol (2000
mg/kg/day) for up to 2 years (Blood, 1965).
6.3.2. Inhalation. Pertinent data regarding the cardnogenlclty of
Inhaled ethylene glycol could not be located 1n the available literature.
0105h -25- 07/09/87
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