United States
Environmental Protection
Agency
PROGRAM OFFICE DR
ECA0-CIN-019
April, 1904
SEPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS
PROFILE FOR
ETHYLENE THIOUREA (2-IMIDAZOLIDINETHIOI
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and
Assessment Office
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DRAFT DO NOT CITE OR QUOTE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 Its technical accuracy and policy Implications.

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DISCLAIMER
This document Is a preliminary draft. It has not been formally releasee
by the U.S. Environmental Protection Agency and should not at this stage b€
construed to represent Agency policy. It 1s being circulated for cotrments
on Us technical accuracy and policy Implications.
11

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TABLE OF CONTENTS
Page
1.	INTRODUCTION			1
1.1.	STRUCTURE AND CAS NUMBER		1
1.2.	CHEMICAL AND PHYSICAL PROPERTIES 		1
1.3.	PRODUCTION DATA		 . . .	?
1.4.	USE DATA		2
2.	ENVIRONMENTAL FATE AND TRANSPORT PROCESSES		3
3.	EXPOSURE		8
4.	PHARMACOKINETICS		9
4.1.	ABSORPTION		9
4.2.	DISTRIBUTION 		9
4.3.	METABOLISM		1|
4.4.	EXCRETION		12
5.	EFFECTS		13
5.1.	CARCINOGENICITY		13
5.2.	MUTAGENICITY		21
5.3.	TERATOGENICITY		26
5.4.	OTHER REPRODUCTIVE EFFECTS 		33
5.5.	CHRONIC AND SUBCHRONIC TOXICITY		33
5.6.	OTHER RELEVANT INFORMATION 		35
6.	AQUATIC TOXICITY		36
6.1.	ACUTE TOXICITY		36
6.2.	CHRONIC EFFECTS		36
6.3.	PLANT EFFECTS		36
6.4.	RESIDUE		36
6.5.	OTHER RELEVANT INFORMATION 		36
7.	EXISTING GUIDELINES AND STANDARDS 		37
7.1.	HUMAN		37
7.2.	AQUATIC		37
8.	RISK ASSESSMENT		38
9.	REFERENCES		*0
APPENDIX A: Literature Searched 		A-l
APPENDIX B: Cancer Data Sheet for Derivation of q-j		B-l
APPENDIX C: Cancer Data Sheet for Derivation of q-|		C-l
111

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LIST OF TABLES
No.	TUIe	Page
5-1 Summary of Oral Carcinogenicity Study of BRL, 1968; and
Innes et al., 1969	 U
5-2 Summary of Oral Carcinogenicity Study of Welsburger
et al., 1981	 16
5-3 Summary of Oral Carcinogenicity Study of Ulland et al.,
197	2	 17
5-4 Summary of Oral Carcinogenicity Study of Graham et al.,
1975 	 18
5-5 Summary of Oral Carcinogenicity Study of Graham et al.,
197	3	 Ifl
5-6 Genotoxlclty Testing of ETU	 22
5-7 Studies on the Potential Teratogenicity of ETU	 27
W

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LIST OF ABBREVIATIONS
CNS	Central nervous system
cpm	Counts per minute
DNA	Deoxyribonucleic acid
Gi	Gastrointestinal
1.p.	Intraperitoneal
LCjq	Concentration lethal to 50% of recipients
LOjp	Oose lethal to SOX of recipients
MID	Maximum tolerated dose
NAOPH	Reduced Nicotinamide Adenine Dlnucleotlde Phosphate
ppm	Parts per million
TLC	Thin layer chromatography
TSH	Thyroid-stimulating hormone
UV	Ultraviolet
v

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1. INTRODUCTION
1.1.	STRUCTURE AND CAS NUMBER
Ethylene thiourea {ETU) 1s the common name for 2-1m1dajol idlnethlone.
This compound 1s also known as 4,5-dlhydrolmldazolt«.?(3H)-th1one,
N,N'-ethylene-thiourea, 1,3-ethylene-2-th1ourea, 2-1m1dazol1ne-2-th1ol,
t
2-mercapto1m1dazo1e and 2-thlol-dlhydroglyoxlne. It 1s produced under the
following trade names: NA-22, NA-22-0, Pennac CRA, Sodlum-22 neoprene
accelerator and Warecure C (N10SH, 1983; IARC, 1974). The structure of ETu
Is given below (IARC, 1974):
6= cr
Molecular formula: C^H^N^S
Molecular weight: 102.2
The Chemical Abstracts Service (CAS) Registry Number for this compound 1s
96-45-7.
1.2.	CHEMICAL AND PHYSICAL PROPERTIES
ETU Is a white, crystalline solid with the following physical properties:
Melting point:	Z03-204°C (Ulndholz, 1976)
Solubility:	1n 100 ml of water -- 2 g at 30°C, ~ g
at 60°C and 44 g at 90"C; moderately
soluble In methanol, ethanol, ethylene
glycol and pyridine; Insoluble In acetone,
ether, chloroform, berzene and Hgroln
(Wlndholz, 1976).
Log octanol/water
partition coefficient: -0.66 (Hansch and Leo, 1981)
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1.3.	PRODUCTION DATA
ETU Is produced by Mke Chemical, Inc., NUro, WV, with an annual
production volume of between 100,000 and 1,000,000 pounds/year {U.S. EPA,
1977; SRI, 1983). The 1982 Directory of Chemical Producers (SRI. 198?) also
lists Pennwalt Corp., Wyandotte, MI, as a producer of ETU. 'The 197 7 1SCA
Production file (U.S. EPA, 1977) also lists the following Importers:
	Importer			locatlon		Volume (lbs/year)
Akron Chemical Co.	Akron, OH	10,000-100,000
Henley and Co, Inc.	New York, NY	no report
Hobay Chemical Corp.	Pittsburgh, PA	no report
Mlllmaster Chemical Co.	Berkeley Heights, NO	<1000
Prochlmle International, Inc. New York, NY	10,000-100,000
The synthesis of ETU may be accomplished by reacting ethylenedlamlne
with carbon disulfide, followed by ring closure by refluxlng with hydro-
chloric acid (Johnson and Edens, 1942); however. It Is unknown If 1t 1s
produced commercially by this route (IARC, 1974).
1.4.	USE OAT A
The primary use of ETU 1s as a curing agent for eplchlorohydr1n elasto-
mers {Vanderberg, 1979) and as an accelerator for neoprene rubber (IARC,
1974).
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2. ENVIRONMENTAL FATE AND TRANSPORT PROCESSES
Although ETu Is used primarily In the rubber and plastics Industry, H
Is Introduced Into the environment because U Is a degradation product of
ethyleneb1sd1th1ocarbamate fungicides, such as maneb and zlnetf-riARC, 1974),
and H 1s also an Impurity of at least 28 formulations of these agricultural
chemicals (Bontoyan et al., 1972).
The fate and transport of E1U 1n soil have been studied by several
Investigators. Removal of ETU from soil by microbial degradation with the
release of CO^ was reported by Lyman and Lacoste (1975), but only an
abstract of the study was available, so further details were lacking.
Kaufman and Fletcher (1973) found that 2 days after application of 20 ppm
1 *C-£TU to Hagerstown sllty clay loam or Lakeland sandy loam, all the
radlolabel was present as ethyleneurea, 43% of which was degraded to
1 'COp by the fourth day. Results using autoclaved soil Indicated that
the conversion of 1*C-ETU to **C-ethyleneurea was accomplished chemi-
cally (perhaps by reaction with free radicals since degradation of E1U by
Fenton's reagent was rapid), while further degradation to C0^ was accom-
plished mlcroblally.
In a field study In Delaware, Rhodes (1977) found that when 14C-ETU
was applied at a rate of 2 pounds/acre to 4-1nch diameter sections of roll
(Keyport sllty loam) Isolated by 12-Inch long sections of stainless steel
tubing driven into the ground (runoff was prevented by a protruding Hp),
the total 14C residues disappeared with a half-life of <4 weeks. The
half-life for disappearance of Intact E1II was actually <1 week. The total
rainfall for the 1-week period was 0.56 Inches. Most of the radioactivity
was confined to the top 1-5 Inches of the soil column; however, detectable
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amounts (0.2%) were found In depths of B-12 Inches by 12 weeks after appli-
cation. After 52 weeks 16% of the Initial radio activity was present In the
top 1 Inch, 4% 1n 1-3 Inches, 1.0% In 3-5 Inches. 0.5% 1n 5-8 Inches and
0.1% 1n 8-12 Inches (total rainfall for 52 weeks was 54 Inclfej.). E1U did
not, therefore, leach to any great extent under these conditions. The over-
all half-Hfe for the degradation products (hydantoln, ethyleneurea, Joffe's
base and glycine) was 4 weeks. Some of the degradation may have occurred by
microbial action, but this was not investigated. Blazque2 (1973) sprayed
ETU on the surface of prepared soil beds (Immokalee fine sand) at a rate of
2 pounds/100 gallons of water and found that -47% disappeared after 1 day,
60% by 6 days, 69% by 13 days, and only a trace was detected after 27 days.
No statement was made regarding the mechanism of disappearance.
In soli mobility studies using 14C-ETU, Helling and Thompson (1974)
reported the values for the compound when leached onto soil TLC plates
to be 0.96 In Norfolk sandy loam, 1.00 In Lakeland sandy loam, 0.96 1n
Hagerstown s11ty clay loam, 0.83 In Barnes clay loam and 0.61 In Celeryvllle
muck. The organic matter content of the first five soil types ranged from
0.14-6.9%, while Celeryvllle muck contained 90.4%. Thus, ETU was very
Teachable except on soil with high organic matter content. ETU was Immobi-
lized by drying the soil or by Incubating the compound prior to leaching.
Indicating that El U was eUher irreversibly adsorbed or substantially
degraded. These authors also found no Indication of photodegradatlon of E1U
when the soil plates were exposed to continuous fluorescent Illumination.
Upon incubation or drying, the Immobile origin spot. Identified as
ethyleneurea, Increased (Helling and Thompson, 1974). Experiments using
moist stored soil (mlcroblally active) or dry stored soil (mlcroblally
Inactive) shaken with nutrient broth failed to confirm microbial degradation.
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Only 10% of 1.5 ppm 14C-ETU aqueous solution, shaken with 1 g of
Hagerstown soil, was adsorbed within 2 hours. . By 66 hours, 2S!4 was
adsorbed. This weak adsorbtlon property 1n moist soils Is consistent with
the high leaching ability of ETU (Helling and Thompson, 1974).
In microagroecosystem chamber studies, Nash and Beall (1980) reported
"half-Hfe" values (time to reduce the maximum chemical concentration at
application by one-half for ETU 1n Galestown sandy loam (pH 6.7; organic
matter content, 5.3%) of 3 days when generated from maneb, and 0.5 days when
generated from zlneb when these fungicides were sprayed on tomato plants
growing in the chambers. ETU was detectable only on the first 2 days
following fungicide treatment. Thus, ETU 1s weakly adsorbed to soil, 1s
highly mobile In moist soil, but Is Immobilized by dry soil. Degradation
appears to be accomplished readily by both chemical and biological means
and, thus, ETU does not persist in soil.
Since ETU has a relatively high water solubility. It Is likely to enter
the aquatic environment through runoff and leaching through soil. Removal
from water may be accomplished by chemical reactions, photolysis or micro-
bial degradation.
The hydrolysis of ETU has been studied by several Investigators.
Blazquez (1973) reported residual concentrations of 100 ppm ETU In 100® ml
of delonlzed water maintained at 20°C to be 9554 by day 1, 80% by day 7 and
50% by day 21. In ditches containing 500 g ETU/946 t of water, 50%
disappeared 1n 1 day, 75% In 7 days and -90% in 14 days. Crulckshank and
Harrow (1973), however, reported that ETU was not readily degraded In 1%
aqueous solutions at pH 5, pH 7 or pH 9 when held at room temperature or at
90°C for as long as 3 months. These investigators demonstrated that photo-
lysis of ETU Is. a major pathway of degradation. ETU was slowly degraded
when exposed to near UV light (>285 nm) on silica gel (100
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This degradation was greatly enhanced by the addition of 1-acetonaphthone as
a sensitizer, with 70% loss of ETU occurring after 20 hours of exiosure.
When Irradiated with a GE sunlamp for 20 hours, degradation of 1 vg
ETU/cmJ was 99% In the presence of the sensitizer. IdentlflWas photoly-
sis products were bis (1m1daza11n-2-yl) sulfide and 2-1m1dazolIdone {ethyl -
eneurea).
Ross and Crosby ( 1973) found that exposure of solutions of E1U (0.5-50
mg/t) 1n delonlzed water to summer sunlight or to UV light (F40 81 GE
lamp) resulted In no photolysis except In the presence of acetone (5 mg/i)
or other sensitizers (95% loss from 0.64 mg/i solutions after 4 hours of
exposure). Boiled agricultural drainage ditch water samples fortified with
ETU at 0.5 mg/t resulted 1n 50-90% degradation following Irradiation by
lamp for 3 days or by sunlight for 24 hours Indicating that natural photo-
sens1t1zat1on may play an Important role In photodegradlng ETU In natural
water. No degradation was observed after exposure to darkness. The prod-
ucts of photodegradatlon were Identified as ethyleneurea and glycine sulfate.
Rhodes (1977 ) reported that exposure of aqueous solutions of 1*C-tTU
to a mercury vapor UV lamp resulted In 99% degradation after 6 hours, and
after 3 hours In the presence of 0.1 H acetone as sensitizer. The products
were Identified as glycine sulfate, ethyleneurea, hydantoln and Jaffe's ba?e.
No Information regarding microbial degradation of ETU 1n aquatic media
was found, but extrapolation from the soil data may be appropriate. Also,
Information concerning the bloconcentratlon of ETll was not encountered, but
a low tendency for bloconcentratlon can be predicted from the low value of
the log octanol-water partition coefficient, -0.66 (Hansch and Leo, 1981).
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The only Information regarding the fate or transport of £TU 1n the atmo
sphere was reported 1n a study of the fate of maneb and ztneb in mlcroagro
ecosystem chambers (Nash and Bea11. 1980). Air from chambers In wh1c:
tomato plants sprayed with the fungicides were growing was trtapped by poly
urethane foam filters and analyzed for the parent compounds as well as for
the degradation product, ETU. The results Indicated that ETU was volatile,
comprising -10% of the volatilized components, and had a "half-life" of B-S
days 1n air. The concentration In the chamber air was -1 ng/m3 on the
first day after application and declined rapidly after 7 days, perhaps due
to sprinkle Irrigation reduction of ETU levels.
Although from the results of Nash and Bea 11 (1980) ETU appears to be
volatile, Its high solubility, ability to undergo photolysis 1n the presence
of natural sensitizers, and Its expected degradabllUy by chemical means
{free radical reactions and hydrolysis) Indicate that any ETU entering the
atmosphere through volatilization would be partly removed from the air by
rain, and would be partly degraded by photochemical or chemical means.
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3. EXPOSURE
No monitoring data on ETU were contained 1n ST ORE T, and no other Infor-
mation regarding ambient levels In air, water or soil was available.
Human exposure to ETU 1s primarily the result of resldujl ethylenebls
d1thlocarbamate fungicides on food crops. Of 167 food samples produced in
or Imported by Canada, 56 contained detectable levels of ETU ranging from
<0.02 ppm for most Items to 0.047 and 0.083 ppm for canned spinach and
orange peel, respectively (Pecka et a 1 .. 1975 ]. Although little, If any,
residual ETU was found on harvested apples, tomatoes, grapes, pears, pota-
toes, cucumbers, squash or cantaloupes, the cooking, processing and storing
of such foods have resulted 1n detectably Increased levels (Ross et al.,
1978; Ripley and Cox, 1978; Ripley et al., 197B; Ripley and Simpson, 1977;
Pease and Holt, 1977 ; Uno et al., 1978; Cseh-Szepessy, 1978; Watts et al.,
1974).
It has been shown that the ethyleneblsdlthlocarbamate fungicides degrade
to ETU at high temperature and humidity (Bontoyan and Looker, 1973) and when
stored (Petroslnl et al., 1963; Stanculescu et al., 1979).
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4. PHARMACOKINETICS
4.1. ABSORPTION
Rats receiving a single oral dose of 40 nig l4C-ETU/kg excreted 8?% of
the administered radioactivity 1n the urine; 90X of the urinary radio-
activity was excreted In the first 24 hours. The majority of radiocarbon
given orally to two rhesus monkeys at a dose of 40 mg 1*C-ETU/kg was
excreted In the urine (47 and 64%) in 48 hours (Allen et a!., 1978). These
elimination data Indicated that most of the ETU dose was absorbed by the G1
tracts of the rats and monkeys.
Absorption of ETU from the 61 tracts of pregnant mice and rats was
rapid. Peak plasma levels of radioactivity were achieved at 1.4 and 1.3
hours, respectively, post-treatment with 240 mg 14C-ETU/kg administered
orally to mice or rats and 240 mg 3sS-ETU/kg to rats (Ruddlck et al.,
1976a,b, 1977). Kato et al. (1976) reported similar results 1n pregnant
rats treated orally with 100 mg 14C-ETU/kg. Radioactivity was detected 1n
the blood as early as 5 minutes, Increasing rapidly- to peak levels at 2
hours.
Teshlma et al. (1981) reported relatively slow absorption of ETU from
application to Intact skin of guinea pigs. No Information on dose levels
was provided 1n the available abstract.
4.2., DISTRIBUTION
The distribution of radioactivity from 14C-ETU has been studied In
rats, mice, guinea pigs, monkeys, and pregnant rats and mice.
Allen et al. (1978) found very little accumulation of radiocarbon 1n
muscle, blood, skin and liver of rats (0.73%) 48 hours after oral dosing
with 40 mg 14C-ETU/kg (the position of the label was not specified);
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however, rhesus monkeys retained -25% of the administered dose, wUh the
greatest accumulation 1n muscle (11.6%). Newsome (1974) reported a range of
residue levels of ETU, detected by gas-liquid chromatography In liver,
kidney, heart and muscle, of 0.010-0.086 ppm 1n rats and guinea pigs 96
hours following oral doses of 20 mg ElU/kg; the thyroid levels were consi-
derably higher at 0.824 ppm 1n rats and 0.75 ppm In guinea pigs. Thyroid
accumulation of ETU 1n guinea pigs was also reported 1n an abstract of a
study by Teshlma et al. (1981).
Ruddlck et al. (1976b) noted In pregnant rats treated with 14C-ETU at
doses of 240 mg/kg on day 11, 12 or 15 of gestation that radlolabel binding
to red blood cells was reversible and that label did not accumulate 1n
blood, livers or kidneys of the dams or the fetuses. The radioactivity
detected 1n fetuses appeared to be uniformly dispersed. Similar results
were obtained by Kato et al. (1976) on the distribution of (2-14C]-ETU 1n
pregnant rats and fetuses; however, examination of the thyroid revealed
accumulation of radiocarbon 1n this tissue, with levels of radioactivity
equivalent to 0.346, 0.483 and 0.651 ymole ETU/g tissue at 2, 6 and 24
hours, respectively, after dosing with 100 mg [2-14C ]-ETU/kg (935
ymole/kg). Distribution of radioactivity 1n pregnant mice given a single
oral dose of 240 mg [4,5-14C]-ETU/kg was similar to that of rats at 3
hours after dosing, but the radioactivity was eliminated faster from mice
than from rats (Ruddlck et al.t 1976a, 1977).
4.3. METABOLISM
The metabolism of ETU has been studied In mice, rats and cats 1n both ]_n
v1 vo and Wi vitro systems. Savolalnen and Pyysalo (1979) Identified the
main urinary metabolite found 1n mice treated orally with [2-14C]-ETU,
[4,5-14C]-ETU or ,SS-ETU at 67 mg/kg as 2-1m1dazol1n-2-yl-sulfonate,
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which contained all radlolabels. The same metabolite was found after jn
vitro Incubation with mouse liver microsomal NADPH preparations. Metabolism
was believed to occur via sulfoxidation of ETU. Ethyleneurea was also
identified as a metabolite of ETU 1n mice.
In pregnant rats given [4,5-14C]-ETu by gavage, 1*C0^ was expired,
but only trace amounts of radlolabel were expired from rats given
[2-1*C]-ETU. This Indicated that CO^ was formed from fragmentation of
the Imidazoline ring and the decarboxylation of the 4 or 5 carbon atom of
ETU (Kato et al., 1976).
Rats treated with 4.0 mg/kg [4,5-1*C]-ETU excreted 8?.774 of the radio-
activity In the 24-hour urine, 62.6% of which was Identified by TIC as
unchanged ETU, 18.3% was ethyleneurea, 4.9% Imldazolone, 1.9% Imidazoline
and 12.3% other metabolites (Iverson et al., 1980). vitro formation of
ETU and Imldazolone using the rat liver mlcrosomal-NADPH system suggested an
oxidative desulfuratlon reaction (Iverson et al., 1980). High performance
liquid chromatography of urine from ETU treated rats Identified a thlolml-
dazole, Indicative of a dehydrogenatlon reaction without the formation of
ethyleneurea. Other sulfur-containing metabolites Identified by high
performance liquid chromatography were thlohydantoln, N-methyl ETU and
N-methyl thlo1m1da2ole (Iverson et al., 1979). Kobayashl et al. (1982)
Identified 1-methylthlourea In the plasma of rats 2 hours after a ?00 mg
ETU/kg oral dose. The TLC analysis of the 24-hour urinary metabolites from
cats treated orally with 4 mg [4,5-14C]-ETUAg revealed 28.0% unchanged
ETU, 3.5% ethyleneurea and 64.3% S-methyl ETU (not Identified 1n rats),
while no Imldazolone or Imidazoline were detected (Iverson et al., 1980).
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4.4. EXCRETION
Rapid elimination of ETU 1n the urine of rats and guinea pigs was note
by Newsome (1974}, with 18% of the administered dose eliminated at 6 hour
and 43% at 24 hours from rats, and 18% ai 6 hours and 27% at 24 hours frc
guinea pigs. Excretion was essentially complete at 48 hours. The feces o
rats and guinea pigs contained negligible amounts of ETU. Allen et al
(197B) found that rhesus monkeys excreted -50% of tt\e administered Oose o
1 *C-ETLI In the 48-hour urine, while at that time for rats, 8?% of th<
radlolabel was detected. Similar findings for urinary elimination wer<
found by Kato et al. (1976), who also found expiration of l4C0^ fror
pregnant rats administered [4,5-*«C]-ETU. Elimination from plasma wa"
blphaslc with rapid loss by 4 hours, followed by a slower phase which wa;
complete at 24 hours after dosing of rats with [2-i*C]-ETU {Kato et al.,
1976). Ruddlck et al. (1976b) calculated the half-Hfe for plasma elimina-
tion (assuming first-order kinetics! for pregnant rats as 10 hours. Excre-
tion of radioactivity at 12 hours after administration of 240 mg
[4,5-14C]-ETU/lcg was -50% complete from rats and -60% complete from mice.
By 48 hours, the total amount excreted (70-80%) was similar for the two
species (Ruddlck et al., 1976a, 1977).
Thus, it appears that ETU 1s rapidly absorbed upon oral dosing In
several species, 1s metabollred with little accumulation In tissues except
for the thyroid, and Is eliminated rapidly. Elimination Includes a substan-
tial amount of unmetabollzed ETU. There also appear to be some interspecies
differences 1n metabolism.
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5. EFFECTS
S.I. CARCINOGENICITY
An NTP (1903) bloassay for the carcinogenicity of ETU has begun, and the
chronic test 1s in progress. The results of five chronic feeding studies In
rats (Welsburger et al., 1981; U1 land et al., 1972; Graham fcfc'j.al , 1973,
1975) and one In two hybrid strains of mice (BHL, 1968; Innes et al., 1969}
are sumoarlred In Tables 5-1 through 5-5.
BRl (1968) and Innes et al. (1969) reported significantly Increased
Incidences of hepatomas 1n both sexes of two strains of mice and signifi-
cantly Increased Incidences of lymphoma 1n females of one strain when
compared with controls. In comparison with pooled controls, dietary
administration of E1U at the H7D {350 ppm) significantly (p<0.05) Increased
the Incidence of thyroid follicular carcinoma 1n both male and female
Charles River CO rats {Welsburger et al., 1981).
Ulland et al. (1972) also reported Increased (p<0.05) thyroid carcinoma
Incidence In rats fed ETU at the HTD for IB months.
Charles River rats developed thyroid gland carcinomas and adenocarcImas
at dietary levels of 250 and 500 ppm when treated for 1 or 2 years (Graham
et al., 1973, 1975). Further details of dose levels, exposure periods and
tumor Incidence are given 1n Tables 5-1 through 5-5.
An abstract of a French study (Gale et al., 1976} reported that ETU *as
not carcinogenic to hamsters fed up to 200 mg ETU/mg for life, but thyroid
adenocarcinomas were Induced by lifetime feeding of 60 mg ETU/kg to male
mice and 200 mg ETU/kg to female mice.
In addition to the chronic feeding studies, BRL (1968) reported no
significant increased tumor Incidence 1n 86C3F^ or B6AKF^ male or female
mice given a single subcutaneous Injection of 1000 mg ETU/kg and killed and
necropsled -18 months later.
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1ABU S I
Summary of Oral Carcinogenicity Study of BRl. 1968 and Innes el a) . 1969
Species/	Dose or	Duration of	Duration Purity of	largel	tumor	tumor
Strain Sci liposure	Treatment	of Study Compound	Vehicle or Physical Stale	Organ	type Incidence
|P value)
Rice/
B6AI' >
Mice/
BMfKI
HUe/
B6AfKI
. Nice/
—B6AFK1
i
Nice/
B6C3FI
Mice/
B6C1II
Nice/
B6C3II
Nice/
BbOl I
Nice/
B6AFKI
N
f
N
f
N
Initially
?1S mg/kg
followed by
646 ppa
Initially
?IS mg/kg
followed by
Mi ppn
(nil la I ly
215 mg/kg
fol lowed by
(ti pp»
Initially
?1S mg/kg
fol lowed by
646 pp
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UBU S-l (tint )
™ Spec let/
Strain
Sci
Oose or
(iposure
Duration of
Treatment
Our a I Ion
of Study
Purity of
Compound
Vehicle or Physical State
large!	Tumor	lumor
Organ	type Incidence
(P value)
Rice/
B6AIK1
Hlce/
SbAFRl
Initially
?IS mq/k9
followed by
(46 pp«
Initially for
3 weeks by )a
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UBlf 5 2
Summary of Oral Carcinogenicity Study of Melsburger el a I.. 1981

CD
T3
Specle»/	Duration	Ourallon	Purity of Vehicle or	Tumor
Strain Sen Dote	of	of Study Compound	Physical large! Organ	Tumor Type	Incidence
Treatment	Slate	(P value)
i
Rat/
Charles
River CO
Rat/
Char let
River CO
Ral/
Charles
River CO
Rat/
Char let
River CO
Rat/
Charles
River CO
3SO ppm 78 weeks	104 weeks
3(0 ppm It weeks	104 weeks
ITS ppm IB weeks	104 weeks
US ppm 16 weeks
0 ppm HA
104 weeks
104 weeks
90*
90*
90*
90*
HA
diet
diet
diet
diet
MA
thyroid gland
thyroid gland
thyroid gland
thyroid gland
thyroid gland
follicular carcinoma
paplIlary careinoma
follicular carcinoma
paplIlary carcI noma
follicular carcinoma
papillary carcinoma
follicular carcinoma
papillary carcinoma
follicular carcinoma
papillary carcinoma
lS/?b
2/2t
t/2 6
2/21
2/2 6
1/26
2/2 6
\/2f>
0/20
0/20
Rat/
Charles
River CO
0 ppm MA
104 weeks
NA
NA
thyroid gland
follicular carcinoma
papillary carcinoma
0/?0
0/?0
o
M
o
CO
Strengths of Study:
Weakness of Study:
Overall Adequacy:
Comnents:
QUALITY Of IVIPCNCt
the compound was tested by a natural route at two dose levels (MTO and one-half M10} The animals were treated for a
significant portion of their lifespan
The matched control group was small (10 animals). However, no thyroid carcinomas were found In pooled controls, and only
I follicular cell and I C-cell carcinoma were found In 184 male negative controls, and none was found among 184 female
negative controls
Adequate
The Incidence of thyroid follicular carcinoma was Increased I lgn1 f Hani ly |p<0 0?) In both seies at 350 ppm, but not at
US ppm. In comparison to pooled controls
NA • Not applicable

-------
1 ABl t V3
Sunurj of Oral Carcinogenicity Study of Ulland et il., 19??
cr>
ao
•a
Spec let/
Strain
Se«
Oose
Our atIon
of
treatment
Ourat Ion
of Study
Pur Ity of
Compound
Vehlc It or
Physical
State
Pr Imar y
large! Organ
Pr Imary
Tumor type
Tumor
Inctdence
(P value)
Rat/
Char Ws
River CD
Rat/
Charles
River CD
Rat/
Char let
River CD
Rat/
Char let
, River CO
7* Rat/
Char lei
River CD
Rat/
Char let
River CD
3)0 ppo IS Month! ?~ months	technical	diet
grade (97X1
350 pp« 18 months	?4 months	technical	diet
grade (9HI)
l?S ppm	18 Months	?4 Months	technical	diet
grade <9?X)
175 pp«	18 Months	?4 months	technical	diet
grade (9f%)
0 ppM	NA	?4 months	NA	MA
0 ppM	NA	?« months	NA	NA
thyroid gland
lung
thyroid gland
thyroid gland
thyroid gland
thyroid gland
thyroid gland
thyroid
carcinoma
metastases
thyroid
carcInoma
thyroid
carcinoma
thyroid
carcI noma
thyroid
carcinoma
thyroid
carcInoma
1)/?fc
2/?b
e/?6
3/M>
3/2b
0/3?
0/3?
QUAIHT Of tVIOtNCt
Strengths of Study: The compound was tested by a natural route at two dose levels. The animals were treated for a significant portion of
their lifespan
Overall Adequacy: Adequate
NA . Not applicable

u
o

-------
I ABU 5 4
Sumary of Oral Cart Inogenlc lly Study o( Graham el al , I9J5

QUALITY or motNct
lhe compound was tested by a natural route at five dose levels. The animals were treated for a significant portion of
Ihelr lifespan
lhe tumor Incidence -In each se* was not specified. The purity of the test compound was not staled. Tumor Incidence was
given only for rats tested for 24 months, and not for rats fed only 12 months (See Table 5-5 for 17-month data of
Graham et al., 1913 }
Adequate
lhe authors state that (ID Is a thyroid carcinogen for Charles River rats when fed at levels of 250 and 500 ppm In the
diet for 2 years.
^NA • Not applicable,
ao
NR
Hot reported

-------
1AB1I 5-5
0	Summary of Oral Carcinogenicity Study of Graham et al., 19/3
4*
cr>
CD
x> 	
Species/
Strain
Sea
Ooie
Duration
of
treatment
Our allon
of Study
Pur 1ty
of
Compound
Vehicle or
Physleal
Slate
Pr tmary
target Organ
Pr Imary
lumor lype
lumor
Incidence
|P value)
Bat/
Char lei
River CD
H
500 ppa
12 aonths
12 monthi
MR
diet
thyroid
adenocarc1 noma
10/13
Ral/
Char let
River CO
f
500 ppn
12 Months
12 months
MR
diet
thyroid
adenocarcInoma
5/12
Ral/
Char let
River CD
H
250 ppa
12 months
12 months
NR
diet
thyroid
adenocarc Inoma
3/13
Rat/
Char lei
River CD
f
250 ppa
12 months
12 monthi
NR
diet
thyroid
adenocarcInoma
0/10
>
Rat/
Char let
River CD
n
125 fifm
12 monthi
12 months
NR
diet
thyroid
adenocarcInoma
0/11
Rat/
Char lei
River CD
f
125 ppa
12 months
12 monthi
NR
diet
thyroid
adenocarcinoma
0/11
Rat/
Char lei
River CO
H
25 ppm
12 onnthi
12 monthi
NR
diet
thyroid
adenocarcinoma
0/11
Rat/
Char lei
River CO
f
25 pp*
12 monthi
12 monthi
NR
diet
thyroid
adenocarcinoma
0/10
Rat/
Char lei
River CD
a
5 ppn
12 months
12 Aonths
NR
diet
thyroid
adenocarc 1 notya
0/11
>Ral/
jChar lei
>R1*ei CD
i
5 ppn
12 months
1? months
NR
diet
thyroid
adenocarcInonu
0/10


-------
lABlf 5 1 (conl )
©»
a>Spec let/
¦° Strain
Se*
Bote
Otirat Ion
of
Treatment
Our it Ian
of Study
Pur lly
of
Compound
Vehicle or
Physical
Slate
Pr liur |
tirgtl Organ
Pr lisary
Tumor Type
Tumor
lotIdrnce
(P value)
Rat/
Char let
River CO
Rat/
Char let
River CD
0 ppm
0 ppa
HA
NA
I? months
1? months
NA
HA
NA
NA
thyroid
thyroid
adenocarcI noma
adenocarc tnoma
Q/U
0/1
QUAUIT Of IV101 WCI
Strength! of Study: Ihe conpound wat letted by a natural route at five dote levels to both males and femalei
Weakness oF Study; Ihe itudy was conducted for only I year, but the data were reported for an Interim kill during a ?-year study (See lable
5.4, Grahaa et al.. I97S|.
rljC
0
1
Overall Adequacy:
ntt:
Inadequate In light of the longer feeding study (see coiment above).
Ihe authors state that thyroid carcinomas were produced al doset of ?S0 and $00 ppm; under the conditions of thli study
t1U is a carcinogen.
MA » Hot applicable; KB - Hot reported
o
u
to
o

-------
An abstract of a human study on occupational exposure of female workers
to rubber containing ETU reported no Increased Incidence of thyroid cancers
(Smith. 1976).
5.2. MUTAGENICITY
Table 5-6 summarizes the results of many genotoxlclty stgd.les. ETU was
positive In some strains of Salmonella typhlmur1um 1n the reverse mutation
assay to hlstldlne Independence (Seller, 1974; Schupbach and Hummler, 1977;
Teramoto et al., 1977 ), 1n B. subtil 1s spores in the rec assay (Kada, 1981),
In a cell transformation assay with hamster kidney cells (Daniel and Dehnel,
1981), and In the unscheduled ONA synthesis of cultured HeLa cells (Martin
and McDermld, 1901) In the absence but not presence of a microsomal meftbo-
11c activating system. Intraperitoneal Injection of 100 mg ETU/kg to mice
resulted In 96% inhibition of »H-thym1dlne Incorporation Into ONA (Seller,
1977a). ETU also was positive In the mitochondrial DNA petite mutation
assay In Saccharomyces cerevlslae (D1ala et al., 1980; Eg 11 sson et al.,
1979). Several of the studies using S. typhlmurlum considered the negative
response to ETU to be a false-negative response In view of the known carcin-
ogenic potential of the compound (Baker and Bonln, 1981; Venltt and
Crofton-Sleigh, 1981; Rowland and Severn, 1981; Brooks and Oean, 1981).
In addition to the studies summarized 1n Table 5-6, Seller (1975, 1977b)
reported positive results using ETU 1n combination with NaNO^ (N-nltr^oso-
ETU) 1n the S. typhlmurlum reverse mutation assay and In mlcronuclel forma-
tion. in bone marrow erythrocytes from N-n1troso-ETU-treated mice. The
N-nltroso-ETU gave greater responses than either NaNO^ or ETU alone.
0468p
-21-
02/08/84

-------
1 ABlI i t
Genoloitdty letting of I 111
taiay
Indicator/
Application
Concentrat ton
Ac tlvat tng
Reipome4
Cormwnl
Reference
OtfMltn


or Doie

System




S. tvphtmurtun
ipot test
I0-75.000 ppm

S9
•
weakly positive ulth doie reipome at
Seller. 19)4
¦ultHon
itraln CU






>10 ppm It was unclear ai to what the









ppm referred (t e . the concenlra 1 ton









on the plate or In Ihe drop applied to









the plate)

Reverie
S. tiohlaurtuB






• >?0 mq/plale with doie reiponie
Schupbach and
wlitlon
C4t
plate
IncorporalIon
0, ?0. 40. 00 or
NR
-
tncreaie; positive results were alio
Hjimler, 1976. 19) J

1*1530
plate
IncorporalIon
?00 mg/plale


•
obierved tn a ipol test


1*1531
plate
IncorporalIon



-



1*153?
plate
IncorporalIon



-



1AI964
plate
Incorporalton



-


Reverie
S typhlaurtua






« only at concentration of 10.000
teramoto el al..
Mital Ion
1*1535
plate
tncorporalIon
0. 10. 100. 1000
»
S9
•
»g/plate without metabolic activation
19?/; Shtraiu ct

1*1536
plate
Incorporal ton
or 10.000 iig/plate
•
S9
c

al.. 1976a

1A t SSI
plate
Incorporalton

•
S9
c



1A1S38
plate
tncorporalton


S9
&



G«6
plate
Incorporalton

»
S9
m


Reverie
S 1vohtnurlua






• at >5000 iig/plale with doie reipome
Teramoto et al..
nalilIon
1*1535
plate
Incorporation
0. 5000. 10.000.
*
S9
•
tncreaie without SI.
197 7

1A100
plate
tncorporat ton
IS.000 or 70.000
»
S9
t






itg/plale





Reverie
S. tvphtmurturn






NC
Baker and Bontn.
Mutation
1*1535
plate
Incorporation
0-1000 wQ/plale
•
S9
B

1981

1*153?
plate
Incorporalton
0-1000 pq/plale
»
S9
B



1*1538
plate
IncorporalIon
0-1000 wq/plate
*
S9
«



1*98
plate
tncorpora tIon
0-1000 wQ/plate
1
S9
C



1*100
plate
Incorporation
0-1000 |iq/plate
»
S9
B


Revert*
S. l»phtmurturn






NC
Vrnllt and
wUllon
1A98
plate
tncorporat ton
0.5-100 vg/plale
•
S9
-

Crof ton-Slelqh. 1981

1AI00
plate
Incorporation
or 10-500 yq/plale
*
S9
¦


Reverie
S tvphtmurlufli






NC
Rowland and Severn.
aulalton
1A1S35
plate
tncorporat Ion m
0 1-7000 nq/plale
•
S9
-

1981

IAI537
piale
tncorporalIon
•
S9
¦-



IAIS38
plale
Incor por a 1 Ion

»
S9
i



IA98
p Idle
tncorpor at Ion

»
S9




1A100
p lale
tncorporat ton

4





-------
Ass ay	Indicator/	Application	Concentration
OrganlsM	or Dote

S. typhliMirlun


Mutation
TAIS37
plate
Incorporat Ion

1498
plate
incorporation

1AI00
plate
incorporation
Reverse
S typhlMurluM


Mutation
1A1S3S
plate
incorporatIon

1A1 S3?
plate
IncorporatIon

1AIS38
plate
IncorporatIon

1A98
plate
IncorporatIon

1AI00
plate
Incorporat Ion

1A9?
plate
Incorporation

S. tvphlMurlin


Mutation
64b
host-Mediated rats.
646
Reverse S. IiiiMwcH
Million UIS30
G4fr
Hewerse C. coll
Mutation MPZ her*
her"
Reverie
Mutation
I- «U
MP? Sir
UP? uvrA
UP2 uvrA/
pkH 101
bacteria Injected
l.p.
host-Mediated alee,
bacteria Injected
l.p.
host-Mediated Mice,
bacteria Injected
l.p.
host-Mediated Mice,
bacteria Injected
1 p.
Nil
NR
0.2-2000 Mg/p1atc
3 ¦ 200 ng/kg
3 * 400 ntg/kg
oral ly
3 « 200 Mq/kf
3 m 400 rag/kg
orally
0-6000 mq/kg
Intramuscularly
0-6000 mq/kg
IntranuscularIf
0-10,000 119/plalt
0-10,000 i«g/plal<
plate IncorporatIon NR
plate Incorporation NR
plate Incorporation NR
Reverie t. call
aula I Ion UP? (pl(pkMIOI) plate Incorporation
UP? uvr (p)
(pkHIOI)
plate IncorporalIon
0 5-100 |ig/pl4le
or 10-500 uq/plat
0 5-100 Mq/plale
or I0-S00 i>g/plal
1ABU S-t> (cont )
Activating Response4	Comment	Reference
Sftltn
"C	Nagao and lakahastil,
•	«	)9ai
•	S9
•	S9
"C	Brooks and Oean,
•	S9	-	1981
•	S9
. SI
•	S9
•	S9
i
NC	leranoto et at.,
NA	191)
NA
NA
NA
weakly (2 4 times) but significantly	Schupbach and
NA	•	Increased at bOOO nq/kg	Hunroler. 197b, 19F?
NA
NC	leraMoto et at.,
. S9	.	191?; SMrasu et
•	S9	al , Wfca
NC	Natsushlma et al.,
•	S9	-	I9B1
•	S9
•	S9
NC	Venltt and
•	S9	CrofIon-Sleigh. 1981
•	S4

-------
Muy	Indicator/
Orjinlia
Application
Contentful ton
or Oose
Rcc lit!) B. subtllls
HII~Rec1
M4S Rec*
Rec usiy B. :.MI1U
spores
spot test
(Inhibition of
growth)
spot test
(Inhibition of
growth)
70-4000 wg/dlsk
20-4000 wg/dlsk
2 mg/dlsk
ua. dose
Nilotic
cross-
over
Repair
test
S. leretlslie
*1
»2
S.
14
Petite
•utatIon
mttochon-
dr tal DMA
plate Incorporation
plate Incorporation
spot test
spot test
1000 *g/ml
1000 yg/mt
SO nt of a
0 1-1.OX solution
40 pi of 4
0.I-I.OX solutIon
plate Incorporation 0 5-20 mg/at
Petite
nutation
mltochon-
drlal ON*
S. cerevlslae
plate Incorporation 5.00 nM
Sea- 0. melinoqaster
linked *y/o Males
recessive mated with
lethal Berlin females
NR
2.5X IIU In
sugar water
Rate of	0. melanoqaster
dominant	gametes from
lethals	i|/o males ¦
Berlin females
Chromo-	Chinese hamsler
tome	DON cells
aberra-
1 1
NR
ce 11 culture
4 concentral Ions
(not specified)
1000 nq/nl
3200 uq/ral
lABlt 5 t (tori )
Activating Response'	Comment	Reference
System
no growth Inhibition lone at any	leramoto et al ,
MR	concentration	19?/; Shlrasu el
NR	al.. 1916a
without melabcllc activation, HU was Kada. 1981
•	Si	»	weakly »
•	SS (rat)	with Si from fish, there was a killing
•	S9	el let! without DMA damage
(yeI lowtalI
f lsh|
NC	Kasslnova et al..
» S9	«	19B1
» S9
NC	Kasslnova el al .
-	S9	1981
-	S9
slight but positive response	Otala el al.. 1980
NR	•
NC	(gllsson et al.,
NR	•	19/9
NC	Hoi let. 1915
NR
Ihr rale of dominant lethals Increased NoHrt, 19/S
NO	slightly with high concentraltons, bul
not slgnlfleantly
NR
severe cytotoxic effect al 3200 pg/ret
leramolo el al ,
I9M, Shir j\u et

-------
1ABl I S 6 (conl |
Assay
Indicator/
Organise
Application
ConcentratIon
or Oose
Ac I IvalIng
Syllem
Response'
Comment

Cell
Irani•
for*at Ion
Baby hamster
kidney cells
cell culture
LC$o *6000 wq/mt
• $9
»
*
NC
Oantel and Dehnel,
1981
Unsched-
uled ON*
synthesis
rat ^patocytes
hepatocytes
cell culture
3.2 * 10*H to
Hi IO~»M/p1ate
none
¦
NC
Althaus el al.. 1982
Unsched-
uled DNA
synthesis
HeLa cells
cell culture
0 1-100 n9/at
• S9
i
• without metabolic activation
Bar tin and
ItcDermld. 1981
Chromo-
some
aberra-
tions
rats
orally
?00 or 400 mg/kg
or
?-5 i 50-400 mg/kg
at ?4-hr intervals
NA
-
there was increased frequency of
numerically aberrant bone marrow celts
of treated animals, but It was not
statistically significant
leramoto et at .
19??. Shtrasu et
al.. 1976b
Coal nant
lethal
¦ice
male wtce treated
orally then mated
300 or (00 mq/kg
for S days
NA
-
no differences in numbers of corpus
lutea, Implantation* and live embryos
compared with controls
leramoto et al.,
197?; Shtrasu et
al.. I97bc
Dominant
lethal
¦ice
¦ale Mice treated
orally then mated
400. 1000 or
3i00 mg/kg
NA
-
NC
Schupbach and
Humaler, 1976. 191?
Ntcro-
nuc leus
test
¦ Ice
? oral doses,
?4 hours apart
700. I6S0 or
6000 mg/kg
NA
-
NC
Schupbach and
Huonler, 1976, 19??
Inhlbl-
1 Ion of
DMA
synthesis
¦Ice
l.p. Injection
100 M9/kg
NA
•
9M Inhalation of 'HTdR Incorporation
Seller, 1177a
MA • Nol ippllcibU; NC • No conwnt; NR • Not reported
'Responses: », pot Hive; negative, >, negative with and without S9 activation system; », poitttve with and negative without S9 activation
j, negative with and pot I live without S9 activation sytltni

-------
5.3. TERATOGENICITY
Table 5-7 summarizes studies of ETU teratogenicity In a number
species And under a variety of exposure and observation conditions. ETU w<
a potent teratogen 1n rats at dally oral doses as low as 2(5-40 mg/kg durU
gestation with no toxicity to dams (Khera, 1973; Khera and Tfyphonas, 197'
Chernoff et a 1, 1979; Teramoto et al., 1975a). The fetal responses Indue
CNS abnormalities such as exencephaly, hydrocephalus, hydranencephalu<
menlngoencephalus and menlngorrhea (Khera, 1973; RuddUk and Khera, 197c.
Khe-a and Tryphonas, 1977; Chernoff et al., 1979; Lu et al., 1980; Mungkorr
karn and Bal, 1978). Skeletal anomalies were also observed by these Intes
tlgators. ETU did not appear to be teratogenic to rabbits (Khera, 1973)
cats (effects were seen at doses that were maternally toxic) (Khera an
Iverson, 1978), mice or guinea pigs (Chernoff et al., 1979). Teramoto e
al. (1980b) did observe some teratogenic effects In mice, however, that wer
fed ETU In combination with sodium nitrite (study not Included In Tabl
5-7). CNS and skeletal defects were produced 1n offspring of hamster
treated with ETU at relatively high single oral dose levels of >1200 mg/k
(Khera et al., 1980), although Lu et al. (1980) found fetal abnormalities 1
hamsters at repeated doses of >120 mg/kg and CNS defects with multiple dose
of 300 or 360 mg/kg (Lu et al., 1980; Su et al., 1981).
Dermal application of ETU to pregnant rats at a relatively low dose o
SO mg/kg/day for 2 gestational days also resulted In CNS and skeletal abnor
malltles tit fetuses (Stula and Krauss, 1977); however. Inhalation of ETi
aerosols (Qllley et al., 1977) or Intraamnlotlc Injections of ETU (Teramot<
et al., 1980a) produced no teratogenic effects 1n rats.
Details of experimental protocols and progression of abnormalities
during organogenesis and postnatally are given In Table 5-7.
0468p
-26-
02/08/8'

-------
IABI1 S 1
Studies on the Potential I eratogentclly of I IU
Route
Spec lei,
Strain
Oral
rat/Wtslar
Oral
Ora I
Oral
Oral
ral/Mlslar
rabbit/
New Zealand
rat/Ulstar
No. Oams
at Start
10 controls
S3 treated
13 controls
52 treated
U controls
64 treated
J controls
26 treated
Vehtc le
distilled
water
distilled
water
distilled
water
distilled
water
Dally Oose treatment Observation Haternal
or fiposure Days	Day	Response
I eta I Response
Reference
NR - a total distilled
of 60 litters water
from treated
dams were
examined
0. *. 10.
?0 or 40
og/kg
0. 5. 10,
?0. 40 or
BO mg/kg
0. 5, 10.
70 or 40
mg/kg
0. 10. 20.
40 or 80
mg/kg
?40 mg/kg
?t-4? day
of pre-
pregnancy
to day IS
of
gestation
6-15
??'
22
1-20	22
1-20	30*
one of ??a
days 6-?l
none
80 mg/kg
for / days
pr oduced
9/11 deaths
none
CNS deformities eiencephaly men- Khera, 19*3
Ingoenc epha lot ele, menlngorrhea,
hydrocephalus, agenettc cerebel-
lum. disoriented ependymal layer,
obliterated neural canal
Skeletal defects abnormal pelvic
limb, caudal abnormalitles. these
effects were seen In all experimental
rats In a dose-ielated manner.
-No effects were observed below
10 mg/kg t 'U
Increased number of resorption
sites and decreased brain weight
at 00 mg/kg
When eaposed on day 6. 1, B or )
no malfunctions were seen
-day 10 - defective eaternal
genitalia (6%). hydronephrosis
I/OX), absent or short tall |?0%)
Khera. 1113
Ruddlek and
Khera. ISIS
¦ day 11 - spina bifida (301).
fused ribs (100%). renal abnormali-
ties Icaudal anomalies ( 100%)
-day l?-IS - hydrocephalus (91%),
e>encephaly (91%). brachygnathta 166%).
forellmh mlcromella (99*1. scoliosis
(100X1, renal abnorma 11 Hes (100%)
-day 16 - hydranencepha ly (100%). clef I
palate (100%). kidney anomalies (100%)
day I/-19 - hydranenrephaIy and renal
defe.ts (100%)
ilay ?0 or ?1 -rrnal defects only
(?<) a»<) 4?%)

-------
1*811 S-7 (cont )
<7> 	
CO
° Route
Spec let.
Strain
Mo. Dim
at Starl
Vehicle
Oal1y Dose
or (tposure
treatment
Oays
Observation
Day
HaternaI
Response
fetal Response
Reference
Oral
nt/Utslir
6-12/group
distilled
water
0, 30 or
4S mg/kg
IS*
Oral
rv>
00
1	Oral
rat/Mlstar
rat/Wis tar
S-10/group
13
distilled
water
distilled
water
0, IS or
30 nq/kg
0 or 45
mg/kg
IS*
ISa
jO
N
*3
3
S
X
first day
ot birth
up to 9
weeks of
age
NR
day of	NR
btr th up to
64 weeks of
age.
17. 20 and
72 of
gestation
or 2.7. 10
or IS
postnala1.
NR
High postnatal mortality: all at Khera and
4S 
-------
1*011 S I |cont )
Route	Spec In,	No. Dm	Vehicle Dally Dote treatment Observation
Strain	at Start	or [xposure Days	Day
Oral
tat
14 controls
41 treated
gelatIn
capsule
0. S. 10
30. 60 or
120 mg/kg
16 35
46a
Oral
(waiter/	Nit
Syrian Golden
aqueous 600, l?00,
gelatIn 1800 or
suspension 2400 mg/kg
ll<
tern
Oral
mouse/CO-1
66
dlst11 led
water
0, 100 or
?00 mg/kg
/ 16
18'
HaternaI
Response
Fetal Response
Refer ence
progressIve
weight loss,
atada,
tr emori,
hind limb
paralysis In
24 cats at
>10 mg/kg
II cats died
or were
killed In
morI bund
state At
tern, there
were 10
treated cats
and I control
cats
none
7-day-old pups - patchy disorgani-
zation and thinning of cerbrat
tortex-progresslve neural and
ependymaI necrosis to IS days.
No treatment-related effect on Khera and
mortality or fetal weigh! Inct- Iverson, 1916
dence of anomalies were 1/12 for
IPO mq/kg group, 0/10 for 30 mg/kg,
1/4 for 5 mg/kg and 0/33 for controls.
One felus had eaencephaly, hydro-
cephaly and cleft palate, another had
kyphoscoliosis and umbilical hernia
ll/JS live fetuses from cats kilted
in moribund conditions were malformed
with coloboma In 4. umbilical hernia
in 4, cleft palate In 2 and spina
bifida In 1
-Increased mortality and reduced
weight at 2400 mg/kg
Khera et al
I960
a I 700 mg/kg,
Inc 1200
mg/kg
hydrocephalus - 11-61% (range for
dose 1200-2400 mg/kgJ
hypoplastic cerebellum - 4-J2X;
deft palate - I/-0SX,
delayed calvarlal osslfl'fTtlon -
0 SIX, ectrodactyly - 0-13%
at 200 mg/kg - Increased number
of rlbs (p<0 OS)
Chernof f
et al., 19/9

-------
1ABLI 5-? (cont )
Route	Species,	No. Dams Vehicle Dally Dose treatment Observation Maternal
Strain	al Start	or Exposure Oays	Day	Response
fetal Response
Reference
Oral
Oral
Oral
Oral
rat/	109
Sprague-Oawley
hamster/
Ela: ENG
guinea pig/
Hartley
.amster/
Co Iden
49
NR
NR
distilled
water
0. S. 10.
?0. 30. 40
or 80 mg/kg
distilled
water
distilled
water
distilled
water
0. ?S, 50
or 100
mg/kg
0, SO or
100 ng/kg
0. 60. I?0.
300 or 600
ng/kg (I)
1-21
?1J
?4X
mortaIlly
at BO mg/kg
S-10
I?
7-14
15a
?0b
NR
none
none
Chernoff
1979
Increased mortality, decreased
body weight, decreased osstflca- et al
Hon, skeletal defects, CMS defects
(hydrocephalus, encephalocele)
cleft palate In majority of fetuses
at BO mg/kg (p<0.0011.
At 40 rog/kg-reduced fetal weight and
ossification, high rale of CHS defects
(not as much as at BO mg/kg).
Hydrocephalus was seen In some fetuses
at ?0 and 30 mg/kg No effect at
10 i»q/kg.
No treatment-related abnormalities Chernoff
et al.. 1979
No treatment-re la ted abnormalities
al >I?0 mg/kg- short snout, miss-
ing innominate artery, edema,
reduced number of lung lobes, bent
digits, hydroureter. fused ribs
and fused slernebrae
Chernoff
et al.. 1979
lit et al..
19B0
Oral
Oral
hamster/
Golden
hamster/
Golden
NR
NR
distilled
water
distilled
water
0. 300 or
360 mg/kg
3i/day (II)
0 or 360
mg/kg 3*/
day (III)
7-11
NR
10-11
NR
none
at 60 mg/kg - cleft palate
Resorption rate higher than In lu et al.,
III. Cleft palale. oligodactyly, 1980
menlngorrhea, micrognathia, hydro-
ureter, hydronephrosis, fused
digits, fused ribs, ¦t|LI'n9 r"M
and renal agenesis 1n IT and III.
fientngocele, eiencephaly. anoph- Lu el al.,
thatmla, edema, short trunk, un- 1980
descended lestes, decreased numb*'
of lung lobes In II. hyperplastic
IImbs In III.

-------
1 ADi I J l (cont )
Route	Species,	No. Dans	Vehicle Dally Oose treatment Observation Maternal
Strain	at Start	01 liposure Days	Day	Response
Oral
rat/Ulstar
NR
NR
Oral
rat/Wlslar
NR
NR
S0-?00
mg/kg
100 i*g/kg 12
one of JO*1
days 6-14
Nil
13^	NR
14 or later
fetal Response
Reference
No effect on viability, no anooa- leraaoto et
lies on day b-8. on day 9 or later, a!.. l9JSa
meningocele, mtcroagnathla. cleft
palate and atresia, short tall,
hyperplastic digits, these effects
were dose related
fitenslve cell necrosis In neutral leraanto et
tube at day I], at day 14 or	al . 19?Sb
later, rosette tarnation Indicated
regeneration but development was
Inhibited
Oral
rat/Wlstar
S
20
controls
treated
distilled
water
0 or 300
i»g/kg
I?
??c
NR
Reduced body weight Of 196
fetuses from treated dans 38* had
eaencepha ly, 30* hydrocephalus
(also short or absent tall), 20*
hydroencephaly associated with
agnalhla. micrognathia, abnormal
I imtis and tat Is
Hungkornkarn
and Ba1, 1918
Oral
hamster/
Golden
NR
distilled
water
0 or 360
mg/kg
3> day
8. 9.
or 11
10
IS*
none
fetal weight was significantly
reduced In 8 or 9 day groups
Increased Incidence In resorption
In B or 9 day fetuses, not In II
Coimon ma (format Ions were cleft
palate, menlgocele, mentngorrhea,
and o I Igodac tyly
Su et <1.
I9BI
On day 8 - enlarged kidney, eien-
cephaly edema, mlcromella, micro-
stoma.
On day 9 - amella, anal atresia,
cleft Hp, renal agen^l^and
short neck
On day 10 - bent digit, fused
dibits, renal agenesis and wavy rib
On day II - hydronephosIs, hydro-
ureter. hyperplastic Mmb. open eye,
unite M rndrd trsles

-------
A target organ of til) carcinogenicity {see Section 5.1.) and toxicity
(see Section 5.3.) 1s the thyroid gland. Lu and Staples (1978) conducted a
teratogenicity study 1n rats In which the dams had altered thyroid :unct1on
(either by thyroidectomy or by administration of thyroxine). ETU was given
to hypothyroid, euthyroid or hyperthyrold pregnant rats aC a dose of 40
mg/kg from days 7-15 of gestation, and, although fetuses were found to be
abnormal on day 20, the abnormalities were not related to maternal thyroid
status.
5.4.	OTHER REPRODUCTIVE EFFECTS
No morphological anomalies were observed In pups bom to rats ^tiat
received 30 mg £lU/kg/day orally from day 7 of pregnancy to day IS post-
partum, although 4 of 9 Utters died within 24 hours of delivery. Two more
Utters died during the first postnatal week; the pup of the surviving
litters developed hydrocephaly. The dams were observed to have milk, but
they failed to nurse (Kavlock and Chernoff, 1978).
Lactatlng rats given ETU at single oral doses of 20, 50, 75 or 100 mg/kg
continued to nurse their pups. The pups had Increased thyroid weights at
all dose levels and decreased survival rates at the two highest exposure
levels, and developed hypoprotelnemla with Increased serum amlnopeptldase
activity at 100 mg ETU/kg (Lewerenz and Schnaafc, 1978).
5.5.	CHRONIC m SU&CHR0NIC TOXICITY
Graham and Hansen (1972) studied the effects of feeding ETU to groups of
20 male Qsborne-Hendel rats, at dietary levels of 0, 50, 100, 500 and 750
ppm for up to 120 days, on the thyroid gland morphology and uptake of
1»*1. At 30-day Intervals, rats were killed at 4 or 24 hours following an
1.p. Injection of 5 pCI	Four hours after Injection, the uptake of
1#11 (cpm/mg tissue) was statistically significantly decreased at the 500
0466p
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and 750 ppm levels at each Interim kill. At 24 hours after Injection, the
decreased 1#11 uptake was statistically significant at 100 ppm E1U.
Histological examination revealed no difference 1n the thyroid of rats fed
SO ppm ETU for 90 days, but slight hypertrophy was evident at the 100 ppm
level, becoming progressively more marked at 500 and 150,ppm ETU, with
evidence of adenoma at these levels.
The feeding of ETU at levels of 0, 1, 5, 25, 125 or 625 ppm in the diet
for up to 90 days produced toxic effects In rats at >125 ppm ETU as eviden-
ced by altered thyroid function and morphology (Freudenthal et al., 1977).
Serum levels of triiodothyronine and thyroxine, and Iodine uptake ^ere
reduced 1n rats fed 625 ppm ETU. Serum 1SH levels were elevated in both the
125 and 625 ppm groups. Because no consistent effects were observed at 25
ppm, the authors considered this level of ETU 1n the diet to be a no-effect
level for subchronlc exposure.
Charles River rats were fed ETU In the diet at levels of 0, 5. 25. 125.
250 or 500 ppm for 2, 6 or 12 months (Graham et al., 1973). Each group
consisted of 68 males and 68 females. Ten animals of each sex were given
l.p. Injections of 5 pC1	at the end of each feeding period and
killed after a 24-hour fast for analysis of 1,11 uptake (cpm/mg thyroid
tissue) and for organ-to-body weight ratio measurement. Additional rats not
Injected with J>1I were also killed for histological examination of
tissues after 6 and 12 months. In animals fed ETU for 2 months, 11ver-
to-body weight ratios were significantly higher at >125 ppm ETU than were
control ratios. At the 500 ppm level, male rats had Increased ratios for
kidneys and testes. The thyroid gland was the most affected tissue with
significantly Increased thyro1d-to-body weight ratios at >250 ppm ETU for
males and >125 ppm levels for females (p<0.001) when compared with control
0468p
-34-
02/08/84

-------
rats. The uptake of »»*I was decreased for males at 500 ppm ETu for
months. For females, Ingestion of >125 ppm ETU for 6 months caust
decreased	uptake, while for 1? months at these levels, uptafc
Increased. The pattern of Increased organ-to-body weight ratios at 6 and 1
months was similar to that at 2 months, with the thyroid weight Increasln
up to 18 times the control value. Comprehensive histological examination o
tissues from 5 male and 5 female rats fed at the 500 ppm level for 6 month
revealed hyperplastic thyroids with adenomatous nodules and some carcinomas
but no treatment-related changes 1n other organs.
Examinations of tissues from 9-13 rats/group treated for 12 mQjith
revealed morphological changes In the thyroid at all dose levels, progress
Ing from nodular hyperplasia In the 125 ppm males to carcinomas 1n 23% o
the 250 ppm and 77* of the 500 ppm males, and from acinar epithelium papll
latlon and parafol1Icular capillaries In the 5 ppm females to carcinomas W
42% of the 500 ppm females. The remaining animals In this study were con-
tinued on the feeding regimen for another year (Graham et al., 1975 ) wltr
further thyroid tumorIgenesls evident (see Section 5.1. J.
Kameda 11982) fed three dogs a "diet containing a 0.1% ETU solution" for
6 months and observed thyroid glands hypertroph^ed to 30 times the size
observed In normal control dogs, with histological changes 1n C cells
(calcitonin secreting cells) and follicular cells. It was not clear wheiner
the diet contained 0.1% ETU or 1f an undisclosed volume of a 0.1% solution
was added to the diet.
5.6. OTHER RELEVANT INFORMATION
The oral LD^ for ETU was 3000 mg/kg for mice (Teramoto et al., 1980b)
and 1832 mg/kg for rats (Graham and Hansen, 1972). The dose that was lethel
to 50% of mice In 7 days (LD^ ?) after l.p. Injection of ETU was 1770
mg/kg (Salamone,'1981).
0468p	-35-	02/08/84

-------
6. AQUATIC TOXICITY
6.1.	ACUTE TOXICITY
The toxicity of ETU was examined In the creek chub, Semotllus atromaci
latus (Gllletc et al., 1952). A critical toxic range of 6000-8000 mg,
was determined. The lowest value {6000 mg/i) represents th£ concentratk
at which no test animals {n * 4/group) died during a 24-hour exposur
{24-hour LCq). The upper limit (8000 rag/a) represents the level a
which all creek chubs died within the 24-hour exposure (24-hour
The authors noted that volatilization of the test compound was possible, s
actual toxic levels may be lower than the nominal concentrations (6111ete e
al., 1952).
6.2.	CHRONIC EFFECTS
Pertinent data regarding the effects of chronic ETU exposure In aquatl
organisms were not located In the available literature.
b.3. PLANT EFFECTS
Pertinent data regarding the toxic effects of ETU on algae or aquatl<
plants were not located In the available literature.
6.4.	RESIDUE
Pertinent data regarding ETU residues In aquatic organisms were not
located In the available literature.
6.5.	OTHER RELEVANT INFORMATION
Additional Information relevant to the aquatic toxicity of ETU was not
located In the available literature.
0468p
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02/06/64

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7. EXISTING GUIDELINES AND STANDARDS
7.1.	HUMAN
A NIOSH Current Intelligence Bulletin recommended that ETU be regard'
1n the workplace as a carcinogen and as a CNS teratogen (Stein et al
1978). Based upon toxicity and carcinogenicity studies la -animals, Kc
(1974) also recommended that workers take care In handling pestiddf
containing ETU.
7.2.	AQUATIC
Guidelines and standards for the protection of aquatic organisms frc
the toxic effects of ETU were not located 1n the available literature.
0468p
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02/08/04

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8. RISK ASSESSMENT
There Is adequate evidence that ETU Is a teratogen In rats and
carcinogen 1n mice and rats. The teratogenicity of ETU was evidenced t
severe CNS abnormal Hies In rat pups at oral maternal doses as low as 20 r
ETU/kg, with no toxicity to dams (Khera, 1973; Khera and Tfyphonas, 197:
Chernoff et al., 1979; Teramoto et al., 1975a).
The carcinogenicity of ETU was demonstrated In chronic feeding studies
In mice hepatomas were Induced 1n both sexes of two strains, and there wa
Increased Incidence of lymphomas In females of one strain following l
months of maintenance on diets containing 646 ppm of E1U (BRL, 1968; Innes
et al., 1969J. In rats, the thyroid was the target organ for ETU carc®1no
genlclty, with thyroid carcinomas Induced 1n 6/52 Charles River rats fed 17
ppm and In 25/52 rats fed 350 ppm ETU for 18 months and observed for
months compared with 0/64 1n controls (Ulland et al., 1972). Similar tumo
Incidences were reported by Welsburger et al. (1981) 1n this strain of rat-
at the same dietary levels. High Incidences of thyroid adenocarcinoma1
(16/69 rats at 250 ppm; 62/70 rats at 500 ppm; 2/72 controls) were Inducec
In Charles River rats by dietary administration of ETU for 2 years (Grahan
et al., 1975).
The Cancer Assessment Group of the U.S. EPA concluded that ETU was
oncogenic 1n mice and rats (U.S. EPA, 1977) and N1QSH has recommended ihat
ETU be handled as a carcinogen and as a teratogen In the workplace (Stein et
al., 1978). IARC {1962) has concluded that evidence of ETU as a carcinogen
to animals Is sufficient, but the evidence of ETU as a carcinogen In humans
Is not adequate. In evaluating the carcinogenic risk of ETU to humans, IARC
(1982) has assigned ETU to Group 2B {"probably carcinogenic to humans").
0468p
-38-
02/08/84

-------
A carcinogenic potency factor (q^) can be derived; however, u was
difficult to decide which study, Ulland et al. (1972) or Graham et al
(1975), would give the most conservative estimate .because of the differences
In dose levels and numbers of animals studied. Using the data of Ulland et
al. (1972) that the Incidence of thyroid adenocarcinomas 1» male rats fed
ETU 1n the diet for IB months and observed for 6 additional months was 0/32,
3/26 and 17/26 for the control, the 175 ppm group and the 350 ppm group,
respectively, a q^* of 1.83xl0-1 (mg/kg/day)_1 can be derived for
humans. The corresponding dose associated with an Increased lifetime cancer
risk of 10"s Is 5.46xl0~5 mg/kg/day or 3.82*10"® mg/day for a 70 kg
man.
Using the data of Graham et al. ( 1975 ) that the Incidence of thyroid
adenocarcinomas In male and female rats fed ETU 1n the diet for 2 years was
2/72 for controls, 2/75 at 5 ppm, 1/73 at 25 ppm, 2/73 at 125 ppm, 16/69 at
250 ppm and 62/70 at 500 ppm, a q^ of 3.627x10'* (mg/kg/day)"1 can be
derived for humans. The corresponding dose associated with an Increased
lifetime cancer risk of 10"* Is 2.76xl0~4 mg/kg/day, or 1.93x10"*
mg/day for a 70 kg man. Thus, the data of Graham et al. (1975 ) give a
slightly more conservative risk level than do the data of Ulland et al.
(1972), but the values are similar.
The q^ values were calculated using the linearized multistage model
developed by Kenneth Crump and adopted by the U.S. EPA (1980). Complete
data for the derivation of the are presented 1n Appendices 8 and C.
0468p
-39-
02/08/84

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0468p
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0468p
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0468p
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Nagao, H. and Y. Takahashl. 1981. Mutagenic activity of 42 coded compounds
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Rhodes, R.C. 1977. Studies with manganese (UC)ethylenebls(dlthlocarb
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Ruddlck, J.A. and K.S. Khera. 1975. Pattern of anomalies following s 1 ngl
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APPENDIX A
literature Searched
This profile Is based on data Identified by computerized literature
searches of:
CA SEARCH (F ties 308, 309, 310, 311 , 320)
TOXLINE
HE DLI HE
RTECS
SCI SEARCH
OHM TAOS
STORE!
SRC Environmental Fate Data Bases
SANSS
AQUIRE
EPCASR
Chemical Industry Notes
Host of these searches were conducted 1n February, 1983; a few were con-
ducted March-May, 1983. In addition, hand searches were made of Chemical
Abstracts (Collective Indices 7 and 8th), and the following secondar)
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1980. TIVs: Documentation of the Threshold Limit Values. 4th ed.
(Includes Supplemental Documentation, 1981). Cincinnati, OH.
486 p.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1982. Documentation of the Threshold Limit Values for ChemUal
Substances In Work A1r. Cincinnati, OH. 94 p.
8ru1n, P., G.J. Bergen and J.J. Desta, Ed. 1980. Handling Chemi-
cals Safely. 2nd ed. Dutch Assoc. of Safety Experts, Dutch Chemi-
cal Industry Assoc., and Dutch Safety Institute, The Netherlands.
1013 p.
Claytpn, 6.0. and F.E.
Hygiene and Toxicology.
Sons, NY. 2878 p.
Clayton, G.D. and F.E.
Hygiene and Toxicology.
Sons, NY. 2879-3816 p.
Clayton, Ed.
3rd rev. ed.
Clayton, Ed.
3rd rev. ed.
Clayton, G.D. and F.E. Clayton, Ed.
Hygiene and Toxicology. 3rd rev. ed.
Sons, NY. 3617-5112 p.
1981. Patty's Industrial
Vol. 2A. John Wiley and
1981. Patty's Industrial
Vol. 2B. John Wiley and
1982. Patty's Industrial
Vol. 2C. John Wiley and
A-l

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Hamilton, A. and H.l. Hardy. 1974. Industrial Toxicology. .3rd
ed. Publishing Sciences Group, Inc., MA. 575 p.
ITI1 (International Technical Information Institute). 1982. Toxic
and Hazardous Industrial Chemicals Safety Manual for Handling and
Olsposal with Toxicity and Hazard Data. ITII. Tokyo, Japan. 700 p.
Hulr, 6.0., £d. 1977. Hazards In the Chemical Laboratory. 2nd
ed. The London Chemical Society, London. 473 p.
NTP (National Toxicology Program). 1982. Carclnogenesfs Testing
Program. Chemicals on Standard Protocol. Management Status.
Report date: December 31, 1982.
Proctor, N.H. and J. P. Hughes. 1978. Chemical Hazards of the
Workplace. J.B. llpplncott Co., Philadelphia. 533 p.
Sax, I.N. 1979. Dangerous Properties of Industrial Materials.
5th ed. Van Nostrand Relnhold Co., NY.
A-2

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APPENDIX B
Cancer Data Sheet for Derivation of
Compound: Ethylene thiourea
Reference: inland et al., 1972
Species, Strain, Sex: Rat, Charles River, male
Body Weight: 0.3S leg (assumed)
Length of Exposure (1^) = 548 days
Length of Experiment () e 730 days
Lifespan of Animal (L) » 730 days
Tumor SUe and Type: thyroid gland, adenocarcinoma
Route, Vehicle: oral, diet
Incidence
Experimental Doses Transformed Dose	No. Responding/
or Exposures {mg/kg/day)	No. Tested (or Examined)
0 0	0/32
175 ppm « 8.75 mg/kg/day 6.57	3/26
350 ppm e. 17.5 mg/kg/day 13.1	17/26
Human q^* * 1.83xl0_1 (mg/kg/day)"1
10"® risk level • 5.46x10"* mg/kg/day ¦ 3.82xl0~a	mg/day for 70 kg man
B-l

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APPENDIX C
Cancer Data Sheet for Derivation of
Compound: Ethylene thiourea
Reference: Graham et al., 1975
Species, Strain, Sex: Rat, Charles River
Body Weight: 0.6 kg (measured)
Length of Exposure (1 ) > 730 days
e
Length of Experiment (Le) « 730 days
Lifespan of Animal (L) * 730 days
Tumor Site and Type: thyroid gland, adenocarcinoma
Route, Vehicle: oral, diet
Experimental Ooses
or Exposures
Transformed Dose
(mg/kg/day)
Incidence
No. Responding/
No. Tested (or Examined)
0
0
2/72
5 ppm
0.25
2/75
25 ppm
1.25
1/73
125 ppm
6.25
2/73
250 ppm
12.50
16/69
500 ppm
25.0
62/70
Human « 3.63x10"* (mg/kg/day)"1
10"" risk level ¦ 2.75*10~* mg/kg/day « 1.93x10"* mg/day for 70 kg man
C-l

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