United States
Environmental Protection
Agency
FINAL DRAF1
ECAO-CIN-G044
August, 1988
r Research and
t*<<- Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR ETHYLENEDIAMINE
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE
NOTICE
This document 1s a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It Is being circulated for comments
on Us technical accuracy aijoV policy Implications.
U.S. Envi-Vonraentnl Protection Agenay
Library. Room 2*01 P.M-211-A
401 M Street, S.W.
Washington. DC 20460
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DISCLAIMER
This report 1s an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Waste and Emergency Response (OSHER). This document series
1s Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained for Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for 1n this document
and the dates searched are Included In "Appendix: Literature Searched."
Literature search material Is current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document 1s sent to the Program Officer (OSHER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfDs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD, 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 focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfOs Is the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfDs are not estimated. Instead,
a carcinogenic potency factor, or q-j* (U.S. EPA, 1980), 1s provided.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxlclty and carclno-
genlclty are derived. The RQ 1s used to determine the quantity of a hazard-
ous substance for which notification Is required 1n the event of a release
as specified under the Comprehensive Environmental Response, Compensation
and Liability Act (CERCLA). These two RQs (chronic toxlclty and cardno-
genlclty) represent two of six scores developed (the remaining four reflect
1gn1tab1lHy, reactivity, aquatic toxlclty, and acute mammalian toxlclty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxlclty and cancer based RQs are defined In U.S.
EPA, 1984 and 1986b, respectively.
Ill
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EXECUTIVE SUMMARY
Ethylenedlamlne (CAS number 107-15-3) 1s commonly known as EDA (Spitz,
1979). It 1s a colorless liquid at room temperature with an unpleasant,
ammonlacal odor (Spitz, 1979). Two commercial processes are used to manu-
facture ethylenedlamlne In conjunction with higher ethyleneamlnes: reaction
of aqueous ammonia with EDC and catalytic amlnatlon of HEA (Spitz, 1979).
Ethylenedlamlne Is manufactured by Dow Chemical In Freeport, TX, Texaco 1n
Conroe, TX and Union Carbide In Taft, LA (CHR, 1988). During 1986, 66.328
million pounds of this compound was produced 1n the United States (USITC,
1987). The use pattern for ethylenedlamlne 1s as follows (CMR, 1988):
exports (mainly for carbamate fungicides), 45%; chelatlng agents (mainly EDA
tetraacetlc acid tetrasodlum salt), 25%; oil and gas additives, 5%; poly-
amides. 5%; am1noethylethano1-am1ne-based surfactants, 5%; ethylene(bls)-
stearamlde, 5%; and others, Including urethane additives, 10%. Ethylene-
dlmanlne Is also used as a pharmaceutical aid (e.g., as an Injection
stabilizer for am1nophyH1ne) (Windholz, 1983).
In the atmosphere, ethylenedlamlne 1s expected to exist almost entirely
In the vapor phase (Perry and Green, 1984; E1senre1ch et al., 1981). This
compound 1s expected to react with photochemlcally generated hydroxyl
radicals In the atmosphere and the half-life for this reaction 1s estimated
to be 6 hours under typical conditions (Atkinson, 1987). Ethylenedlamlne
may also react with C0_ to form Insoluble carbonate; however, the
half-life for this reaction was not available. Loss of ethylenedlamlne In
precipitation may also occur. In water, ethylenedlamlne may undergo aerobic
blodegradatlon (Hills and Stack, 1955; Price et al., 1974; PHter. 1976) or
It may react with CO-, humlc materials or metallic Ions found 1n natural
1v
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haters (Wlndholz, 1983; Spitz, 1979). Reaction with photochemically
generated hydroxyl radicals, physical adsorption to suspended solids and
sediments, bloaccumulatlon 1n aquatic organisms and volatilization are not
expected to be significant fate processes 1n water. Blazquez (1973) found
that ethylenedlamlne had a half-life of <14 days 1n ditch water. In soil,
ethylenedlamlne may blodegrade or react with CO,,, humlc materials or
metallic Ions found In soil (Wlndholz, 1983; Spitz. 1979). Ethylenedlamlne
1s expected to be highly mobile 1n soil; however, rapid degradation should
limit leaching Into groundwater. This compound may volatilize from dry soil
surfaces. Ethylenedlamlne was not detected on the soil surface of a plant
bed 27 days after spraying (Blazquez, 1973).
No monitoring data were available regarding contamination of ambient
air, surface water, groundwater, drinking water or food with ethylene-
dlamlne. Skin sens1t1zat1on has been observed among the general population
because of the use of ethylendlamlne as a stabilizer In pharmaceutical
creams (Beard and Noe, 1981). Skin sens1t1zat1on 1s less likely to occur as
a result of Industrial exposures because occupational contact with ethylene-
dlamlne 1s less Intimate and damaged skin 1s usually not Involved (Beard and
Noe, 1981). NIOSH (1985) estimated that 9033 workers are potentially
exposed to ethylenedlamlne In the United States (NIOSH, 1985); however, the
survey did not Include exposure to trade name products containing this com-
pound, and the number of occupational exposures may be considerably higher.
The acute toxlclty of ethylenedlamlne to fish was reported for brown
trout [48-hour TLm=230 mg/i, Woodlwlss and Fretwell (1974)], golden orfe
[48-hour LC50=405 mg/i, Ouhnke and Luedemann (1978)], fathead minnow
(96-hour LC50=115.7 mg/i), Japanese medaka [48-hour TLm=1000 mg/B.,
Tonogal et al. (1982)], kllUflsh [48-hour LC50*1000 mg/l, Tonogal and
Ito (1984)] and guppy [96-hour LC5Q=275 mg/i. Van Leeuwen et al. (1985)].
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The acute toxIcUy of ethylenedlamlne to aquatic Invertebrates was reported
for brine shrimp [24-hour TLm=14 mg/l, Price et al. (1974)] and daphnlds
[24-hour TLm, 24-hour LC,.n and 48-hour LCCft of 14, 16 and 26.5 mg/l.
'50
50
respectively (Brlngmann and Kuehn, 1982, 1977a; Van Leeuwen et al., 1985)].
The 10-day LC_ of ethylenedlamlne 1n frogs was 250 mg/l (Birch and
Prahlad, 1986). ToxIcUy of ethylenedlamlne to bacteria, protozoa and algae
ranged from 0.5-20.4, 1.8-103 and 0.08-100 mg/l, respectively (Brlngmann,
1975; Brlngmann and Kuehn, 1976, 1977b, 1978a,b, 1980, 1981; Van Leeuwen et
al., 1985).
Absorption of ethylenedlamlne dlhydrochlorlde In rats following oral or
endotracheal administration was rapid, with peak plasma levels of the com-
pound being reached at 0.5-0.75 hours after dosing (Yang and Tallant, 1982).
At doses of 50 and 500 mg/kg, the absorption of ethylenedlamlne dlhydro-
chlorlde by the lung was -100%; absorption by the gastrointestinal tract was
slightly less (I.e., 80-95X) (Yang and Tallant, 1982). The absorption rate
constant for orally-administered ethylenedlamlne dlhydrochlorlde In rats did
not vary with age or sex, and was not appreciably different In animals
chronically exposed to the compound; an absorption rate constant of between
-3 and 6 hours"1 was determined for orally-administered ethylenedlamlne
dlhydrochlorlde (Yang et al., 1984a). Percutaneous absorption of ethylene-
dlamlne was slow but tended to Increase In significance at higher dose
levels (I.e., 1020 or 2040 jig/cm2), possibly due to degeneration of the
epidermis caused by exposure to ethylenedlamlne (Yang et al., 1987).
Forty-eight hours after single oral or endotracheal doses of radlolabeled
ethylenedlamlne dlhydrochlorlde (5, 50 or 500 mg/kg), the highest tissue
levels of radioactivity were found 1n the kidneys, liver, bone marrow and
thyroid (Yang and Tallant, 1982). The volume of distribution of ethylene-
dlamlne (expressed 1n terms of I/kg bw) appears to decrease with age 1n
vl
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the rat; presumably, this 1s due to an Increase 1n body fat In older animals
and an Inability of the water soluble ethylenedlamlne to distribute to this
fat tissue (Yang et al., 1984a). The small amount of radioactivity absorbed
following percutaneous administration of ethylened1am1ne to rats was
distributed primarily to liver, kidney, brain and lung (Yang et al., 1987).
N-Acetylethylened1am1ne has been Identified as the principal metabolite of
ethylenedlamlne 1n the urine and feces of rats following dally administra-
tion of ethylenedlamlne dlhydrochloMde (500 mg/kg/day) for 4 days (Yang and
Tallant, 1982). Other metabolic pathways Involving amlnoacetaldehyde
formation (Yang and Tallant, 1982; Hoshlka, 1967; Muraoka et al., 1966} and
glydne production through deamlnation of ethylenedlamlne (Caldwell and
Cotgreave, 1984) have also been proposed. Following single oral or endo-
tracheal doses of radlolabeled ethylenedlamlne dlhydrochlorlde to rats and
mice (5-500 mg/kg), radioactivity was excreted 1n the feces, exhaled air
and, primarily, the urine (Yang and Tallant, 1982; Yang et al., 1978,
1984a). Values for the percentages of administered radioactivity excreted
by the various routes ranged from -40-70% for urine, 3-30% for feces and
6-22% for exhaled radlolabeled C0?. Semi logarithmic plots of plasma
ethylenedlamlne concentration vs. time following administration of single
oral or endotracheal doses to rats (50 or 500 mg/kg) or topical administra-
tion of the compound (1020 or 2040 v9/cm2) suggested a two-compartment
model for elimination of the compound (Yang et al., 1984a; Yang and Tallant,
1982; Yang et al., 1987). Terminal half-lives for elimination of ethylene-
dlamlne from the plasma 1n these studies were determined to range from
-4.5-7 hours.
Perhaps because of the difficulty of ethylened1am1ne-vapor generation,
studies on the effects of ethylenedlamlne In experimental animals following
Inhalation exposure are not readily found In the available literature.
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A 30-day Inhalation study Indicated that exposure of rats to the two highest
levels of ethylenedlamlne used (225 and 484 ppm) resulted 1n death,
decreased body weight gain, Increased liver and kidney weights, cloudy
swelling of the liver and of the loop and convoluted tubules of the kidneys,
and degeneration of the convoluted tubules of the kidneys (Pozzanl and
Carpenter, 1954). Oral exposure of rats to ethylenedlamlne dlhydrochlorlde
In the diet for 3 months at a level that provided a dose of 1000 mg/kg/day
also resulted In Hver and kidney effects (Yang et al., 1983). A decrease
In the weight of these organs was noted and serum enzyme levels Indicative
of liver damage (I.e., elevated SGOT and SGPT levels) and hepatocellular
pleomorphlsm was noted 1n treated females. A variety of hematologlc effects
(I.e., depression of red blood cell counts, Increased mean corpuscular
volume and depression of hematocrlt and hemoglobin) were also observed 1n
treated animals. A reduction In liver and kidney weights was noted 1n rats
and mice 1n a 7-day dietary study 1n which ethylenedlamlne dlhydrochlorlde
was provided at a dose level of 1500 mg/kg/day to the rat and 2500 mg/kg/day
to the mouse (Yang et al., 1983). Additional acute toxldty Information
(I.e., LD50 values) for ethylenedlamlne dlhydrochlorlde and ethylene-
dlamlne 1s given 1n Table 6-1. Apparently, ethylenedlamlne can function as
a GABA mimetic agent and cause a depression of neuronal firing In the
central nervous system (Lloyd et al., 1982; Stone and Perkins, 1984; Blaxter
and Cottrell, 1985; Oavles et al., 1982, 1983; Perkins and Stone, 1981;
Boklsch et al., 1984; Strain et al., 1984). Contact dermatitis, which Is
due to sensltlzatlon to ethylenedlamlne Is fairly well documented and
appears to have an Incidence 1n the population of between ~2 and 13% (Rudner
et al., 1973, 1975; Angel1n1 et al., 1985; Prystowsky et al., 1979; Baer et
al., 1973). Reports 1n the Russian literature Indicate that occupational
exposure to ethylenedlamlne 1s associated with vascular dysfunction,
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^neurasthenic syndrome, narrowing of peripheral vision, bronchitis, bronchial
asthma and blood disorders (Valeeva, 1976; Valeeva et al., 1975, 1976, 1979;
Assa, 1975).
Pertinent data regarding the cardnogenlcHy of ethylenedlamlne follow-
ing Inhalation or oral exposure In experimental animals were not located In
the available literature cited 1n Appendix A. A 2-year combined oncogenlc-
ity/toxlclty study following oral administration of ethylenedlamlne dlhydro-
chlorlde to rats has been performed by Union Carbide Corporation (Yang et
al., 1984a) but was unavailable for the preparation of this document.
Ethylenedlamlne applied as a 1% solution to the skin of male C3H mice did
not produce epidermal tumors (DePass et al., 1987). Results from mutagen-
1c1ty studies on ethylenedlamlne are equivocal. Ames-type testing 1n
bacteria Indicates that ethylenedlamlne Is weakly mutagenlc (Haworth et al.,
1983; Hulla et al., 1981; Hedenstedt, 1978), whereas mutation studies using
mammalian cells (I.e., CHO cells and rat hepatocytes) have been negative
{Sleslnskl et al., 1983) {Table 6-2). Recessive lethal tests 1n DrosophUa
(Zlmmerlng et al., 1985) and dominant lethal tests In rats (Sleslnskl et
al., 1983) have also been negative. Administration of ethylenedlamlne
dlhydrochloHde 1n the diet of pregnant Fischer 344 rats during days 6-15 of
gestation at a dose level of 1040 mg/kg/day produced signs of fetotoxlclty
(I.e., decreased fetal weights and crown-rump length and an Increase In the
percentage of Utters with one or more resorptlons), but no signs of terato-
genlclty (DePass et al., 1987). A 2-generat1on study of the reproductive
effects of ethylenedlamlne dlhydrochlorlde following oral administration 1n
rats Indicated that the compound was not associated with reproductive
toxlclty even at dose levels (I.e., 500 mg/kg/day) that produced decreased
body weight gain and changes 1n organ weights In the parental generation
(Yang et al., 1984b).
1x
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; Derivation of a q,* for ethylenedlamlne was not possible because no
data were available on the cardnogenlclty of ethylenedlamlne following
either Inhalation or oral exposure. A subchronlc Inhalation RfD of 0.3
mg/kg/day was calculated for ethylenedlamlne based on a 30-day Inhalation
study by Pozzanl and Carpenter {1954}. This study was not considered to be
of sufficient duration for determination of a chronic Inhalation RfD even
with the use of an uncertainty factor to approximate chronic exposure. A
subchronlc oral RfD for ethylenedlamlne of 0.2 mg/kg/day was derived from a
3-month dietary study using rats by Yang et al. (1983). Chronic oral
toxldty data on ethylenedlamlne were not available; therefore, a chronic
oral RfD for ethylenedlamlne of 0.02 mg/kg/day was derived from the sub-
chronic oral RfD by division of an uncertainty factor of 10 to extrapolate
from subchronlc to chronic exposure. A chronic toxldty RQ of 1000 was
calculated based on results from a two-generation reproduction study by Yang
et al. (1984b). It was not possible to derive an RQ for ethylenedlamlne
based on cardnogenlclty because of the lack of cardnogenldty data follow-
ing Inhalation or oral exposure In either experimental animals or humans.
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 4
2. ENVIRONMENTAL FATE AND TRANSPORT 5
2.1. AIR 5
2.1.1. Reaction with Hydroxyl Radicals 5
2.1.2. Other Reactions 5
2.1.3. Physical Removal Processes 5
2.2. HATER 6
2.2.1. Chemical Degradation 6
2.2.2. Mlcroblal Degradation 6
2.2.3. Volatilization 7
2.2.4. Bloaccumulatlon 7
2.2.5. Absorption 7
2.2.6. Persistence 7
2.3. SOIL 8
2.3.1. Chemical Degradation 8
2.3.2. H1crob1al Degradation 8
2.3.3. Adsorption 8
2.3.4. Volatilization 8
2.3.5. Persistence 8
2.4. SUMMARY 8
3. EXPOSURE 10
4. AQUATIC TOXICITY 11
4.1. ACUTE TOXICITY 11
4.2. CHRONIC EFFECTS 13
4.3. EFFECTS ON AQUATIC PLANTS AND BACTERIA 13
4.4. SUMMARY 15
5. PHARMACOKINETCS 16
5.1. ABSORPTION 16
5.2. DISTRIBUTION 18
5.3. METABOLISM 20
5.4. EXCRETION 21
5.5. SUMMARY 24
x1
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TABLE OF CONTENTS (cont.)
Page
6. EFFECTS 26
6.1. SYSTEMIC TOXICITY 26
6.1.1. Inhalation Exposure 26
6.1.2. Oral Exposure 27
6.1.3. Other Relevant Information 28
6.2. CARCINOGENICITY 33
6.2.1. Inhalation 33
6.2.2. Oral 33
6.2.3. Other Relevant Information 33
6.3. HUTAGENICITY 33
6.4. TERATOGENICITY 34
6.5. OTHER REPRODUCTIVE EFFECTS 36
6.6. SUMMARY 39
7. EXISTING GUIDELINES AND STANDARDS 42
7.1. HUMAN 42
7.2. AQUATIC 42
8. RISK ASSESSMENT 43
8.1. CARCINOGENICITY 43
8.1.1. Inhalation 43
8.1.2. Oral 43
8.1.3. Other Routes 43
8.1.4. Weight of Evidence 43
8.1.5. Quantitative Risk Estimates 43
8.2. SYSTEMIC TOXICITY 43
8.2.1. Inhalation Exposure 43
8.2.2. Oral Exposure 46
9. REPORTABLE QUANTITIES 50
9.1. BASED ON SYSTEMIC TOXICITY 50
9.2. BASED ON CARCINOGENICITY 56
10. REFERENCES 59
APPENDIX A: LITERATURE SEARCHED 75
APPENDIX B: SUMMARY TABLE FOR ETHYLENEDIAMINE 78
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LIST OF TABLES
No. Title Page
1-1 Current Domestic Manufacturers and Their Production
Capacities 3
6-1 Acute Tox1c1ty of Ethylenedlamlne and Ethylenedlamlne
Dlhydrochlorlde 32
6-2 Mutagenlclty Testing of Ethylenedlamlne and Ethylenedlamlne
Dlhydrochlorlde 35
9-1 Toxlclty Summary for Ethylenedlamlne and Ethylenedlamlne
Dlhydrochlorlde 51
9-2 Oral Composite Scores for Ethylenedlamlne Using the Rat ... 53
9-3 Ethylenedlamlne: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 57
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LIST OF ABBREVIATIONS
ALT
AST
BOD
bw
CAS
CHO
COD
CS
DLM
DNA
EDC
GABA
HC1
KOC
Kow
LD50
LOAEL
MEA
MED
NOAEL
PEL
pKa
ppm
RfD
RQ
Alanlne amlnotransferase (formerly SGPT)
Aspartate amlnotransferase (formerly SGOT)
Biochemical oxygen demand
Body weight
Chemical Abstract Service
Chinese hamster ovary
Chemical oxygen demand
Composite score
Dominant lethal mutation
Deoxyrlbonuclelc acid
1,2-Dlchloroethane
Y-acnlnobutyrU add
Hydrochloric add
Soil sorptlon coefficient
Octanol/water partition coefficient
Dose lethal to 50% of recipients
Lowest-observed-adverse-effect level
Honoethanolamlne
Minimum effective dose
No-observed-adverse-effect level
Permissible exposure level
Negative log-jo of dissociation constant
Parts per million
Reference dose
Reportable quantity
x1v
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RVe
SCE
SGOT
SGPT
TBOD
TLm
TLV
TWA
UDS
v/v
w/v
LIST OF ABBREVIATIONS (cent.)
Dose-rating value
Effect-rating value
Sister chromatld exchange
Serum glutamlc oxaloaceUc transamlnase
Serum glutamlc pyruvlc transamlnase
Theoretical biological oxygen demand
Median tolerance limit, the concentration at
which 50% of the test animals are killed
Threshold limit value
Time-weighted average
Unscheduled DNA synthesis
Volume per volume
Weight per volume
xv
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1 . INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Ethylenedlamlne Is commonly known as EDA (Spitz, 1979). It 1s also
known as dlamlnoethane and 1 ,2-ethaned1am1ne (Verschueren, 1983). The
structure, CAS Registry number, empirical formula and molecular weight are
as follows:
Molecular weight: 60.1
Empirical formula: C2HgN2
CAS Registry number: 107-15-3
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Ethylenedlamlne Is a colorless liquid at room temperature, with an
unpleasant, ammonlacal odor (Spitz, 1979). It 1s slightly soluble with
ether and Is soluble with water, alcohol and with benzene unless the
ethylenedlamlne 1s Insufficiently dried (Wlndholz, 1983). Ethylenedlamlne
readily absorbs C02 from air to form a nonvolatile carbonate (Wlndholz,
1983), and It undergoes reactions typical of compounds containing a primary
amlne group (Spitz, 1979). Selected physical and chemical properties of
this compound are as follows:
Melting point:
Boiling point:
Vapor pressure:
Mater solubility:
Koc:
Density:
10.8°C
117.0°C
33 mm Hg (20°C)
completely mlsdble
-1.22 (estimated)
9.928 (25°C)
6.848 (25°C)
0.8931 (25°C)
Spitz, 1979
Spitz, 1979
Perry and Green, 1984
Spitz, 1979
U.S. EPA, 1987a
PerMn, 1964
Perrln, 1964
R1dd1ck et al., 1986
0122d
-1-
07/18/88
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Flashpoint: 40°C Spitz, 1979
{Tag closed cup)
Odor threshold values:
Air: 1.0 ppm (v/v) Amoore and Hautula,
Hater: 16,000 ppm (w/v) 1983
Air conversion factors
at 20°C: 1 mg/m3 =0.40 ppm Verschueren, 1983
1 ppm =2.50 mg/m9 Verschueren, 1983
1.3. PRODUCTION DATA
Two commercial processes are used to manufacture ethylenedlamlne:
reaction of aqueous ammonia with EDC and catalytic amlnatlon of MEA. The
EDC-ammonia process 1s the older of the two methods and 1s the major commer-
cial route for production of ethyleneamlnes. Both of these processes yield
athylenedlamlne 1n conjunction with higher ethyleneamlnes. Depending upon
narket demand for the other ethyleneamlnes, the actual yield of ethylene-
111 amine from these processes may be varied by altering reaction conditions.
Current domestic manufacturers and their production capacities are given 1n
'able 1-1. During 1986, 66.328 million pounds of ethylenedlamlne was
iroduced 1n the United States (USITC, 1987).
'.4. USE DATA
Ethylenedlamlne 1s a versatile chemical Intermediate with many Indus-
rial applications. The use pattern for ethylenedlamlne 1s as follows (CMR,
1988): exports (mainly for carbamate fungicides), 45X; chelatlng agents
mainly EDA tetraacetlc add tetrasodlum salt), 25%; oil and gas additives,
%; polyamldes, 5X; am1noethylethanol-am1ne-based surfactants, 554; ethylene-
io1s)stearam1de, 5X; and others, Including urethane additives, 10X.
Ethylenedlamlne 1s also used as a pharmaceutical aid (e.g.. as an Injection
stabilizer for aminophylline) (Wlndholz, 1983).
0122d -2- 07/18/88
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TABLE 1-1
Current Domestic Manufacturers and Their Production Capacities3
Company/Location
Capac1tyb
(millions of pounds/year)
Dow Chemical, Freeport, TX
Texaco, Conroe, TX
Union Carbide, Taft, LA
45
10
80
aSource: CMR, 1988
^Figures are 45% of total ethylenamlne plant capacity, which Is an
estimate of ethylenedlamlne yield under optimum conditions.
0122d
06/13/88
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1.5. SUMMARY
Ethylened1am1ne (CAS number 107-15-3) 1s commonly known as EDA (SpHz,
1979). It 1s a colorless liquid at room temperature with an unpleasant,
ammonlacal odor (Spitz, 1979). Two commercial processes are used to manu-
facture ethylenedlamlne 1n conjunction with higher ethyleneamlnes: reaction
of aqueous ammonia with EDC and catalytic amlnatlon of MEA (Spitz, 1979).
Ethylenedlamlne Is manufactured by Dow Chemical 1n Freeport, TX, Texaco 1n
Conroe, TX and Union Carbide 1n Taft, LA (CNR, 1988). During 1986, 66.328
million pounds of this compound was produced 1n the United States (USITC,
1987). The use pattern for ethylenedlamlne Is as follows (CMR, 1988):
exports (mainly for carbamate fungicides), 45%; chelatlng agents (mainly EDA
tetraacetlc add tetrasodlum salt), 25%; oil and gas additives, 5%; poly-
amides, 5%; am1noethylethanol-am1ne-based surfactants, 5%; ethylene(bls)-
stearamlde, 5%; and others. Including urethane additives, 10%. Ethylene-
dlmanlne Is also used as a pharmaceutical aid (e.g., as an Injection
stabilizer for amlnophylllne) (Wlndholz, 1983).
0122d -4- 07/14/88
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2. ENVIRONMENTAL FATE AND TRANSPORT
Pertinent data regarding the environmental fate and transport of
ethylenedlamlne are limited. Whenever possible, Information concerning the
environmental fate and transport of this compound was derived from physical
properties or molecular structure.
2.1. AIR
Based on a vapor pressure of 33 mm Hg at 20*C {Perry and Green, 1984),
ethylenedlamlne 1s expected to exist almost entirely 1n the vapor phase 1n
the atmosphere (E1senre1ch et al.t 1981).
2.1.1. Reaction with Hydroxyl Radicals. The rate constant for reaction
of ethylenedlamlne vapor with photochemlcally generated hydroxyl radicals
has been estimated to be 6.16x10"" cm3/molecule-sec at 25°C using the
method of Atkinson (1987). Assuming a typical ambient hydroxyl radical
concentration of 5.0x10* molecules/cm' (Atkinson, 1987), the hydroxyl
radical reaction half-life has been estimated to be 6 hours. Thus, reaction
of ethylenedlamlne with hydroxyl radicals 1n the atmosphere Is expected to
be an Important fate process.
2.1.2. Other Reactions. Ethylenedlamlne 1s not susceptible to reaction
with ozone 1n the atmosphere (U.S. EPA, 1987b). Ethylenedlamlne may react
with COp molecules In the atmosphere and form a nonvolatile carbonate
(Wlndholz, 1983); however, data regarding the rate of this reaction were not
located In the available literature.
2.1.3. Physical Removal Processes. The complete water solubility of
ethylenedlamlne (Spitz, 1979), In addition to chemical degradation, suggests
that small amounts of this compound may be lost through wet deposition.
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2.2. HATER
2.2.1. Chemical Degradation. Ethylenedlamlne 1s a relatively strong base
(pK.p9.93, pK2=6.85) (Perrln, 1964)) and Is expected to exist largely
1n Its mono- and dlprotonated forms under environmental conditions (pH 5-9).
It may combine readily with CCL to form nonvolatile carbonate (Wlndholz,
1983); however, experimental data regarding the rate of this reaction could
not be located 1n the available literature. Ethylenedlamlne also has the
ability to form relatively stable fWe-membered rings by coordination of the
two unshared electrons on the nitrogen atoms with metallic Ions (Stumm and
Morgan, 1981). Metallic Ions In soils or natural waters may therefore
combine with ethylenedlamlne, but data on these reactions In natural systems
could be not found 1n the available literature. Humlc adds that occur In
natural waters contain aldehyde groups, which could potentially react with
the amlne groups to form adducts; however, experimental data regarding this
kind of reaction are not available (Spitz, 1979). The rate constant for the
reaction of ethylenedlamlne with photochemically generated hydroxyl radicals
1n water has been estimated to be 6.5xl07 and l.OxlO8 H~l sec"1 at
pH 5 (Anbar and Neta, 1967; Dorfman and Adams, 1973). Assuming an average
ambient hydroxyl radical concentration of lxlO~17 mol/l (Mill et a!.,
1980), the half-life for this reaction has been estimated to be between 22
and 34 years. These values suggest that reaction with photochemically
generated hydroxyl radicals Is not an environmentally significant fate
process.
2.2.2. Mlcroblal Degradation. In general, screening studies have shown
that ethylenedlamlne 1s susceptible to rapid blodegradatlon, particularly In
the presence of acclimated microorganisms. Ethylenedlamlne, at an Initial
concentration of 50 ppm, underwent a loss of 67% TBOD In 5 days and 81% TBOD
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In 10 days 1n acclimated freshwater (obtained from the Kanawha River) (Mills
and Stack, 1955). In a screening study done In a batch system using adapted
activated sludge as Inoculum, ethylened1am1ne at an Initial concentration
equivalent to 200 mg/i COD underwent 97.5% COD removal 1n 5 days (Fitter,
1976). Standard dilution tests with unaccllmated sewage as seed showed that
ethylened1am1ne at an Initial concentration of 7-10 ppm underwent 24 and 47%
loss of TBOD In 5 and 20 days, respectively, 1n freshwater, and 2 and 16%
loss of TBOD, respectively, 1n saltwater (Price et al., 1974). In standard
BOD dilution water with acclimated sewage as seed, 7-10 ppm ethylened1am1ne
underwent 36 and 70% loss of TBOD 1n 5 and 20 days (Price et al., 1974).
Under slmlHar conditions, using unaccllmated sewage as seed, Takemoto et
al. (1981) observed 0.6 and 0.17% TBOD removal In 5 days 1n freshwater and
seawater, respectively.
2.2.3. Volatilization. Ethylenedlamlne has a measured Henry's Law
constant of 1.8x10~» atm-mVmol at 25*C (H1ne and Hooker jee, 1975).
This value of Henry's Law constant suggests that volatilization would be
unimportant as an Intermedia transfer mechanism from water (Thomas, 1982).
2.2.4. B1oaccumulat1on. The complete water solubility and relatively low
KOW of ethylendlamlne (Spitz, 1979; U.S. EPA. 1987a) suggest that this
compound would not bloaccumulate significantly 1n aquatic organisms.
2.2.5. Adsorption. Based on the complete water solubility of ethylene-
dlamlne and an estimated K value of 5 (Section 2.3.2.), physical adsorp-
tion to suspended solids and sediments 1s not expected to be significant.
2.2.6. Persistence. The residual concentrations of ethylened1am1ne 0, 1,
7, 14 and 21 days following application to dlonlzed water were (in ppm) 100,
45, 40, 40, 40 and trace, respectively (Blazquez, 1973). The residual
concentrations remaining 0, 1, 7, 14 and 21 days after application to ditch
water were 40, 10, trace and 0 ppm, respectively (Blazquez, 1973).
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2.3. SOIL
2.3.1. Chemical Degradation. It appears that ethylenedlamlne may react
with CO., metallic Ions and humlc materials found In soil; however.
Information regarding the kinetics of these reactions were not located In
the available literature cited In Appendix A (see Section 2.2.1.).
2.3.2. H1crob1al Degradation. Based on results of blodegradatlon screen-
Ing studies conducted In aqueous systems, 1t appears that ethylenedlamlne
would be susceptible to rapid microblal degradation 1n soil under aerobic
conditions, with the rate of degradation being fastest In acclimated systems.
2.3.3. Adsorption. A K of 5 has been estimated for this compound
using the following linear regression equation (Lyman. 1982): log K =
0.544 log KQW + 1.377, where the log KQW value Is -1.22 (U.S. EPA,
1987a). This K value and the complete water solubility of ethylene-
dlamlne (Spitz, 1979) suggest that ethylenedlamlne would be very highly
mobile In soil (Swann et al., 1983).
2.3.4. Volatilization. A vapor pressure of 33 mm Hg at 20°C (Perry and
Green, 1984) and expected low adsorption to soil (see Section 2.3.2.)
suggest that some evaporative loss from dry soil surfaces may occur.
2.3.S. Persistence. Residual concentrations of ethylenedlamlne on the
soil surface of a plant bed 0, 1, 6, 13 and 27 days after spraying were 40,
22, 15, 20 and 0 ppm, respectively (Blazquez, 1973).
2.4. SUMMARY
In the atmosphere, ethylenedlamlne Is expected to exist almost entirely
In the vapor phase (Perry and Green, 1984; E1senre1ch et al., 1981). This
compound Is expected to react with photochemlcally generated hydroxyl
radicals In the atmosphere and the half-life for this reaction 1s estimated
to be 6 hours under typical conditions (Atkinson, 1987). Ethylenedlamlne
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may also react with CO. to form Insoluble carbonate; however. Information
on the half-life for this reaction was not available. Loss of ethylene-
dlamlne 1n precipitation may also occur. In water, ethylenedlamlne may
undergo aerobic blodegradatlon (Mills and Stack, 1955; Price et a!., 1974;
Fitter, 1976) or It may react with C02, humlc materials or metallic Ions
found In natural waters (Hlndholz, 1983; Spitz, 1979). Reaction with photo-
chemlcally generated hydroxyl radicals, physical adsorption to suspended
solids and sediments, bloaccumulatlon in aquatic organisms and volatiliza-
tion are not expected to be significant fate processes 1n water. Blazquez
(1973) found that ethylenedlamlne had a half-life of <14 days In ditch
water. In soil, ethylenedlamlne may blodegrade or react with CO., humlc
materials or metallic Ions found In soil (Wlndholz, 1983; Spitz, 1979).
Ethylenedlamlne 1s expected to be highly mobile 1n soil; however, rapid
degradation should limit leaching Into groundwater. This compound may
volatilize from dry soil surfaces. Ethylenedlamlne was not detected on the
soil surface of a plant bed 27 days after spraying (Blazquez, 1973).
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3. EXPOSURE
No monitoring data were available regarding contamination of ambient
air, surface water, groundwater, drinking water or food with ethylene-
dlamlne. Skin sensltlzatlon has been observed among the general population
because of the use of ethylendlamlne as a stabilizer In pharmaceutical
creams (Beard and Noe, 1981). Skin sensltlzatlon 1s less likely to occur as
a result of Industrial exposures because occupational contact with ethylene-
dlamlne 1s less Intimate and damaged skin Is usually not Involved (Beard and
Noe, 1981). N10SH (1985) estimated that 9033 workers are potentially
exposed to ethylened1am1ne 1n the United States (NIOSH, 1985); however, the
survey did not Include exposure to trade name products containing this
compound. The number of occupational exposures, therefore, may be
considerably higher.
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4. AQUATIC TOXICITY
4.1. ACUTE TOXICITY
The acute toxlclty of ethylenedlamlne to aquatic life was assessed In
several studies with fish and aquatic Invertebrates. Gillette et al. (1952)
exposed creek chub, SemotUus a. atromaculatus. to ethylenedlamlne for 24
hours at temperatures ranging from 15-21°C. Control and treatment solutions
were aerated during the exposure phase. Dilution water was obtained
directly from the East Channel of the Detroit River and used untreated.
Four fish were used per treatment. The authors did not Indicate whether the
treatments were replicated. All fish survived exposure to 30 ppm ethylene-
dlamlne for 24 hours but all fish died when exposed to 60 ppm for 24 hours.
Loeb and Kelly {1963} force-fed encapsulated ethylenedlamlne at 129, 143
and 159 mg/kg to carp, Cyprlnus carplo. that were collected 1n the field and
weighed from 1-10 pounds (average ~3 pounds). Tests were conducted at 65°F.
Mortality occurred In <60 hours. The authors did not specify the levels of
mortality observed within each treatment. The authors concluded that the
results of this study and of those for 1495 other chemicals could not be
adequately explained because of the lack of trends In the results.
Hood1w1ss and Fretwell (1974) exposed brown trout, Salmo trutta. to
ethylenedlamlne In dechlorlnated aerated tapwater at 10°C for 48 hours 1n
static tests and reported a 48-hour TLm of 230 mg/l. Juhnke and Luedemann
(1978) studied the acute toxldty of ethylenedlamlne In the Golden Orfe,
Leuclscus 1dus melanotus. and reported a 48-hour LCQ, LC5Q and LC,QO
of 360, 405 and 450 mg/l, respectively.
Curtis and Hard (1981) exposed the fathead minnow, PImepha1es promelas.
to ethylenedlamlne In reconstituted water at 22°C for 96 hours In static
tests. Concentrations of ethylenedlamlne were determined at the beginning
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and end of the test. A 96-hour IC (with 95% confidence Intervals) of
115.7 mg/i (98.6-131.6) was reported. Tonogal et al. (1982) exposed
groups of 10 Hlmedaka or Japanese medaka, Oryzlas latlpes. to ethylene-
dlamlne 1n tapwater at 25°C for 48 hours 1n static tests. Average fish
weight was -0.2 g. The 24- and 48-hour TLm values were 1000 mg/t. TLm
values for a series of aliphatic amines were also 1000 mg/l. whereas those
for aromatic nitrogen compounds were <50 mg/l.
Tonogal and Ito (1984) reported a 24- and 48-hour U of 1000 mg/l
for ethylenedlamlne In k1H1f1sh. N1sh1uch1 (1984) reported a 3-hour LC&0
for ethylenedlamlne 1n frog tadpoles at 25°C of 150 ppm; 6-, 12-, 24- and
48-hour LCj-gS were 130 ppm. Van Leeuwen et al. (1985) exposed gupples,
PoeclHa retlculata. to ethylenedlamlne 1n a static-renewal acute study, and
reported a 96-hour LC5Q (with 95X confidence limits) of 275 mg/l
(180-560).
Price et al. (1974) exposed brine shrimp, Artetnla sallna. to ethylene-
dlamlne 1n artificial seawater at 24.5"C for 24 hours In static tests and
reported a 24-hour TLm of 14 mg/a. Brlngmann and Kuehn (1982) exposed
Daphnla maqna to ethylenedlamlne 1n reconstituted water at 20°C for 24
hours. All treatments were replicated. The Investigators reported a
24-hour EC5Q (with 95% confidence Intervals) based on Immobilization of 19
mg/l (13-28). They also reported ECQ and EC10Q of 1.2 and 150 mg/l,
respectively. In an earlier study, Brlngmann and Kuehn (1977a) generated a
24-hour LC5Q of 16 mg/l for daphnlds, D. maqna. exposed to ethylene-
dlamlne In chlorine-free tapwater. The LCQ and LC10Q values were 6.4
and 115 mg/l, respectively. Van Leeuwen et al. (1985) exposed J). maqna to
ethylenedlamlne 1n a static-renewal acute study 1n which tests with amines
were conducted 1n sealed vessels. A 48-hour LC50 (with 95% confidence
limits) of 26.5 mg/a (20.4-34.4) was reported.
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4.2. CHRONIC EFFECTS
Birch and Prahlad (1986) exposed embryos of the South African clawed
toad, Xenopus laevls. to ethylenedlamlne to assess the potential teratogenU
effects and toxUUy of this substance as a degradation product of the
fungicide nabam (ethyleneblsdlthlocarbamate dlsodlum salt). Twenty embryos
(stages 10-12} per container were exposed at 22°C to ethylenedlamlne 1n
covered glass storage dishes containing 250 ml of medium until hatching.
At least 60 embryos were exposed to each treatment. Five- to 12-day-old
tadpoles were tested In a similar manner. Mortality was defined as the
cessation of heartbeat 1n tadpoles observed at 2Sx on a dissection
microscope. The Investigators reported a 10-day LC5Q of 250,000 yg/B.
(0.02554) for ethylenedlamlne 1n tadpoles. Teratogenlc effects were not
observed 1n tadpoles exposed to ethylene dlamlne at concentrations of
100-10,000 pg/l.
4.3. EFFECTS ON AQUATIC PLANTS AND BACTERIA
Effects of exposure of a green algae, Scenedesmus quadrlcauda. and a
blue-green algae, H1crocyst1s aeruglnosa. to ethylenedlamlne were reported
by BMngmann (1975) and Brlngmann and Kuehn (1976, 1978a,b). Cultures were
Incubated with a series of ethylenedlamlne concentrations for 8 days at 27°C
to determine the tox1c1ty threshold, which was defined as the concentration
of ethylenedlamlne Inhibiting multiplication of cells In suspension. The
Inhibition was measured turbldlmetrlcally as a >3X extinction of the primary
light of monochromatic radiation at 436 nm for a layer of cells 10 mm thick.
Toxldty threshold levels for exposure of M. aeruglnosa and S. quadrlcauda
to unneutrallzed ethylenedlamlne were 0.04 and 3.2 mg/i, respectively,
while the toxlclty threshold levels for exposure of H. aeruglnosa and S_.
quadrlcauda to neutralized ethylenedlamlne were 0.08 and 0.85 mg/s.,
respectively.
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Effects of exposure of an aquatic bacteria, Pseudoroonas put1da. a green
algae, Scenedesmus quadrlcauda. and a flagellated protozoan, Entoslphon
sulcatum. to ethylenedlamlne were reported by Brlngmann and Kuehn (1980).
Effects on protozoa were determined by cell counts on a Coulter counter.
The toxlclty threshold with protozoa was defined as a 5% reduction 1n cell
counts obtained mathematically from regressions between ethylenedlamlne
concentrations and cell counts. Bacterial suspensions were exposed to
ethylenedlamlne for 16 hours at 25°C, algal suspensions for 7 days at 27°C,
and protozoan cultures for 72 hours at 25°C. Toxldty thresholds of 0.85,
0.85 and 1.8 mg/l were reported for the bacteria, algae and protozoan,
respectively. Previously, Brlngmann and Kuehn (1976, 1977b) reported a
toxlclty threshold of 0.5 mg/i for P. pjuUda exposed to unneutrallzed
ethylenedlamlne. Subsequently, Brlngmann and Kuehn (1981) assessed the
effects of exposure of a holozolc bacterlovorous flagellated protozoan,
Entoslphon sulcatum Stein, a holozolc bacterlovorous ciliated protozoan,
Uronema parduczl Chatton-Lwoff and a saprozolc ciliated protozoan,
ChUomonas paramedum Ehrenberg, to ethylenedlamlne. Reported toxlclty
threshold values were 1.8, 52 and 103 mg/B., respectively.
Van Leeuwen et al. (1985) conducted toxlclty tests with algae, Chlorella
pyrenoldosa. luminescent bacteria, PhotobacteMum phosphoreum. and nitrify-
ing bacteria, NUrosomonas and NUrobacter. Algal bloassays were conducted
at 20°C with an Initial cell density of ~10» cells/I. The Investigators
reported that tests with ethylenedlamlne were conducted 1n Infuse bottles.
The 96-hour EC5Q was calculated for the average specific growth rate (100
mg/fi.) and yield (61 mg/i). The EC value for £. phosphoreum exposed
to ethylenedlamlne was defined as the concentration of ethylenedlamlne
resulting In a 50% reduction 1n bacterial luminescence after 15 minutes.
0122d
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Tests were conducted In accordance with methodologies for the Mlcrotox
assay. The 15-ralnute EC50 (with 95% confidence limits) for P. phosphoreum
exposed to ethylenedlamlne was 20.4 mg/l (18.1-23.0). The effects of
exposure to ethylenedlamlne on the nitrification process of a mixed culture
of Nltrosomonas and NUrobacter were monitored by using a pH Indicator
mixture that assessed the conversion of ammonia via nitrite Into nitrate.
The lowest effective concentration or minimum Inhibiting concentration of
ethylenedlamlne on the nitrification process after 3 hours was 3.2 mg/l.
4.4. SUMMARY
The acute toxlclty of ethylenedlamlne to fish was reported for brown
trout [48-hour TLm=230 mg/t, Wood1w1ss and Fretwell (1974)], golden orfe
[48-hour LC5Q=405 mg/l, Juhnke and luedemann (1978)], fathead minnow
(96-hour LC50=115.7 mg/l), Japanese medaka [48-hour TLm=1000 mg/l,
Tonogal et al. (1982)], k1H1f1sh [48-hour LC50*1000 mg/l, Tonogal and
Ito (1984)] and guppy [96-hour LC5Q=275 mg/t, Van Leeuwen et al.
(1985)]. The acute toxUHy of ethylenedlamlne to aquatic Invertebrates was
reported for brine shrimp [24-hour TLm*14 mg/l, Price et al. (1974)] and
daphnlds [24-hour ECCft, 24-hour LCcn and 48-hour LCcn of 14, 16 and
bU bU t>U
26.5 mg/s., respectively (Brlngmann and Kuehn, 1982, 1977a; Van Leeuwen et
al., 1985)]. The 10-day LC5Q of ethylenedlamlne 1n frogs was 250 mg/l
(Birch and Prahlad, 1986). Toxlclty of ethylenedlamlne to bacteria,
protozoa and algae, measured by calculating EC, ranged from 0.5-20.4,
1.8-103 and 0.08-100 mg/l, respectively (Brlngmann, 1975; Brlngmann and
Kuehn, 1976, 1977b, 1978a,b, 1980, 1981; Van Leeuwen et al., 1985).
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5. PHARMACOKINETICS
5.1. ABSORPTION
A comparison of the absorption of ethylenedlamlne dlhydrochlorlde was
made following administration of the compound to rats by three different
routes (I.e., oral, endotracheal or Intravenous) (Yang and Tallant, 1982).
Groups of male Hilltop Wlstar rats (3-8 rats/group) were given single doses
of ethylenedlamlne dlhydrochlorlde (a mixture of 14C-labeled and cold
compound) at dose levels of 5, 50 or 500 mg/kg. The compound was dissolved
1n distilled water before oral administration and In distilled water and,
later. In physiological saline (to reduce trauma) before endotracheal admin-
istration. In the case of Intravenous dosing, the compound was dissolved In
saline and Injected via the tall vein. The endotracheal route was used as
an approximation to Inhalation exposure because of the difficulties asso-
ciated with delivering a single pulse of vapor to the animals quantitatively
(Pozzanl and Carpenter, 1954). The Intravenous dosing was Included to
examine the extent of absorption by the oral and endotracheal routes. The
endotrachael route bypasses the nasal mucosa and the upper respiratory
tract, but the absorption of ethylenedlamlne by the lung can be approximated
using this route of administration. Following dosing, blood samples were
removed at various times from a cannula Inserted In the right external
jugular vein and analyzed for ethylenedlamlne. Absorption of ethylene-
dlamlne following either oral or endotracheal administration was rapid, with
peak plasma levels of the compound being reached at 0.5 to 0.75 hours after
dosing. B1oava1lab1l1ty of ethylenedlamlne following oral or endotracheal
administration was calculated by dividing the respective areas under the
blood concentration vs. time curves by the area under the curve obtained
following Intravenous administration (the fraction of the dose absorbed
0122d
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following Intravenous administration was assumed to be 100%). At doses of
50 and 500 mg/kg, the b1oava11ab111ty of ethylenedlamlne following endo-
trachael administration was 10054, indicating that ethylenedlamlne 1s
completely absorbed from the lung. Unavailability of ethylenedlamlne was
-9554 following oral administration of 50 mg/kg, but dropped to -80% follow-
ing administration of 500 mg/kg. Yang and Tallant (1982) suggested that
this Indicated a lower capacity for absorption of ethylenedlamlne by the
gastrointestinal tract compared with the lung. An alternative explanation
for the reduced bloavallabllUy of ethylenedlamlne following administration
by the oral route may be that following absorption by the small Intestine.
the compound undergoes biliary excretion and never reaches the systemic
circulation. A considerable level of biliary excretion (or Intestinal
secretion) was observed following Intravenous administration of a 500 mg/kg
dose of ethylenedlamlne dlhydrochlorlde. At the lowest dose (5 mg/kg),
bloavallabllUy was -60% following administration by either the oral or the
endotracheal route. This reduced bloavallabllUy observed at the low dose
of ethylenedlamlne was attributed to a "first pass" metabolic effect In the
liver and lung, which may reduce the b1oava1labH1ty of a low dose, but have
a lesser effect on bloavallabllUy of a higher dose.
Another study on the pharmacoklnetlcs of ethylenedlamlne 1n the rat was
performed In conjunction with a 2-year chronic tox1c1ty/oncogen1c1ty study
of the compound (Yang et al., 1984a). For the pharmacoklnetlc study,
Fischer 344 rats were given a single oral dose of ethylenedlamlne dlhydro-
chlorlde (50 mg/kg total dose containing a mixture of 14C-rad1olabeled and
unlabeled compound). Blood was sampled at various times within the 24-hour
period after dosing from a cannula Inserted 1n the right external jugular
vein, and was analyzed for ethylenedlamlne. The 2-year chronic toxlclty
0122d -17- 07/14/88
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study was designed to determine the effects of age, sex and chronic
ethylenedlamlne exposure on the pharmacoklnetlcs of the compound. In the
2-year study, Fischer 344 rats were given dietary radlolabeled doses of 20,
100 and 350 mg EDA»2HCl/kg/day and were studied at day 0 (naive rats) and
6 and 18 months Into the study. At the 6- and 18-month time points, the
animals consisted of control rats and rats given the highest dietary dose of
ethylenedlamlne (350 mg ethylenedlamlne d1hydrochlor1de/kg/day). Yang et
al. (1984a) concluded that there were no apparent age-, sex- or chronic
doslng-related differences In the absorption rate constant, and that the
value of this constant was between -3 and 6 hours'1 (equivalent to absorp-
tion half-lives of between 0.23 and 0.12 hours) for the various groups of
rats tested.
Yang et al. (1987) studied the percutaneous absorption of ethylene-
dlamlne In male Mlstar rats exposed to aqueous solutions of radlolabeled
ethylenedlamlne (>99.9% pure) at dosages of 408, 1020 or 2040 wg/cm2.
The rats were placed In metabolism cages for 24 hours; blood, urine and
feces were collected during the 24-hour period and analyzed for radio-
activity. At the end of the experiment, the animals were sacrificed and
selected tissues (the carcass and the skin of the dosing area) were analyzed
to determine the extent of ethylenedlamlne absorption. At the lowest dose
level, -12% of the dose was absorbed. The percentage of applied dose
absorbed Increased to -60X at the two highest dose levels; Yang et al.
(1987) attributed this Increase In absorption to ethylened1am1ne-1nduced
degeneration of the epidermis. An absorption rate constant of -0.96
hour"1 (equivalent to an absorption half-life of 4.67 hours) was calcu-
lated for the two highest doses; analytical limitations prevented a determi-
nation of this constant for the lowest dose. Yang et al. (1987) noted that
0122d -18- 07/14/88
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percutaneous uptake of ethylenedlamlne by rats 1s relatively slow 1n compar-
ison with uptake following administration by the oral or endotracheal routes.
5.2. DISTRIBUTION
The tissue distribution of radioactivity was studied 1n Hlstar rats 48
hours after Intravenous, oral or endotrachael administration of single
radlolabeled doses of 5, 50 or 500 mg ethylenedlamlne d1hydrochlor1de/kg bw
(Yang and Tallant, 1982). Twenty-six different tissues were analyzed for
radioactivity. Tissue concentration values following Intravenous adminis-
tration were reported 1n terms of pg ethylenedlamlne equ1valents/g of
tissue; these levels were highest 1n the kidneys, Hver, bone marrow and
thyroid (0.75, 0.82, 0.74 and 1.09 vg/g, respectively, at the lowest
ethylenedlamlne dlhydrochlorlde dose level). These values were similar
following oral or endotracheal administration of the compound. Tissue
distribution levels Increased In direct proportion to Increasing dose (I.e.,
as dose was Increased from 5 to 50 to 500 mg/kg, radioactivity In the
tissues Increased at a ratio of -1:10:100). The authors suggested that this
Indicated that these dose levels may still be In the range of linear
pharmacoklnetlcs as far as tissue distribution 1s concerned.
Yang et al. (1984a) observed an effect of aging on the distribution of
ethylenedlamlne. After administration of a single oral dose of ethylene-
dlamlne dlhydrochlorlde (14C-rad1olabeled 50 mg/kg) of Fischer 344 rats at
various stages of a chronic toxldty study (I.e., on the first day of the
study and at 6 and 18 months), there was a significant decrease 1n the
volume of distribution with age, which the authors attributed to an Increase
In body fat In older animals. Ethylenedlamlne Is a highly water soluble
molecule with little or no affinity for fat tissue. Its volume of distri-
bution (expressed 1n terms of i/kg bw) would therefore be expected to
decrease 1n animals with more body fat (I.e., older animals).
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The distribution of radioactivity was examined 24 hours after applica-
tion of an aqueous solution of radlolabeled ethylenedlarolne dlhydrochlorlde
to the skin of male Wlstar rats (doses of 408, 1020 or 2040 tig/cm2)
(Yang et al., 1987). At the 2040 Pg/cm* level, a2.9X of the applied
radioactivity was found 1n the liver, kidney, brain and lungs, 17.9X of the
radioactivity was found 1n the carcass, and 10.8% of the radioactivity left
at dosing area.
5.3. METABOLISM
Yang and Tallant (1982) studied the metabolism of ethylenedlamlne 1n 12
male Wlstar rats dosed dally by Intubation with 500 mg/kg/day ethylene-
dlamlne dlhydrochlorlde for 4 days. The first dose contained radlolabeled
ethylenedlamlne dlhydrochlorlde and the subsequent doses contained only the
cold compound. Urine was collected dally and pooled. The major urinary
metabolite (which represented over half of the urine radioactivity) was
Identified as N-acetylethylened1am1ne, which was also the major metabolite
1n the feces. An additional but unidentified peak 1n the chromatography
columns used to Identify urinary metabolites suggested an alternative or
secondary pathway of ethylenedlamlne metabolism besides N-acetylat1on. Yang
and Tallant (1982) proposed that this secondary pathway may be enzymatic
formation of amlnoacetaldehyde from ethylenedlamlne. Amlnoacetaldehyde may
then be further metabolized to ethanolamlne and eventually to CO-.
Ethylenedlamlne 1s capable of reducing cytochrome C In the presence of amlne
oxldase from Asperglllus nlger (Hoshlka, 1967; Muraoka et al., 1966).
Ammonia Is released from ethylenedlamlne 1n this reaction and the subsequent
formation of amlnoacetaldehyde has been proposed. CaIdwe11 and Cotgreave
(1984) proposed that deamlnatlon of ethylenedlamlne to produce glydne was a
metabolic pathway 1n rats and humans. When the compound was Incubated with
0122d -20- 07/18/88
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rat liver homogenates, there was an enzyme and time-dependent disappearance
of radlolabeled ethylenedlamlne that was accompanied by the appearance of
radlolabeled glydne. Deamlnation of ethylenedlamlne to produce glyclne was
also observed 1n human liver homogenates, although the activity observed In
human liver was <15% of the activity observed In rat liver. Ca Id we 11 and
Cotgreave (1984) proposed that this deamlnation reaction Is catalyzed by the
enzyme dlamlne oxldase.
5.4. EXCRETION
The excretion of ethylenedlamlne has been studied extensively. The fate
of single oral and endotracheal doses of radlolabeled ethylenedlamlne
dlhydrochlorlde was studied In male Wistar rats given doses of 5, 50 or 500
mg ethylenedlamlne d1hydrochlor1de/kg bw (Yang and Tallant, 1982). The rats
were Immediately placed 1n metabolism cages, and exhaled air was collected
In a series of traps, and urine and feces were collected at 24-hour
Intervals (I.e., 0- to 24- and 24- to 48-hour experimental periods).
Radioactivity was excreted via exhaled air, urine and feces, but the primary
route of excretion was through the urine. Host of the radioactivity was
excreted by all three routes during the first 24 hours, but at the highest
dose level (500 mg/kg), Increased excretion during the 24- to 48-hour
experimental period was observed following both oral and endotracheal
administration of the compound. Yang and Tallant (1982) suggested that this
was Indicative of the Involvement of a capacity-limited process at this high
dose level. Following oral dosing of ethylenedlamlne at the two lower dose
levels (5 and 50 mg/kg), -55% of the administered radioactivity was excreted
1n the urine during the first 24 hours; this dropped to 45.7% at the highest
dose level (500 mg/kg). During the first 24 hours, the percentage of
orally-administered radioactivity excreted 1n the feces Increased with
0122d -21- 07/14/88
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Increasing dose; 4.5, 13.8 and 16.2% were excreted at the 5, 50 and 500
mg/kg dose levels, respectively. The percentage of radioactivity excreted
as C0? 1n the exhaled air remained fairly constant with Increasing dose
and amounted to 6-9% of the administered dose. Following endotracheal
administration of ethylenedlamlne dlhydrochloMde, the excretion of radio-
activity 1n the feces during the first 24 hours did not Increase with
Increasing dose (as was the case following oral administration), but Instead
remained at a constant level of -10% of the administered dose. These data
suggest that the Increasing fecal excretion of radioactivity observed
following Increasing oral doses of ethylenedlamlne dlhydrochlorlde may have
been due to Increasing amounts of the compound passing unabsorbed through
the gastrointestinal tract or to Increasing levels of biliary excretion
comparable to those found after Intravenous Injection.
The finding that most of the radioactivity 1s excreted 1n the urine
following oral or endotracheal administration of radlolabeled ethylenedla-
mlne has been confirmed by other material balance experiments. Forty-eight
hours following oral administration of 5 mg ethylened1am1ne/kg to Wlstar
rats, 61% of the administered dose was found 1n the urine, 3% was found In
the feces and 9% of the radioactivity was exhaled as radlolabeled C0?
(Yang et al., 1978). This excretion pattern was similar In Swiss Webster
mice following oral administration of 5 mg ethylened1am1ne/kg; urinary and
fecal excretion and radlolabeled C0? production amounted to ~70, 5 and
12%, respectively, of the administered dose (Yang et al., 1978). Another
material balance study was conducted with Fischer 344 rats following a
single oral dose of radlolabeled ethylenedlamlne dlhydrochlorlde (50 mg/kg)
(Yang et al., 1984a). Forty-eight hours following administration of the
compound, 10-22% of the administered radioactivity appeared as radlolabeled
0122d
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C02, 39-51% of the administered radioactivity appeared In the urine and
11-30% appeared 1n the feces. The pattern of excretion of radioactivity
changed when ethylenedlamlne was administered percutaneously rather than
orally or endotracheally. Application of aqueous solutions of ethylene-
dlamlne to the shaved backs of male Wlstar rats (doses of 1020 or 2040
vg/cm2} resulted 1n the excretion of -35% of the applied dose 1n the
urine and 2% 1n the feces (Yang et al.. 1987). This was substantially lower
than the value of 60% of the administered dose reported for urinary and
fecal excretion following oral and endotracheal administration (Yang and
Tallant, 1982); however, this lower value may simply reflect the relatively
poor absorption of ethylenedlamlne following topical administration. If
this value of 35% of the applied dose for urinary and fecal excretion 1s
corrected by an absorption factor of 0.58, a corrected excretion of radio-
activity 1n the urine and feces of 60% of the applied dose 1s obtained
following topical administration, which agrees with the excretion values
obtained following oral and endotracheal administration of the compound.
In addition to material balance determinations, the disappearance of
ethylenedlamlne from the blood (Including determination of the terminal
half-life) has also been studied 1n a number of pharmacoklnetlc Investiga-
tions. A semi logarithmic plot of plasma ethylenedlamlne concentration vs.
time following administration of a single oral dose of radlolabeled
ethylenedlamlne dlhydrochlorlde (50 mg/kg) to Fischer 344 rats Indicated
that the elimination kinetics of the compound could be described by a
2-compartment model (Yang et al., 1984a). Terminal half-lives of -6-7 hours
were determined for ethylenedlamlne 1n the plasma and did not appear to
depend on the route of administration of the compound (oral, endotracheal or
Intravenous) or on the administered ethylenedlamlne dose (5, 50 or 500 mg/kg)
0122d -23- 07/18/88
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(Yang and Tallant, 1982). The plasma pharmacoklnetlcs of ethy1ened1am1ne In
the rat observed following percutaneous administration of the compound were
similar to those observed following oral or endotracheal administration. A
semi logarithmic plot of plasma ethylenedlamlne concentration vs. time
following topical application of either 1020 or 2040 vq ethylenedlamlne
dlhydrochlorlde/cm2 Indicated that elimination could be described by a
2-compartment model, with a terminal half-life of elimination of ~4.5 hours
(Yang et al.t 1987).
5.5. SUMMARY
Absorption of ethylenedlamlne dlhydrochlorlde 1n rats following oral or
endotracheal administration was rapid, with peak plasma levels of the com-
pound being reached at 0.5-0.75 hours after dosing (Yang and Tallant, 1982).
At doses of 50 and 500 mg/kg, the absorption of ethylenedlamlne dlhydro-
chlorlde by the lung was -100%; absorption by the gastrointestinal tract was
between 80 and 95% (Yang and Tallant, 1982). The absorption rate constant
for orally-administered ethylenedlamlne dlhydrochlorlde 1n rats did not vary
with age or sex, and was not appreciably different 1n animals chronically
exposed to the compound; an absorption rate constant of between ~3 and 6
hours'1 was determined for orally-administered ethylenedlamlne dlhydro-
chlorlde (Yang et a!., 1984a). Percutaneous absorption of ethylenedlamlne
was slow at low dose levels, but tended to Increase significantly at higher
dose levels due to possible degeneration of the epidermis caused by
ethylenedlamlne (Yang et al,, 1987). Forty-eight hours after single oral or
endotracheal doses of radlolabeled ethylenedlamlne dlhydrochlorlde (5, 50 or
500 mg/kg), the highest tissue levels of radioactivity were found In the
kidneys, liver, bone marrow and thyroid (Yang and Tallant, 1982). The
volume of distribution of ethylenedlamlne (expressed 1n terms of 8,/kg bw)
0122d
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07/14/88
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appears to decrease with age In the rat; presumably, this 1s due to an
Increase In body fat 1n older animals and an Inability of the water soluble
ethylenedlamlne to distribute to this fat tissue (Yang et al., 1984a). The
small amount of radioactivity absorbed following percutaneous administration
of ethylenedlamlne to rats was distributed primarily to liver, kidney, brain
and lung (Yang et al., 1987). N-Acetylethylenedlamlne has been Identified
as the principle metabolite of ethylenedlamlne 1n the urine and feces of
rats following dally administration of ethylenedlamlne dlhydrochlorlde (500
mg/kg/day) for 4 days (Yang and Tallant, 1982). Other metabolic pathways
Involving amlnoacetaldehyde formation (Yang and Tallant, 1982; Hoshlka,
1967; Muraoka et al., 1966) and deamlnation of ethylenedlamlne to produce
glyclne (Caldwell and Cotgreave, 1984} have been proposed. Following single
oral or endotracheal doses of radlolabeled ethylenedlamlne dlhydrochlorlde
to rats and mice (5-500 mg/kg), radioactivity was excreted 1n the feces,
exhaled air and, primarily, the urine (Yang and Tallant, 1982; Yang et al.,
1978, 1984a). Values for the percentages of administered radioactivity
excreted by the various routes ranged from ~40-70% for urine, 3-30% for
feces and 6-22% for exhaled radlolabeled CO-. Semi logarithmic plots of
plasma ethylenedlamlne concentration vs. time following administration of
single oral or endotracheal doses to rats (50 or 500 mg/kg} or topical
administration of the compound (1020 or 2040 iig/cm2) suggested a
2-compartment model for elimination of the compound (Yang et al., 1984a;
Yang and Tallant, 1982; Yang et al.. 1987). Terminal half-lives for elimi-
nation of ethylenedlamlne from the plasma 1n these studies were determined
to range from -4.5-7 hours.
0122d
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6. EFFECTS
6.1. SYSTEMIC TOXICJTY
6.1.1. Inhalation Exposure.
6.1.1.1. SUBCHRONIC -- A 30-day Inhalation study of the tox1c1ty of
ethylenedlamlne In rats was conducted by Pozzanl and Carpenter (1954).
Because of the difficulty of generating and delivering ethylenedlamlne
vapor, the nominal exposure concentrations of 0, 125, 250, 500 and 1000 pptn
were recalibrated to actual concentrations of 0, 59, 132, 225 and 484 ppm
(0, 145, 324.5, 553.1 and 1189.7 mg/m3). There were 15 Sherman rats/sex
1n each group and exposure was 7 hours/day, 5 days/week. Following expo-
sure, the liver and both kidneys of each rat were weighed, and hlstologlcal
examination was made of the lungs, heart, liver, kidney, adrenal gland and
spleen; only the kidneys, lung and liver were examined 1n rats from the 59
ppm exposure group. All 30 rats exposed to the highest concentration of
ethylenedlamlne (484 ppm) died within 20 days of the Initial exposure. In
addition, depllatlon was observed following the sixth day of exposure and
damage to the lungs, kidneys and livers was revealed In affected animals at
autopsy. Cloudy swelling was seen 1n 23 of 28 livers and was also observed
1n the loop and convoluted tubules of most of the kidneys. Degeneration of
the convoluted tubules of the kidneys and congestion of the lungs and
adrenal cortex were also noted. At the next highest exposure level (225
ppm), 4/30 rats survived the 30-day exposure period. The survivors had a
significantly lowered weight gain and Increased liver and kidney weights.
H1stopatholog1cal findings consisted of a cloudy swelling of the liver and
of the loop and convoluted tubules of the kidney. The two lower ethylene-
dlamlne exposure levels (59 and 132 ppm) produced no compound-related toxic
effects 1n any of the exposed rats, although a slight depilatory effect
persisted at the 132 ppm level.
0122d
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07/18/88
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6.1.1.2. CHRONIC -- Pertinent data regarding the toxlclty of
ethylenedlamlne following chronic Inhalation exposure were not located 1n
the available literature cited In Appendix A.
6.1.2. Oral Exposure.
6.1.2.1. SUBCHRONIC The oral toxlclty of ethylenedlamlne does not
appear to be affected by the addition of two hydrochlorlde groups to the
molecule to form ethylenedlamlne dlhydrochlorlde. Yang et al. (1983)
demonstrated that acute oral toxlclty values for the two compounds
(ethylenedlamlne and ethylenedlamlne dlhydrochlorlde} were the same when the
doses were corrected for molecular weight differences between the two
compounds. The Investigators attributed this to the apparently Innocuous
effect of additional HC1 1n the stomach.
Groups of Fischer 344 rats (10/sex/group) were fed a diet containing
ethylenedlamlne dlhydrochlorlde at dose levels of 0, 50, 250 and 1000
mg/kg/day for 3 months (Yang et al.t 1983). Body weights and diet consump-
tion were determined on a weekly basis, and water consumption was measured
monthly. Ur1nalys1s was performed on all rats ~1 week before sacrifice.
Blood samples for clinical chemistry and hematologlc measurements were
collected Immediately before sacrifice. A complete gross necropsy was
performed on all rats, and organ weights were determined for the brain,
liver, kidneys, spleen, heart, adrenals and testes. HlstopathologU
evaluation of the tissues was also performed. At the highest dose level
(1000 mg/kg/day}, a significant reduction In body weight gain was seen In
both sexes. A reduction 1n the weights of the liver and heart was seen In
both sexes; kidney and spleen weight was reduced In males, whereas adrenal
and brain weights were reduced In females. Hematologlc measurements
revealed changes 1n both sexes (I.e., depression In red blood cell counts
0122d -27- 07/14/88
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and Increased mean corpuscular volume). In females, there was also depres-
sion of hematocrlt and hemoglobin, and an Increase 1n mean corpuscular
hemoglobin. Blood clinical chemistry revealed a reduction 1n serum glucose
and elevations In the activities of alkaline phosphatase, AST (formerly
SGOT) and ALT (formerly SGPT) In both sexes. Ethylened1am1ne dlhydro-
chlorlde treatment at the highest dose level lowered the urinary pH 1n both
sexes, and females developed a hepatocellular pleomorphlsm that consisted of
an Increase In the size of both hepatocytes and hepatocyte nuclei. At this
high dose level, there was also decreased food and water consumption In
females. At the Intermediate dose level, an Increase In the activity of
serum ALT was seen In males; there was a significant reduction 1n heart
weight and water consumption 1n females and an Increase 1n mean corpuscular
volume. In this study (Yang et al., 1983}, only minimal effects on diet and
water consumption 1n female rats were seen at the lowest dietary level of 50
mg/kg/day.
6.1.2.2. CHRONIC Apparently, a chronic oral study of the toxlclty
of ethylenedlamlne dlhydrochloMde was performed by the Bushy Run Research
Center of Union Carbide Corporation {Yang et al., 1984a). This study was
unavailable for review because It Is classified as Confidential Business
Information (Hlmler, 1988).
6.1.3. Other Relevant Information. In a 7-day study of the effects of
dietary administration of ethylenedlamlne dlhydrochlorlde to rats and mice
(Yang et al., 1983), groups of Fisher 344 rats (5/sex/group) were given
dietary ethylenedlamlne dlhydrochlorlde doses of 0, 150, 500 and 1500
mg/kg/day. For the mouse study, groups of B6C3F1 mice (5/sex/group) were
administered ethylenedlamlne dlhydrochlorlde In the diet at dose levels of
0, 156, 625 and 2500 mg/kg/day for 7 days. Diet and water consumption, body
0122d -28- 07/14/88
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weight change, liver and kidney weights, and mortality were evaluated for
both species. The highest dose level 1n rats (1500 mg/kg/day) produced a
reduction In body weight In both sexes and a reduction In liver and kidney
weights (and relative kidney weight) 1n females. The Intermediate dose
level (500 mg/kg/day) produced a decrease 1n relative kidney weight In
female rats, and the lowest dose level (150 mg/kg/day) was without effect In
either sex. In mice, the highest dose level (2500 mg/kg/day) produced a
reduction 1n body weight, liver weight and kidney weight 1n both sexes. The
Intermediate (625 mg/kg/day) and lowest dose level (156 mg/kg/day) were
without effect In both male and female mice.
A large body of literature exists on the ^ri vitro y-am1nobutyr1c acid
(GABA) mimetic action of ethylenedlamlne In a variety of tissue prepara-
tions. Many of these studies have been performed 1n rat brain preparations
and Indicate that, like GABA, ethylenedlamlne functions to depress neuronal
activity 1n the central nervous system. Because behavioral effects were not
reported In the toxldty studies summarized 1n Sections 6.1.1. and 6.1.2.,
the brain does not appear to be a target organ for ethylenedlamlne, making
an In-depth examination of the pharmacological Information regarding this
GABA mimetic action of ethylenedlamlne Irrelevant to this document.
Ethylenedlamlne appears to exert Us action on GABAerglc systems by a
number of different mechanisms. The Inhibitory effect of ethylenedlamlne on
the firing rate of neuronal cells 1n rat brain slices has been attributed to
an ethylenedlamlne-lnduced stimulation of the release of the Inhibitory
neurotransmltter GABA (Lloyd et al., 1982; Stone and Perkins, 1984; Blaxter
and Cottrell, 1985; Davles et al., 1982, 1983). Alternatively, ethylene-
dlamlne may function to depress neuronal firing directly by functioning as a
GABA receptor agonist (Perkins and Stone, 1981; Stone and Perkins, 1984;
0122d -29- 07/14/88
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Boklsch et a"!., 1984). A third proposed mechanism of action 1s an Inhibi-
tory effect on the neuronal uptake of 6ABA (Strain et al., 1984; Blaxter and
Cottrell, 1982). Regardless of the mechanism of action, many of the effects
on the central nervous system appear to be blocked by the GABA antagonist
blcuculUne (Perkins and Stone, 1981; Stone and Perkins, 1984) and ethylene-
dlamlne, like GABA, appears to enhance the binding of benzodlazepam to Us
receptors In the rat brain (Morgan and Stone, 1982, 1983; Davles et al.,
1982). The qualitative manner 1n which ethylenedlamlne enhances this
binding, however, may not be similar to the manner In which GABA potentiates
dlazepam binding. Ethylenedlamlne may function to Increase the number of
dlazepam receptors, whereas GABA Increases the affinity of benzodlazepam for
these receptors (Morgan and Stone, 1982, 1983; Stone and Perkins, 1984).
The GABA mimetic action of ethylenedlamlne has also been studied In the
Isolated Intestine of the guinea pig (Kerr and Ong, 1984, 1987; Ong and
Kerr, 1987), rat retina (Sarthy, 1983) and rabbit oviduct (Erdo et al.,
1986). The \n_ vitro efflux of radlolabeled GABA from all of these tissues
has been demonstrated to be stimulated by the addition of ethylenedlamlne.
Contact dermatitis resulting from exposure to ethylenedlamlne Is fairly
well documented 1n the literature. Skin patch testing 1n various groups of
patients and volunteers has revealed Incidences of sensitivity ranging from
-2-13%. Rudner et al. (1975) reported a 6% Incidence of sensitivity to
ethylenedlamlne In 3216 males and females tested during 1972-1974 by the
North American Contact Dermatitis Group, who also reported a 7% Incidence of
sensitivity 1n 1200 Individuals tested during the years 1971-1972 (Rudner et
al.. 1973). Low Incidences of sensitivity to ethylenedlamlne following skin
patch testing (-2-3%) were reported by Angel1n1 et al. (1985) In 8230
patients, and by Prystowsky et al. (1979) 1n 1158 adult volunteers. A high
0122d -30- 06/13/88
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Incidence of 13.2% was reported in 158 patients tested by the New York
University Skin and Cancer Unit (Baer et al., T973). In 337 workers occupa-
tlonally exposed to ethylenedlamlne In the air (concentrations of ~1 ppm),
the latency period of the sensitivity reaction (I.e., time from start of
ethylenedlamlne exposure to onset of respiratory symptoms) was found to be
decreased significantly In smokers (7 months) compared with nonsmokers (37.3
months) (Aldrlch et al., 1987). Apparently, the guinea pig 1s able to serve
as an animal model for the contact sensitivity produced by ethylenedlamlne.
These animals were sensitized by Intradermal Injections of a 0.554 solution
of ethylenedlamlne, followed by epidermal application of a 10% ethylene-
dlamlne solution (Erlksen, 1979). Challenge of these sensitized animals by
an occluded patch test Indicated that 70% of the animals had been sensitized
to ethylenedlamlne.
Information from the Russian literature on the effects of occupational
exposure to ethylenedlamlne was available only In the form of translated
titles and abstracts that provided few details. Valeeva et al. (1979)
reported vascular dysfunction and neurasthenic syndromes In a group of 140
workers occupatlonally exposed to ethylenedlamlne (exposure levels not
reported). Assa (1975) reported a 20% Incidence of narrowing of the periph-
eral vision In workers exposed to ethylenedlamlne 1n a petrochemical plant.
Chronic bronchitis, occupational bronchial asthma and blood disorders
consisting of retlculocytosls, monocytosls and eoslnophllla were reported 1n
workers Involved 1n ethylenedlamlne production (Valeeva, 1976; Valeeva et
al., 1975, 1976). In addition, elevated levels of total serum protein,
gamma-globulins and s1a11c adds were observed.
Additional acute toxldty Information (I.e., LD5Q values) on ethylene-
dlamlne or ethylenedlamlne dlhydrochlorlde for various species and routes of
exposure are presented In Table 6-1.
0122d -31- 06/13/88
-------
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6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data concerning the cardnogenlclty of
ethylenedlamlne following Inhalation exposure were not located 1n the
available literature cited In Appendix A.
6.2.2. Oral. Apparently, a chronic (2-year) study on the cardnogenlclty
of orally-administered ethylenedlamlne dlhydrochlorlde 1n rats was performed
by the Bushy Run Research Center of Union Carbide Corporation (Yang et al.,
1984a); however, this study was unavailable for review because 1t has been
classified Confidential Business Information (Hlmler, 1988).
6.2.3. Other Relevant Information. A lifetime study of the dermal
oncogenlclty of ethylenedlamlne 1n male C3H mice was performed by DePass et
al. (1984). Two samples of ethylenedlamlne (both at least 99.IX pure) were
tested at a concentration In delonlzed water of 1%. Twenty-five pi of
this solution was applied to the skin of mice (50 mice/test sample) 3 times/
week until the death of the animals. A negative control group (50 mice) was
treated with delonlzed water and a positive control group (40 mice) was
treated with a 0.1% solution of 3-methylcholanthrene 1n acetone. Complete
necropsies were performed on all animals and the dorsal skin and all gross
lesions were examined hlstologlcally. There were no epidermal tumors
observed In the mice treated with either ethylenedlamlne sample. In
contrast, 98% of the mice treated with 3-methylcholanthrene had skin tumors
and 92% had squamous cell carcinomas. DePass et al. (1984) concluded that
there was no evidence for cutaneous oncogenlclty of ethylenedlamlne 1n mice.
6.3. MUTAGENICITY
Results of studies regarding the mutagenldty of ethylenedlamlne are
equivocal. Several studies (Haworth et al., 1983; Hulla et al., 1981;
Hedenstedt, 1978) using Ames-type testing for mutagenldty 1n several
0122d
-33-
07/14/88
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strains of Salmonella typhlmurlum Indicated that ethylenedlamlne 1s weakly
mutagenlc both with and without metabolic activation (Table 6-2). Recessive
lethal tests IDrosophUa (Z1mmer1ng et al., 1985)] and dominant lethal tests
[rats (Sleslnskl et al., 1983)] (Section 6.5.). however, have been negative.
In addition, assays 1n other mammalian systems (I.e., SCE 1n CHO cells,
HGPRT mutation 1n CHO cells, and UDS In rat hepatocytes) have all been
negative (Sleslnskl et al.. 1983) (see Table 6-2).
6.4. TERATOGENICITY
A study of the possible teratogenlc effects following admlnstratlon of
ethylenedlamlne dlhydrochlorlde 1n the diet of rats was conducted by DePass
et al. (1987). Pregnant Fischer 344 rats were fed diets that provided
ethylenedlamlne dlhydrochlorlde at measured doses of 0, 60, 310 and 1040
mg/kg/day on gestation days 6-15 (nominal doses were 0, 50, 250 and 1000
mg/kg/day). There were 20 rats 1n each treatment group and 40 control rats.
On day 21 of gestation, the pregnant females were euthanized and the fetuses
delivered by Cesarean section. Fetuses were examined for viability, body
weight, crown-rump length and skeletal and visceral alterations. At the
highest dose level (1040 mg/kg/day), maternal weight gain, food consumption,
fetal weight and crown-rump length were reduced significantly. The percent-
age of litters with one or more resorptlons was also Increased signifi-
cantly. Fetal examinations revealed the presence of missing or shortened
Innominate arteries and delayed ossification of the cervical vertebrae or
phalanges In the high-dose group. The next highest dose level of ethylene-
dlamlne dlhydrochlorlde (310 mg/kg/day) produced a decrease 1n maternal
weight gain and diet consumption but had no effect on the fetus. The lowest
dose level (60 mg/kg/day) had no effect on either the dams or the fetuses.
0122d -34- 07/14/88
-------
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The missing or shortened Innominate arteries 1n fetuses from the high-dose
ethylenedlamlne dlhydrochlorlde treatment group were further examined
because It was unclear whether these effects arose from ethylenedlamlne
dlhydrochlorlde treatment or whether they were the result of malnutrition
caused by a decrease In maternal food consumption. Therefore, a pair-
feeding study was performed In which 20 pregnant female rats were fed
ethylenedlamlne dlhydrochlorlde on gestation days 6-15 at the 1000 mg/kg/day
dose level and a pair-fed untreated control group of 20 pregnant females was
fed the same amount of food that was consumed by the treated group. In
addition, an untreated control group was fed ad_ libitum. The results from
this pair-feeding study Indicated that the reductions In maternal weight
gain, fetal body weight and length and Innominate arterial length were the
result of ethylenedlamlne dlhydrochlorlde treatment rather than malnutrition
caused by decreased diet consumption. Ethylenedlamlne dlhydrochlorlde
treatment was apparently not responsible for the Increased Incidence of
missing Innominate arteries because the Incidence of this effect was the
same 1n both the ethylenedlamlne dlhydrochlorlde treatment group and the
pair-fed control group. A shortening of the Innominate artery 1n the fetus
was not considered to be a teratogenlc effect because 1t was felt that this
would not result 1n a functional deficit, and might be a reversible effect.
The Investigators concluded that ethylenedlamlne dlhydrochlorlde was not
teratogenlc 1n the Fischer 344 rat.
6.5. OTHER REPRODUCTIVE EFFECTS
A 2-generatlon study of the reproductive effects of ethylenedlamlne
administered 1n the diet of Fischer 344 rats was conducted by Yang et al.
(1984b). The first generation (FQ) males and females were given ethylene-
dlamlne dlhydrochlorlde 1n the diet for 100 days before mating at concen-
tratlons that provided dosages of 0, 50, 150 and 500 mg/kg/day. There were
0122d -36- 07/14/88
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26 females and 25 males In each treatment group; the untreated control group
consisted of 52 females and 50 males. Hating took place over a 15-day
period during which the rats continued to receive ethylened1am1ne dlhydro-
chloMde at dietary concentrations that were appropriate for the respective
female groups. Body weight and diet consumption were measured for the FQ
animals and mortality was recorded [following establishment of the F^
generation, the FQ males 1n this study (Yang et a!., 19845) were used 1n a
related ethylenedlamlne dlhydrochlorlde dominant lethal study (Sles1nsk1 et
al., 1983} summarized below]. The F. generation produced by this mating
was separated according to sex and continued to receive ethylenedlamlne
dlhydrochlorlde In the diet at the dose levels given above until they
reached 100 days of age. These F, animals were then mated (15 males and
26 females/group) using the previously described procedures to produce the
F~ generation. Necropsies were performed on representative animals from
the F.| weanlings, the FI adults and the F- weanlings. Organ weights
were determined for the liver, kidneys, spleen, heart, brain, adrenals and
testes. An extensive hlstologlcal examination Involving -40 tissues was
performed. In addition, various reproductive Indices were examined; I.e.,
fertility Index, gestation Index, gestation survival Index, various
offspring survival Indices, the number of pups born alive/litter and the
number of days from first mating to parturition. The highest dosage level
(500 mg/kg/day) produced a significant depression in body weight gain in
both the FQ and FI generation animals. Male F, adults had signifi-
cantly decreased liver weights and F, female adults had significantly
Increased absolute and relative kidney weights. Hlstopathologlcal examina-
tion revealed hepatocellular pleomorphlsm 1n adult F, males and females,
with greater prevalence and severity of this lesion 1n the female. At the
0122d
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two lower doses of ethylenedlamine dlhydrochlorlde (50 and 150 mg/kg/day).
effects were reported In FQ and F, adult animals (decreased body weight
gain and decreased liver weight and Increased kidney weight}; however, these
effects were not consistent between the two generations, and their statis-
tical significance was questionable, since the p-values associated with
these effects were fairly high. No treatment-related effect was noted for
any of the reproductive Indices examined at any of the ethylened1am1ne
dlhydrochlorlde dosage levels; Yang et al. (1984b) concluded that ethylene-
dlamlne dlhydrochlorlde treatment was not associated with reproductive
toxlclty In the Fischer 344 rat.
A dominant lethal study of ethylenedlamlne dlhydrochlorlde following
administration of the compound to male Fischer 344 rats was performed by
Sles1nsk1 et al. (1983) (see Table 6-2). The rats, which were obtained from
the FQ generation In the study by Yang et al. (1984b), were fed ethylene-
dlamlne dlhydrochlorlde In the diet at dose levels of 0, 50, 150 and 500
mg/kg/day for 23 weeks before mating. There were 20 rats/treatment group.
The negative control group consisted of 40 rats, and a positive control
group of males (number not reported) was given a single 1ntraper1toneal dose
of 0.25 mg tr1ethy1enemelam1ne/kg. The dosed and control males were mated
for three consecutive weekly periods with one virgin female/week. Thirteen
days after the appearance of a vaginal plug (or 17 days after the first day
of mating), the females were euthanized and a number of fertility parameters
were measured; I.e., number of total Implants, number of viable Implants,
Utters with all fetuses viable, prelmplantatlon loss, number of fetal
deaths, number of females with early fetal deaths, number of females with
late fetal deaths and number of females with early and late fetal deaths.
0122d
-38-
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The dominant lethal mutation (DLH) percentage was calculated In the follow-
ing manner: DLNJt = (1 - live Implants per pregnant female of the test
group/live Implants per pregnant female of the control group) x 100. Males
treated with the various doses of ethylenedlamlne dlhydrochlorlde for 23
weeks had no significant differences In any of the fertility parameters
measured compared with the negative control group. In contrast, significant
differences were noted for the positive control group (I.e.. trlethylene-
melamlne treated) with respect to total number of Implants and numbers of
dead and live Implants. Sleslnskl et al. (1983) concluded that ethylene-
dlamlne dlhydrochlorlde lacked the potential to produce significant chromo-
some damage 1n this in vivo assay. A battery of 1^ vitro testing. Including
CHO gene mutation assay, SCE test and UDS assay with primary rat hepato-
cytes, were also performed 1n this study (Sleslnskl et al., 1983) and no
genotoxlclty was observed In these in v1tro mammalian systems employed.
6.6. SUMMARY
Perhaps because of the difficulty of generating and delivering ethylene-
d1am1ne-vapor studies on the effects of ethylenedlamlne In experimental
animals following Inhalation exposure are not readily found 1n the available
literature. A 30-day Inhalation study using rats Indicated that exposure to
the two highest levels of ethylenedlamlne (225 and 484 ppm) resulted 1n
death, decreased body weight gain. Increased liver and kidney weights,
cloudy swelling of the liver and of the loop and convoluted tubules of the
kidneys, and degeneration of the convoluted tubules of the kidneys (Pozzanl
and Carpenter, 1954). Oral exposure of rats to ethylenedlamlne dlhydro-
chlorlde In the diet for 3 months at a level that provided a dose of 1000
mg/kg/day also resulted In liver and kidney effects (Yang et al., 1983). A
decrease 1n the weight of these organs was noted and Increase 1n serum
0122d
-39-
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'enzyme levels (alkaline phosphatase, SGOT and S6PT) Indicated liver damage;
hepatocellular pleomorphlsm was noted 1n treated females. A variety of
hematologlc effects (depression of red blood cell counts. Increased mean
corpuscular volume and depression of hematocrlt and hemoglobin) were also
observed 1n treated animals. A reduction In liver and kidney weights was
noted 1n rats and mice In a 7-day dietary study 1n which ethylenedlamlne
dlhydrochlorlde was provided at a dose level of 1500 mg/kg/day in the rat
and 2500 mg/kg/day 1n the mouse (Yang et a~l., 1983). Additional acute
toxldty Information (LD, values) for ethylenedlamlne dlhydrochlorlde and
ethylenedlamlne 1s given In Table 6-1. Apparently, ethylenedlamlne can
function as a GABA mimetic agent and cause a depression of neuronal firing
1n the central nervous system (Lloyd et al., 1982; Stone and Perkins, 1984;
Blaxter and Cottrell, 1985; Davles et al., 1982, 1983; Perkins and Stone,
1981; Boklsch et al., 1984; Strain et al., 1984). Contact dermatitis, which
1s due to sensltlzatlon to ethylenedlamlne, 1s fairly well documented and
appears to have an Incidence 1n the population of between -2 and 13% (Rudner
et al., 1973, 1975; Angellnl et al., 1985; Prystowsky et al., 1979; Baer et
al., 1973). Reports In the Russian literature Indicate that occupational
exposure to ethylenedlamlne 1s associated with vascular dysfunction,
neurasthenic syndrome, narrowing of peripheral vision, bronchitis, bronchial
asthma and blood disorders (Valeeva, 1976; Valeeva et al., 1975, 1976, 1979;
Assa, 1975).
Pertinent data regarding the carclnogenldty of ethylenedlamlne follow-
ing Inhalation or oral exposure 1n experimental animals were not located In
the available literature cited 1n Appendix A. A 2-year combined oncogenlc-
1ty/tox1c1ty study following oral administration of ethylenedlamlne dlhydro-
chlorlde has been performed with rats by Union Carbide Corporation (Yang et
0122d
-40-
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al., 1984a); the study was not available for the preparation of this
document. Ethylenedlamlne applied as a 1% solution to the skin of male C3H
mice did not produce epidermal tumors (DePass et al., 1987). Mutagenlclty
studies on ethylenedlamlne are equivocal. Ames-type testing In bacteria
Indicates that ethylenedlamlne 1s weakly mutagenlc {Haworth et al., 1983;
Hulla et al., 1981; Hedenstedt, 1978), whereas mutation studies using
mammalian cells (CHO cells and rat hepatocytes) have been negative
(Sleslnskl et al., 1983) (Table 6-2). Recessive lethal tests 1n DrosopMla
(Z1mmer1ng et al., 1985) and dominant lethal tests 1n rats {Sleslnskl et
al., 1983) have also been negative. Administration of ethylenedlamlne
dlhydrochlorlde 1n the diet of pregnant Fischer 344 rats during days 6-15 of
gestation at a dose level of 1040 mg/kg/day produced signs of fetotoxldty
(decreased fetal weights and crown-rump length and an Increase 1n the
percentage of litters with one or more resorptlons), but no signs of terato-
genlclty (DePass et al., 1987). A 2-generat1on study of the reproductive
effects of ethylenedlamlne dlhydrochlorlde following oral administration to
rats Indicated that the compound was not associated with reproductive
toxlclty even at dose levels (500 mg/kg/day) that produced decreased body
weight gain and changes 1n organ weights 1n the parental generation (Yang et
al., 1984b).
0122d
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUNAN
A TLV-TWA of 10 ppm (25 mg/m3} has been adopted for ethylenedlamlne
(ACGIH, 1987). This TLV-TWA was chosen to prevent hypersensHlvlty
reactions associated with exposure to ethylenedlamlne (ACGIH, 1986). A PEL
of 10 ppm (25 mg/m3) has been established for ethylenedlamlne by OSHA
(1985).
7.2. AQUATIC
Guidelines and standards for the protection of aquatic organisms from
the effects of ethylenedlamlne were not located In the available literature.
0122d
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8. RISK ASSESSNENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the carclnogenlclty of
ethylenedlamlne following Inhalation exposure were not located 1n the
available literature cited 1n Appendix A.
8.1.2. Oral. Apparently, a 2-year oral carclnogenlclty study of
ethylenedlamlne In rats was performed by Union Carbide Corporation (Yang et
a!., 1984a) but has been classified as Confidential Business Information and
was unavailable for review 1n the preparation of this document.
8.1.3. Other Routes. A lifetime study of the dermal oncogenldty of
ethylenedlamlne In male C3H mice was performed by DePass et al. (1984). No
epidermal tumors were observed following application of a 1% solution of
ethylenedlamlne 3 times/week. A positive control group treated with
3-methylcholanthrene responded appropriately.
8.1.4. Weight of Evidence. No data are available regarding the carclno-
genlclty of ethylenedlamlne following Inhalation or oral exposure In either
humans or experimental animals. Accordingly, ethylenedlamlne Is placed In
EPA Group D - Not Classifiable as to Human Carclnogenlclty.
8.1.5. Quantitative Risk Estimates. Because no data were available on
the carclnogenlclty of ethylenedlamlne following Inhalation or oral exposure
1n either experimental animals or humans, 1t was not possible to derive a
q * for ethylenedlamlne for either route of exposure.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) In a 30-day
Inhalation ethylenedlamlne tox1c1ty study conducted by Pozzanl and Carpenter
(1954), Sherman rats were exposed 7 hours/day, 5 days/week to concentrations
af 0, 59. 132, 225 and 484 ppm {0, 145, 324.5, 553.1 and 1189.7 mg/m3).
ill 22d
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Exposure to the highest concentration (484 ppm) produced death, depllatlon,
cloudy swelling of the Hver and of the loop and convoluted tubules of the
kidney, degeneration of the convoluted tubules and congestion of the lungs
and adrenal cortex. Exposure to the next highest level (225 ppm) was asso-
ciated with death, decreased body weight gain, Increased liver and kidney
weights and cloudy swelling of the liver and of the loop and convoluted
tubules of the kidney. The two lower ethylenedlamlne exposure levels (59
and 132 ppm} produced no toxic effects 1n any of the exposed rats, although
a slight depilatory effect was persistent at the 132 ppm level. In this
study (Pozzanl and Carpenter, 1954), the ethylenedlamlne exposure level of
59 ppm was designated a NOAEL.
The Pozzanl and Carpenter (1954) 30-day Inhalation study was chosen for
development of a subchronlc Inhalation RfD for ethylenedlamlne because It
was the only suitable Inhalation study found on the compound; however, this
study may not be of suitable duration for derivation of a subchronlc Inhala-
tion RfD. The pharmacoklnetlc data of Yang et al. (1984a) and Yang and
Tallant (1982) Indicated that the terminal half-life of ethylenedlamlne In
the plasma following either oral or endotracheal administration of the
compound 1s ~7 hours. Using an equation published 1n Glbaldl and Perrler
(1975), which relates the time required to reach a certain fraction of the
steady-state level of the compound 1n the blood with the elimination half-
life for the compound, 1t can be calculated that 99% of the steady-state
level of ethylenedlamlne In the blood would be reached after ~2 days of
exposure. This Indicates that steady-state levels of ethylenedlamlne 1n the
blood are established fairly quickly. The NOAEL In this study (145 mg/m3)
was multiplied by an Inhalation rate for the rat of 0.123 ma/day (U.S.
EPA, 1980) and divided by the rat body weight (0.144 kg) determined from
0122d
-44-
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experimental measurements provided by the Investigators. The result (123.8
mg/kg/day) was expanded to continuous exposure by multiplying by 7 hours/24
hours and by 5 days/7 days to gWe a transformed animal dose of 25.8 mg/kg/
day. Division of this transformed animal dose by an uncertainty factor of
100 {10 for Interspecles extrapolation and 10 to protect sensitive human
populations) results 1n a subchronlc Inhalation RfD for ethylenedlamlne of
0.3 mg/kg/day. Multiplication of the transformed animal dose (25.8
mg/kg/day) by the reference human body weight of 70 kg (U.S. EPA, 1986a) and
division by the appropriate uncertainty factor (100) gives an RfD (In units
of mg/day) of 18 mg/day, and division of this value by a reference human
Inhalation rate of 20 mVday (U.S. EPA, 1986a) gives a subchronlc
Inhalation RfD (1n units of mg/m3) of 1 mg/m3.
Confidence 1n the subchronlc Inhalation RfD for ethylenedlamlne Is
medium. A sufficient number of exposure levels were used In the study
chosen for RfD determination (Pozzanl and Carpenter, 1954) to enable
distinction between a NOAEL and a LOAEL for ethylenedlamlne exposure, and
the number of animals of both sexes at each exposure level was sufficient.
The duration of the study (30 days) was short, however, and although pharma-
coklnetlc data suggested that this was of sufficient duration to establish
steady-state blood levels of ethylenedlamlne. It 1s still uncertain whether
this study was of sufficient duration to provide adequate data on the nature
of the toxic effects from subchronlc exposure to this compound.
8.2.1.2. CHRONIC EXPOSURES Pertinent data regarding the systemic
toxlclty of ethylenedlamlne following chronic Inhalation exposure were not
located In the available literature cited 1n Appendix A. The 30-day Inhala-
tion study of ethylenedlamlne toxlclty In rats by Pozzanl and Carpenter
(1954) was not used In the determination of a chronic Inhalation RfD for
0122d
-45-
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ethylenedlamlne because U was felt that even with the use of an uncertainty
factor to approximate chronic exposure, this study was of Insufficient
duration for chronic RfD determination.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) A 3-month study
of the effects of dietary administration of ethylenedlamlne dlhydrochlorlde
to Fischer 344 rats was conducted by Yang et al. (1983). The doses of
ethylenedlamlne dlhydrochlorlde administered In this study (0, 50, 250 and
1000 mg/kg/day) were corrected by multiplying by a factor of 0.452 (mol. wt.
ethylenedlamlne/mol. wt. ethylenedlamlne dlhydrochlorlde), resulting 1n
equivalent doses of ethylenedlamlne of 0, 22.6, 113 and 452 mg/kg/day.
Exposure to the highest dose level of ethylenedlamlne (452 mg/kg/day)
produced a reduction In body weight gain, hematologlc alterations, elevation
of serum enzyme activities suggestive of liver damage (alkaline phosphatase,
AST and ALT), reduction 1n organ weights (liver, kidney, spleen, heart,
adrenal and brain), lowered urinary pH, and hepatocellular pleomorphlsm 1n
females. The next highest level of ethylenedlamlne exposure (113 mg/kg/day)
was associated with an elevation of ALT activity In males and a reduction In
water consumption and heart weight, and Increased mean corpuscular volume 1n
females. The exposure level of 22.6 mg ethylened1am1ne/kg/day proved to be
a NOAEL 1n this study.
A 2-generatlon study of the effects of ethylenedlamlne dlhydrochlorlde
administration In the diet on reproductive parameters In Fischer 344 rats
was conducted by Yang et al. (1984b). In this study, members of the F,
generation (both sexes) that were exposed to ethylenedlamlne dlhydrochlorlde
at a dose of 500 mg/kg/day (226 mg ethylened1am1ne/kg/day) continuously for
100 days had depressed body weight gain and developed hepatocellular
0122d
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pleomorphlsm. A significantly decreased liver weight was observed In males
and significantly Increased absolute and relative kidney weight was observed
1n females. At the two lower doses of ethylenedlamlne dlhydrochloMde used
1n this study (50 and 150 mg/kg/day), decreased body weight gain and
Increased kidney weight were reported In FQ and F, adult animals exposed
for 100 days, but these effects were not consistent between the two
generations and their statistical significance was questionable, since the
p-values associated with these effects were fairly high. The dose level of
150 mg ethylenedlamlne d1hydrochlor1de/kg/day (67.8 mg ethylenedlamlne/
kg/day} was determined to be the NOAEL for this study.
The 3-month study of the effects of dietary ethylenedlamlne dlhydro-
chlorlde administration 1n Fischer 344 rats (Yang et al., 1983) was chosen
for subchronlc oral RfD development for ethylenedlamlne. This study was
selected for RfD development In preference to the reproductive study (Yang
et al., 1984b) because more parameters of systemic toxUUy (urlnalysls,
clinical chemistry and hematologlc evaluation) were Investigated In the
toxldty study (Yang et al., 1983) than 1n the reproductive study (Yang et
al., 1984b). The NOAEL 1n the subchronlc toxlclty study (Yang et al.. 1983}
was determined to be 50 mg ethylenedlamlne d1hydrochlor1de/kg/day (22.6 mg
ethylened1am1ne/kg/day). Division of this transformed animal dose by an
uncertainty factor of 100 (10 for Interspedes extrapolation and 10 to
protect sensitive Individuals) results 1n a subchronlc oral RfD for
ethylenedlamlne of 0.2 mg/kg/day. Multiplication of the transformed animal
dose NOAEL (22.6 mg/kg/day} by the reference human body weight (70 kg) (U.S.
EPA, 1986a) and division by the appropriate uncertainty factors of 100
results In a subchronlc oral RfD (In units of rug/day) of 16 mg/day.
0122d
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Confidence In the subchronlc oral RfD 1s medium. The study chosen for
RfD development (Yang et al., 1983} was a well-conducted study that used an
adequate number of animals of both sexes and a wide range of ethylenedlamlne
dlhydrochloHde dose levels. A reproductive toxldty study (Yang et al.,
1984b) confirmed the toxic effects (liver and kidney effects) found 1n the
study chosen for RfD development; however, both of these studies (Yang et
al., 1983, 1984b) were conducted by the same research group (Union Carbide
Corporation) 1n the same animal species (Fischer 344 rat). For higher
confidence In any RfD resulting from these data, corroborative results from
different research groups and toxldty Information from different species
would be desirable.
8.2.2.2. CHRONIC EXPOSURES Apparently, a 2-year oral toxldty
study 1n the rat was conducted by Union Carbide Corporation (Yang et al.,
1984a), but this study has been classified as Confidential Business Informa-
tion and was unavailable for review In the preparation of this document.
Because Information from this study was unavailable for development of a
chronic oral RfD for ethylenedlamlne and because this appears to be the only
chronic oral study on the compound. It was necessary to develop a chronic
oral RfD for ethylenedlamlne from the subchronlc oral RfD determined 1n
Section 8.2.2.1. The subchronlc oral RfD for ethylenedlamlne was based on a
transformed animal dose NOAEL of 22.6 mg/kg/day determined 1n a subchronlc
study by Yang et al. (1983). Division of this subchronlc NOAEL by an
uncertainty factor of 1000 (10 for Interspecles extrapolation, 10 to protect
sensitive Individuals and 10 to extrapolate from subchronlc to chronic
exposure) results In a chronic oral RfD for ethylenedlamlne of 0.02 mg/kg/
day. Multiplication of the transformed animal dose NOAEL (22.6 mg/kg/day)
0122d
-48-
07/14/88
-------
by the reference human body weight (70 kg) and division by the appropriate
uncertainty factors results In a chronic oral RfD for ethylenedlamlne (1n
units of nig/day) of 2.0 mg/day.
Confidence 1n the chronic oral RfD for ethylenedlamlne Is low, primarily
because no oral or Inhalation chronic toxlclty data were available on the
compound for RfD determination.
o
0122d -49- 06/13/88
-------
9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
" The toxldty of ethylenedlamlne was discussed 1n Chapter 6 of this
document and dose-response data are summarized 1n Table 9-1. The Inhalation
toxldty study In rats that was performed by Pozzanl and Carpenter (1954)
and was used to develop a subchronlc Inhalation RfD for ethylenedlamlne was
not considered for development of a chronic toxlclty RQ for ethylenedlamlne,
because It was of too short a duration (30 days}.
The most severe effect resulting from ethylenedlamlne exposure was
fetotoxIcHy, which was observed 1n a teratogenldty study using rats by
DePass et al. (1987). The observed fetotoxIcHy consisted of decreased
fetal weight and crown-rump length, an Increase In the percentage of Utters
with one or more resorptlons, missing or shortened Innominate arteries 1n
the fetus and delayed ossification of cervical vertebrae or phalanges.
FetotoxIcHy occurred at an equivalent human dose of 80.4 mg/kg/day and
multiplication of this dose by the reference human body weight of 70 kg
results In an MED of 5628 mg/day. This MED 1s associated with an RVd of
1. Fetotoxldty Is associated with an RV of 8 and multiplication of this
RV by the RV. gives a CS of 8, associated with an RQ of 1000
(Table 9-2).
The next most severe effect was an Increase In the absolute and relative
kidney weights of female rats 1n the 2-generat1on reproduction study by Yang
et al. (1984b). This effect was assigned an RV of 4 and occurred at a
human equivalent dose of 30.8 mg/kg/day. This dose, however, was subchronlc
1n duration and division by an uncertainty factor of 10 to approximate
chronic exposure resulted In an equivalent human dose of 3.08 mg/kg/day.
0122d -50- 07/14/88
-------
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Multiplication of this dose by the reference human body weight of 70 kg
resulted 1n an MED of 215.6 mg/day, which 1s associated with an RVrf of
2.0. Multiplication of this RVd by the RVg resulted In a CS of 8,
associated with an RQ of 1000.
Most of the other effects listed 1n Table 9-1 were equal 1n severity to
an Increase In the absolute and relative weight of the kidney (I.e., heroato-
loglc changes suggestive of anemia, biochemical changes suggestive of liver
damage, hepatocellular pleomorphlsm, depression of body weight gain and
changes In the weights of other organs) or of lesser severity (I.e., lowered
urinary pH, reduction 1n serum glucose and reduction In food and water
consumption) occurred at equivalent human doses that were higher than the
dose (3.06 mg/kg/day) at which an Increase 1n absolute and relative kidney
weight was observed 1n the Yang et al. (1984b) study. Because these effects
are of equal or lesser severity and because they occurred at equivalent
human doses that were higher than the dose associated with Increased kidney
weight, H was not necessary to calculate a CS for these effects; the CS
calculated for these effects would be lower than the CS (8) calculated above
for Increased kidney weight. There are three exceptions to this; I.e.,
1) Increased ALT activity In male rats receiving an equivalent human dose of
ethylenedlamlne of 18.3 mg/kg/day, 2) a decrease In water consumption and
heart weight was observed 1n females receiving an equivalent human dose of
14.7 mg/kg/day, and 3) the Increased mean corpuscular volume occurring In
female rats receiving 14.7 mg/kg/day (Yang et al., 1983) (see Table 9-1).
The third effect was not considered for RQ development because this effect
occurred In the absence of other hematologlc effects suggestive of anemia
and Us significance 1s unclear. As for the first case, 1n the absence of
other Indicators of liver damage In male rats receiving 18.3 mg ethylene-
d1am1ne/kg/day, the effect of Increased ALT activity was assigned an RV
D122d -54- 07/14/88
-------
of 3. The dose at which this effect occurred (18.3 mg/kg/day) was based on
a subchronlc exposure, and division of this dose by an uncertainty factor of
10 to approximate chronic exposure resulted In an equivalent human dose of
1.83 mg/kg/day. Multiplication of this equivalent human dose by the
reference human body weight of 70 kg results In an MED of 128.1 mg/day,
which 1s associated with an RV of 2.3; multiplication of this RVrf by
the RVe results In a CS of 6.9. This CS 1s associated with an RQ of 1000.
A decrease In the heart weight of female rats receiving 14.7 mg ethylene-
d1am1ne/kg/day was of unknown toxlcologlcal significance and was judged to
be of lesser severity than an Increase 1n organ weight, such as Increase 1n
absolute and relative kidney weights. Because the toxlcologlcal signifi-
cance of decreased heart weight 1s unclear, 1t was assigned an RV& of 3 to
reflect the lower degree of severity associated with this change 1n organ
weight. The equivalent human dose at which this effect occurred (14.7
mg/kg/day) was divided by an uncertainty factor of 10 to approximate chronic
exposure and multiplied by the reference human body weight of 70 kg to give
an MED of 102.9 mg/day, which Is associated with an RVd of 2.5; multipli-
cation of this RVd by the RVfi results 1n a CS of 8. This CS 1s asso-
ciated with an RQ of 1000.
Decreased water consumption 1n female rats given an equivalent human
dose of 14.7 mg ethylened1am1ne/kg/day occurred at the same dose at which a
reduction In heart weight was noted (Yang et al., 1983) (see Table 9-1).
Because this effect (decreased water consumption) was judged to be of lesser
severity than decreased heart weight, a CS was not calculated; as It would
be lower than the CS calculated for decreased heart weight.
0122d
-55-
07/14/88
-------
The study chosen for derivation of a chronic toxldty RQ for ethylene-
dlamlne was the reproduction study by Yang et al. (1984b) 1n which an
Increase 1n absolute and relative kidney weights was observed at an MED that
resulted 1n a CS of 8 and an RQ of 1000 (Table 9-3). This study was chosen
for RQ derivation 1n preference to the teratogenldty study by DePass et al.
(1987) and the subchronlc toxldty study by Yang et al. (1983). although
effects were observed In all three studies that resulted 1n a CS of 8. The
effect of fetotoxlclty observed 1n the DePass et al. (1987) study was not
chosen for RQ development because the MED at which this effect occurred
(5628 mg/day) was outside the range of sensitivity for RV assignment and
was given a default value of 1. The effect of decreased heart weight
observed 1n female rats (Yang et al.. 1983) was not chosen for RQ develop-
ment because, as stated above, the toxkologlcal significance of this effect
was unclear, making the assignment of an RV of 3 somewhat arbitrary.
9.2. BASED ON CARCINOGENICITY
A 2-year study on the carclnogenlcUy of ethylenedlamlne following oral
administration 1n rats was conducted by Union Carbide Corporation (Yang et
al., 1984a), but has been classified as Confidential Business Information
and was unavailable for review In the preparation of this document. No
epidermal tumors were found In a lifetime study of the dermal oncogenlcUy
of ethylenedlamlne In male C3H mice (DePass et al., 1987). Because there
are no available data regarding the carclnogenUHy of ethylenedlamlne
following Inhalation or oral exposure 1n either humans or experimental
animals, ethylenedlamlne 1s placed 1n EPA Group D - Not Classifiable as to
Human Carclnogenlclty, for Interim purposes. The Interim status reflects
the fact that the CB1 data base will be evaluated as a separate task at a
later date.
C122d
-56-
10/03/88
-------
TABLE 9-3
Ethylened1am1ne
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 215.6 mg/day
Effect: Increased absolute and relative kidney weights
Reference: Yang et al., 1984b
RVd: 2.0
RVe: 4
Composite Score: 8
RQ: 1000
'Equivalent human dose
i3122d -57- 06/13/88
-------
The lack of available cardnogenldty data on ethylenedlamlne following
Inhalation or oral exposure 1n either experimental animals or humans pre-
cluded the derivation of a Potency Factor for this compound. In addition,
there was no other evidence that ethylenedlamlne was carcinogenic 1n either
humans or experimental animals; therefore, 1t Is tentatively placed 1n EPA
Group D; I.e., not classifiable as to human cardnogenldty. Because H is
not possible to assign a Hazard Ranking for Group D compounds, an RQ for
ethylenedlamlne could not be derived based on cardnogenldty.
0122d -58- 08/24/88
-------
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0122d -67- 07/14/88
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0122d
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1)122d -69- 07/14/88
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0122d -70- 07/14/88
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0122d -71- 10/12/88
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0122d -72- 07/14/88
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3122d
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o
1)122d -74- 06/13/88
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APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
CHEMLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
These searches were conducted In February 1988, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1987. TLVs: Threshold Limit Values for Chemical Substances In the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2B. John Wiley and
Sons, NY. p. 2879-3816.
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John WHey and
Sons, NY. p. 3817-5112.
0122d
-75-
06/13/88
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Grayson, M. and D. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, HA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, WHO, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, Henlo
Park, CA.
NTP (National Toxicology Program). 1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report 1n the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call In Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
0122d
-76-
06/13/88
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In addition, approximately 30 compendia of aquatic toxlclty data were
reviewed. Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxldty
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water
Prepared for the Resources Agency of
Quality Control Board. Publ. No. 3-A.
Quality Criteria, 2nd ed.
California. State Water
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: "loxlcology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0122d
-77-
06/13/88
-------
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