TECHNICAL REPORT DATA
(fttae read /attractions on the revent before completing)
1. REPORT NO.
EPA/600/8-88/Q39
2.
3. RECIPIENT'S ACCESSION NO
PB88-180260/AS
4. TITLE AND SUBTITLE
Health Effects Assessment for Ethyl Ether
ft. REPORT DATE
6. PERFORMING ORGANIZATION CODE
. AUTHOR(S)
I. PERFORMING ORGANIZATION REPORT NO
9. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT 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 PERIOO COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
15 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
thj's 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, RfD5 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.lDENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Group
8. DISTRIBUTION STATEMENT
Public
10. SECURITY CLASS (Thu Report I
Unclassified
21. NO. Of PAGES
20. SECURITY CLASS (This page I
Unclassified
22. PRICE
F«nn 2220-1 (R«». 4-77) PREVIOUS COITION if OMOLETE
" //J
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EPA/600/8-88/039
May, 1987
HEALTH EFFECTS ASSESSMENT
FOR ETHYL ETHER
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 In 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 ethyl
ether. All estimates of acceptable Intakes and carcinogenic potency
presented 1n this document should be considered as preliminary reflecting
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-Hne literature searches of the
TOXLINE and the CHEMFATE/DATALOG data bases. The basic literature searched
supporting this document 1s 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 following Office of Health and Environmental Assess-
ment (OHEA) sources have been extensively utilized:
U.S. EPA. 1986b. Integrated Risk Information System (IRIS).
Reference dose (RfO) for oral exposure for ethyl ether. Online.
(Verification date 6/11/86, final approval pending). Office of
Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH.
The Intent In these assessments 1s 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 1n
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard associated with exposure or risk to the chemlcal(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 llfespan).
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 1s 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$j) and oral (RfD$g)
exposures.
The RfD (formerly AIC) 1s similar 1n concept and addresses chronic
exposure. It 1s an estimate 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
RfO 1s route-specific and estimates acceptable exposure for either oral
(RfDg) or Inhalation (RfDj) with the Implicit assumption that exposure
by other routes 1s Insignificant.
111
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Composite scores (CSs) for noncarclnogens have also been calculated
where data permitted. These values are used for ranking reportable quan-
tities and the methodology for their development 1s explained In U.S. EPA
(1983).
For compounds for which there Is sufficient evidence of cardnogenld ty
RfD$ and RfD 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 1s 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 1f 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.
Ethyl ether has not been adequately assessed for cardnogenlclty,
chronic toxldty or teratogenldty. A recent 90-day oral toxldty study
(American 81ogen1cs Corp., 1986) with rats showed dally doses of 2000 and
3500 mg/kg to be associated with accelerated rates of mortality; whereas,
500 mg/kg/day was a NOAEL. From these data, an RfO^o of 350 mg/day and an
RfDfj of 35 mg/day for a 70 kg human, were derived. A CS of 10 was
calculated for mortality observed 1n rats at 2000 mg/day 1n the same study
(American B1ogen1cs Corp., 1986).
Inhalation exposure data at a single concentration suggested treatment-
related changes In relative organ weights 1n rats and guinea pigs, but the
data were Inadequate for derivation of an RfD$i or RfDi. For Informa-
tion only, an RfDj of 854 mg/day could be calculated from the ACGIH (1986)
TLV of 400 ppm (-1200 mg/m3). This value may be adopted as the RfD$i as
well. These values are not recommended because the basis for the TLV 1s
very weak.
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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.
3.
4.
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. . . .
3.4. TOXICANT INTERACTIONS
CARCINOGENICITY
4.1. HUMAN DATA
4.2. BIOASSAYS
4.3. OTHER RELEVANT DATA
4.4. WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
Page
. . . 1
. . . 3
. . . 3
. . . 3
. . . 4
. . . 4
. . . 4
. . . 5
. . . 5
. . . 5
. . . 5
. . . 6
6
7
. . . 7
. . . 7
. . . 7
7
9
. . . 10
6.1. SUBCHRONIC REFERENCE DOSE (RfDs) ............. 10
6.1.1. Oral (RfDso) ................... 10
6.1.2. Inhalation (RfDSI) ................ 10
6.2. REFERENCE DOSE (RfD) ................... 11
6.2.1. Oral (RfD0) ................... 11
6.2.2. Inhalation (RfDj) ................ 11
6.3. CARCINOGENIC POTENCY (q-j*) ................ 14
7. REFERENCES ............................ 15
APPENDIX: Summary Table for Vanadium and Compounds .......... 21
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LIST OF ABBREVIATIONS
CS Composite score
PEL Frank-effect level
Koc Soil sorptlon coefficient
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
PEL Permissible exposure limit
ppm Parts per million
RfD Reference dose
RfDj Inhalation reference dose
RfDQ Oral reference dose
RfD$i Subchronlc Inhalation reference dose
RfD$Q Subchronlc oral reference dose
RVj Dose-rating value
RVe Effect-rating vaTue
SGOT Serum glutamlc oxaloacetlc transamlnase
SGPT Serum glutamlc pyruvlc transamlnase
STEL Short-term exposure level
TLV Threshold-limit value
TWA Time-weighted average
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected physical and chemical properties and environmental fate of
ethyl ether are listed In Table 1-1.
In the atmosphere, ethyl ether 1s expected to exist primarily In the
vapor phase. The atmospheric half-life listed In Table 1-1 Is based on
experimentally determined rate constants ranging from 8.9xlO~12 to
9.3xlO~12 cm3 molecule"1 sec"1 for the reaction of ethyl ether with
HO radical at 25°C and an ambient HO radical concentration of S.OxlO5
molecules cm"3 (Atkinson et al., 1979; Graedel, 1978). In aquatic
systems, H appears that volatilization would be an Important removal
process; ethyl ether 1s reported to volatilize very rapidly from the surface
layer of dilute aqueous solutions (Pemberton and Counsel!, 1978). Using the
method of Lyman et al. (1982) and an estimated Henry's Law constant of
1.26xlO~3 atm-m3/mol at 25°C (Hlne and Mookerjee, 1975), the volatiliza-
tion half-life from water 1 m deep has been calculated to be ~6 hours.
Based on Us K , ethyl ether 1s not expected to be significantly
removed and transported through suspended partlculate matters and sediments
In water. Bloaccumulatlon In aquatic organisms also Is not expected to be
significant.
The half-life of ethyl ether 1n soil could not be located 1n the
available literature. Its high vapor pressure (442 mm Hg at 20°C) and rapid
volatilization from aqueous solution suggest that ethyl ether should
volatilize rapidly from moist and dry soil surfaces. High mobility In soil
Is suggested by K values of 24-73 and detection of ethyl ether 1n
groundwater below municipal and Industrial waste landfill sites (Sabel and
Clark, 1984; DeWalle and Chlan, 1981).
OllOh -1- 02/11/87
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TABLE 1-1
Selected Physical and Chemical Properties
and Environmental Fate of Ethyl Ether
Property
Value
Reference
CAS number:
Chemical class:
Molecular weight:
Vapor pressure:
Water solubility:
Log octanol/water
partition coefficient:
pKa:
B1oconcentrat1on factor:
Soil adsorption
coefficient:
Half-lives:
Air
Water
Soil
60-29-7
aliphatic ether
74.12
442 mm Hg at 20°C
6.46x10* mg/S. at 20°C
0.89
-3.59
2.8 (estimated)
24-73 (estimated)
26-27 hours
~6 hours
NA
Weber et al., 1981
Valvanl et al., 1981
Hansch and Leo, 1985
Kulevsky et al., 1969
Lyman et al., 1982
Lyman et al., 1982;
Sabljlc, 1984
Atkinson et al.,
1985; Graedel, 1978
H1ne and Mookerjee,
1975; Lyman et al.,
1982
NA = Not available
OllOh
-2-
02/11/87
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Pertinent data regarding the absorption of ethyl ether after oral Intake
could not be located 1n the available literature.
2.2. INHALATION
Henderson and Haggard (1943) estimated -that a man of average weight
would absorb a maximum of 1.25 g of ethyl ether, resulting 1n a blood
concentration of 0.018 g/l, when exposed to an atmospheric concentration
of 400 ppm (1200 mg/m3). Further details, such as the duration of
exposure, were not provided 1n the ACGIH (1986) review of this study.
Cowles et al. (1972) exposed pentobarbltal-anestheslzed mongrel dogs to
mixtures of four anesthetic gases Including 0.65X ethyl ether, by endo-
tracheal Intubation, for 100 minutes. Inspired and end-tidal gas samples
were measured every 1-2 minutes. Blood samples were taken from several
sites. Including the femoral artery, periodically throughout the exposure.
The authors found that It took 78.9 minutes for the partial pressure of
ethyl ether In alveolar gas and 92.5 minutes for the partial pressure 1n
arterial blood to reach 50% of the partial pressure In Inspired air. These
results Indicated that the uptake of ethyl ether after Inhalation exposure
was relatively slow compared with the other anesthetics tested. Because the
focus of this experiment was the prediction of concentrations of anesthetic
gases In various tissues, additional quantitative data regarding respiratory
uptake of ethyl ether were not provided.
OllOh -3- 10/28/86
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. In a preliminary draft of an American Blogenlcs Corp.
(1986) 90-day gavage study, 30 albino rats/sex were given 0, 500, 2000 or
3500 mg/kg/day ethyl ether. Body weight and food consumption values were
recorded weekly; hematologles, clinical chemistries and uMnalyses were
measured at an unspecified Interim period, and upon study completion, organ
weight measurements and gross necropsies were performed. H1stopatholog1cal
analyses are 1n progress.
During the study, 4/60 rats (2 males and 2 females) given 2000 mg/kg/day
and 15/60 rats (6 males and 9 females) given 3500 mg/kg/day died. Male rats
had Inhibitions In body weight gain at 2000 and 3500 mg/kg/day and decreased
food consumption at 3500 mg/kg/day. High-dose males had significant
decreases In hemoglobin and hematocrU values, and a slight Increase 1n red
cell count. SGPT and serum cholesterol levels were significantly Increased
at 3500 mg/kg/day. Although the relative weights of the brain, kidneys and
testes/ep1d1dym1des were Increased at the high dose, the significant
reductions In body weight gain 1n this group make Interpretation difficult.
Females given the high dose had Inhibitions In body weight gain, elevated
SGOT levels and significantly Increased llver-to-body weight ratios. The
dose of 2000 mg/kg/day resulted 1n a transient Increase 1n serum cholesterol
and elevated relative Hver weights In females. There were no other
treatment-related effects on hematology, clinical chemistry, urlnalysls
parameters or organ weights at either 500 or 2000 mg/kg/day.
The Investigators observed signs of light anesthesia at 2000 mg/kg/day
and, especially, at 3500 mg/kg/day. Before the final sacrifice, ophthalmic
examination revealed retinal atrophy 1n the eye of one 500 mg/kg/day female,
OllOh ' -4- 02/11/87
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two 2000 mg/kg/day females and two 3500 mg/kg/day males. Necropsies of rats
given the 2000 and 3500 mg/kg/day dosages revealed lung and liver discolora-
tion, and dlstentlon and discoloration of the stomach.
3.1.2. Inhalation. Chenoweth et al. (1972) studied the effects of
repetitive ethyl ether exposure on the growth, hlstopathologlcal, hemato-
loglcal and biochemical (SGOT and SGPT) parameters of 10 rats/sex, 6 guinea
pigs/sex and 2 rabbits/sex. Each species was exposed to 2000 ppm (6063
mg/m3) ethyl ether, 7 hours/day, 5 days/week. The number of exposure days
was 34/44 for rats and 33/43 for guinea'pigs and rabbits. Treatment had no
effect on terminal body weights In rats or guinea pigs, but H significantly
decreased relative heart and liver weights 1n rats, and Increased relative
testlcular weights In guinea pigs. Because only two rabbits/sex were used,
1t was difficult to assess effects of treatment on organ weights. No other
treatment-related effects were observed.
3.2. CHRONIC
3.2.1. Oral. Pertinent data regarding the chronic oral toxlclty of ethyl
ether could not be located In the available literature.
3.2.2. Inhalation. ACGIH (1986) reviewed the limited data available
regarding Inhalation exposure to ethyl ether and concluded that narcosis and
general anesthesia are the primary effects, which occur at exposures to
-3.6-6.5 volume % (109-197 g/m3). Respiratory arrest has been associated
with concentrations of 7-10 volume % (212-303 g/m3); higher concentrations
are fatal. Symptoms In occupatlonally exposed workers Include anorexia,
exhaustion, headache, sleepiness, dizziness, excitation and psychic disturb-
ances. Blood dyscraslas, particularly In women, and albumlnurla are also
seen. Nelson et al. (1943) reported that 200 ppm (-600 mg/m3) was approx-
imately the threshold of nasal Irritation and that 300 ppm (-900 mg/m3)
OllOh ' -5- 02/11/87
-------
was an objectionable working atmosphere. Cook (1945), on the other hand,
suggested that exposure should be limited to 500 ppm (-1520 mg/m3) to
avoid Irritation, and stated that exposure to 500-1000 ppm (-1520-3030
mg/m3) was not associated with demonstrable Injury to health.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
There were no data available on the reproductive effects of ethyl ether
In humans or on Its teratogenldty In experimental animals. Land et al.
(1981) studied the effects of acute high level Inhalation exposure to ethyl
ether on spermatozoa morphology. Male mice were exposed to 0.32 or 1.6
volume % (9700 or 48,500 mg/m3, respectively) ethyl ether, 4 hours/day for
5 consecutive days. Ep1d1dymal spermatozoa were examined for morphological
aberrations 28 days after the last exposure day. Neither concentration had
a significant effect upon the percentage of abnormal spermatozoa, compared
with control values.
3.4. TOXICANT INTERACTIONS
Ethyl ether Inhibits the metabolism of hexobarbltal (Vermeulen et al.,
1983), acetaminophen (Watklns et al., 1984), gentamldn and tobramycln
(Hlgashl et al., 1982), amlnopyrene (Hanew et al., 1984), ethanol (Hobara et
al., 1985) and N-n1trosod1methylam1ne (Keefer et al., 1985). Watklns et al.
(1984) showed that ethyl ether Inhibited conjugation of acetaminophen with
sulfate, glutathlone and glucuronlc add, thus slowing the rate of detoxifi-
cation. In most of these studies, plasma clearance of the Interacting
toxicant was depressed by co-administration of ethyl ether, while volumes of
distribution were unchanged. Keefer et al. (1985) found, however, that
clearance of N-n1trosod1methylam1ne was unaffected by prior treatment with
ethyl ether. The small dose of N-n1 trosod1methylam1ne used 1n this study,
compared with the doses of toxicants used by other Investigators, may
»
account for this difference.
OllOh -6- 02/11/87
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4. CARCINOGENICITY
4.1. HUMAN DATA
Pertinent data regarding the potential cardnogenldty In humans after
ethyl ether exposure eould not be located 1n the available literature.
4.2. BIOASSAYS
Pertinent data regarding the cardnogenlcl ty of ethyl ether after
chronic administration In experimental animals could not be located In the
available literature. The National Toxicology Program has not scheduled
ethyl ether for cardnogenldty testing (NTP, 1986).
4.3. OTHER RELEVANT DATA
Inhaled ethyl ether stimulated tumor growth 1n mice with subcutaneously
or Intravenously Implanted tumor cells (Frld et al., 1984). In the same
study, the mltotlc Index of Implanted tumor cells In rats was not affected
by administration of an unspecified concentration of ethyl ether.
Ethyl ether did not Increase the number of revertants In five strains of
Salmonella typh1mur1um, nor did It cause mutagenldty In three Escher 1ch1a
coll strains deficient In tryptophan synthesis (DeFlora et al., 1984).
Results were the same with or without S-9 mix. Abe and Sasaki (1982) found
that ethyl ether had no effect on the number of sister chromatid exchanges
1n cultured Chinese hamster ovary cells. Ma et al. (1984) reported that
ethyl ether gas did not Increase mlcronucleus formation In the plant,
Tradescantla palldosa.
4.4. HEIGHT OF EVIDENCE
Because of the lack of human and experimental animal data regarding the
cardnogenldty of ethyl ether, the chemical should be categorized In IARC
Group 3, Cannot Be Classified, or CAC- Group 0, Not Classified, applying the
OllOh -7- 10/28/86
-------
criteria for weight of evidence (U.S. EPA, 1986a). These categories are
reserved for chemicals with Inadequate evidence of animal cardnogenldty In
the absence of human data.
OllOh -8- 03/16/87
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5. REGULATORY STANDARDS AND CRITERIA
The ACGIH (1985) adopted a TLV-TWA of 400 ppm (-1200 mg/m3) for an
8-hour exposure to ethyl ether, and a TLV-STEL of 500 ppm (-1500 mg/m3).
The ACGIH (1986) cited occupational data Indicating that higher concentra-
tions In man result In Irritation and narcosis. The OSHA (1985) PEL Is also
1200 mg/m3.
U.S. EPA (1986b) derived an RfD for oral exposure of 0.5 mg/kg/day or 35
mg/day for a 70 kg human. In this derivation, an uncertainty factor of 1000
was applied to the low dose of 500 mg/kg/day (NOAEL) In the 90-day gavage
study using rats by American B1ogen1cs Corp. (1986).
OllOh -9- 03/16/87
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfO$)
6.1.1. Oral (RfDSQ). The only subchronlc oral study available for
derivation of an RfDso 1s the 90-day gavage study using rats by the
American B1ogen1cs Corp. (1986). The high mortality rate at 3500 mg/kg/day
clearly Indicates a PEL. At 2000 mg/kg/day, 4/60 rats died, and Inhibitions
In body weight gain, transient Increases 1n serum cholesterol and relative
hepatic weights, retinal atrophy and gross necropsy aberrations were
observed. Since one rat treated with 500 mg/kg/day had retinal atrophy, but
no other effects were observed 1n this treatment group. H1stopatholog1cal
examinations did not reveal any ethyl ether-related lesions; thus, the 500
mg/kg/day dose may be considered as a NOAEL. An uncertainty factor of 100
(10 for Interspedes extrapolation and 10 for the range of Intraspedes
sensitivity) 1s applied to the NOAEL of 500 mg/kg/day to attain an RfDSQ
of 5.0 mg/kg/day, or 350 mg/day for a 70 kg human.
6.1.2. Inhalation (RfOQT). The study by Chenoweth et al. (1972)
O 1
suggested treatment-related effects of ethyl ether exposure on relative
organ weights of rats and guinea pigs. Since the decreases In relative
heart and liver weights In rats and the Increased relative testlcular weight
In guinea pigs were not accompanied by changes 1n serum enzyme levels or
hlstopathologlcal appearance, the significance of these effects 1s unclear.
The short duration of the Chenoweth et al. (1972) study may have been Inade-
quate for assessment of the cumulative effects of longer-term exposure to
ethyl ether. No other data were adequate for quantitative risk assessment.
OllOh -10- 05/13/87
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6.2. REFERENCE DOSE (RfD)
6.2..1. Oral (RfOQ). An RfDQ of 0.5 mg/kg/day or 35 mg/day for a 70
kg human can be derived from the RfD~Q of 5.0 mg/kg/day calculated In
Section 6.1.1., by applying an additional uncertainty factor of 10 to expand
from subchronlc to chronic exposure. The RfD- should be re-assessed when
adequate chronic toxlclty or reproductive toxlclty data reveal the presence
of adverse effects at 500 mg/kg/day. This analysis agrees with a recent
U.S. EPA (1986b) analysis In which an RfD of 35 mg/day was derived in an
Identical manner.
Table 6-1 shows the derivation of a CS for oral Intake using the
American B1ogen1cs Corp. (1986) results. Although dally exposure to 500
mg/kg ethyl ether was associated with retinal atrophy, this effect was seen
grossly In only one rat, and results have not yet been confirmed hlstologl-
cally. The dally dose of 2000 mg/kg, which resulted 1n the deaths of four
rats. Is a more suitable value for CS derivation. Division of this dose by
10 (to approximate chronic exposure), and subsequent multiplication by the
cube root of the average rat body weight to the assumed human body weight
(70 kg) results 1n a human MED of 2311 mg/day for a 70 kg man. The human
MED corresponds to an RV of 1.0. The RV for Increased mortality Is
10, for a CS of 10.
6.2.2. Inhalation (RfD.). The only available toxlclty study regarding
chronic or subchronlc Inhalation exposure to ethyl ether was by Chenoweth et
al. (1972). Data from this study were Inadequate for derivation of an
RfD, because only one level was tested ^nd the duration of the experiment
(44 days) was too short to evaluate the subchronlc toxldty of ethyl ether.
OllOh -11- 05/13/87
-------
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The ACGIH (1986) TLV of 400 ppm (-1200 mg/m3} may be considered as a
basis for an RfDj. The TLV of 400 ppm appears to be based primarily on
the data of Cook (1945), who stated that exposures to 500-1000 ppm
(-1520-3030 mg/m3) did not result 1n demonstrable Injury to health and
recommended that exposures should be limited to 500 ppm to avoid Irritation.
Nelson et al. (1943), however, reported that 200 ppm (-600 mg/m3) was a
threshold for nasal Irritation and that 300 ppm (-900 mg/m3) was objec-
tionable 1n the workplace. The TLV of 400 ppm, therefore, Is Intended to
protect against Irritation, narcosis and demonstrable Injury to health. In
derivation of an RfD, for ethyl ether, a transformed dose of 122 mg/kg/day
1s calculated by expanding to continuous exposure and assuming that humans
weigh 70 kg and Inhale 10 m3 of air during the workday. Application of an
uncertainty factor of 10 results 1n an RfDSI of 12.2 mg/kg/day, or 854
mg/day for a 70 kg human. Because of the weak basis for the TLV, this
RfD. Is not recommended, and 1t 1s suggested that a subchronlc Inhalation
experiment of at least 90 days duration with multiple species and multiple
exposure levels be performed.
The Chenoweth et al. (1972) results can be used 1n the derivation of a
CS. Inhalation of 2000 ppm (-6060 mg/m3) ethyl ether, 7 hours/day for
33-34 exposure days resulted In decreased relative weights of the hearts and
livers of rats and Increased testlcular weights 1n male guinea pigs.
Chenoweth et al. (1972) stated that the mean terminal body weight of the
exposed guinea pigs was 687 g. Assuming a guinea pig of this weight Inhales
0.33 m3 of air/day [using the formula of U.S. EPA (1986c)], and converting
to continuous exposure, the air concentration of 6060 mg/m3 1s equivalent
to a dose of 652 mg/kg/day. Division of this equivalent dose by 10 (to
approximate chronic exposure), and multiplication by the cube root of the
OllOh -13- 05/13/87
-------
I
ratio of animal to human body weights results In a human MED of 977 mg/day
for a 70 kg human. This MED corresponds to an RV of 1.0. When the RV
Is multiplied by an RV of 4 (for changes In organ weights), the resulting
CS Is 4.0 (see Table 6-1).
6.3. CARCINOGENIC POTENCY (q^)
Because of the lack of cardnogenldty data for ethyl ether, determina-
tion of carcinogenic potency Is not possible.
OllOh -14- 02/11/87
-------
7. REFERENCES
Abe, S. and M. Sasaki. 1982. SCE as an Index of mutagenesls and/or card-
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ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986.
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American Blogenlcs Corp. 1986. 90-Day gavage study 1n rats using ethyl
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Chenoweth, M.B., B.K.J. Leong, G.L. Sparschu and T.R. Torkelson. 1972.
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animals on repeated Inhalation at subanesthetlc concentrations. JJK Cell.
B1ol. Toxlclty Anesth., Proc. Res. Symp., Dow Chemical, Midland, MI.
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OllOh -15- 10/28/86
-------
Cook, W.A. 1945. No title provided. Ind. Med. 14: 936. (Cited In ACGIH.
1986)
Cowles, A.L., H.H. Borgstedt and A.J. Gillies. 1972. Uptake and distri-
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anesthesia on the tumorlgenlc process In experimental animals. Eksp. Onkol.
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OllOh -16- 10/28/86
-------
Henderson, Y. and H.W. Haggard. 1943. Noxious Gases, 2nd ed. Relnhold
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Keefer, L.K., W.A. Garland, N.F. Oldfleld, J.E. Swagzdls and B.A. M1co.
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Kulevsky, N., C.T. Hang and V.I. Stenberg. 1969. Photochemical oxidations.
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OllOh -17- 10/28/86
-------
Lyman, W.J., W.F. Reehl and D.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Method. Environmental Behavior of Organic Compounds.
McGraw-Hill Book Co., New York. p. 5-5.
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OSHA (Occupational Safety and Health Administration). 1985. Safety and
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Sabel, G.V. and T.P. Clark. 1984. Volatile organic compounds as Indicators
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OllOh -18- 10/28/86
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Sabljic, A. 1984. Predictions of the nature and strength of soil sorptlon
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OllOh -19- 02/11/87
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Valvanl, S.C., S.H. Yalkowsky and T.J. Roseman. 1981. Solubility and
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Influence of ether anesthesia. J. Pharmacol. Exp. Ther. 226(1): 201-205.
Watklns, J.8., C.P. Siegers and C.D. Klaassen. 1984. Effect of dlethyl
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177(1): 168-175.
Weber, R.C., P.A. Parker and M. Bowser. 1981. Vapor pressure distribution
of selected organic chemicals. U.S. EPA, Cincinnati, OH. 39 p. EPA
600/2-81-021.
OllOh -20- 10/28/86
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