United States 500ECAOCING004
Environmental Protection
Agency
EPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR DICHLOROBUTENES
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
Protection
230 South Dearborn Street
DRAFT: DO NOT CITE OR QUOTE50' lllln°ls 60604^ ^
NOTICE
This document Is 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.
-------
DISCLAIMER
This report is 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.
11
-------
PREFACE
Health and Environmental Effects Documents (HEEOs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document series
Is 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 from 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 (OSWER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfDs)
for chronic and subchronic exposures for both the inhalation and oral
exposures. The subchronic or partial lifetime RfD, Is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time interval, for example, one 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 subchronic estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronic RfDs 1s the same as traditionally employed for chronic estimates,
except that subchronic data are utilized when available.
In the case of suspected carcinogens, RfOs are not estimated. A
carcinogenic potency factor, or q-|* (U.S. EPA, 1980), is provided instead.
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 toxlcity and carcino-
genlclty are derived. The RQ is used to determine the quantity of a hazar-
dous substance for which notification is required in the event of a release
as specified under the CERCLA. These two RQs (chronic toxlcity and cardno-
genlcHy) represent two of six scores developed (the remaining four reflect
1gn1tab111ty, reactivity, aquatic toxlcity, and acute mammalian toxlcity).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxlcity and cancer-based RQs are defined in U.S.
EPA, 1983a and 1986a, respectively.
111
-------
EXECUTIVE SUMMARY
Dlchlorobutenes are liquids at room temperature (Weast, 1985). When
heated to decomposition, these compounds are expected to emit toxic chlorine
fumes (Sax, 1984). These compounds are almost Insoluble 1n water but are
soluble In a variety of organic solvents {Weast, 1985). The U.S. EPA TSCA
Production File (U.S. EPA, 1977) listed one manufacturer for trans-1,4-di-
chloro-2-butene and 1,3-d1chloro-2-butene, two manufacturers for cis-l,4-di-
chloro-2-butene, three manufacturers for 1,4-d1chloro-2-butene and no manu-
facturers for 1,4-dlchloro-l-butene during 1977. As of January, 1986, SRI
(1986) listed no domestic manufacturer for the dlchlorobutenes. Current
production data on dlchlorobutene Isomers were not located 1n sources of
chemical production and sales Information. 1,4-D1chloro-2-butene, 3,4-dl-
chloro-1-butene and 1,3-d1chloro-2-butene are used as Intermediates in the
manufacture of chloroprene (IARC, 1977; 3ohnson, 1979). 1,4-01chloro-2-
butene 1s also used as an Intermediate for hexamethylenedlamlne production
(IARC, 1977).'
In the atmosphere, dlchlorobutenes are expected to exist .predominantly
In the vapor phase. Reactions with ozone and hydroxyl radicals are expected
to be the primary removal mechanisms. Estimated half-lives for reaction
with hydroxyl radicals range between 4 and 9 hours, and half-lives for
reaction with ozone range between 2 and 25 hours (U.S. EPA, 1987b). Small
amounts of these compounds may also be removed from the atmosphere by wet
deposition. In water, dlchlorobutenes are not expected to be oxidized or
photolyzed (Jaber et al., 1984), bloaccumulate in aquatic organisms or
adsorb significantly to suspended solids or sediments. The estimated
hydrolysis half-lives of dlchlorobutenes at neutral pH range from 26 days
1v
-------
for l,4-d1chloro-2-butene to 721 days for 3,4-dichloro-l-butene (Jaber et
al., 1984). Although these reactions are too slow to be environmentally
significant, dlchlorobutenes are expected to form hydrochloric acid upon
reaction with water (U.S. EPA/NIH, 1986). Based on analogy to 1,2-d1chloro-
ethylene, It has been speculated that volatilization of dlchlorobutenes
would be significant from all waters. Pertinent data regarding the
mlcroblal degradation of dlchlorobutenes were not available. In soil,
dlchlorobutenes should be moderately to highly mobile and volatilization
from soils may also be significant. Oxidation and photolysis are not
expected to be environmentally relevant.
Pertinent data regarding the exposure to dlchlorobutenes through water,
food, air and dermal contact were not located In the available literature
cited in Appendix A. Dlchlorobutenes are released to the environment
primarily from the effluents of manufacturing plants during the use of these
compounds in the manufacture of chloroprene and hexamethylened1am1ne.
Exposure to dlchlorobutenes Is likely to occur from occupational situations.
Based on the National Occupational Exposure Survey, NIOSH (1984) estimated
that 20 workers are occupationally exposed to 1,4-d1chloro-2-butene; no
estimates were provided for the other dlchlorobutene Isomers. This figure
can be questioned because higher numbers of exposed individuals were shown
in a mortality study (E.I. DuPont de Nemours and Co., 1985a,b).
Little Information was available concerning toxldty of dlchlorobutenes
to aquatic organisms. Gelger et al. (1985) reported a 96-hour LC5Q of
9.33 mg/8. 3,4-dichloro-l-butene for fathead minnows, Plmephales promelas.
Konemann (1981) reported a 7-day LC_0 of 39.5 mg/l 1,4-d1chloro-2-butene
for gupples, Poecilia reticulata. Applegate et al. (1957) found that 5
mg/l of 1,4-d1chloro-2-butene or 3,4-d1chloro-2-butene was not lethal to
-------
rainbow trout, Sal mo qalrdneM. bluegllls, Lepomls macrochlrus. or sea
lampreys, Petromyzon marlnus. exposed for 24 hours. There were no data
concerning Invertebrates, marine organisms or aquatic plants.
Pertinent data regarding the pharmacoklnetlcs of the various Isomers of
dlchlorobutene are very limited. According to E.I. DuPont de Nemours and
Co. (1985a), l,4-d1chloro-2-butene liquid and vapors penetrate human skin
and hydrolyze to hydrochloric add, which produces severe tissue damage.
Van Duuren et al. (1975) suggested that trans-1,4-d1chloro-2-butene may
be metabolized to an epoxlde Intermediate, which 1s analogous In structure
to open-chain B-chloro ethers.
Effects of subchronlc exposure to some Isomers of dlchlorobutene were
reported 1n studies from the Russian literature; however, adequate experi-
mental protocols and details were not reported. Decreased spermatogenesls
(Bal'yan et al., 1983a) and Increased urinary chloride and creatlnlne
excretion (Petrosyan et al., 1983) were reported when 1,4-d1chloro-2-butene
was administered to rats by Inhalation and IntragastMc doses for up to 6
months. Effects on the central nervous system, liver, lungs, kidney
(Petrosyan and Glzhlaryan, 1982a) and nitrogen metabolism (Erzhkalsyan,
1985) were reported In rats caused by Inhalation and Intragastrlc doses of
3,4-d1chloro-l-butene. Central nervous system effects were observed In rats
after Inhalation exposure for 30 days to 1,4-dlchloro-l-butene (Petrosyan
and Glzhlaryan, 1982b). Inhalation exposure of rats to 1,3-d1chloro-2-
butene resulted In degenerative changes In the liver, changes 1n the liver
alkaline phosphatase activity and changes 1n the metabolism of glycogen and
fat (Vartazaryan and Mezhlumyan, 1974).
Rats exposed by Inhalation to 1,4-d1chloro-2-butene at 0.5, 1.0 or 5.0
ppm (2.6, 5.1 or 25.6 mg/m3), 6 hours/day, 5 days/week for 90 days had
squamous flattening of the trachea! epithelium {E.I. DuPont de Nemours and
v1
-------
Co., 1985a, 1986). At 5.0 ppm, there was hypertrophy and atrophy of the
nasal epithelium. Long-term exposure of the rats to 0.1-1.0 ppm (E.I.
DuPont de Nemours and Co., 1985a) and 0.5-5.0 ppm (E.I. DuPont de Nemours
and Co., 1986), 6 hours/day, 5 days/week resulted 1n statistically signifi-
cant dose-related Increased Incidences of benign and malignant nasal cavity
tumors. Hyperplasla and metaplasia of respiratory tissue were also
observed. Increased mortality was secondary to the carcinogenic effect.
trans-1,4-D1chloro-2-butene produced no carcinogenic response when
administered in a chronic skin painting study or in a two-stage promotion/
Initiation skin painting study (Van Duuren et al., 1975). The compound was
found to elicit low but statistically significant incidences of local
sarcomas when Injected 1n mice either subcutaneously or 1ntraper1toneally
once weekly over their lifetime (Van Duuren et al., 1975).
An epidemiology study was conducted using 598 workers of DuPont exposed
to.l,4-d1chloro-2-butene at the Victoria Plant In order to determine cancer
Incidences (1956-1983) and mortality (1957-1980). E.I. DuPont de Nemours
and Co. (1985a) concluded that employees were not at an increased risk of
developing cancer. This conclusion 1s questionable, since a significant
Increase In pancreatic cancer was shown. The evidence is deemed inadequate,
although suggestive.
1,4-D1chloro-2-butene was mutagenlc in S>. typhimurium (Bartsch et al.,
1976, 1980; Barbln et al., 1978), £.. coll (Mukal and Hawryluk, 1973) and D.
melanogaster (Vogel, 1979; Lee et al., 1983). 3,4-D1chloro-l-butene was
mutagenlc In S. typhimurium (Bartsch et al., 1976, 1980;'Barbln et al.,
1978) and increased the frequency of sister chromatld exchanges 1n human
lymphocytes 1n vitro (Gu, 1981). Exposure of pregnant Charles River CD rats
to l,4-d1chloro-2-butene vapors during pregnancy was neither embryotoxlc nor
-------
teratogenic to the fetuses. The only Indication of maternal toxldty was a
significantly reduced rate of weight gain 1n the dams at the high dose level
(Kennedy et al.. 1982).
The weight of evidence of Increased Incidences of nasal tumors 1n both
sexes of rats using relevant routes of exposure In two adequate studies and
several exposure levels was considered sufficient to classify 1,4-d1chloro-
2-butene as an EPA Group B2 chemical; that Is, a probable human carcinogen
(U.S. EPA, 1986b). Data for the cardnogenlcHy of other dlchlorobutene
Isomers were lacking; therefore, these Isomers were classified In EPA
Group 0.
A q * of 9.3 (mg/kg/day)"1 for Inhalation exposure was derived for
1,4-d1chloro-2-butene based on the data for nasal tumors 1n male rats used
1n the E.I. Du Pont de Nemours and Co. (1986) report. The concentrations In
air associated with Increased lifetime risk of cancer at risk levels of
10"5, 10~« and 10~7 are 4xlO~*, 4xlO~7 and 4xlO"8 mg/m3,
respectively. A q * for oral exposure was not derived and was not
extrapolated from the Inhalation data because of the limited Information and
the particular circumstances Involved 1n the previously cited report. An F
factor of 63 (mg/kg/day)"1 was calculated, which places
1,4-d1chloro-2-butene 1n Potency Group 2. An EPA Group 82 and Potency Group
2 chemical has a MEDIUM hazard ranking under CERCLA; therefore, the RQ based
on cardnogenlclty Is 10.
Data were considered Inadequate or Inappropriate for deriving RfDs or
RQs based on chronic toxldty for any of the dlchlorobutene Isomers.
-------
TABLE OF CONTENTS
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS REGISTRY NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 1
1.4. USE DATA 1 5
1.5. SUMMARY 5
2. ENVIRONMENTAL FATE AND TRANSPORT 6
2.1. AIR 6
2.1.1. Reaction with Hydroxyl Radicals 6
2.1.2. Reaction with Ozone 6
2.1.3. Physical Removal Processes 7
2.2. WATER 7
2.2.1. Hydrolysis 7
2.2.2. Oxidation 7
2.2.3. Photolysis 7
2.2.4. Adsorption 7
2.2.5. Bloaccumulatlon 7
2.2.6. Volatilization 8
2.3. SOIL 8
2.3.1. Chemical Degradation 8
2.3.2. Leaching 8
2.3.3. Volatilization 8
2.4. SUMMARY 9
3. EXPOSURE 10
4. AQUATIC TOXICITY 11
4.1. ACUTE TOXICITY 11
4.2. CHRONIC EFFECTS. 11
4.3. PLANT EFFECTS 11
4.4. SUMMARY 11
5. PHARMACOKINETCS . 12
1x
-------
TABLE OF CONTENTS (cont.)
6.
8.
EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposures. .
6.1.2. Oral Exposures
6.1.3. Other Relevant Information
6.2. CARCINOGENICITY
6.2.1. Inhalation
6.2.2. Oral
6.2.3. Other Relevant Information
6.3. MUTAGENICITY
6.4. TERATOGENICITY
6.5. OTHER REPRODUCTIVE EFFECTS
6.6. SUMMARY
EXISTING GUIDCLINES AND STANDARDS
7.1. HUMAN
7.2. AQUATIC
RISK ASSESSMENT -. . .
8.1. CARCINOGENICITY
8.1.1. Inhalation
8.1.2. Oral
8.1.3. Other Routes
8.1.4. Weight of Evidence
8.1.5. Quantitative Risk Estimates
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure
8.2.2. Oral Exposure
REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
9.2. BASED ON CARCINOGENICl 1 Y
REFERENCES
IDIX A: LTMKA1URC SEARCHED
IOIX B: CANCER DATA SHEEIS FOR DERIVATION OF q-|*s. ......
IDIX C: SUMMARY TABLE FOR 1,4-DICHLORO 2-BUTENE
Page
. . 13
. . 13
. . 13
. . 18
. . 19
. . 21
. . 21
. . 25
, , 25
. . 26
. . 31
. . 33
. . 34
. . 37
. . 37
, . 37
. . 38
. . 38
. . 38
. . 38
. . 39
. . 39
40
, . 43
. . 43
. . 44
, . 45
. . 45
. . 48
, , 51
. . 62
. . 65
. . 68
-------
LIST OF TABLES
No. Title Page
1-1 Structure, Synomyns and CAS Registry Numbers For Selected
Dichlorobutenes 2
1-2 Physical Properties of Selected Dichlorobutenes 3
1-3 1977 Production Data for Dichlorobutene Isomers 4
6-1 Incidence of Nasal Tumors in Charles River CD Rats Exposed
by Inhalation to 1,4 -Oichloro 2 -Butene in a 2-Year Study. . . 23
6-2 Incidence of Nasal Tumors in Male Charles River CD Rats
Exposed by Inhalation to 1,4-Dichloro 2-Butcne for 19
Months Followed by 5 Months Observation 24
6-3 Results of Epidemiology Study of 1,4-Dichloro 2 hutcne
at Victoria Plant: Observed and Expected Deaths 1957-1900
in Male Cohort, No Latency (Selected. Causes) 27
6 4 Results of Epidemiology Study of 1,4-Dichloro 2-butene at
Victoria Plant: Observed and Expected Cancer 1956-1983 in
Male Cohort, No Latency (All Cancer and Selected Sites) ... 28
6-5 Results of Epidemiology Study of 1,4 -Dichloro-2-butene
at Victory Plant: Observed and Expected Events in Male
Wage Roll Cohort; 15-Year Latency (All Cancer and
Selected Sites) . 29
6-6 Mutagenicity Testing of 1,4-Dichloro-2-butene and
3,4-D1chloro-l-butene 30
9-1 Dichlorobutene: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 46
9-2 Derivation of Potency Factor (F Factor) for
1,4-Dichloro-2-butene 49
x1
-------
LIST OF ABBREVIATIONS
BCF B1oconcentrat1on factor
CAS Chemical Abstract Service
DNA Deoxyrlbonuclelc add
Koc Soil sorptlon coefficient
Kow Octanol/water partition coefficient
LC5Q Concentration lethal to 50% of recipients
1050 Dose lethal to 50% of recipients
MED Minimum effective dose
ppm Parts per million
RNA Rlbonuclelc acid
RQ Reportable quantity
RV(j Dose-rating value
RVe Effect-rating value
TWA Time-weighted average
-------
1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
The structure, synonyms and CAS Registry numbers for selected dlchloro-
butenes are provided 1n Table 1-1. All of the dlchlorobutene Isomers have a
molecular weight of 125.00 and the empirical formula C.H,C12.
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Dlchlorobutenes are liquids at room temperature. 1,4-D1chloro-2-butene
1s colorless and 1,3-d1chloro-2-butene Is clear to straw-colored (Hawley,
1981). Dlchlorobutenes are soluble In alcohol, ether, acetone and benzene
(Weast, 1985). When heated to decomposition dlchlorobutenes are expected to
emit toxic chlorine fumes (Sax, 1984). Selected physical properties are
listed 1n Table 1-2.
1.3. PRODUCTION DATA
Table 1-3 lists 1977 production data for the dlchlorobutene Isomers from
the U.S. EPA TSCA Production File (U.S. EPA,. 1977); no production data were
available for l,4-d1chloro-l-butene. E.I. . Dupont 1n Victoria, TX, was
listed as the only domestic manufacturer of 1,4-d1chloro-2-butene as of
January, 1985 (SRI, 1985) and E.I. Dupont In Victoria, TX, and Trinity Chem.
Corp. In San Antonio, TX, were listed as the only domestic manufacturers of
this compound in 1984 (SRI, 1984). SRI (1986) contained no Information on
this compound. Recent production data for the other dlchlorobutene isomers
could not be located 1n the available literature, which Indicated that these
compounds have little commercial significance In the United States.
1,4-D1chloro-2-butene and 3,4-d1chloro-2-butene are manufactured by the
vapor phase chlorination of butadiene at elevated temperatures (Kirshenbaum,
1978; Johnson, 1979; Smiley, 1981). 1,4-D1chloro-2-butene contains 95-98%
trans-1somer and 2-5% ds-lsomer (IARC, 1977). Methods for manufacturing
0031d -1- 06/09/87
-------
_
1
LU
1
^^
CO
<
|M»
I/I
1
^^
3
.O
O
k»
0
JC
U
«f"B
a
o
4->
jj
O>
0)
oo
i_
o
u
O)
^
g
3
2£ i
^
L.
4->
. I/I
*K
' o*
o
Q£
co
«c
(J
^
c
t>
I/I
£
C
0
>>
I/I
o
l_
3
4"*
U
3
L.
-U
OO
a>
t_
3
U
3
1_
4>J
OO
>»
u
4->
i/i &.
3;
ijj £
Q£ 3
^j
oo
5
i/i
£
C
0
C
^^
OO
r
eg
u
*
£
^-
u
0
CM
Z
U\ /
f ^
II
f ^
/ \
r^ *f
U
CM
^p*
^b>
<_>
Ul
1
,
r«>
1
^O
r~
^~
i
a>
c
0)
*J
3
1
CM
O
i_
o
.c
u
o
1
*
»
p
1
^ «
fvl
qj
c
-(-1
^3
/^)
1
CM
1
O
1_
o
^
' U
1
^*
»
fi-B
1
v>
»^"
u
o
CM
X
^x xJ
^ ^
II
^J
^x \
a:
^J
Og
^«
Mhk
<_;
^
I
f
y^
1
O
^»
^M
a>
c
3>
H->
3
1
CM
O
!_
O
. n
J=
u
a
i
^
»
r
1
^-*
uu
-*->
^3
1
CM
1
0
L.
O
p
.c
u
o
i
^^
r-*
1
Wl
C
^
H->
1
CM
5
u
ii
^c
fBJ
1
CM
^^
f, ^
1
U
a
i
)^
^~
i
^
iff
r~
03
^J
d
Qj »
0 0)
1- >
^- 41
U 3
«- .a
o o
t.
Q^ O
C f
CD f
r U
^^ M"*
4-> "O
3 I
wrf ^^
1
CM r
1
l/l
C
CD
c -o
CD C
W
1 X
^*- «
£
3;
f , ^
1 1
C«^-^J
11
32
0
1
CM
3^
f ^
1
"
00
1
r-
U1
i
±Q
CM
C7I
O£
z.
V
c
3j
4BJ
3
^3
1
CM
1
O
(_
O
J=
u
*^
o
1
CO
<-?
1
CM
<_)
1
CM
^C
1
32
^ ^
II
31
f ^
1
"
«*
i
CM
cn
1
co
CM
^-
r
co
Q£
^
CD
C
G^
4^
3
^5
1
f
1
O
t_
O
f
u
4
o
1
^>
r-~
CM
3: i
C ^< 3
1
31 p"
!_><_)
1
s
f ^
II
CM
^«*
^
U
tg
1
eo
CM
1
o
t^
p^.
CD
C
J>
1
eo
i
0
^
o
p^
£
o
n~
o
1
CM
»
~
0)
c '
0)
4->
3
^3
1
^~
1
O
^
O
x:
u
4~
C3.
1
*
eo*
"^
CD
4->
i_
O
a.
CD
l_
4-1
o
IZ
II
(%*
b^^
0031 d
-2-
05/20/87
-------
VI
C
01
*J
o
o
.c
u
a
to
CNl "u
1 1)
01
uu cv)
^
09 u.
^r rt
5
0}
01
£
"«
U
^
^
a.
0
o o
r C
U -w
SI
1 1
^ fftf
CO
)
o
0 01
r- C
J= 0)
U «-»
^"" 3
a .a
i i
c
01
3
.0
CM
O
0
I
u
C3
t
^_-
Ol
£ 'x"
If
1 VI
(M C
0 U
l_ .«*
O
S. C
U (Q
a i
r vi
,-"
i
o
0 01 -~
i C 1
^Z O) VI
U ' C
o .a i.
«« CM »
"
1
O
a to
"~ c T
U «* l/l
3 «-
a a o
»
1
CO
1
u
o
*IW
^4
c
I
Ol
e
Ol
u
3^
i
Q
<
z
«e
z
u
CT
i
u
Ol
z
i
m
in
CM
f^f
u
3
VI
vt
01
Q.
1
o
O
in
o
en
r>
3
CO
m
o
r*
in
CO
in
CO
^y
r*
in
CO
en
^t
^^
1^ O
«* *r»
A CM
3
VI
U !
||
n-
u
r
CM
01
CO
CM
a
*
s
V
uB
i^
a
o
-j
C3
CM
o
«
z
J3
sO
^
CO
09
1
in
09
«
in
00
oo
pH
^^
*»
^
o>
u
Ik.
U
01
n.
0 0
CM CM
m r
r- f
* -a
GO
^ r CM
^C ^C
z z
n
o
CM
CM
on
~o
~ . ' «
o
oo
on
i in
13
in
CM
r*
CO
«r a
' CO
i in
e
- o
a.
u
"S <**
iv VI
"S 5
CC u.
I
o
i
c
VI
W5
01
O)
"§
^;
CM
00
en
^
*
01
c
I
-_-
o
<3
i
^
o»
a
CM
. on
m
09 O
en i
II
3 C/)
f Ol
CD e
^
S c"
o
O) ra
41 3
z o-
at
0 01
JC
o
-w C
Ol O
»*
E
^ >» o
oo a k
m an u-
00 -0
en oi-o
^- »J Ol
- $ i i
VI U u *^
<0 -0 i *^
Ol ^ ig v>
3 < O uj
IO -Q U -O
Ph
ao
en
~
S
LU
«/)
3
^^
*O
a>
«^
UJ
0)
^3
iq
^_
<«
Z
<
0031 d
-3-
05/20/87
-------
TABLE 1-3
1977 Production Data for Dlchlorobutene Isomers*
Isomer
Company/Location
Import/Production Volume
(million pounds)
c1s-l,4-D1chloro-
2-butene
trans-1,4-D1chloro-
2-butene
l,4-D1chloro-
2-butene
(mixed Isomers)
l,3-D1chloro-
2-butene
3,4-D1chloro-
1-butene
E.I. Oupont
La Place, LA
Columbia Organic Chemicals
Columbia, SC
E.I. Dupont
La Place, LA
Denka Chem. Corp.
Houston, TX
Columbia Organic Chemicals
Columbia, SC
E.I. Dupont
Victoria, TX
E.I. Dupont
Louisville, KY
Denka Chemical Corp.
Houston, TX
E.I. Dupont
La Place, LA
E.I. Dupont
Victoria, TX
100-500
<0.001
100-500
10-50 (site limited use)
0.010-0.100
<0.001
confidential
1.00-10.00
10-50 (site United use)
100-500 (site limited use)
confidential
*Source: U.S. EPA, T977
0031 d
-4-
05/20/87
-------
other dlchlorobutenes could not be located 1n the available literature as
dted In Appendix A.
1.4. USE DATA
1,4-D1chloro-2-butene 1s used as an Intermediate In the manufacture of
hexamethylened1am1ne and chloroprene (IARC, 1977). 3,4-01chloro-2-butene
and 1,3-d1chloro-2-butene are also used as Intermediates for chloroprene
{Johnson, 1979). Uses for 1,4-d1chloro-l-butene could not be located in the
available literature as dted In Appendix A. There has been research on the
use of 1,4-d1chloro-2-butene as an intermediate In the preparation of
polymeric quaternary ammonium compounds, which may be used as bacterlcldes
~~a~nd fungicides (Luloff and Ellender, 1975; Green et al.f 1975; Stockel and
Jelling, 1985).
1.5. SUMMARY
Dlchlorobutenes are liquids at room temperature (Weast, 1985). When
heated to decomposition, these compounds are expected to emit toxic chlorine
fumes (Sax, 1984). These compounds are almost Insoluble In water but are
soluble In a variety of organic solvents (Weast, 1985). The U.S. EPA TSCA
Production File (U.S. EPA, 1977) listed one manufacturer for trans-1,4-d1-
chloro-2-butene and 1,3-d1chloro-2-butene, two manufacturers for cis-l,4-d1-
chloro-2-butene, three manufacturers for 1,4-d1chloro-2-butene and no
manufacturers for 1,4-d1chloro-l-butene during 1977. As of January, 1986,
SRI (1986) listed no domestic manufacturer for the dlchlorobutenes. Current
production data on dlchlorobutene Isomers were not located In sources of
chemical production and sales Information. 1,4-01chloro-2-butene, 3,4-dl-
chloro-1-butene and 1,3-d1chloro-2-butene are used as intermediates in the
manufacture of chloroprene (IARC, 1977; Johnson, 1979). 1,4-D1ch1oro-2-
butene 1s also used as an Intermediate for hexamethylenedlamlne production
(IARC, 1977).
0031d -5- 06/09/87
-------
2. ENVIRONMENTAL FATE AND TRANSPORT
Limited data concerning the environmental fate and transport processes
of dlchlorobutenes could be located 1n the available literature as cited 1n
Appendix A. Information concerning the fate and transport of these com-
pounds was derived from physical property data or molecular structures.
2.1. AIR
2.1.1. Reaction with Hydroxyl Radicals. Based on the relatively high
vapor pressures of the dlchlorobutene Isomers, these compounds are expected
to exist primarily 1n the vapor phase In the atmosphere (E1senre1ch et al.,
1981). The estimated half-lives for 1,4-d1chloro-2-butene, 1,3-d1chloro-2-
butene, 1,4-d1chloro-l-butene and 3,4-d1chloro-l-butene vapor reacting with
photochemlcally generated hydroxyl radicals In the atmosphere are 4, 5, 12
and 9 hours, respectively, using an ambient hydroxyl radical concentration
of. 8xlOs molecule/cm3 and respective 'rate constants of 6.55X10"11,
4.58xlO~", 1.97X10'11 and 2.83X10'11 cmVmolecule-sec at 25°C (U.S.
EPA, 1987b). These half-lives suggest that significant amounts of dlchloro-
butenes would be removed from the atmosphere by reaction with hydroxyl
radicals.
2.1.2. Reaction with Ozone. The estimated half-lives for 1,4-d1chloro-2-
butene, 1,3-d1chloro-2-butene, 1,4-d1chloro-l-butene and 3,4-d1chloro-l-
butene vapor reacting with ozone 1n the atmosphere are 2, 2, 25 and .25
hours, respectively, using an ambient ozone concentration of 6.0xl012
molecules/cm3 and respective rate constants of 2.0xlO~ls, 2.0xlO~16,
1.3xlO"17 and l.SxlO'*7 cm3/molecule-sec at 25°C (U.S. EPA, 1987b-).
These half-lives suggest that significant amounts of dlchlorobutenes would
be removed from the atmosphere by reaction with ozone.
OOSld -6- 05/20/87
-------
2.1.3. Physical Removal Processes. Removal from the atmosphere by dry
deposition should not be environmentally Important since these compounds
should exist predominantly 1n the vapor phase (see Section 2.1.1.). Given
the estimated solubilities listed In Table 1-2, It appears that these
compounds may be removed from the atmosphere by wet deposition; however,
chemical reaction with hydroxyl radicals and ozone would limit the signifi-
cance of wet deposition as an atmospheric removal process.
2.2. WATER
2.2.1. Hydrolysis. The calculated hydrolysis half-lives of 1,4-dlchloro-
2-butene, 1,4-d1chloro-l-butene and 3,4-d1chloro-l-butene at neutral pH are
72, 26 and 721* days, respectively, based on reaction rate constants of
4xlO~4, 8xlO~4 and 4xlO~5 hours"1, respectively {Jaber et al.,
1984). Upon reaction with water, dlchlorobutenes are expected to. form
hydrochloric add (U.S. EPA/NIH, 1986).
2.2.2. Oxidation. Dlchlorobutenes are not expected to be oxidized by
photochemlcally generated hydroxyl radicals, singlet oxygen and alkyl peroxy
radicals 1n water (Jaber et al., 1984).
2.2.3. Photolysis. Photolysis of dlchlorobutenes 1s not expected to be
environmentally relevant (Jaber et al., 1984).
2.2.4. Adsorption. Given the estimated K values of 94-343 for
dlchlorobutene Isomers (Section 2.3.2.), physical adsorption of these
compounds to suspended solids and sediments In water Is not expected to be
significant.
2.2.5. B1oaccumulat1on. Given the estimated log K values In Table
ow
1-2, BCFs of 11, 3, 3 and 19 were estimated using the equation, log BCF =
0.76.log KQW - 0.23 (Lyman et al., 1982). These BCF values suggest that
bloaccumulatlon In aquatic organisms would be Insignificant.
0031d -7- 06/09/87
-------
2.2.6. Volatilization. Henry's Law constants for ds- and trans-1,2-di-
chloroethylene are 3.3xlO~3 and 6.6xlO~3 atm-mVmol, respectively, at
25°C (H1ne and Mookerjee, 1975). Henry's Law constants for the dlchloro-
butenes are expected to be on the same order of magnitude because of the
s1m1l1ar1t1es In the molecular structure of 1,2-d1chloroethylenes and
dlchlorobutenes. Based on these values, volatilization from water Is
predicted to be significant (Lyman et al., 1982).
2.3. SOIL
2.3.1. Chemical Degradation. The significance of hydrolysis for the
dlchlorobutenes 1n soils cannot be predicted from the Information available
In the'literature or hydrolysis data In aquatic media (see Section 2.2.1.).
Dlchlorobutenes are not expected to be oxidized 1n soil or photolyzed on
soil surfaces since these reaction are not environmentally important in
water (see Sections 2.2.2. and 2.2.3.).
2.3.2. Leaching. The estimated K values of 1,4-d1chloro-2-butene,
1,3-d1chloro-2-butene, 1,4-d1chloro-l-butene and 3,4-d1chloro-l-butene were
-112, 94, 112 and 94, respectively, using the quantitative 'structure-
activity method of Sabljic (1984). K values were 198, 343, 343 arid 181,
respectively, using log K values listed in Table 1-2 and the equation,
log KQC = 0.544 log KQW + 1.377 (Lyman et al., 1982). Based on these
K values, dlchlorobutenes are expected to be moderately to highly mobile
in soil (Swann et al., 1983).
2.3.3. Volatilization. The relatively high vapor pressures of the
dlchlorobutenes (4-20 mm Hg at 25°C, see Table 1-2), Indicate that volatili-
zation of these compounds from dry soil surfaces may be significant.
Evaporation from moist soils may also be significant since these compounds
are not expected to adsorb strongly to soil and are predicted to volatilize
rapidly from water and soil (see Sections 2.3.2. and 2.2.6.).
0031d -8- 06/09/87
-------
2.4. SUMMARY
In the atmosphere, dlchlorobutenes are expected to exist predominantly
In the vapor phase. Reactions with ozone and hydroxyl radicals are expected
to be the primary removal meachanlsms. Estimated half-lives for reaction
with hydroxyl radicals range between 4 and 9 hours and half-lives for
reaction with ozone range between 2 and 25 hours (U.S. EPA, 1987b). Small
amounts of these compounds may also be removed from the atmosphere by wet
deposition. In water, dichlochlorobutenes are not expected to be oxidized
or photolyzed (Jaber et al., 1984), bloaccumulate In aquatic organisms or
adsorb significantly to suspended solids or sediments. The estimated
hydrolysis half-lives of dichlorobutenes at neutral pH range from 26 days
for 1,4-dichloro-2-butene to 721 days for 3,4-dichloro-l-butene (Jaber et
al., 1984). Although these reactions are too slow to be environmentally
significant, dlchlorobutenes are expected to form hydrochloric acid upon
reaction with water (U.S. EPA/NIH, 1987). Based on .analogy to 1,2-dichloro-
ethylene, 1t has been speculated that volatilization of dichlorobqtenes
would be significant from all waters. Pertinent data regarding the
mlcroblal degradation of dlchlorobutenes were not available. In soil,
dlchlorobutenes should be moderately to highly mobile and volatilization
from soils may also be significant. Oxidation and photolysis are not
expected to be environmentally relevant. No pertinent data on the microbial
degradation of dlchlorobutenes in soil were available.
0031d -9- 05/20/87
-------
3. EXPOSURE
Pertinent data regarding the exposure to dlchlorobutenes through water,
food, air and dermal contact could not be located 1n the available litera-
ture as cited In Appendix A. Dlchlorobutenes are released to the environ-
ment primarily from the effluents of manufacturing plants during the use of
these compounds 1n the manufacture of chloroprene and hexamethylenedlamlne.
Exposure to dlchlorobutenes 1s likely to occur from occupational situations.
Based on the National Occupational Exposure Survey, NIOSH (1984) estimated
that 20 workers are occupatlonally exposed to 1,4-d1chloro-2-butene; no
estimates were provided for the other dlchlorobutene Isomers. However, E.I.
DuPont de Nemours (1985a,b) conducted an epidemiology study that used 598
workers exposed to 1,4-d1chloro-2-butene. Therefore, the NIOSH estimate was
probably lower than actual occupational exposure.
0031d -10- 06/09/87
-------
4. AQUATIC TOXICITY
4.1. ACUTE TOXICITY
LUtle Information Is available concerning toxldty of dlchlorobutenes
to aquatic organisms. Gelger et al. (1985) reported a 96-hour LC5Q of
9.33 mq/l 3,4-d1chloro-l-butene for fathead minnows, Plmephales promelas.
Konemann (1981) reported a 7-day LC5Q of 39.5 mg/a. 1,4-d1chloro-2-butene
for gupples, Poedlla retlculata. Applegate et al. (1957) found that 5
mg/a, of 1,4-d1chloro-2-butene or 3,4-d1chloro-2-butene was not lethal to
rainbow trout (Salmo qalrdnerl). bluegllls (Lepomls macrochirus) or sea
lampreys (Petromyzon marlnus) exposed for 24 hours.
4.2. CHRONIC EFFECTS
Pertinent data regarding chronic toxldty of dlchlorobutenes to aquatic
organisms could not be located 1n the available literature as cited In
Appendix A.
4.3. PLANT EFFECTS
Pertinent data regarding effects of dlchlorobutenes on aquatic plants
could not be located In the available literature as cited 1n Appendix A.
4.4. SUMMARY
Little Information was available concerning toxldty of dlchlorobutenes
to aquatic organisms. Gelger et al. (1985) reported a 96-hour LC-_ of
9.33 mg/a. 3,4-d1chloro-l-butene for fathead minnows, Plmephales promelas.
Konemann (1981) reported a 7-day LC of 39.5 mg/8. 1,4-d1chloro-2-butene
for gupples, Poec111a retlculata. Applegate et al. (1957) found that 5
mg/8. of 1,4-d1chloro-2-butene or 3,4-d1chloro-2-butene was not lethal to
rainbow trout, Salmo qalrdnerl. bluegllls, Lepomls macrochirus. or sea
lampreys, Petromyzon marlnus. exposed for 24 hours. There were no data
concerning Invertebrates, marine organisms or aquatic plants.
0031d -11- 06/09/87
-------
5. PHARMACOKINETICS
Pertinent data regarding the pharmacoklnetlcs of the various Isomers of
dlchlorobutene are very limited. According to E.I. DuPont de Nemours and
Co. (1985a), l,4-d1chloro-2-butene liquid and vapors penetrate, human skin
and hydrolyze to hydrochloric add, which produces severe tissue damage.
Van Duuren et al. (1975) suggested that trans-1,4-d1ch1oro-2-butene may
be metabolized to an epoxlde Intermediate, which Is analogous In structure
to open-chain 8-chloro ethers.
0031d -12- 06/09/87
-------
6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposures.
6.1.1.1. SUBCHRONIC In a 2-year study using Charles River CD rats
(Section 6.1.1.2.}, a 90-day Interim sacrifice of 10 rats/sex/group exposed
by Inhalation to 1,4-d1chloro-2-butene at 0, 0.5 or 5.0 ppm (0, 2.6 or 25.6
mg/m3), 6 hours/day, 5 days/week revealed hypertrophy and atrophy of nasal
olfactory epithelial cells 1n 5.0 ppm males and females (E.I. DuPont de
Nemours and Co., 1986). Cuboldal to squamous flattening of the tracheal
epithelium occurred in 3/10 females at 0.5 ppm and all rats at 5.0 ppm.
When sacrificed, 5.0 ppm males and females.had nasal carcinomas and tracheal
epithelial metaplasia.
In another long-term study (Section 6.1.1.2.), Charles River CD rats
were exposed to 1,4-d1chloro-2-butene at 0, 0.1, 0.3 or 1.0 ppm (0, 0.5, 1.5
or 5.1 mg/m3), 6 hours/day, 5 days/week (E.I. DuPont de Nemours and Co.,
1985a). Interim sacrifices were performed as follows: groups of 10 control
rats at 3 and 12 months; groups of 10 rats at 1.0 ppm at 3, 6, 9, 10, 11 and
12 months; and groups of 10 rats at 0.1 and 0.3 ppm at 12 months. At 3
months, 1.0 ppm rats had focal mucosal atrophy of the nasal mucosal epithe-
lial cells and basal cell squamous hyperplasla. These lesions were not seen
In controls. At subsequent kills of 1.0 ppm rats, nasal lesions became more
pronounced; a benign tumor first appeared at 10 months. At 12 months, nasal
lesions occurred In 0/10 controls, 1/10 rats at 0.1 ppm, 1/10 rats at 0.3
ppm and 7/10 rats at 1.0 ppm. There were no statistically significant
differences In body weights or 1n absolute or relative organ weights In
treated rats compared with controls.
0031d -13- 06/09/87
-------
Kidney function was evaluated 1n groups of -15 male and female white
rats exposed by Inhalation for 4 months to 1,4-d1chloro-2-butene at concen-
trations of 8.7, 1.77 or 0 mg/m3 or 3,4-d1chloro-l-butene at concentra-
tions of 203.4, 126.2, 14.5 or 0 mg/m3 (Petrosyan et al., 1983). The
exposure schedule was not stated. Renal function was monitored by measure-
ment of dally diuresis, specific gravity of urine and blood serum and
urinary concentrations of creatlnlne and chlorides. The rats were killed
after 4 months and kidneys were examined hlstologlcally and hlstochemlcally.
No significant changes 1n renal function were observed at any concentration
of 3,4-d1chloro-l-butene. At 8.7 and 1.77 mg/m3 1,4-d1chloro-2-butene,
significant Increases In urinary chlorides and creatlnlne were observed com-
pared with control rats, Indicating some loss of renal filtration function.
Unspecified numbers of male and female white rats were exposed by
Inhalation to 203.4, 126.2, 14.5 or 0 mg/m3 of 3,4-d1chloro-l-butene, 4
hours/day for 4 months .{Petrosyan and Glzhlaryan, 1982a). Hlstological
examinations were performed on cerebral cortex, cerebellum, . heart, lungs,
liver, kidneys, spleen, stomach, adrenals and testes. Bronchopneumonla was
reported at the highest concentration. Granular degeneration and necro-
blosls of the hepatocytes 1n the central lobule of the Hver was observed.
Dystrophy and necrosis were observed 1n the lungs and kidneys, and DNA and
RNA were decreased in the neurons in the brain. Morphological alterations
were also observed in brain neurons. These effects were observed at 203.4
mg/m3 and, to a lesser extent, at 126.2 mg/m3; no structural alterations
were observed at 14.5 mg/m3.
Petrosyan and Glzhlaryan (1982b) studied the central nervous system
response In white rats exposed by Inhalation to 1,4-d1chloro-2-butene at
levels of 21.2, 8.7, 1.77 and 0 mg/m3 for 4 hours/day for 30 days.
0031d " -14- 05/20/87
-------
The effects Included neuron dystrophy and necrosis, and proliferation of
lymphoid cells around the capillaries of the cortex and pla mater. The
authors stated that these effects were concentration-related, but specific
details were not clearly reported.
Vartazaryan and Mezhlumyan (1974) evaluated alterations In the livers of
12 rabbits exposed for 3 months and 76 white rats exposed for 5 months to
l,3-dichioro-2-butene at levels of 0, 0.1 or 0.2 mg/l, 6 days/week for 4
hours/day. Results In rabbits were not reported. At 0.2 mg/t, degenera-
tive and necrobiotlc changes were observed in the liver parenchymatous cells
In rats. Hemodynamlc changes, such as hemorrhages and "plasmorrhagla" were
also reported. In addition, changes were observed In the metabolism of
glycogen and fat, and decreases In the liver alkaline phosphatase activity.
It was stated that "characteristic changes only appeared In the second month
1n the livers of the rats exposed to the 0.1 mg/s. concentration."
Gasparyan and Barsegyan (197Q) reported necroblotlc changes In the
-myocardium, liver, kidney and spleen, gllal proliferation In the brain and
pulmonary Ischemia In rats and rabbits exposed to 0.1 mg/s. of l,3-d1-
chloro-2-butene, 6 hours/day for 4.5-5.5 months. None of these effects were
reported In rats exposed on the same schedule to the compound at 0.01
mg/a. Specific experimental detail was not provided.
Pertinent data regarding the subchronlc Inhalation exposure to any of
the other Isomers of dlchlorobutene could not be located In the available
literature as cited 1n Appendix A.
6.1.1.2. CHRONIC E.I. Du Pont de Nemours and Co. (1986) reported a
long-term study performed at the Haskell Laboratory from 1976-1978. In this
study, groups of 140 male and 140 female Charles River CD rats were exposed
0031d -15- 06/09/87
-------
by Inhalation to 1,4-d1chloro-2-butene (35+10% c1s-1somer, 65+10% trans-
Isomer, <0.5% 3,4-dlchloro-l-butene and <0.05% 1,3,4-trichloro-2-butene) at
concentrations of 0, 0.5 or 5.0 ppm (0, 2.6 or 25.6 mg/ma), 6 hours/day, 5
days/week. The control and 0.5 ppm groups were exposed for 2 years. The
high-level group was exposed for -1 year, with the following modifications:
after 117 exposures (test day 176) and until 140 exposures (test day 212),
the duration of exposure was reduced to 4 hours/day; from exposure 141 (test
day 213) to exposure 245 (test day 366), the exposure level was reduced to
2.5 ppm (12.8 mg/m3) and the duration was raised to 6 hours/day. At test
day 366, the exposure was terminated and the high-level group was held for
an additional year. Although these manipulations would result in a TWA
concentration <5.0 ppm, for practical purposes, the high-level group will be
referred to as the 5.0 ppm level group until equivalent doses are calculated
'(Chapter 8).
Body weight measurements and clinical observations, were made regularly.
Hematologlcal and clinical chemistry parameters were examined In 10 rats/
group at 90 days, 1 year, 18 months and 2 years. Comprehensive gross and
hlstologlcal examinations were performed on all rats that died, on 10 rats/
group after 90 days and 1 year, on 10 rats of the control and 0.5 ppm groups
at 18 months, and on all rats surviving until 2 years.
Reduced body weight gain occurred 1n the 5.0 ppm males and females, but
not In the 0.5 ppm group, compared with controls. Mortality was signifi-
cantly Increased (p<0.05, Fisher Exact test) In the 5.0 ppm rats (82-84%)
compared with controls (39%). Mortality in the 0.5 ppm group (34%) was
slightly less than control. The increased mortality was considered to be
secondary to the carcinogenic effect (Section 6.2.1.). No treatment-related
effects on hematologlcal or clinical chemistry parameters were observed In
any group at any analysis.
0031d -16- 06/09/87
-------
Results of the 90-day and 1-year Interim kills were reported In Section
6.1.1.1. The hlstologlcal examination at 18 months and 2 years revealed
primarily a carcinogenic effect (Section 6.2.1.). In addition to the tumors
at 2 years, flattening and metaplasia of the nasal and tracheal epithelium
were compound-related and occurred In both dose groups. High level rats had
greater Incidences of rhinitis, tracheal lumlnal exudate, atelectasls,
pneumonia and hyperplastlc bone marrow, which were considered secondary to
the primary respiratory lesions.
E.I. Du Pont de Nemours and Co. (1985a) reported another long-term
Inhalation study conducted at the Haskell Laboratory from 1980-1982. In
this study, groups of 128-160 male Charles River CD rats were exposed to
1,4-d1chloro-2-butene (composition as stated previously In this section)
vapors at concentrations of 0, 0.1, 0.3 or 1.0 ppm (0, 0.5, 1.5 or 5.1
mg/m3), 6 hours/day, 5 days/week for up to 19 months and observed for an
additional 5 months. Body weights and clinical observations were monitored
regularly. As this study was designed to determine the time- and dose-
response relationships for respiratory lesions, Interim kills were performed
as follows: 10 rats each from the control and 1.0 ppm group at 3 months, 10
rats from the 1.0 ppm group at 6, 9, 10, 11 and 18 months (no controls) and
10 rats/group (all exposures and control) at 12, 15 and 19 months. All
surviving rats were killed at 24 months. Comprehensive gross pathological
and hlstologlcal examinations of the entire respiratory tract, cervical
lymph nodes and brain were performed on all rats that died or were killed.
There was no compound-related effect on body weight. After ~6 months,
respiratory infection by Corynebacter1um kutscheri developed in control and
treated rats and resulted in high mortality. When mortality was adjusted to
0031d -17- 06/09/87
-------
eliminate scheduled sacrifices and rats with C_. kutscherl Infection, the
mortality rate was significantly higher (p<0.05, Fisher Exact test) In the
1.0 ppm group compared with the control group.
Results of the 3, 6, 9, TO, 11 and 12-month sacrifice were reported
previously In Section 6.1.1.1. At the 15-month sacrifice, malignant tumors
of the nasal cavity were observed In treated rats (Section 6.2.1.). Other
lesions Included basal cell flattenlng/hyperplasia and atrophy and disorgan-
ization of the olfactory mucosa In all exposed groups, but not In controls.
All three treated groups had significant and dose-related decreased mean
absolute lung weight. At subsequent sacrifices nasal tumors predominated.
Pertinent data regarding chronic Inhalation exposure to the other
Isomers of dlchlorobutene could not be located In the available literature
as cited 1n Appendix A.
6.1.2. Oral Exposures.
6.1.2.1. SUBCHRONIC Erzhkalsyan (1985) orally administered 3,4-dl-
chloro-1-butene at doses of 0 or 200 mg/kg/day to groups of 15 male albino
rats for 5 months and evaluated nitrogen metabolism. Significant decreases
were observed 1n serum and urine urea nitrogen. Serum amlno nitrogen was
significantly Increased as well as the ratio of a-amlno nitrogen to
residual serum nitrogen. Similar changes In the urine were also observed.
The author hypothesized that amlno add metabolism was disturbed.
Groups of -15 white rats were administered Intragastrlc doses of either
l,4-d1chloro-2-butene at levels of 0.1, 0.01, 0.001 and 0 mg/kg for 6 months
or 3,4-d1chloro-l-butene at levels of 0.01, 0.1, 1 and 0 mg/kg/day for 6
months (Petrosyan et al., 1983). Changes 1n renal function including
decreased diuresis, Increased excretion of chlorides and a decrease In
creatlnlne In the blood with an Increase 1n the urine were observed In the
0031d -18- 06/09/87
-------
rats treated with 0.01 and 0.1 mg/kg/day 1,4-d1chloro-2-butene and 3,4-d1-
chloro-1 -butene, but by the end of the test period, renal function was
normal. Only parameters of kidney function were examined and the study
results- were not clearly presented. Other data regarding subchronlc oral
exposure to other Isomers of dlchlorobutene could not be located In the
available literature as cited In Appendix A.
6.1.2.2. CHRONIC Pertinent data regarding chronic oral exposure to
any of the Isomers of dlchlorobutene could not be located 1n the available
literature as cited 1n Appendix A.
6.1.3. Other Relevant Information. In an abstract of a Russian study of
chlorobutene struettire-actlvlty relationships (Glzhlaryan, 1981), l,4-d1-
chloro-2-butene was reported to be more toxic than 1,3-d1chloro-2-butene,
which 1n turn was more toxic than 3,4-dlchloro-l-butene. The tox1c1ty of
the chlorinated butenes was dependent upon the position and number of
chlorine atoms. The greater toxldty of 1,4-d1chloro-2-butene was attrib-
uted to the terminal position of the chlorine atoms.
Clary (1977) reported 1,4-d1chloro-2-butene to be acutely toxic In rats,
with a 4-hour LC5Q value of 86 ppm (440 mg/m3) and an oral ID,., of 89
mg/kg. The dermal LD5Q In rats was 0.62 ml/kg. The compound was
reported to be a severe eye and skin Irritant, causing burns that result In
Irreversible eye damage. Single exposures (details not specified) to
1,4-d1chloro-2-butene caused necrotlc changes In the central nervous system,
kidney, liver, myocardium, stomach, adrenal and testls. Hlstochemlcal
changes Included reduced RNA In the brain, liver and kidney, decreased liver
glycogen, and increased llpids in the hepatocytes and hepatic epithelium
(Petrosyan et a!., 1981). In white rats, acute Intragastrlc administration
0031d -19- 06/09/87
-------
of 1,4-d1chloro-2-butene at doses of 60 and 180 mg/kg and 3,4-d1chloro-l-
butene at doses of 220 and 66 mg/kg resulted 1n nephrotoxic changes mani-
fested by disruption of canallcular reabsorptlon and development of necrotlc
nephrosls. The nephrotoxic effects were more severe In the 1,4-d1chloro-2-
butene treated rats (Petrosyan et al., 1983).
Clary (1977) reported a 4-hour Inhalation LC5Q for 1,3-d1chloro-2-
butene In rats to be 546 ppm (2791 mg/m3). The liver, spleen, thymus,
lung and kidney were target organs following acute Inhalation exposure. The
compound caused disturbances In carbohydrate metabolism, changes 1n the
peripheral blood, and skin and eye Irritation. A single 4-hour Inhalation
exposureto 1,3-d1chloro-2-butene at concentrations of 5 or 0.5 mg/i
resulted In damage to the epithelium of the proximal parts of the nephron,
disturbed vessel permeability and caused hemolysls at the high dose
(Oganesyan and Akopdzhanyan, 1969). A single exposure at the low dose
caused stasis In the glomerull and dystrophlc changes of the tubular epithe-
lium. 1,3-01chloro-2-butene at 5 or 0.5 mg/i was reported by Hlrzabekyan
et al. (1967) to produce granularity and degeneration In the epithelial
cells of the thyroid gland follicles. Petrosyan et al. (1984) reported
acute toxic effects on the kidney 1n rats 1 minute after Inhalation of 1100
mg/m3 of 1,3-d1chloro-2-butene.
A 4-hour Inhalation exposure to 100 mg/m3 of 1,4-dlchloro-l-butene or
oral administration of 150 g/kg 1n rats caused progressive decreases In the
RNA 1n the brain (Petrosyan and Glzhlaryan, 1982b). Hypervolemla of the
brain and cerebellum vessels led to neuron dystrophy and necrosis. Within
3-6 days, dystrophy and a decrease In the cytoplasm RNA occurred In the
neuroglla. A single 4-hour Inhalation exposure of 1000 mg/m3 l,4-d1-
chloro-2-butene caused narcosis 1n rats followed by a bloody exudation
0031d -20- 05/20/87
-------
(Petrosyan, 1983). Hypervolemla, swelling and hemorrhages developed In all
organs and the kidneys showed necrotlc nephrosls. Dystrophy and necroblosls
occurred In the liver and spleen.
In an abstract of a study by Glzhlaryan et al. (1984) the LC5Qs for
3,4-d1chloro-l-butene for mice and rats were reported to be 5700 and 24,200
rog/kg, respectively; however, the unit of measure was most likely to be
mg/m3. The respective LDj-ns for the two species were reported to be
724.4 and 880.0 mg/kg. The central nervous system was reported to be the
primary target of the acute Intoxication. A single Inhalation exposure of
3,4-d1chloro-l-butene at 7400-39,000 mg/m3 to rats and 2000-12,000 mg/m3
to mice or an oral dose of 300-1300 mg/kg to rats and 500-1000 mg/kg to mice
resulted In hypervolemla and stasis 1n the brain cortex, cerebellum, lungs,
liver, spleen, stomach mucosa, adrenals, kidneys and testls (Petrosyan and
Glzhlaryan, 1982a).
6.2. CARCINOGENICITY
6.2.1. Inhalation. In the long-term study reported by E.I. DuPont de
Nemours and Co. (1986) (see Section 6.1.1.2.), Inhalation exposure of rats
to l,4-d1chloro-2-butene at 0.5 and 5.0 ppm (2.6 or 25.6 mg/m3), 6 hours/
day, 5 days/week resulted In high Incidences of benign and malignant tumors
of the nasal cavity. The malignant tumors were highly Invasive.
In a summary of the tumor Incidences, E.I. DuPont de Nemours and Co.
(1985b) reported slightly different tumor Incidences than those provided In
the full report by E.I. DuPont de Nemours and Co. (1986). The discrepancy
Involved the number of nasal tissues examined. The full report, however,
also provided Individual rat pathology data. Inspection of the Individual
data, eliminating rats for which nasal tissue was not examined but Including
partially autolyzed rats, resulted In the tumor Incidences presented In
0031d -21- 05/20/87
-------
Table 6-1. Rats from the 90-day Interim kill were excluded from the tumor
analyses. The first tumors were observed in rats that died or were killed
at ~1 year.
Dose-related statistically significant Increased Incidences of nasal
tumors were also found 1n a second long-term Inhalation study reported by
E.I. DuPont de Nemours and Co. (1985a). Details of the protocol of this
study were provided 1n Section 6.1.1.2. Lifetime tumor Incidences were
estimated by the Kaplan-Meier procedure (Kaplan and Meier, 1958). Tumor
Incidences were analyzed by the method of Peto et al. (1980) where all
tumors were assumed to be Incidental. For analysis, adenomas and papillary
adenomas were combined Into the category of benign nasal tumors. The
following nasal neoplasms were combined Into the category of malignant nasal
tumors: unclassified sarcoma, spindle cell sarcoma, rhabdomyosarcoma, adeno-
carclnoma, carcinoma, squamoadenocardnoma and mixed carcinoma.
Rats in .all the groups became Infected by C. kutscherl. .which caused
«
necrotlzlng bronchopneumonla. Because the necrotlzlng bronchopneumonla
occurred in the lung, the presence of Infection did not Interfere with the
detection of nasal tumors, although the early mortality associated with the
Infection reduced the number of rats at risk.
Tumor incidence data are reported in Table 6-2. When analyzed by the
method of Peto et al. (1980), there were statistically significant dose-
related trends 1n the Incidence of both benign and malignant nasal tumors
when analyzed Independently or when both tumor types were combined. The
Increase In tumor Incidence was statistically significant at all exposure
levels for benign tumors and at the 1 ppm level for malignant tumors. When
the Incidences of benign and malignant tumors were combined, statistically
significant Increases were observed 1n the 0.3 and 1.0 ppm groups. No other
compound-related tumors were observed.
0031d -22- 05/20/87
-------
TABLE 6-1
Incidence of Nasal Tumors In Charles River CD Rats Exposed by
Inhalation to 1,4-D1chloro-2-Butene 1n a 2-Year Study3
Tumor Incidence0
Sex
M
F
Concentration
(ppm)b
0
0.5
5.0
0
0.5
5.0
Duration of
Exposure
(years)
NA
2
1
NA
2
1
Ben1gnd
0/127
33/1 30f
2/129
0/128
23/128f
5/1 28f
Malignant6
0/127
11/1 30f
114/1 29f
0/128
2/128
114/128f
Benign or
Malignant
0/127
42/1 30f
114/1 29f
0/128
24/1 28f
112/128f
Strengths of study:
Weaknesses of study:
Overall adequacy:
QUALITY OF EVIDENCE
Compound administered by relevant route to both sexes
of one species at two levels. Comprehensive histo-
loglcal examination and statistical analyses were
performed.
High concentration was toxic and was reduced after 30
weeks, and further exposure was terminated after an
additional 23 weeks.
Adequate
aSource: E.I. DuPont de Nemours and Co., 1986
bFor details of exposure protocol, see Section 6.1.1.2.
Clnc1dence exposed as number of rats with tumors/number of rats with nasal
tissues examined
^Benign tumors Include adenomas and hemanglomas.
eMa!1gnant tumors Include adenocardnoma, squamous cell carcinoma, mixed
carcinoma, cardnosarcoma, rhabdomyosarcoma
fp<0.05, Fisher Exact test
NA = Not applicable
0031 d
-23-
05/20/87
-------
TABLE 6-2
Incidence of Nasal Tumors 1n Male Charles River CD Rats Exposed
by Inhalation to 1,4-D1chloro-2-Butene for 19 Months
Followed by 5 Months Observation2
Concentration
(ppm)b
0
0.1
0.3
1.0
Ben1gnc
0/159
3/1 46e
12/1486
23/1 26e
Incidence of Tumors
Mal1gnantd .
1/159
1/146
2/148
18/1266
Benign or
Malignant
1/159
4/146
14/1486
35/1266
Strengths of study;
Weakness of study:
Overall adequacy:
QUALITY OF EVIDENCE
Compound administered by a relevant route to a large
number of rats at several dose levels for a significant
portion of the Hfespan. Statistical analyses and h1s-
tologlcal examination of target organs were performed.
Mortality and lung lesions due to bacterial Infection.
Adequate
aSource: E.I. DuPont de Nemours and Co.. 1985a
&6 hours/day, 5 days/week
cBen1gn tumors Include adenoma and papillary adenomas.
^Malignant tumors Include adenocardnoma, carclnosarcoma, mixed carcinoma,
sarcoma, spindle cell sarcoma and rhabdomyosarcoma.
ep<0.05, method of Peto et al. (1980)
0031d
-24-
05/20/87
-------
Pertinent data regarding the carclnogenlclty of Inhalation exposure to
the other Isomers of dlchlorobutene could not be located In the available
literature as cited 1n Appendix A.
6.2.2. Oral. Pertinent data regarding the oral carclnogenlclty of the
various Isomers of dlchlorobutene could not be located In the available
literature as dted 1n Appendix A.
6.2.3. Other Relevant Information. Van Duuren et al. (1975) tested
trans-1,4-d1chloro-2-butene for carclnogenlclty 1n female ICR/HA Swiss mice
by lifetime skin application, subcutaneous and Intraperltoneal injection,
and 1n a two-stage promotion/Initiation skin painting study. 1,4-D1chloro-
2-butene produced no carcinogenic response when applied to the skin of a
group of 30 mice, 3 times/week at a dose of 1.0 mg In 0.1 ml acetone for
537 days. Similarly, 1,4-d1chloro-2-butene did not elicit local papllloma
or squamous carcinoma development 1n mouse skin In a two-stage promotion/
Initiation study with phorbol myrlstate acetate as the promoting agent.
When Injected either subcutanedusly or 1ntraper1toneally once per week for
537 days at a dose of 0.05 mg 1n 0.05 ma trlcaprylln, a statistically
significant (p<0.05) Incidence of local sarcomas were produced In the mice.
The Incidences of local sarcomas were 3/30 by subcutaneous Injection and
2/30 by Intraperltoneal Injection. The Incidence of tumors distant from the
sites of application of 1,4-d1chloro-2-butene, however, were reported to be
comparable with those observed In the vehicle and untreated control groups.
The weekly dose used to elicit the local tumors was low, equivalent to -1.67
mg/kg (U.S. EPA, 1983b), but this was reportedly the highest possible dose
that gave minimal cytotoxlc effects (Van Duuren et al., 1975).
E.I. DuPont de Nemours and Co. (1985a) reported a retrospective cohort
study of 598 male employees exposed to 1,4-d1chloro-2-butene at the Victoria
0031d -25- 06/09/87
-------
Plant. 1,4-D1chloro-2-butene 1s formed by the reaction of chlorine and
butadiene. Mortality was traced from 1957 through 1980 using the company
mortality file and Social Security Administration and state health
department records. Cancer Incidence for active employees was traced from
1956 through 1983 using the DuPont Company Cancer Registry. The cohort of
598 was subdivided Into 525 hourly and 73 salaried employees. Exposures
were not quantified. The .observed and expected numbers of deaths and cancer
cases are presented 1n Tables 6-3 and 6-4. As noted 1n the tables,
pancreatic cancer cases were significantly elevated above what would be
expected based upon company and U.S. rates. Because a latency period of 15
years for chemical carclnogenesls (the number of years for cancer to develop
after Initial contact) 1s often used, the data were reanalyzed to account
for latency. The results are shown 1n Table 6-5. Again, no statistically
significant differences were found. Both pancreatic cancer cases and deaths
were significantly elevated when a 15-year latency Is considered. Since
this Is the only study which demonstrated evidence of an association between
pancreatic cancer and exposure to 1,4-d1chloro-2-butene, and since the
number of pancreatic cases In the study was small, the human evidence for
carclnogenldty would have to be considered Inadequate. Continued follow-up
of this cohort with attention to dose-response, exposure levels of
1,4-d1chloro-2-butene and Information on other Isomers should be helpful In
evaluating the human evidence for carclnogenldty of this chemical.
6.3. MUTAGENICITY
The mutagenlc effects of 1,4-d1chloro-2-butene and 3,4-d1chloro-l-butene
are presented 1n Table 6-6. Pertinent data regarding the mutagenldty of
the other Isomers of dlchlorobutene could not be located In the available
literature as cited 1n Appendix A.
0031d -26- 09/10/87
-------
TABLE 6-3
Results of Epidemiology Study of 1,4-D1chloro-2-butene at
Victoria Plant: Observed and Expected Deaths 1957-1980
1n Male Cohort, No Latency (Selected Causes)*
Cause of Death
WAGE ROLL
All causes
All malignant
neoplasms
Lung cancer
Pancreatic cancer
SALARY ROLL
All causes
All malignant
neoplasms
Observed
Deaths
23
7
4
2
8
1
Expected Deaths
Based on DuPont
Rates
29.6
6.6
2.5
0.4
4.8
1.3
Expected Deaths
Based on U.S. Rates
44.1
8.4
2.9
0.4
8.5
1.8
*Source: E.I. DuPont de Nemours and Co., 1985a
0031 d
-27-
05/20/87
-------
TABLE 6 4
Results of Epidemiology Study of 1,4-01chloro-2-butene at Victoria Plant:
Observed and Expected Cancer Cases 1956-1983 In Male Cohort,
No Latency (All Cancer and Selected Sites)3
Cause of Death
WAGE ROLL
All malignant
neoplasms
Lung cancer
Pancreatic cancer
Malignant melanoma
Observed
Deaths
13
2
3
Expected Deaths
Based .on DuPont
Rates
12.7
2.2
0.3b
0.6
Expected Deaths
Based on U.S. Rates
15.0
3.3
0.4b
0.8
SALARY ROLL
All malignant
neoplasms
2.2
2.8
aSource: E.I. OuPont de Nemours and Co., 1985a
bp<0.01, as calculated by the Carcinogen Assessment Group, U.S. EPA.
0031d
-28-
09/08/87
-------
TABLE 6-5
Results of Epidemiology Study of 1,4-D1chloro-2-butene at
Victory Plant: Observed and Expected Events 1n Male Wage Roll Cohort;
15-Year Latency (All Cancer and Selected Sites)3
Cause of Death
Observed
Deaths
Expected Deaths
Based on DuPont
Rates
Expected Deaths
Based on U.S. Rates
CANCER DEATHS 1957-1980
All malignant
neoplasms
Lung cancer
Pancreatic cancer
4
2
4.6
1.9
0.3b
5.7
2.2
0.3b
CANCER CASES 1956-1983
All malignant
neoplasms
Lung cancer
Pancreatic cancer
2
2
8.3
1.7
0.2b
9.4
2.4
0.3b
aSource: E.I. OuPont de Nemours and Co., 1985a
bp<0.05, as calculated by the Carcinogen Assessment Group, U.S. EPA.
0031d
-29-
09/08/87
-------
u
c
.»*
JS
I
e^
o
a
f
u
*?
co"
o
c
Ol
e
Ol
*
3
SM
e
o
\^
(j
i
^H
U-
°
O»
^j
41
I"
U
~^|
1>
*3
^?
X
0)
u
c
01
k.
01
Ol
at
^^
c
QJ
ff
o
0
Ol
VI
9
VI
Ol
at
01
c
> VI
(/r
«
c
o
Z* Ol
TO VI
k. O
c
w o
e
o
u
c
o .
^
u
^"
CV
Q.
^c
o
3
O
t
O
u
u.
3 S
^* 1/1
u "e
S o>
e i_
1-1 O
>^
01
VI
Ol
01
at
CO CO
c 03 en en c oo
. r- i i r- en
^en ***denr*»
f-TO C^C^ r»TO 1 TO r
enee- TOS'QSfenoa* co
i *~ ^ u < « en
«^- 4^ 3K «^ >» VI f*^ 1^*01 ^
O TO TO k. TO k. ^* *O TO Ol CO
oo ^t y n 3 i- so oi oioo
1 On ^ 3TO 3TO TO Cn ** O OlCn 3
TO I 11 XXXZeOTOf Ol» -J r (9
o
CD 1 O 01
0. TO U_ >
C k. 3 CO 01 3 Ol
01 TO Ol E 1 VI u -w
VI > O TO
a -3 >< -a v u
§0 f 4) »J VI
H U * k. C VI
u c c u TO a c
E3TOTO»- OIQ.O
o-oE^c cviS
k.C3COIC_) U «-OIOI O U U
u- j: u o> z z r k. -o z z z
CC.CC. < < Of
Z Z +1 Z Z Z
01
TO
5 1
i °
1
ce cc -at at
Z Z vu. z u
111 i r- i i
0 0 O O k. O O
k. ki k. k.r»aiu. u
O 0 O O E 0 0
Ol fOJ£OIJ=OI AOlvifO) fOI
c oeucuc uc*-wcz uc
41 ^~ QJ ^* Ol ^~ Ol ^ & 1 ^~ CU ^~ u
' -o ^ -o -o > -o »- vi -o ^ -n
3 131313 I3CI3 13
1 vl*!*! *lk,*l *t
CM r CM^-CMCOr r CM *< * CM CO^
k.
|| " ce
^ * k. VI
£ M^M 5J^i«/l
3 3 3 TO^OOOI
E£E i vi o <-
v. u TJ s£ C i£ co *: >.
3 £ f fOTO U
E o k. Q aocr cec o
o > oi >o oc oi oocj:
.CO -*^ .£ <**O viTOf S ^ * Ol TO CV
OF- U r , Or k. k.COlEE
>< V1O < k.OIOI CJlTOk.3>«
i-* I c/)| uj u toll Q E co alco u o j: i
oi -a -
c > oi o
o «* o> k.
.^ vi * k. TO C **
.4^ VI TO Ol E *fl *^"
TO fll ^Z ^* O ^Z ^
«- O *» VI k. U
3 oi oi j= x ^e
Ol
^
TO
U
cv
Q.
^^
O
c
II
5
*
i
k.
0
01
^.J
0
c
II
ce
z
c
I
O
u
o
II
(J
z
0031 d
-30-
05/20/87
-------
1,4-01chloro-2-butene and 3,4-d1ch1oro-l-butene were reported to be
mutagenic to Salmonella typh1mur1um strain TA100 In the Ames plate Incorpo-
ration and vapor exposure.assays, respectively (Bartsch et al., 1976, 1980;
Barbln et al., 1978) and the effect was enhanced by the addition of mouse
liver homogenate S-9 fraction. Mukal and Hawryluk (1973) also reported
positive responses with 1,4-d1chloro-2-butene to S>. typhlmurlum and Esche-
rlchla coll; however, the studies were reported In an abstract and addi-
tional details were not available. An Increased frequency of sex-linked
recessive lethal mutations were produced 1n DrosophUa melanogaster after
males were exposed to 1,4-d1chloro-2-butene (Vogel, 1979; Lee et al., 1983).
Gu (1981) reported that exposure to 3,4-d1chloro-l-butene Increased the
frequency of sister chromatld exchanges 1n human lymphocytes jji vitro.
In an abstract of a Russian study reported by Nalbandyan and Glzhlaryan
(1985), chromosome damage was observed In bone marrow cells of rats Inhaling
l,4-d1chloro-2-butene at 1.7 or 7.9 mg/m3 or 3,4-dlchloro-l-butene at 13.7
or 81.3 mg/m3, 4 hours/day, 5 days/week for 30-120 days. At the lower
exposure levels, chromatld damage was observed after the 30- to 120-day
exposure period and disappeared after a 45-day recovery period. At the high
dose levels, chromatld damage was observed after 1 day of exposure and did
not disappear after a 45-day recovery period. The authors concluded that
the extent of chromatld damage was correlated positively with concentration
and exposure time and 1,4-d1chloro-2-butene was more mutagenic than
3,4-d1chloro-l-butene.
6.4. TERATOGENICITY
Kennedy et al. (1982) tested 1,4-d1chloro-2-butene (70% trans; 30% cis)
for teratogenldty 1n Charles River CD rats. Groups of 21-23 pregnant rats
were exposed by Inhalation to 0, 0.5 (2.6 mg/m3) or 5.0 ppm (25.6 mg/m3)
l,4-d1chloro-2-butene 6 hours/day on days 6-15 of gestation. The rats were
0031d -31- 09/08/87
-------
killed 1 day before natural delivery and fetuses were examined for external
and skeletal development, and structure and Integrity of the Internal
tissues and organs. The only clinical sign of maternal toxldty observed
was a significantly reduced (p<0.05) rate of weight gain 1n the dams exposed
at the 5.0 ppm level relative to the controls. No treatment-related effects
on the number of Implantations, resorptlons, live fetuses/Utter and fetal
measurements were observed. The types and Incidences of external, visceral
and skeletal anomalies, and malformations among treated Utters were not
different from controls, with the exception of a dose-related Increase 1n
the Incidence of wavy ribs. The incidences of wavy ribs were 0/120 fetuses
(0/23 Utters) in the controls, 4/98 fetuses (2/21 litters) at the low
exposure level and 15/108 fetuses (7/21 litters) at the high exposure level.
The authors considered the wavy ribs effect a minor anomaly. The struc-
tural change was reported not to effect fetal survival and was not
associated w.lth any other abnormality such as chondrodystrophy. The high
exposure level of 5.0 ppm In this study caused signs of maternal toxldty
and produced nasal tumors 1n rats following lifetime inhalation exposure
(see Section 6.2.1.). The high exposure levels used seem appropriate for
determination of teratogenic potential. It was concluded that 1,4-di-
chloro-2-butene was neither embryotoxlc nor teratogenic in the rat under
these experimental conditions.
In contrast to the previous study, data from the Russian literature
Indicated a fetotoxic effect. Petrosyan et al. (1982) studied the effects
of Inhalation and oral exposure of 1,4-d1chloro-2-butene on pregnant and
nonpregnant white rats for 21 days. The inhalation exposure levels were 8.3
and 1.8 mg/m3 and the Intragastric doses were 0.1, 0.01 and 0.001 mg/kg.
0031d -32- 09/08/87
-------
No further details concerning doses were reported. Effects Included
Increased postlmplantatlon mortality, hemorrhages In the diaphragm and liver
of the fetuses, plethoric placentas, dilation of the capillaries and
lacunae, and decreased RNA content In hepatocytes, 1n cerebral g!1a,
alveolar cells of the lungs and In the epithelium of the glomerull. Because
specific data were not reported, H was difficult to associate effects with
dose or route of exposure.
Bal'yan et al. (1983a) evaluated the embryotoxlc effect of Inhalation
exposures of 1,4-d1chloro-2-butene at levels of 0, 1.6, 9.2 and 33.9 mg/m3
administered to rats for the first 20 days of pregnancy. The number of
corpora lutea, number of fetuses and resorptlons, prelmplantatlons, post-
Implantations and embryonic mortality were evaluated. A significant
Increase 1n postlmplantatlon mortality was seen at the high dose level, and
the number of normal embryos 1n all dose groups was less than that in the
controls; however, the high dose caused maternal toxlclty, since -50% of the
rats at this exposure level died between day 18 and 20 of pregnancy.
Degenerative changes 1n the liver and hemorrhages 1n the diaphragm were
reported In the exposed fetuses but not 1n the controls. Morphological
changes 1n the placenta of the dosed groups were also reported. Experi-
mental details were lacking, and H was difficult to determine dose-effect
relationships.
Pertinent data regarding the teratogenlclty of the other Isomers of
dlchlorobutene could not be located In the available literature as dted In
Appendix A.
6.5. OTHER REPRODUCTIVE EFFECTS
Bal'yan et al. (1983b) studied the effect of Inhalation and oral
exposures to 1,4-d1chloro-2-butene on the reproductive function In male
0031d -33- 09/08/87
-------
rats. The compound was administered to groups of 10-12 rats at Inhalation
concentrations of 0, 1.8 or 8.3 mg/m3 and 1ntragastr1cally at doses of 0,
0.1, 0.01 and 0.001 mg/kg for 2.5 months. No other details concerning
exposure were given. The male rats were mated at the end of the exposure
period to unexposed females and the fetuses were evaluated on the 21st day
of pregnancy. At necropsy of the males, the functional condition of the
spermatozoa was evaluated, the spermatogenlc epithelium 1n the testicles was
evaluated by quantitative morphological Indexes and sections were obtained
from the testicles for hlstologlcal evaluation. Exposure to 1,4-d1chloro-2-
butene resulted In Increased postlmplantatlon mortality of the embryos from
the females mated with treated males and an Increased weight and cranlo-
caudal length of the surviving embryos. It Is not clear 1f these effects
occurred by both routes of exposure. At both Inhalation exposure levels and
at the two highest oral exposure levels, a significant decrease In the DNA
and RNA 1n the rat spermatogenlc epithelium was noted. Significant
decreases 1n the number of spermatozoa, spermatogenlc Index, and the number
of tubules with desquamated epithelium and with the 12th stage of melosls
were also reported at these same doses. In addition, hlstologlcal examina-
tion showed destructive alterations of the epithelial cells, Interstitial
tissue, vascular system and membranes of the testicles at these exposure
levels. Because specific data were not reported, It was difficult to
clearly associate dose with effect.
Pertinent data regarding the reproductive effects of other Isomers of
dlchlorobutene could not be located 1n the available literature as cited 1n
Appendix A.
6.6. SUMMARY
Effects of subchronlc exposure to some of the Isomers of dlchlorobutene
were reported In studies from the Russian literature; however, experimental
0031d -34- 09/08/87
-------
protocols and details were not reported adequately. Decreased spermatogene-
sls (Bal'yan et al., 1983a) and Increased urinary chloride and creatlnlne
excretion (Petrosyan et al., 1983) were reported when 1,4-d1chloro-2-butene
was administered to rats by Inhalation and Intragastrlc doses for up to 6
months. Effects on the central nervous system, liver, lungs, kidney
(Petrosyan and Glzhlaryan, 1982a) and nitrogen metabolism (Erzhkalsyan,
1985) were reported In rats exposed to Inhalation and Intragastrlc doses of
3,4-d1chloro-l-butene. Central nervous system effects were observed 1n rats
after Inhalation exposure for 30 days to 1,4-d1chloro-l-butene (Petrosyan
and Glzhlaryan, 1982b). -Inhalation exposure of rats to 1,3-d1chloro-2-
butene resulted 1n degenerative changes 1n the liver, changes 1n the liver
alkaline phosphatase activity and changes 1n the metabolism of glycogen and
fat (Vartazaryan and Mezhlumyan, 1974).
Rats exposed by Inhalation to 1,4-d1chloro-2-butene at 0.5, 1.0 or 5.0
ppm (2.6, 5.1 or 25.6 mg/m3), 6 hours/day, 5 days/week, for 90 days' had
squamous flattening of the trachea! epithelium (E.I. DuPont de -Nemours and
Co., 1985a, 1986). At 5.0 ppm, there was hypertrophy and atrophy of the
nasal epithelium. Long-term exposure of the rats to 0.1-1.0 ppm (E.I.
DuPont de Nemours and Co., 1985a) and 0.5-5.0 ppm (E.I. DuPont de Nemours
and Co., 1986), 6 hours/day, 5 days/week resulted 1n statistically signifi-
cant dose-related Increased Incidences of benign and malignant nasal cavity
tumors. Hyperplasla and metaplasia of respiratory tissue were also
observed. Increased mortality was secondary to the carcinogenic effect.
trans-1,4-D1chloro-2-butene produced no carcinogenic response when
administered 1n a chronic skin painting study or 1n a two-stage promotion/
Initiation skin painting study (Van Duuren et al., 1975). The compound was
found to elicit low but statistically significant Incidences of local
0031d ' -35- 09/08/87
-------
sarcomas when Injected in mice either subcutaneously or Intraperltoneally
once weekly over their lifetime (Van Duuren et a!., 1975).
An epidemiology study was conducted of 598 workers of DuPont exposed to
l,4-d1chloro-2-butene at the Victoria Plant 1n order to determine cancer
Incidences (1956-1983) and mortality (1957-1980). E.I. OuPont de Nemours
and Co. (1985a) concluded that employees were not at an Increased risk of
developing cancer.
1,4-D1chloro-2-butene was mutagenlc In 5>. typhimurlum (Bartsch et a!.,
1976, 1980; Barbln et al., 1978), £.. coli (Mukal and Hawryluk, 1973) and p_.
melanoqaster (Vpgel, 1979; Lee et al., 1983). 3,4-D1chloro-l-butene was
mutagenlc 1n j>. typhimurlum (Bartsch et al., 1976, 1980; Barbin et al.,
1978) and Increased the frequency of sister chromatid exchanges In human
lymphocytes \n_ vitro (Gu, 1981). Exposure of pregnant Charles River CO rats
to l,4-d1chloro-2-butene vapors during pregnancy was neither embryotoxic nor
teratogenlc to the fetuses and the only Indication of maternal toxlcity was
a significantly reduced rate of weight gain in the dams at the high dose
level (Kennedy et al., 1982).
0031d - -36- 09/08/87
-------
7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
Pertinent guidelines and standards, Including EPA ambient water and air
quality criteria, drinking water standards, FAO/WHO ADIs, EPA or FDA toler-
ances for raw agricultural commodities or foods, and ACGIH, NIOSH or OSHA
occupational exposure limits could not be located In the available litera-
ture as cited in Appendix A.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic organisms from
the effects of dlchlorobutenes could not be located 1n the available
literature as cited 1n Appendix A.
0031d -37- 05/20/87
-------
8. RISK ASSESSMENT
8.1. CARCINQGENICITY
8.1.1. Inhalation. Pertinent data regarding the cardnogenlclty of
dlchlorobutenes other than 1,4-d1chloro-2-butene could not be located 1n the
available literature as cited In Appendix A.
In a long-term Inhalation study reported by E.I. DuPont de Nemours and
Co. (1986), significant Increases 1n the Incidence of benign and malignant
nasal tumors were reported In both male and female rats exposed to l,4-d1-
chloro-2-butene vapors at two levels for periods up to 2 years. Results of
this study are summarized In Table 6-1. E.I. DuPont de Nemours and Co.
(1985a) reported another chronic Inhalation study In male rats at exposure
levels of 1,4-d1chloro-2-butene lower than the preliminary study. Statis-
tically significant Increases 1n the Incidences of nasal tumors were
observed 1n all exposure groups for benign tumors and 1n the the high dose
group for malignant tumors (see Section 6.2.1. and Table 6-2). When the
Incidence of benign and malignant tumors were combined, statistically
significant Increases were observed at the two highest exposure levels. No
other compound-related tumors were reported, and no Information was
available as to the oncogenlclty of the other Isomers of dlchlorobutene by
Inhalation. The data Indicate that 1,4-d1chloro-2-butene Is carcinogenic to
rats when administered by Inhalation exposure. Therefore, It 1s Inappro-
priate to derive an RfD, and a q,* should be derived.
8.1.2. Oral. Pertinent data regarding the oral cardnogenlclty of any of
the Isomers of dlchlorobutene could not be located 1n the available litera-
ture as cited In Appendix A.
8.1.3. Other Routes. trans-1,4-D1chloro-2-butene produced no carcino-
genic response when administered 1n a chronic skin painting study using mice
or In a two-stage promotion/Initiation skin painting study (Van Duuren et
0031d -38- 09/08/87
-------
a!., 1975). The compound, however, was found to elicit low but. statisti-
cally significant incidences of local sarcomas when injected in mice either
subcutaneously or intraperitoneally once weekly over a lifetime (Van Duuren
et a!., 1975).
8.1.4. Weight of Evidence. trans-1,4-d1chloro-2-butene was found to
elicit low but statistically significant incidences of local sarcomas when
injected in mice either subcutaneously or Intraperitoneally once weekly over
the lifetime {Van Duuren et al., 1975). Additionally, 1,4-d1chloro-2-butene
was shown to be mutagenic in S. typhimurium (Bartsch et al., 1976, 1980;
Barbin et al., 1978), E_. coli (Mukai and Hawryluk, 1973) and £. melanogaster
(Vogel, 1979; Lee et al., 1983).
Furthermore, 1,4-dichloro -2-butene was reported to be carcinogenic in
two separate studies to both male and female- rats when administered by
inhalation at levels from 0.1-5 ppm for up to 2 years (E.I. OuPont de
Nemours and Co., 1985a, 1986) (see Section 6.2.1., Tables 6-1 and 6-2). In
a retrospective cohort study involving 598 male employees, E.I. OuPont de
Nemours and Co. (1985a) reported no excesses in cancer cases or deaths
resulting from inhalation exposure to dlchlorobutenes. This conclusion was
not completely accurate since a statistically significant (p<0.01) Increase
in observed pancreatic deaths was shown. It has not been shown, however,
that these deaths were causally related to dichlorobutenc exposure. This
evidence, was considered Inadequate, but suggestive. IARC (1977) evaluated
1,4-dichloro-2-butene and concluded that the available data were insuf-
ficient for evaluation of the carcinogenlcity of the compound; however, the
animal studies showing Increased Incidences of nasal tumors reported by E.I.
DuPont dc Nemours and Co. (1986) were not available at that time nor were
the human studies. Using the U.S. EPA (1986b) criteria, there is sufficient
evidence of carcinogenlcity in animals, given the high incidence of combined
0031d -39- 09/08/87
-------
malignant and benign tumors by a relevant route of exposure In two
experiments (essentially duplicated In the same lab) using several dose
levels (E.I. DuPont de Nemours and Co., 1985a, 1986), and the strong
evidence for mutagenlclty and other genotoxlc effects. These findings were
reported 1n both sexes of one strain of rats. The studies used large
numbers of animals and the exposure periods were long-term. Inadequate data
were available for human exposure. Therefore, compounds with Inadequate
human data and sufficient animal evidence of carclnogenldty are categorized
In EPA Group B2 - probable human carcinogen (U.S. EPA, 1986b). The lack of
data for the other Isomers of dlchlorobutene places them In EPA Group D.
8.1.5. Quantitative Risk Estimates.
8.1.5.1. INHALATION -- As reported In Section 6.2.1. and summarized
1n Tables 6-1 and 6-2, the two long-term Inhalation studies reported by E.I.
DuPont de Nemours and Co. (1985a, 1986) should be considered for quantita-
tive risk assessment. In both studies, large numbers of animals (140-160)/
group were exposed to the compound for a large portion of their lifetime.
The second study used more exposure levels at lower doses but the Inter-
current mortality and lesions from C. kutscheM Infection may have reduced
the number of rats at risk. Infection was not reported to be a problem 1n
the preliminary study, but the high exposure level was reduced to a lower
level after -30 weeks of exposure and the lower dose was administered for
-23 weeks. In both studies, Incidences for benign and malignant nasal
tumors and combined Incidences of benign and malignant nasal tumors were
statistically analyzed. Therefore, 1t seems appropriate to determine q *
values from each study and select the data resulting 1n the highest q *
for further risk characterization.
0031d -40- 09/09/87
-------
The tumor Incidence data used to calculate the three q,* values for
Inhalation exposure are presented In Appendix B. Combined tumor Incidences
were available for .both male and female rats from the preliminary study and
for males only from the second study. In the first study (Appendix B-l),
the lower concentration of 2.6 mg/m3 (0.5 ppm) was converted to a continu-
ous exposure of 0.46 mg/m3 by multiplying by 6/24 hours and 5/7 days (to
correct for continuous exposure). Because Individual body weight data were
not provided, the reference body weight of 0.35 kg and the rat reference
Inhalation rate of 0.223 m3/day were used to calculate an equivalent dose
of 0.29 mg/kg/day. The high concentration of 25.6 mg/m3 (5 ppm) was
administered 6 hours/day, 5 days/week for -1T7 exposures and 4 hours/day, 5
days/week for 23 exposures. Thereafter, the level was reduced to 12.8
mg/m3 (2.5 ppm) and administered 6 hours/day, 5 days/week for 105 expo-
sures. At day 366 of the experiment, exposure of this group was terminated
and the rats were observed for another wear without exposure. Thus, [(25.6
mg/m3 x 117 x 6 hours/24 hours) * (25.6 mg/m3 x 23 x 4 hours/24 hours)
+ (12.8 mg/m3 x 105 x 6 hours/24 hours)] f 366 days = 3.2 mg/m3 TWA
continuous dose for 1 year. Because the rats were observed for an addi-
tional year, the exposure level over the entire experimental period was
therefore (3.2 mg/m3 x 1 year) ^ 2 years = 1.6 mg/m3. Multiplying 1.6
mg/m3 by 0.223 ma/day and dividing by 0.35 kg yields the equivalent dose
of 1.02 mg/kg/day. The unadjusted q,* values were calculated using the
computerized multistage model (Global 82) developed by Howe and Crump
(1982). The unadjusted q * values (Appendices B-l and B-2) from combined
tumors 1n male and female rats from the E.I. DuPont de Nemours and Co.
(1986) study were corrected for Interspecles dose extrapolation by multiply-
ing by the cube root of the ratio of the reference human body weight (70 kg)
to the reference body weight of the rat (0.35 kg). The q * values were
0031d -41- 06/09/87
-------
9.3 and 3.2 (mg/kg/day)"1 resulting from the data on Incidences of com-
bined nasal tumors in male and female rats, respectively.
The tumor Incidences and data used to calculate a q * value from the
second long-term Inhalation study reported by E.I. DuPont de Nemours and Co.
(1985a) are presented In Appendix B-3. The concentrations of 0.1, 0.3 and
1.0 ppm (0.5, 1.5 and 5.1 mg/m3} were transformed to a dose by multiplying
the Inhalation exposure In mg/m3 x 6/24 hours x 5/7 days x the rat Inhala-
tion rate x 19/24 months (length of exposure/length of experiment) and
dividing by the rat body weight. In this study, mean rat body weights were
-0.75 kg (as estimated from. the growth curves). An Inhalation volume of
0.371 m3/day was calculated from the meat! body weights. The unadjusted
human q,* value was calculated using the computerized multistage model
(Global 82) developed by Howe and Crump (1982). A human q,* of 5
(mg/kg/day)"1 was calculated from the unadjusted q * by multiplying by
the cube root of the ratio of the human body weight (70 kg) to the rat body
weight (0.75 kg).
The highest q * of 9.3 (mg/kg/day)""1 resulted from the combined
'Incidences of nasal tumors 1n male rats from the E.I. DuPont de Nemours and
Co. (1986) study and Is recommended for estimating the Increased lifetime
risk of human exposure to 1,4-d1chloro-2-butene. The concentrations of
l,4-d1chloro-2-butene 1n air of 4xlO~«, 4xlO~7 and 4xlO~8 mg/m3,
associated with Increased lifetime risk of cancer at levels of 10~5,
10~6 and 10~7, respectively, were calculated by dividing the risk level
by the q,*, multiplying by 70 kg and dividing by 20 m3/day. Since no
cardnogenldty studies are available for the other Isomers of dlchloro-
butene and no pharmacoklnetlcs Information Is available, 1t 1s Inappropriate
to consider the q,* for 1,4-d1chloro-2-butene protective for all members
of the class.
0031d -42- 06/09/87
-------
8.1.5.2. ORAL Data regarding the oral carclnogenlclty of dlchloro-
butenes were not available. 1,4-D1chloro-2-butene, however, Induced
slte-of-contact tumors (nasal cavity) 1n rats exposed by Inhalation (see
Section 6.2.1.). Since these tumors developed at the site of contact, 1t 1s
reasonable to assume that Ingestlon of 1,4-d1chloro-2-butene may also result
In site of contact tumors, perhaps squamous cell carcinomas of the stomach.
This evidence was considered Inadequate to derive an oral q * because of
the route-to-route extrapolation and the site of contact reactivity. There
were no carclnogenlclty studies available for the other Isomers of
dlchlorobutene as cited 1n Appendix A.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) -- Interim kills
of rats at 3-12 months of Inhalation exposure to 1,4-d1chloro-2-butene
revealed' dose- and time-related Increased Incidences and severity of upper
respiratory tract lesions at concentrations of 0.1-5.0 ppm (0.5-25.6
mg/m3), 6 hours/day, 5 days/week (E.I. DuPont de Nemours and Co., 1985a,
1986). As early as 10 months to 1 year, however, benign and malignant
tumors of the nasal cavity were observed; therefore, even shorter-term
exposure resulted In a carcinogenic effect and 1t 1s probable that the early
lesions were preneoplastlc. Therefore, 1t Is not appropriate to derive an
RfD for subchronlc Inhalation exposure to 1,4-d1chloro-2-butene.
As discussed In Section 6.1.1.2., studies were available from the
Russian literature on subchronlc Inhalation exposure to Isomers of dlchloro-
butene other than 1,4-d1chloro-2-butene (Petrosyan and Glzhlaryan, 1982a,b;
Petrosyan et a "I., 1983; Vartazaryan and Mezhlumyan, 1974; Gasparyan and
Barsegyen, 1970). Translations were obtained for these studies; however,
because of the Inexact reporting of dosing schedules and the lack of
0031d -43- 09/08/87
-------
specific details, It would be Inappropriate to derive RfDs for these Isomers
based on such a .weak data base.
8.2.1.2. CHRONIC EXPOSURES -- Chronic . Inhalation exposure of rats to
l,4-d1chloro-2-butene resulted In a carcinogenic effect (see Section 8.1.);
therefore, calculation of a chronic Inhalation RfD Is not appropriate.
Pertinent data regarding chronic Inhalation exposure to Isomers of dlchloro-
butene other than 1,4-d1chloro-2-butene could not be located In the avail-
able literature as cited 1n Appendix A.
8.2.2. Oral Exposures. Since 1,4-d1chloro-2-butene was considered to be
a carcinogen by the Inhalation route and no data were available by the oral
route, the data were suggestive that the compound was also a carcinogen by
the oral route. .Therefore, an RfD was not derived. Pertinent data
regarding chronic exposure to the dlchlorobutene Isomers could not be
located 1n the available literature as cited In Appendix A.
8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) -- As discussed In
Section 6.1.2.1., two subchronlc oral exposure studies were located from the
Russian literature (Erzhkalsyan, 1985; Petrosyan et al., 1983) on Isomers^
other than 1,4-d1chloro-2-butene. Translations of both studies were
obtained; however, 1n both cases the experimental details were lacking and
therefore no RfD could be generated with any degree of confidence.
8.2.2.2. CHRONIC EXPOSURES -- Pertinent data regarding chronic oral
exposure to Isomers of dlchlorobutene could not be located In the available
literature as cited 1n Appendix A.
0031 d -44- 09/08/87
-------
9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The systemic toxlclty of four Isomers of dlchlorobutene were discussed
1n Chapter 6. Many of the studies were from the Russian literature, and
although translations were obtained (Bal'yan et al., 1983a,b; Petrosyan et
al., 1983; Petrosyan and Glzhlaryan, 1982a,b; Erzhkalsyan, 1985; Vartazaryan
and Mezhlumyan, 1974), experimental details were not reported adequately, so
1t was difficult to associate effects with dose levels and routes of expo-
sure. Dosing schedules generally were not well defined; therefore, trans-
formation of the exposure data Into an animal dose or Into a human equiva-
lent dose could not be accomplished with -any degree of accuracy, which
precludes the derivation of an RQ. In the studies reported by E.I. DuPont
de Nemours et al. (1985a, 1986), Inhalation exposure of rats to 1,4-dl-
chloro-2-butene resulted In the Induction of nasal cavity tumors and other
upper respiratory tract , lesions. There was also Increased mortality. It
would not be appropriate to derive an RQ based on systemic toxlclty from
these data because any "nonneoplastlc lesion" or Increased mortality was
probably preneoplastlc or secondary to the carcinogenic affect (Table 9-1).
Nonetheless, a summary of the data base for each Isomer follows.
Inhalation exposures of 1,4-d1chloro-2-butene ranging from 1.77-8.7
mg/m3 for an unspecified number of hours/day or days/week for up to 4
months In rats were associated with decreased spermatogenesls Index (Bal'yan
et al., 1983a) and Increased urinary chlorides and urinary creatlnlne
(Petrosyan et al., 1983). Similar effects were reported at 1ntragastr1c
doses of 0.1-0.001 mg/kg 1n rats for up to 6 months; however, details of
dosing were unclear and the dose level or levels at which the effects
0031d -45- 09/08/87
-------
TABLE 9-1
Olchlorobutene
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Dose:
Effect:
Reference:
RVd:
RVe:
Composite Score:
RQ: Data are not appropriate for deriving an RQ
based on systemic toxlclty.
0031d -46- 09/08/87
-------
occurred could not be determined. Kennedy et al. (1982) reported no embryo-
toxic or teratogenic effect when 1,4-dichloro-2-butene was administered to
rats by inhalation at 2.6 and 25.6 mg/m3 on days 6-15 of gestation.
Balyan et al. (1983b), however, reported an Increase in postlmplantation
mortality when the compound was administered to rats at 33.9 mg/m3 for the
first 20 days of pregnancy; however, one-half of the dams also died at this
dose. Some fetal effects may also have occurred at lower concentrations
(1.6-9.2 mg/m3), but because of inadequate reporting, no RQ could be
calculated with any degree of confidence.
Effects on the liver, lung, kidney, brain and nitrogen metabolism were
reported when rats were exposed by inhalation to 3,4-dichloro-l-butene at
14.5-203.4 mg/m3 for 4 months (Petrosyan and Gizhlaryan, 1982a) or orally
at 200 mg/kg for 5 months (Erzhkalsyan, 1985). Because of the inadequate
reporting of details, however, no RQ could be derived.
Central nervous' system effects were reported in rats at inhalation
concentrations of 1,4-dichloro-l-butene of 1.77-21.2 mg/m3 for 30 days
(Petrosyan and Gizhlaryan, 1982b). No effects were reported on renal func-
tion when the same compound was administered to rats at inhalation levels of
14.5-203.4 mg/m3 for 4 months or orally at doses of 0.01-1 mg/kg for 6
months (Petrosyan et al., 1983). Again, because experimental details were
missing, an RQ for the isomer could not be derived.
Degenerative hepatic effects, changes In liver alkaline phosphatase
activity and metabolism of glycogen and fat were reported when 1,3-dichloro-
2-butene was administered to rats at inhalation concentrations of 0.1 and
0.2 mg/l for 5 months (Vartazaryan and Mezhlumyan, 1974). Again, Inade-
quate and general reporting precluded derivation of an RQ for the Isomer.
0031d - -47- 09/08/87
-------
Pertinent data regarding the systemic toxicHy of the other Isomcrs of
dichlorobutene could not be located In the available literature as cited In
Appendix A.
9.2. BASED ON CARCINOGENICITY
A cohort study showed a risk of pancreatic cancer from exposure to
1,4-d1chloro-2-butene. However, the study was limited by a low number of
cases and was judged by the Carcinogen Assessment Group not to be adequate
linked epidemiologic evidence. 1,4 -Dichloro-2-butene was carcinogenic to
male and female rats treated by chronic inhalation exposures, as evidenced
by statistically significant Increased incidences of benign and malignant
nasal tumors (E.I. OuPont de Nemours and Co., 1985a, 1986) (see Section
6.2.1. and Tables 6-1 and 6-2). Using the U.S. EPA (1986) criteria, there
is sufficient evidence of carcinogenicity of 1,4-d1chloro 2-butene in
animals based on the increased incidences of combined nasal tumors in these
studies and mutagenicity data. Compounds with no or inadequate human data
and sufficient animal evidence of carcinogenicity are categorized in EPA
Group 82. No pertinent data are available for classification of the other
Isomers of dichlorobutene.
Since 1,4 dichloro 2 -buteno was carcinogenic to rats, it is possible to
calculate a potency factor (F). As discussed in Sections 8.1.5.1. and
8.1.5.2. the highest q * of 9.3 (rng/kg/day)"1 for inhalation exposure
was derived from the combined incidences of benign and malignant nasal
tumors in male rats from the study reported by E.I. OuPont de Nemours and
Co. (1986) (see Appendix B). Using the same data, the unadjusted "1/En-,Q
was calculated using the computerized multistage model (Global 82) developed
by Howe and Crump (1982) (Table 9-2). The unadjusted 1/ED1Q of 10.8
(mg/kg/day)"1 was corrected for Interspecles dose extrapolation by
multiplying by the cube root of the ratio of the human body weight (70 kg)
0031d . -48- 09/08/87
-------
TABLE 9-2
Derivation of Potency Factor (F factor) for 1,4-D1chloro-2-butene
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:
Tumor type:
Transformed doses (mg/kg/day):
Tumor Incidence:
Unadjusted 1/ED10:
Adjusted 1/ED10 (F factor):
E.I. DuPont de Nemours and Co., 1986
Inhalation
rat
Charles River, CD
ma 1 e
air
0.35 kg (assumed)
2 years (low dose); 1 year (high dose)
2 years
2 years
nasal cavity
combined benign and malignant nasal
tumors
Experimental doses/exposures (mg/m3): 0
2.6 (6 hours/day, 1.6 (TWA)*
5 days/week)
0 0.29
0/128 42/130
10.808719 (mg/kg/day)~i
63.209772 (ing/kg/day)'*
1.02
114/129
*See Section 8.1.5.1.
0031d
-49-
09/08/87
-------
to the average weight of the male rat (0.35 kg) 1n the study. The resulting
adjusted 1/EO-,0 or F factor 1s 63 (mg/kg/dayT1.
Since the F factor Is between 1 and 100, 1,4-d1chloro-2-butene Is placed
1n Potency Group 2. A Potency Group 2 chemical with an EPA classification
of 82 ranks MEDIUM 1n the Hazard Ranking scheme under CERCLA. With a medium
hazard ranking, the cancer-based RQ for 1,4-d1chloro-2-butene would be 10.
Insufficient data preclude hazard ranking of the other Isomers of
dlchlorobutene.
0031d -50- 09/08/87
-------
10. REFERENCES
Aldrlch. 1984. Aldrlch Catalog/Handbook of Fine Chemicals. Aldrlch
Chemical Co., Inc., MHwakee, WI. p. 366.
Applegate, V.C., J.H. Howell, J.R. Hall and M.A. Smith. 1957. Tox1c1ty of
4346 Chemicals to Larval Lampreys and Fishes. Spec. Sc1. Rep. Fish. No.
207, Fish Wild!. Serv. USDI, Washington, DC. (Cited In U.S. EPA, 1986b)
Bal'yan, V.V., F.R. Petrosyan and M.S. Glzhlaryan. 1983a. Embryotoxlc
effect of 1,4-d1chloro-2-butene In Inhalation administration. Zh. Eksp.
Klin. Med. 23(2): 118-121. (In Russian with English translation)
Bal'yan, V.V., F.R. Petrosyan and M.S. Glzhlaryan. 1983b. Effect of
1,4-d1chlorobutene on reproductive function 1n experimental animals. B1ol.
Zh. Arm. 36(8): 663-667. (In Russian with English translation)
Barbln, A., G. Planche, A. Crolsy, C. Malavellle and H. Bartsch. 1978.
Detection of electrophlUc metabolites of halogenated olefins with
4-(4-n1tro-benzyl) pyrldlne (NBP) or with Salmonella typhlmurlum. Mutat.
Res. 53: 150.
Bartsch, H., C. Malavellle, A. Barbln, G. Planche and R. Montesano. 1976.
Alkylatlng and mutagenlc metabolites of halogenated olefins produced by
human and animal tissues. Proc. Am. Assoc. Cancer Res. 17: 77.
0031d -51- 09/08/87
-------
Bartsch, H., C. Malavellle, A.M Camus, et al. 1980. Validation and
comparative studies on 180 chemicals with S. typhlmurlum strains and V79
Chinese hamster cells 1n the presence of various metabolizing systems.
Mutat. Res. 76: 1-50.
Clary, J.3. 1977. Toxlclty of chloroprene, 1,3-d1chlorobutene-2 and
l,4-d1chlorobutene-2. Environ. Health Perspect. 21: 269-274.
E.I. OuPont de Nemours and Co. 1985a. Long-term Inhalation Study with
l,4-01chlorobutene-2 (DCB) 1n Rats. Final Report of a study conducted
8/25/80-9/23/82. Haskell Laboratory, Newark, DE. Report No. 477-85.
Mortality and Cancer Incidence Among Workers Exposed to 1,4-D1chlorobutene-2
at the Victoria Plant. OTS 8e Submission Doc. 10 88-8600021. Old Doc ID
8EHQ-1085-0567. Microfiche No. OTS 0509754.
E.I. DuPont de Nemours and Co. 1985b. Summarized Results from a Chronic
Inhalation Study of l,4-D1chloro-2-butene 1n Rats. OTS 8e Submission Doc.
ID 88-8500815. Old Doc ID 8EHQ-0985-0567. Microfiche No. OTS 0509754.
E.I. DuPont de Nemours and Co. 1986. Long-term Inhalation Study with
l,4-D1chlorobutene-2 (DCB) In Rats. Final Report 1n a study conducted
11/1/76-11/7/78. Haskell Laboratory Report No. 43-86. OTS 8(e) Submission
Doc ID 89-8680119. Old Doc. ID 8EHQ-0286-0567. Microfiche No. OTS 0509754.
Elsenrelch, S.J., B.B. Looney and J.D. Thornton. 1981. Airborne organic
contaminants 1n the Great Lakes ecosystem. Environ. Sc1. Techno!. 15(1):
30-38.
0031d -52- 09/08/87
-------
Erzhkalsyan, M.P. 1985. Study of some aspects of nitrogen metabolism In
chronic Intoxication by 3,4-dlchloro-l-butene. Zh. Eksp. Kiln. Med. 25(2):
125-127. (In Russian with English translation)
Gasparyan, E.I. and G.B. Barsegyan. 1970. Pathomorphologlcal changes In
the viscera of experimental animals under the chronic action of l,3-d1-
chloro-2-butene. 10(5): 18-22. (CA 74:97301n)
Gelger, D.L., C.E. Northcutt, D.J. Call and L.J. Brooke, Ed. 1985. Acute
toxldtles of organic chemicals to fathead minnows (Plmepheles promelas) of
Wisconsin - Superior, Center for Lake Superior Studies, p. 54.
Glzhlaryan, M.S. 1981. Toxldty of chlorine-substituted butenes 1n
relation to the position of chlorine 1n a molecule. G1g. Sanlt. 1: 92-93.
(CA 94:133429)
Glzhlaryan, M.S., S.A. Khechumov, F.R. Petrosyan, et al. 1984. Experimental
basis for the maximum allowable concentration of 3,4-d1chlorobutene In the
work environment. G1g. Tr. Prof. Zabol. 9: 45-47. (CA 102:19046r)
Glzhlaryan, M.S., S.A. Khechumov, F.R. Petrosyan, et al. 1985. Experimental
data on the hygienic evaluation of 1,4-d1chloro-2-butene In workplace air.
G1g. Tr. Prof. Zabol. 4: 49-50. (CA 102:216498r)
Green, H.A., J.J. MeManos and A.N. Petroccl. 1975. M1crob1oc1dal poly-
meric quarternary ammonium compounds. U.S. Patent No. 3874870. (Mill
Master Onyx Corp.) (CA 83:73466e)
0031d -53- 09/08/87
-------
Gu, Z. 1981. Cytogenetlc effect of chloroprene by the method of sister
chromatid exchanges. Shans-ha1 T1 1 1 Hsueh Yuan Hsueh Pae. 8: 173-176.
(CA 95:198521y)
Hawley, G.6. 1981. The Condensed Chemical Dictionary, 10th ed. Van
Nostrand Relnhold Co., New York. p. 334.
H1ne, J. and P.K. Mookerjee. 1975. The Intrinsic hydrophlUc character of
organic compounds. Correlations 1n terms of structural contributions. J.
Org. Chem. 40: 292-298.
Howe, R.B. and K.S. Crump. 1982. GLOBAL 82. A Computer Program to
Extrapolate Quantal Animal Toxlclty Data to Low Doses. Prepared for Office
of Carcinogen Standards OSHA. U.S. Dept. of Labor under Contract No.
41USC252C3.
IARC (International Agency for Research an Cancer). 1977. trans-1,4-DI-
chlorobutene. In: IARC Monographs on the Evaluation of the Carcinogen Risk
of Chemicals to Han. Some Fumlgants, the Herbicides 2,4-0 and 2,4,5-T,
Chlorinated D1benzod1ox1ns and Miscellaneous Industrial Chemicals. WHO,
IARC, Lyons, France. Vol. 15, p. 149-154.
Jaber, H.M., W.R. Mabey, A.T. Liu, T.W. Cnou and H.L. Johnson. 1984. Data
acquisition for environmental transport and fate screening. SRI Inter-
national, Menlo Park, CA. EPA 600/6-84/009. NTIS PB84-243906, PB84-243955.
312 p.
0031d -54- 09/08/87
-------
Johnson, J.R. 1979. Chlorocarbons, hydrocarbons (chloroprene). In_: Kirk-
Othmer Encyclopedia of Chemical Technology, 3rd ed., Vol. 5, M. Grayson and
0. Eckroth, Ed. John Wiley and Sons, New York. p. 775-780.
Kaplan, E.L. and P. Meier. 1958. NonparametMc estimation from Incomplete
observations. J. Am. Stat. Assoc. 53: 457-481. (Cited 1n E.I. DuPont de
Nemours and Co., 1985a)
Kennedy, G.L., Jr., R. Cullk and H.J. Trochlmowicz. 1982. Teratogenlc
evaluation of 1,4-d1chlorobutene-2 1n the rat following Inhalation exposure.
Toxlcol. Appl. Pharmacol. 64(1): 125-130. .
Klrshenbaum, I. 1978. Butadiene. ITK Klrk-Othmer Encyclopedia of Chemical
Technology, 1st ed., Vol. 4, R.E. K1rk and D.F. Othmer, Ed. Intersdence
Encyclopedia, Inc, New York. p. 319.
Konemann, H. 1981. Quantitative structure-activity relationships in fish.
Tox1c1ty studies. Part 1. Relationship for 50 industrial pollutants.
Toxicology. 19(3): 209-221.
Lee, W.R., S. Abrahamson, R. Valencia, E.S. Von Halle, F.E. Wurgler and S.
Zlmmerlng. 1983. The sex-linked recessive lethal test for mutagenesls In
Drosophila melanoqaster. A report of the U.S. Environmental Protection
Agency Gene-Tox Program. Mutat. Res. 123(2): 183-279.
Luloff, J.S. and A.L. Eilender. 1975. Antibacterial composition employing
a certain hexamethylenetetramlne adduct. U.S. Patent No. 3928607 12/23/75
(Cosan Chemical Corp.) (CA 84:111661v)
0031d -55- . 09/08/87
-------
Lyman, W.J., W.F. Reehl and D.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Methods. McGraw H111 Book Co., New York. p. 4-9, 5-5,
15-16.
Mlrzabekyan, G.I., K.Kh. Oganesepan and Zh.S. Akopdzhanyan. 1967. Morpho-
logical change In the thyroid gland of rats under the effect of l,3-d1-
chloro-2-butene. (CA 69:17730k)
Mukal, F.H. and I. Hawryluk. 1973. Mutagenldty of some halo-ethers and
halo-ketones. Mutat. Res. 21: 228.
Nalbandyan, T.I. and M.S. Glzhlaryan. 1985. Effect of 1,4-d1chloro-2-
butene and 3,4-d1chloro-l-butene on chromosomes of albino rats. Zh. Eksp.
Klin. Med. 25(4): 335-339. (CA 104:46969s)
Neely, W.B. and G.E. Blau. 1985. Environmental Exposure from Chemicals.
Vol. 1. CRC Press Inc., Boca Raton, FL. p. 30-31.
NIOSH (National Institute for Occupational Safety and Health). 1984. RTECS
(Registry of Toxic Effects of Chemical Substances).
Oganesyan, K. Kh. and Zh. S. Akopdzhanyan. 1969. Hlstologlcal changes In
albino rat kidneys under the Influence of a dlchlorlde [1,3-d1chloro-2-
butene]. Zh. Eksplklln. Med. 9(5): 13-17. (CA 72:88447w)
0031d -56- - 09/08/87
-------
Peto, R., M. P1ke, N. Day, et al. 1980. Guidelines for simple, sensitive,
significant tests for carcinogenic effects In long-term animal experiments.
IARC Monographs on the long-term and short-term screening assays for car-
cinogens. A critical approach. Supplement 2. World Health Organization,
Geneva. p. 311-426. (Cited 1n E.I. de Pont Nemours and Co., 1985a)
Petrosyan, F.R. 1983. Pathological-histological and histochemlcal changes
1n organs of animals In experimental 1,4-d1chlorobutene poisoning. Izv.
S-kh. Nauk. 26(4): 59-63. (CA 99:134978c)
Petrosyan, F.R. and M.S. Glzhlaryan. 1982a.. Morphological alterations In
acute and chronic 3,4-d1chlorobutene poisoning. Zh. Eksp. Klin. Med.
22(3): 225-230. (In Russian with English translation)
Petrosyan, F.R. and M.S. Glzhlaryan. 1982b. Structural changes 1n the
brain during 1,4-d1chlorobutene poisoning. B1ol. Zh. Arm. 35(1): 25-29.
(In Russian with English translation)
Petrosyan, F.R., M.S. Glzhlaryan, A.S. Kazaryan, S.A. Khechumov and A.K.
Evranyan. 1981. Pathomorphologlcal changes 1n animal organs after a single
exposure to 1,4-d1chlorobutene. Blol. Zh. Arm. 34(7): 698-702. (CA-
95:144954y)
Petrosyan, F.R., V.V. Bal'yan and M.S. Glzhlaryan. 1982. Effect of
1,4-d1chlorobutene on the mother-placenta-fetus system. B1ol. Zh. Arm.
35(5): 380-384. (In Russian with English translation)
0031d -57- 09/08/87
-------
Petrosyan, F.R., M.S. Glzhlaryan, S.A. Khechumov, A.K. Ervanyan, N.A.
Darblnyan and G.V. Kavkasyan. 1983. Effect of dlchlorobutenes on the func-
tion and structure of the kidneys. Zh. Eksp. Kiln. Med. 23(5).: 417-421.
(In Russian with English translation)
Petrosyan, F.R., M.S. Glzhlaryan and S.A. Khechumov. 1984. Acute toxlclty
of l,3-d1chlorobutene. Blol. Zh. Arm. 37(1): 73-77. (CA 100:204646h)
Sabljlc, A. 1984. Predictions of the nature and strength of soil sorptlon
of organic pollutants by molecular topology. J. Agrlc. Food Chem. 32:
243-246.
Sax, N.I. 1984. Dangerous Properties of Industrial Materials, 6th ed. Van
Nostrand Relnhold Co., New York. p. 936-937.
Smiley, R.A. 1981. NUrlles. In: K1rk-0thmer Encyclopedia of Chemical
Technology, 1st ed., Vol. 15, R.E. K1rk and D.F. Othmer, Ed. Intersdence
Encyclopedia, Inc., New York. p. 899.
SRI (Stanford Research Institute). 1984. 1984 Directory of Chemical
Producers: United States of America. SRI International, Menlo Park; CA.
SRI (Stanford Research Institute). 1985. 1985 Directory of Chemical
Producers: United States of America. SRI International, Menlo Park, CA.
SRI (Stanford Research Institute). 1986. 1986 Directory of Chemical
Producers: United States of America. SRI International, Menlo Park, CA.
0031d . -58- 09/08/87
-------
Stockel, R.F. and M. Jelling. 1985. Antimicrobial composition for disin-
fecting various objects. U.S. Patent No. 4499077, 2/12/85. (CA 102:191185w)
Swann, R.L., D.A. Laskowskl, P.J. McCall, K. Vander Kuy and H.J. Dlshburger.
1983. A rapid method for the estimation of the environmental parameters
octanol/water partition coefficient, soil sorptlon constant, water to air
ratio and water solubility. Res. Rev. 85: 17-28.
U.S. EPA. 1977. Computer print-out of nonconf1dent1al production data from
TSCA Inventory. OPTS, CIO, U.S. EPA, Washington, DC.
U.S. EPA. 1980. Guidelines and Methodology Used in the Preparation of
Health. Effect Assessment Chapters of the Consent Decree Water Quality
Criteria Documents. Federal Register. 45(231): 49347-49357.
U.S. EPA. 19833, Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxiclty Data. Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1983b. Health and Environmental Effects Profile for Dlchloro-
butene. Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office
of Solid Waste and Emergency Response, Washington, DC.
0031d -59- 09/08/87
-------
U.S. EPA. 1986a. Methodology for Evaluating Cardnogenlclty In Support of
Reportable Quantity Adjustments Pursuant to CERCLA Section 102. Prepared by
the Office of Health and Environmental Assessment, Washington, DC for the
Office of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1986b. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1987a. Graphical Exposure Modeling System (GEMS). CLOGP
computer program. Office of Toxic Substances, U.S. EPA, Washington, DC.
U.S. EPA. 1987b. Graphical Exposure Modeling System (GEMS). Fate of Atmo-
spheric Pollutants (FAP). Office of Toxic Substances, U.S. EPA, Washington,
DC.
U.S. EPA/NIH (National Institute of Health). 1986. OHM-TADS (011 and
Hazardous Materials Technical Assistance Data System). On-Hne: December,
1986.
Van Duuren, B.L., B.M. Goldschmldt and I. Seldman. 1975. Carcinogenic
activity of d1- and trlfunctlonal alpha-chloro ethers and of 1,4-d1chloro-
butene-2 In ICR/HA Swiss mice. Cancer Res. 35(9): 2553-2557.
Vartazaryan, N.D. and L.M. Mezhlumyan. 1974. Morpho-hlstochemlcal altera-
tions 1n the liver 1n experimental dlchlorobutene poisoning. G1g. Tr. Prof.
Zabol. 6: 51-52. (In Russian with English translation)
0031d -60- 09/08/87
-------
Vogel, E. 1979. MutagenlcHy of chloroprene, 1-chloro-l ,3-trans-butadlene,
1,4-d1chlorobutene-2 and 1,4-d1ch1oro-2,3-epoxybutane in Drosophlla melano-
gaster. Mutat. Res. 67(4): 377-381.
Weast, R.C. 1985. CRC Handbook of Chemistry and Physics, 66th ed. CRC
Press, Inc., Boca Raton, FL. p. C-172.
OOSld -61- 09/08/87
-------
APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
TSCATS
CASR online (U.S. EPA Chemical Activities Sta'tus Report)
TOXLINE
TOXBACK 76
TOXBACK 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
These searches were conducted 1n December, 1986. In addition, hand searches
were made of Chemical Abstracts (Collective Indices 5-9), and the following
secondary sources should be reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986-1987. TLVs: Threshold Limit Values for Chemical Substances In
the Work Environment adopted by ACGIH with Intended Changes for
1986-1987. Cincinnati, OH. Ill p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John WHey and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 28. 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 Wiley and
Sons, NY. p. 3817-5112.
0031d -62- . 09/08/87
-------
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, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. WHO, IARC, 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.
SRI International, Menlo Park, CA. EPA 600/6-84-010. NTIS
PB84-243906.
NTP (National Toxicology Program). 1986. 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). 1986. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report In the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call 1n Programs.
Office of Pesticide Programs, Washington, DC.
U.S. EPA. 1985. CS8 Existing Chemical Assessment Tracking System.
Name and CAS Number Ordered Indexes. Office of Toxic Substances,
Washington, DC.
USITC (U.S. International Trade Commission). 1985.- Synthetic
Organic Chemicals. U.S. Production and Sales, 1984, USITC Publ.
1422, Washington, DC. .
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
0031d -63- 09/08/87
-------
In addition, approximately 30 compendia of aquatic toxldty 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 Fish and Aquatic Invertebrates. Summaries of
Toxldty 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 Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
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: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0031d -64- 09/08/87
-------
APPENDIX B-l
Cancer Data Sheet for Derivation of q-j*
Compound: 1,4-d1chloro-2-butene
Reference: E.I. DuPont de Nemours and Co., 1986
Species/straln/sex: rat, Charles River CD, male
Route/vehicle: Inhalation/air
Length of exposure (le) = 2 years (low dose), 1 year (high dose)
Length of experiment (Le) = 2 years
Llfespan of animal (L) = 2 years
Body weight = 0.35 kg (assumed)
Tumor site and type: nasal cavity, malignant and benign
Experimental Dose Transformed Dose Incidence
or Exposure (mg/kg/day) No. Responding/No. Tested
(mg/m3)
0
0.46a
1 . 6b
0
0.29
1.02
0/127
42/130
114/129
Unadjusted q-|* = 1.5846278 (mg/lcg/day)'1
Human q-|* = 9.2673563 (mg/kg/day)'1
a2.6 mg/m3 & hours/day, 5 days/week
bTWA, see Section 8.1.5.1
0031d -65- 09/08/87
-------
DATF
APPENDIX B-2
jata Sheet for Derivation of q-\*
Compound: 1,4-d1chloro-2-butene
Reference: E.I. DuPont de Nemours and Co., 1986
Specles/straln/sex: rat, Charles River CD, male
Route/vehicle: Inhalation/air
Length of exposure (le) = 2 years (low dose), 1 year (high dose)
Length of experiment (Le) = 2 years
Llfespan of animal (L) = 2 years
Body weight = 0.35 kg (assumed)
Tumor site and type: nasal cavity, malignant and benign
Experimental Dose
or Exposure
(mg/m3)
Transformed Dose
(mg/kg/day)
Incidence
No. Responding/No. Tested
0
0.46a
1.6°
0
0.29
1.02 '
0/128
24/128
114/129
Unadjusted q-|* = 5.4277325xlO~1 (mg/kg/day)"1
Human q-|* = 3.1741572 (mg/kg/day)"1
a2.6 mg/m3 6 hours/day, 5 days/week
bTWA, see Section 8.1.5.1
0031 d US. Environmental Protection At&ncy,
Region V, Library
230 South Dearborn Street
Illinois 60604
09/08/87
-------
APPENDIX B-3
Cancer Data Sheet for Derivation of q-j*
Compound: 1,4-d1chloro-2-butene
Reference: E.I. DuPont de Nemours and Co., 1985a
Specles/straln/sex: rat, Charles River CD, male
Route/vehicle: Inhalation/air
Length of exposure (le) = 19 months
Length of experiment (Le) = 24 months
Llfespan of animal (L) = 24 months
Body weight = 0.75 kg (measured)
Tumor site and type: nasal cavity, malignant and benign
Exposure*
(ppm)
0
0.1
0.3
1.0
Unadjusted
Human q-|* =
(mg/m3)
0
0.5
1.5
5.1
Transformed Dose
(mg/kg/day)
0
0.035
0.105
0.357
Incidence
No. Responding/No. Tested
1/159
4/146
14/148
35/126
q-l* = 1.0990859 (mg/kg/day)'1
4.985521 (rng/kg/day)'1
*6 hours/day, 5 days/week
0031d -67- . 09/08/87
-------
4)
U
e i.
e v/> i
o u
0 S
'O
e
41 e 9 3 o
o ** =
f i O vi
>3iis
* -o c i
VI 41 H» 41 .
4i e c JT > vi
o» 01 c u
o>^ ^ * o
3 a c wi i
vi 3 4i e o> 3
u -a o>»>
41
!-
d
a"
S. »
41 >
41 'O
a -o
I 3 >»
O ifl
I JB -3 l_
O
41
u
01
O
Q
X
4)
S"
e «-
o u
e
41
O>
U O
e
e
o u
X
o c
^ 41
Ol
u o
e
e «-
o u
c
e
o
41
iTJ
a
O
Z
0031 d
-68-
09/08/87
------- |