United St.t« f]NAL DRAFT
Environmental Protection ECAO-CIN-G037
Agency February, 1989
Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR 2-CHLORO-1,3-BUTADIENE (CHLOROPRENE)
Prepared for
OFFICE OF SOLID HASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
# Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE HCAMUMTERS U8RARY
EHVmONMENTAL PROTECTION AGENCY
NOT i CE WASHINGTON, D.C. 20460
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.
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DISCLAIMER
This document has been reviewed In accordance with the U.S. Environ-
mental Protection Agency's peer and administrative review policies and
approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Haste and Emergency Response (OSHER). This document series
1s Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained for Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for In this document
and the dates searched are Included 1n "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 subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD 1s an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval I.e., for an Interval that
does not constitute a significant portion of the llfespan. This type of
exposure estimate has not been extensively used, or rigorously defined as
previous risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfDs 1s the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfDs are not estimated. Instead,
a carcinogenic potency factor, or q-|* (U.S. EPA, 1980), is provided.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxlclty and carclno-
genldty are derived. The RQ 1s used to determine the quantity of a hazard-
ous substance for which notification 1s required In the event of a release
as specified under the Comprehensive Environmental Response, Compensation
and Liability Act (CERCLA). These two RQs (chronic toxlclty and carclno-
genlclty) represent two of six scores developed (the remaining four reflect
IgnltabllHy, reactivity, aquatic toxlclty, and acute mammalian toxlclty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxlclty and cancer based RQs are defined 1n U.S.
EPA, 1984b and 1986a, respectively.
Ill
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EXECUTIVE SUMMARY
2-Chloro-l,3-butad1ene (CAS number 126-99-8) Is commonly known as
chloroprene.. It Is a volatile, colorless liquid at room temperature with an
ethereal odor, and H will polymerize spontaneously unless stabllzed with a
polymerization Inhibitor. This compound Is mlsdble with most common
organic compounds. 2-Chloro-l,3-butad1ene 1s produced commercially by vapor
phase chloMnatlon of butadiene (Johnson, 1979). Du Pont 1n Laplace, LA, 1s
the only domestic manufacturer of this compound (SRI, 1987). An estimated
284 million pounds of this compound was produced 1n the United States In
1981 (HSOB, 1988). 2-Chloro-l,3-butad1ene 1s used almost exclusively,
without Isolation, In the production of polychloroprene, a synthetic rubber
used to make such Items as wire and cable covers, gaskets, automotive parts,
adheslves, caulks and flame-resistant cushioning (IARC. 1979).
If released to the atmosphere, 2-chloro-l,3-butadlene Is expected to
exist almost entirely In the vapor phase. The dominant removal mechanisms
are reaction with photochemlcally generated hydroxyl radicals and ozone.
The overall reaction half-life has been estimated to be 7.3 hours (U.S. EPA,
1987c). Anticipated reaction products Include H2CO, H2C=CC1CHO, OHCCHO,
C1COCHO, H2CCHCC10, chlorohydroxy adds and aldehydes (CupHt, 1980). If
released to water, volatilization Is expected to be the dominant removal
mechanism (estimated half-life from a model river Is 2.8 hours). There 1s
also potential for moderate adsorption to suspended solids and sediments.
Chemical hydrolysis, reaction with singlet oxygen and bloaccumulatlon In
aquatic organisms are not expected to be significant fate processes. Insuf-
ficient data are available to predict the significance of blodegradatlon In
1v
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either water or son. If released to soil, H appears that 2-chloro-l,3-
butadlene would either volatilize rapidly or percolate through soil.
Chemical hydrolysis 1s not expected to be an Important fate process.
A limited amount of monitoring data are available on 2-chloro-l,3-buta-
dlene. 2-Chloro-l,3-butadlene was detected 1n 1/204 water samples collected
from 14 heavily Industrialized river basins found 1n the United States
(Ewlng et al., 1977) and 1n 2/63 Industrial wastewater effluents 1n the
United States (Perry et al., 1979). This compound was monitored In the
ambient atmosphere of six cities In New Jersey throughout 1979. The average
concentration at these sites was 0.097 ppb (Markov et al., 1981). During
July 1976, this compound was found In the ambient atmosphere of Houston, TX,
at a concentration of 0.59 ppb (Brodzlnsky and Singh, 1982). 2-Chloro-l,3-
butadlene was not detected In the air samples collected above six abandoned
hazardous waste sites and one active sanitary landfill In New Jersey. The
detection limit In this study was 0.01 ppb (Markov et al., 1985). During
1976, the average atmospheric concentration of the compound 1n 2-chloro-l,3-
butadlene manufacturing plants ranged between 2 and 9 ppm (NIOSH, 1977}. At
one U.S. 2-chloro-l,3-butad1ene polymerization plant, 8-hour TWA exposure
levels In 1975 ranged from 0.51-39.18 ppm (NIOSH, 1977).
Pertinent data regarding the toxldty of 2-chloro-l ,3-butad1ene to
aquatic organisms or aquatic plants were not located In the available
literature.
There 1s little Information regarding the pharmacoklnetlcs of 2-chloro-
1,3-butadlene. Absorption of 2-chloro-l,3-butad1ene following Inhalation or
oral exposure Is Indicated only by effects seen following .admlnstratlon of
the compound 1n toxldty and carclnogenlclty studies. Data regarding the
distribution of 2-chloro-l,3-butad1ene following absorption were not located
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In the available literature. The Initial step 1n 2-chloro-l,3-butad1ene
metabolism appears to be the cytochrome P-450-catalyzed formation of an
epoxlde Intermediate, which may then react with glutathlone or form the
corresponding aldehyde (Summer and Grelm, I960, 1981; Grelm et al., 1981;
Haley, 1978; Bartsch et al., 1979). There Is both In. vivo and U) vitro
evidence for the Involvement of glutathlone In the metabolism of 2-chloro-
1,3-butadlene (Summer and Grelm, 1980, 1981; Grelm et al., 1981; Jaeger et
al., 1975a). In. vitro Russian studies summarized by Haley (1978) Indicate
that 2-chloro-l,3-butad1ene Is capable of taking up oxygen to form
peroxides. Pertinent data regarding the excretion of 2-chloro-l,3-butadiene
were not located In the available literature.
Acute, subchronlc and chronic Inhalation exposure to 2-chloro-1,3-buta-
dlene has been reported to result 1n growth retardation {Nystrom, 1948; E.I.
DuPont de Nemours and Co., 1985a,b,c; Clary et al., 1978). In addition to
this decrease In body weight, changes 1n the relative weights of a variety
of organs were noted. Significant changes were reported 1n the weights of
the liver, kidney, adrenals and lungs of rats following Inhalation exposure
to 2-chloro-l,3-butad1ene (E.I. DuPont de Nemours and Co., 1985a,c; Clary et
al., 1978). Effects of 2-chloro-l,3-butad1ene exposure on the reproductive
system were reported In a Russian study that noted a gonadotroplc effect of
2-chloro-l,3-butad1ene exposure 1n male rats and mice (Sanotskll, 1976).
Some toxldty studies of 2-chloro-l ,3-butad1ene, particularly the early
studies and the Russian studies, are difficult to Interpret because the
method of storage and handling of the compound are not reported. 2-Chloro-
1,3-butad1ene appears to be a particularly unstable compound, subject to
oxidation and dimerlzatlon; Nystrom (1948) has demonstrated tha.t these
reaction products of 2-chloro-l,3-butadiene are several times more toxic
than the pure compound.
vl
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Fasted rats, probably because of a reduction In "liver GSH content,
appear to be particularly susceptible to liver Injury following acute
Inhalation exposure to 2-chloro-l,3-butad1ene (Plugge and Jaeger, 1979;
Jaeger et al., 1975b).
Long-term 2-chloro-l ,3-butad1ene Inhalation cardnogenlclty studies
using rats and hamsters have been conducted. An 18-month hamster study
(E.I. DuPont de Nemours and Co., 1985b) and a 2-year rat study (E.I. OuPont
de Nemours and Co., 1985a) failed to show a carcinogenic effect of 2-chloro-
1,3-butad1ene at exposure levels <50 ppm. Two Russian studies (Khachatryan,
1972a,b) have suggested that 2-chloro-l,3-butad1ene exposure produces an
Increased risk of skin and lung cancer 1n occupatlonally-exposed persons.
These findings were not confirmed 1n studies done 1n the United States
(Pell, 1978). 2-Chloro-l,3-butad1ene also failed to produce a significant
Increase In tumor Incidence In rats exposed to the compound orally over the
course of a lifetime (Ponomarkov and Tomatls, 1980). Also, 2-chloro-l,3-
butadiene was not carcinogenic following application to the skin (Zll'fyan
et al., 1975, 1977).
2-Chloro-l,3-butad1ene has been demonstrated to be mutagenU to bacteria
(see Table 6-2) and caused chromosomal aberrations 1n humans and dominant
lethal effect In rodents (Sanotskll, 1976); this apparent Inconsistency
between the mutagenlclty of 2-chloro-l,3-butadlene and Its lack of a
:arc1nogen1c effect jm vivo has been suggested to be due to metabolic
Inactlvatlon of any carcinogenic Intermediates by glutathlone (Summer and
larelra, 1980). The U.S. EPA (1986c), based on the limited data available,
suggested that 2-chloro-l,3-butadlene 1s a mutagen and a clastogen.
In studies by E.I. DuPont de Nemours and Co. (1985j,k) and by Cullk et
al. (1978), 2-chloro-l,3-butadlene was found not to be teratogenlc In rats.
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There was some fetotoxUUy and lowered weight gain at the two highest
doses, which produced maternal toxIcHy. FetotoxIdty/teratogenUUy has
been reported In the Russian literature (Salnlkova and Fomenko, 1973, 1975;
Sanotskll, 1976) 1n rats exposed to 2-chloro-l,3-butad1ene. Once again, the
nature of the material used In the Russian exposures has been questioned
(Cullk et al., 1978). Reproductive effects In male mice and rats following
exposure to 2-chloro-l,3-butadlene have been reported In the Russian
literature {Sanotskll, 1976; Davtyan, 1972). These reproductive effects
were not observed In studies by E.I. DuPont de Nemours and Co. (1985d,m).
A chronic Inhalation RfD for 2-chloro-l,3-butadlene was calculated using
data from a 2-year Inhalation cardnogenldty rat study (E.I. DuPont de
Nemours and Co., 1985c). A NOAEL of 4.0 mg/kg/day was determined In this
study -and division of this NOAEL by an uncertainty factor of 100 (10 for
Interspedes extrapolation and 10 for sensitive human populations) resulted
1n a chronic Inhalation RfD for 2-chloro-l<3-butad1ene of 0.04 mg/kg/day or
3 mg/day for a 70 kg human. This chronic Inhalation RfD was also adopted as
the subchronlc Inhalation RfD for this chemical. Because of a lack of
pertinent oral toxldty data on 2-chloro-l ,3-butad1enef subchronlc and
chronic oral RfDs were calculated from Inhalation values u.slng appropriate
absorption factors (I.e., 50% absorption by the Inhalation route and 100%
absorption by the oral route). This resulted In subchronlc and chronic oral
RfDs for 2-chloro-l,3-butadlene of 0.02 mg/kg/day or 1.0 mg/day for a 70 kg
human. An Rq of 1000 was determined for 2-chloro-l,3-butad1ene; this RQ was
based on the effect of decreased fetal weight observed In a developmental
toxldty study using rats (E.I. DuPont de Nemours and Co., 1985k).
vlll
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 3
1.5. SUMMARY 3
2. ENVIRONMENTAL FATE AND TRANSPORT 4
2.1. AIR 4
2.1.1. Chemical Reactions 4
2.1.2. Photolysis 4
2.2. WATER 4
2.2.1. Hydrolysis 4
2.2.2. Oxidation 5
2.2.3. Bloaccumulatlon 5
2.2.4. Adsorption 5
2.2.5. Volatilization 5
2.2.6. Blodegradatlon 6
2.3. SOIL 6
2.3.1. Hydrolysis . . . 6
2.3.2. Leaching 6
2.3.3. Volatilization - 6
2.3.4. BlodegradaUon 6
2.4. SUMMARY 6
3. EXPOSURE 8
3.1. WATER 8
3.2. FOOD 8
3.3. INHALATION 8
3.4. DERMAL 9
3.5. SUMMARY 10
4. AQUATIC TOXICITY 11
5. PHARMACOKINETCS -. . . 12
5.1. ABSORPTION 12
5.2. DISTRIBUTION 12
5.3. METABOLISM 12
5.4. EXCRETION 14
5.5. SUMMARY 14
1x
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TABLE OF CONTENTS (cont.)
Page
8.
10,
EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposure
6.1.2. Oral Exposure
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. MUTAGENIC1TY
6.4. TERATOGENICITY
6.5. OTHER REPRODUCTIVE EFFECTS
6.6. SUMMARY
EXISTING GUIDELINES 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 CARCINOGENICITY
REFERENCES
D1X A: LITERATURE SEARCHED
DIX B: SUMMARY TABLE FOR 2-CHLORO-l ,3-8UTADIENE
.... 15
.... 15
.... 15
.... 19
.... 19
.... 23
.... 23
.... 27
.... 28
.... 29
.... 32
.... 34
.... 36
.... 38
.... 38
.... 38
.... 39
.... 39
.... 39
.... 39
.... 39
.... 40
.... 40
.... 40
.... 40
.... 44
.... 46
.... 46
.... 50
.... 53
.... 66
.... 69
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LIST OF TABLES
No.
6-1
6-2
9-1
9-2
Title
Acute Toxlclty of 2-Chloro-l ,3-butad1ene
Mutagen1c1ty Testing of 2-Chloro-l ,3-butadlene
Inhalation Toxlclty Summary for 2-Chloro-l ,3-butad1ene. . . .
Inhalation Composite Scores for 2-Chloro-l ,3-butadlene Using
the Rat
Page
20
30
47
49
9-3 2-Chloro-l,3-butadlene: Minimum Effective Dose (MED) and
Reportable Quantity 51
xl
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AKT Alanlne-a-ketoglutarate transamlnase
BCF Bloconcentratlon factor
bw body weight
CRO Chronic respiratory disease
CS Composite score
DMBA 9,10-D1methyl-l,2-benzanthracene
GSH Reduced glutathlone
K Soil sorptlon coefficient
K Octanol/water partition coefficient
LC5Q Concentration lethal to 50% of recipients
LD5Q Dose lethal to 50% of recipients
LOAEL Lowest-observed-adverse effect level
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
NPSH Non-protein .sulfhydryl groups
PEL Permissible exposure limit
ppb Parts per billion
ppm Parts per million
RfD Reference dose
RQ Reportable quantity
RV. Dose-rated value
RV Effect-rated value
TLV Threshold limit value
TWA Time-weighted average
v/v Volume per volume
xll
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
2-Chloro-l,3-butad1ene 1s commonly known as chloroprene (Johnson, 1979).
The structure, molecular weight, empirical formula and CAS Registry number
for this compound are as follows:
Cl
I
CH2=CH-C=CH2
Molecular weight: 88.54
Empirical formula: C,,HCC1
4 b
CAS Registry number: 126-99-8
1.2. PHYSICAL AND CHEMICAL PROPERTIES
2-Chloro-l,3^butad1ene Is a colorless, mobile, volatile liquid at room
temperature with an ethereal odor slmlllar to that of ethyl bromide.
2-Chloro-1,3-butad1ene autooxldlzes easily, polymerizes spontaneously at
room temperature and forms cyclic dlmers on prolonged standing In the
presence of -polymerization Inhibitors. Many organic and Inorganic compounds
add to the double bonds, usually on the first and fourth carbon atoms. The
chlorine atom, like that of vinyl chloride, 1s very unreactlve. 2-Chloro-
1,3-butad1ene 1s mlsdble with most organic compounds (Johnson, 1979).
Pertinent physical properties are as follows:
Boiling point: 59.4°C Johnson, 1979
Melting point: -130i2°C Johnson, 1979
Vapor pressure (25°C): 220 mm Hg Johnson, 1979
Log Kow: 2.06 U.S. EPA, 1987a
(estimated)
Water solubilty (25°C): 2088 mg/l U.S. EPA, 1987b
(estimated)
0112d -1- 05/05/88
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Density (2Q°C): 0.9585 Johnson, 1979
20
Refractive Index, n* : 1.4583 Johnson, 1979
Flashpoint (open cup): -20°C Johnson, 1979
Explosive limits 1n air: 4.0-20% Johnson, 1979
Odor threshold In air: 15 ppm Amoore and
Hautala, 1983
1n water: 0.024 ppm Amoore and
Hautala, 1983
1.3. PRODUCTION DATA
2-Chloro-l ,3-butad1ene 1s produced mainly from vapor phase chloMnatlon
of butadiene. The three essential steps Involved 1n the manufacture of
chloroprene by this method are as follows:
ChloMnatlon
CH2 = CH - CH = CH2 * C12 » C1CH2 - CH » CH - CH2C1 + C1CH - CHC1 - CH = CH2
Isomerlzatlon
catalyst
C1CH2 - CH = CH - CH2C1 « ± CH2 = CH - CHC1 - CH2C1
Dehydrohalogenatlon
CH2 = CH - CHC1 - CH2C1 + NaOH -» CH2 = CH - CC1 = CH2 * NaCl t H20
D1mer1zat1on, bulk polymerization and the formation of autocatalytlc "pop-
corn" polymer, which Is Insoluble 1n the monomer, are avoided 1n commercial
production by refrigeration at <0°C or by addition of Inhibitors where
higher temperatures or prolonged exposure are necessary (Johnson, 1979).
3-Chloro-l,3-butadlene Is manufactured 1n the United States by Du Pont In
Laplace, LA (SRI, 1987). It 1s estimated that 284 million pounds of
2-chloro-l,3-butad1ene was produced In the United States during 1981 (HSDB,
1988).
0112d -2- 05/05/88
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1.4. USE DATA
2-Chloro-l,3-butad1ene 1s used almost exclusively, without Isolation, 1n
the production of polychloroprene, a synthetic rubber used In wire and cable
covers, gaskets, automotive parts, adheslves, caulks, flame-resistant
cushioning and other applications requiring chemical, oil and weather
resistance or high gum strength {Johnson, 1979). The U.S. Food and Drug
Administration permits the use of 2-chloro-l,3-butad1ene as a component of
adheslves Intended for use 1n food packaging {IARC, 1979).
1.5. SUMMARY
2-Chloro-l,3-butadlene (CAS number 126-99-8) 1s commonly known as
chloroprene. It 1s a volatile, colorless liquid at room temperature with an
ethereal odor; H will polymerize spontaneously unless stabllzed with a
polymerization Inhibitor. This compound 1s mlsdble with most common
organic compounds. 2-Chloro-l,3-butad1ene Is produced commercially by vapor
phase chloMnatlon of butadiene (Johnson, 1979). Du Pont In Laplace, LA, 1s
the only domestic manufacturer of this compound (SRI, 1987). An estimated
284 million pounds of this compound was produced in the United States 1n
1981 (HSDB, 1988). 2-Chloro-l,3-butad1ene Is used almost exclusively,
without Isolation, 1n the production of polychloroprene, a synthetic rubber
used to make such Items as wire and cable covers, gaskets, automotive parts,
adheslves, caulks and flame-resistant cushioning (IARC, 1979).
0112d -3- 05/05/88
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Pertinent data regarding the environmental fate and transport of
2-chloro-l,3-butad1ene are limited. Whenever possible. Information concern-
Ing the environmental fate and transport of this compound was derived from
physical property data or molecular structure.
2.1.1. Chemical Reactions. Using the method of Atkinson (1987), the rate
constant for reaction of 2-chloro-l,3-butadlene vapor with photochemlcally
generated hydroxyl radicals 1n the atmosphere has been estimated to be
2.1X10'11 cm3/molecule-sec at 25°C. Based on this value and assuming an
average ambient hydroxyl radlcaT concentration of S.OxlO5 molecules/cm3,
the half-life for this reaction has been estimated to be 18 hours. The
half-life for reaction of 2-chloro-l,3-butad1ene vapor with ozone 1n the
atmosphere has been estimated to be 12 hours. This 1s based on an average
ozone concentration of 6.0X1011 molecules/cm3 and an estimated reaction
rate constant of 2.6xlO"17 cra3/molecule-sec at 25°C (U.S. EPA, 1987c).
Using these data, the overall reaction half-life of 2-chloro-l,3-butadlene
1n the atmosphere has been estimated to be 7.3 hours. Anticipated reaction
products Include H2CO. H2C=CC1CHO, OHCCHO, C1COCHO, H2CCHCC10, chloro-
hydroxy acids and aldehydes (Cupltt, 1980).
2.1.2. Photolysis. Because of the reactivity of 2-chloro-l,3-butad1ene,
removal from the atmosphere by wet or dry deposition 1s unlikely (CupHt,
1980).
2.2. WATER
2.2.1. Hydrolysis. 2-Chloro-l,3-butad1ene contains no hydrolyzable func-
tional groups; therefore, this compound 1s not expected to undergo chemical
hydrolysis under environmental conditions (Lyman et al., 1982; Jaber et al.,
1984).
0112d -4- 04/19/88
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2.2.2. Oxidation. Based on the molecular structure of 2-chloro-l,3-buta-
dlene, H appears that this compound could potentially react with naturally
occurring singlet oxygen found In surface waters. The half-life for the
reaction of substituted oleflns with singlet oxygen 1s -8 days (Mill and
Mabey, 1985). 2-Chloro-l,3-butadlene Is, however, an extremely volatile
compound, and compared with volatilization, this reaction 1s expected to be
a relatively unimportant removal process (Section 2.2.5.). Pertinent data
regarding reaction of 2-chloro-l,3-butad1ene with other oxldants found 1n
natural water were not located 1n the available literature cited 1n
Appendix A.
2.2.3. B1oaccumulat1on. A BCF of 22 was estimated using a log K w of
2.06 (U.S. EPA, 1987a) and the following linear regression equation (Lyman
et a!., 1982):
log BCF = 0.76 log KQw - 0.23 (2-1)
^^ This BCF value suggests that bloaccumulatlon 1n aquatic organisms Is not a
~ significant environmental fate process for 2-chloro-l,3-butadlene.
2.2.4. Adsorption. An estimated K value of 315 (Section 2.3.1.)
suggests that 2-chloro-l,3-butad1ene may adsorb moderately to suspended
solids and sediments 1n water.
2.2.5. Volatilization. Henry's Law constant for 2-chloro-l,3-butadlene
has been estimated to be 3.1xlO"2 atm-mVmol at 25°C using a method of
bond contributions to Intrinsic hydrophlllc character (Mine and Mookerjee,
1975). This value of Henry's Law constant suggests that volatilization
would be rapid from all bodies of water (Lyman et al., 1982). The half-life
for 2-chloro-l,3-butad1ene volatilizing from a model river 1 m deep, flowing
1 m/sec, with a wind speed of 3 m/sec has been estimated to be 2.8 hours,
using Henry's Law constant and the method of Lyman et al. (1982).
0112d -5- 05/05/88
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2.2.6. Blodegradatlon. Pertinent data regarding blodegradatlon of
2-chloro-l,3-butad1ene were not located 1n the available literature cited In
Appendix A.
2.3. SOIL
2.3.1. Hydrolysis. This compound Is not expected to undergo chemical
hydrolysis under environmental conditions (Lyman et al., 1982; Jaber et al.,
1984).
2.3.2. Leaching. A K of 315 was estimated for 2-chloro-l,3-butad1ene
using a log KQU of 2.06 (U.S. EPA, 1987a) and the following linear regres-
sion equation (Lyman et al., 1982):
log KQC = 0.544 log KQW * 1.377 (2-2)
This K value suggests that 2-chloro-l,3-butadlene would be moderately
mobile In soil (Swann et al., 1983).
2.3.3. Volatilization. The relatively high vapor pressure of 2-chloro-
l,3-butad1ene [220 mm Hg at 25°C (Johnson, 1979)] suggests that this
" compound would volatilize rapidly from dry soil surfaces. It appears that
volatilization from moist soil surfaces' would also be rapid, as this com-
pound does not have a strong tendency to adsorb to soil and H Is expected
to volatilize rapidly from water (see Sections 2.2.4. and 2.3.1.}.
2.3.4. Blodegradatlon. Pertinent data regarding blodegradatlon of
2-chloro-l,3-butad1ene were not located 1n the available literature cited In
Appendix A.
2.4. SUMMARY
If released to the atmosphere, 2-chloro-l,3-butad1ene 1s expected to
exist almost entirely In the vapor phase. The dominant removal mechanisms
are reaction with photochemically generated hydroxyl radicals and ozone.
0112d -6- 04/19/88
-------
The overall reaction half-life has been estimated to be 7.3 hours (U.S. EPA,
1987c). Anticipated reaction products Include H2CO, H2C=CC1CHO, OHCCHO,
C1COCHO, H2CCHCC10, chlorohydroxy adds and aldehydes (CupHt, 1980). If
released to water, volatilization 1s expected to be the dominant removal
mechanism (estimated half-life from a model river 1s 2.8 hours). There 1s
also potential for moderate adsorption to suspended solids and sediments.
Chemical hydrolysis, reaction with singlet oxygen and bloaccumulatlon In
aquatic organisms are not expected to be slgnflcant fate processes. Insuf-
ficient data are available to predict the significance of blodegradatlon 1n
either water or soil. If released to soil, It appears that 2-chloro-l,3-
butadiene would either volatilize rapidly or percolate through soil. Chemi-
cal hydrolysis 1s not expected to be an Important fate process.
0112d -7- 04/19/88
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3. EXPOSURE
3.1. HATER
2-Chloro-l,3-butadhene was detected 1n 1 of 204 water samples collected
between August 1975 and September 1976 from 14 heavily Industrialized river
basins 1n the United States {Ewlng et al., 1977). The U.S. EPA STORET Data
Base (U.S. EPA, 1988) Indicates that 1.0 pg/i 2-chloro-l,3-butad1ene was
found 1n the surface water at one monitoring station. This compound was
Identified In 2 of 63 Industrial wastewater effluents 1n the United States
at concentrations of <10 and 10-100 pg/s. (Perry et al., 1979). During
1975, chlorobutadlenes were detected 1n the Rhine River at Basel, Koln and
Dulsburg at concentrations of 4.4, 0.4 and 0.3 pg/l, respectively
(Sonthelmer et al., 1985).
3.2. FOOD
Pertinent data regarding exposure to 2-chloro-l,3-butadlene by Ingestlon
of contaminated food were not located 1n the available literature cited 1n
Appendix A.
3.3. INHALATION
2-Chloro-l,3-butad1ene was detected 1n the ambient atmosphere of six
cities 1n New Jersey. The sampling sites were located In Elizabeth, Camden,
Newark, Rutherford, South Amboy and Batsto. Sampling In Camden was done
every 6th day from May to December 1979, but sampling 1n the other five
cities was done every 6th day for an entire year (1979). The average
concentration of 2-chloro-l,3-butad1ene at these sites was 0.097 ppb and the
maximum concentration detected was 4.0 ppb (Markov et al., 1981). During
July 1976, 2-chloro-l,3-butadlene was found In 2 of 2 samples of ambient air
from Houston, TX, with an average concentration of 0.59 ppb (Brodzlnsky and
Singh, 1982). During March 1977, ambient air from Baton Rouge, LA, was
0112d -8- 04/19/88
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analyzed, but 2-chloro-l,3-butad1ene was not found (Brodzlnsky and Singh,
1982). The air above six abandoned hazardous waste sites and one active
sanitary landfill 1n New Jersey was analyzed, but 2-chloro-l,3-butad1ene was
not found. A1r samples were collected at each site for 1 week during
1983-1984. The detection limit In this study was 0.01 ppb (Markov et al.,
1985).
In 1977, mean airborne concentrations of 2-chloro-l,3-butad1ene of <0.72
mg/m3 (0.2 ppm) were reported 1n the roll building area 1n a metal
fabricating plant where polychloroprene was applied extensively to metal
cylinders before vulcanization (IARC, 1979). Levels of airborne 2-chloro-
1,3-butadlene ranging from 2-12 ppm were found In the open factory area of a
floor-covering production plant; from 2-6 ppm were found 1n confined areas
where flooring material was applied; and from 2-20 ppm were found 1n areas
near production of dipped goods from polychloroprene latex {Nutt, 1976).
During 1976, the average atmospheric concentrations of 2-chloro-l,3-buta-
dlene In U.S. 2-chloro-l,3-butad1ene manufacturing plants ranged between 2
and 9 ppm (NIOSH, 1977). During 1973, at one U.S. 2-chloro-l,3-butadlene
polymerization plant, airborne concentrations of 2-chloro-l,3-butadlene were
found In the range of 50-5000 mg/m3 (14-1420 ppm) in the make-up area,
440-24,300 (130-6760 ppm) 1n the reactor area, 10-1500 mg/m3 (6-440 ppm)
1n the monomer recovery area and 400-900 mg/m3 (113-252 ppm) In the latex
area (IARC, 1979). At the same plant, 8-hour TWA exposure levels in 1975
ranged from 0.51-39.18 ppm (NIOSH, 1977). These levels were considerably
below those found in 1973 (NIOSH, 1977).
3.4. DERMAL
Pertinent data regarding exposure to 2-chloro-l,3-butadiene by dermal
contact were not located in the available literature cited in Appendix A.
0112d -9- 05/05/88
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3.5. SUMMARY
A limited amount of monitoring data are available on 2-chloro-l,3-buta-
dlene. 2-Chloro-l,3-butadlene was detected 1n 1/204 water samples collected
from 14 heavily Industrialized river basins {Ewlng et al., 1977) and 1n 2/63
Industrial wastewater effluents In the United States (Perry et al., 1979).
This compound was monitored \n the ambient atmosphere of six dtles In New
Jersey throughout 1979. The average concentration at these sites was 0,097
ppb (Harkov et al., 1981). During July 1976, this compound was found 1n the
ambient atmosphere of Houston, TX at a concentration of 0.59 ppb (Brodzlnsky
and Singh, 1982). 2-Chloro-l,3-butad1ene was not detected 1n the air
samples collected above six abandoned hazardous waste sites and one active
sanitary landfill In New Jersey. The detection limit 1n this study was 0.01
ppb (Harkov et al., 1985). During 1976, the average atmospheric
concentration of the compound In 2-chloro-l,3-butadlene manufacturing plants
ranged between 2 and 9 ppm (NIOSH, 1977). At one U.S.
2-chloro-l,3-butadlene polymerization plant, 8-hour TWA exposure levels In
1975 ranged from 0.51-39.18 ppm (NIOSH, 1977).
0112d -10- 05/05/88
-------
4. AQUATIC TOXICITY
Pertinent data regarding the toxlclty of 2-chloro-l ,3-butad1ene to
aquatic organisms or aquatic plants were not located 1n the available
literature.
0112d -11- 04/19/88
-------
5. PHARMACOKINETICS
5.1. ABSORPTION
Although studies regarding the toxlclty and carclnogenlcHy of 2-chloro-
1,3-butadlene Indicate that the compound 1s absorbed following oral and
Inhalation exposure, no studies dealing specifically with the rate or extent
of absorption of 2-chloro-l ,3-butadlene were located In the available
literature cited 1n Appendix A.
5.2. DISTRIBUTION
Pertinent data regarding the distribution of 2-chloro-l,3-butadlene
following Inhalation or oral exposure were not located In the available
literature cited In Appendix A.
5.3. METABOLISM
It has been postulated that because of structural similarities between
2-chloro-l,3-butadlene, vinyl chloride and vinylldene chloride, the metabo-
lism of the three compounds 1s similar (Haley, 1978).. The first step In
2-chloro-l,3-butad1ene metabolism 1s therefore assumed to be cytochrome
P-450-mediated formation of an epoxlde Intermediate (Summer and Greim, 1980,
1981; Greim et a!., 1981; Haley, 1978). The epoxlde could then combine with
glutathlone or give rise to the corresponding aldehyde (Haley, 1978),
Evidence for epoxlde formation In the metabolism of 2-chloro-l,3-butadlene
comes from the study by Bartsch et al. (1979) in which a gaseous mixture of
2-chloro-l ,3-butadiene was passed through a mouse-Hver mlcrosomal
suspension and then through a solution of 4-(4-n1trobenzyl)pyr1d1ne 1n a
specially designed siphon-type apparatus to trap any alkylating
metabolite(s) that may have been formed. The demonstration that an
alkylating intermediate was formed led Bartsch et al. (1979) to propose that
epoxlde formation had occurred and that one or both of the two Uomerlc
0112d -12- 03/13/89
-------
epoxldes, 2-chloro-l,2-epoxy-butene-3 and 2-chloro-3,4-epoxy-butene-l, had
been formed, |n vivo studies In rats In which there was a decrease 1n
hepatic GSH levels 3 hours after administration of a single oral dose of the
compound (100-200 mg/kg) provide evidence for the Involvement of gluta-
thlone In 2-chloro-l,3-butad1ene metabolism (Summer and Greim, 1980, 1981).
In these Ui vivo studies, there was also an Increase 1n urinary thloether
excretion (I.e., GSH conjugates and mercapturlc add) following oral admin-
istration of 2-chloro-l,3-butad1ene (Greim et al.t 1981; Summer and Greim,
1980, 1981). Experiments that demonstrate GSH depletion in Isolated rat
hepatocytes Incubated with 2-chloro-l,3-butadlene (0.5-3.0 mM) provide in
vitro evidence for the Involvement of glutathlone In 2-chloro-l,3-butadlene
metabolism (Summer and Greim, 1980; Greim.et a!.. 1981). Indirect evidence
for the Involvement of glutathlone conjugation In the metabolism of
2-chloro-l,3-butadlene comes from a biochemical toxicology study by Jaeger
et al. (1975a). In this study, the effects of short-term (I.e., 4 hours)
Inhalation exposure to 2-chloro-l,3-butad1ene 1n rats at concentrations of
<10,000 ppm (36 g/m3) were compared for fed and fasted animals and for
animals exposed at different times during their clrcadlan rhythm. At night
and In fasted animals, the content of GSH 1n the rat liver Is greatly
diminished. Exposure of fasted rats to 2-chloro-l,3-butadlene and exposure
of rats to 2-chloro-l,3-butad1ene at night enhanced the hepatotoxlc effects
of the compound compared with the effects seen In fed rats or rats exposed
during the day.
Findings from j_n vitro Russian studies as reviewed by Haley (1978) Indi-
cate that 2-chloro~l,3-butad1ene Is capable of taking up oxy
-------
5.4. EXCRETION
Pertinent data regarding the excretion of 2-chloro-l,3-butad1ene were
not located 1n the available literature dted In Appendix A.
5.5. SUMMARY
There Is Uttle Information regarding the pharmacoklnetlcs of 2-chloro-
1,3-butadlene. Absorption of 2-chloro-l,3-butad1ene following Inhalation or
oral exposure 1s Indicated only by effects seen following admlnstratlon of
the compound 1n toxldty and cardnogenlcHy studies. Data regarding the
distribution of 2-chloro-l,3-butad1ene following absorption were not located
1n the available literature. The Initial step 1n 2-chloro-l ,3-butadlene
metabolism appears to be the cytochrome P-450-catalyzed forma-tlon of an
epoxlde Intermediate, which may then react with glutathlone or form the
corresponding aldehyde (Summer and Grelm, 1980, 1981; Grelm et al., 1981;
Haley, 1978; Bartsch et al.. 1979). There Is both jm vivo and Vn vitro
evidence for the Involvement of glutathlone In the metabolism of 2-chloro-
1,3-butadlene (Summer and Grelm, 1980, 1981; Grelm et al., 1981; Jaeger et
al., 1975a). in vitro Russian studies summarized by Haley (1978) Indicate
that 2-chloro-l,3-butadlene 1s capable of taking up oxygen to form
peroxides. Pertinent data regarding the excretion of 2-chloro-l,3-butad1ene
were not located In the available literature.
0112d -14- 04/19/88
-------
6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposure.
6.1.1.1. SUBCHRONIC ~ Toxlclty studies of 2-chloro-l,3-butad1ene are
complicated by the fact that the compound 1s unstable and 1s subject to
autooxldatlon and d1mer1zation to form polyperoxldes (Clary, 1977). The
degradation products formed from 2-chloro-l,3-butad1ene are apparently more
potent than the parent compound with respect to the production of toxic
effects; Nystrom (1948) demonstrated that 2-chloro-l,3-butad1ene stored for
several days at room temperature In the presence of air Is ~4 times more
toxic than the pure compound.
Nystrom (1948) exposed two groups of rats (10/group - strain and sex not
specified) to 2-chloro-l,3-butadlene concentrations' of 56 and 334 ppm (203
and 1210 mg/m3). Exposure was 8 hours/day for 5 months. At the high
JUt concentration, half of the animals died by the end of week 13 of exposure.
This exposure level (334 ppm) also led to significant decreases In body
weight, red blood cell count and blood hemoglobin concentrations. Blood
leukocyte levels Increased. Statistical analyses of these changes were not
given and only mean values were reported. Ihese changes 1n body weight and
blood were not observed In animals exposed to 56 ppm 2-chloro-l,3-butad1ene,
and this exposure level therefore constitutes a NOEL for this study. Data
from this study (Nystrom, 1948) were obtained from a summary provided by
NIOSH (1977); more detailed Information pertaining to the purity of the
compound, exposure schedule, the existence of a control group of animals and
other parameters gf toxlclty evaluated was not provided.
A 26-week subchronic study on the Inhalation toxlclty of 2-chloro-l,3-
butadiene In rats was performed by E.I. DuPont de Nemours and Co. (1985a).
0112d -15- 03/13/89
-------
Four groups of Wlstar rats (40/sex/group) were exposed to atmospheres
containing 2-chloro-l,3-butad1ene (purity not reported) at concentrations of
0, 10, 33 and 100 ppm (0, 36, 120 and 362 mg/rn3). The exposure schedule
was 6 hours/day, 5 days/week. Following exposure, gross and comprehensive
microscopic pathology, hematology and biochemistry were evaluated.
Urlnalyses were also performed. No mortality was observed and the condition
of the animals and their behavior was not visibly affected by 2-chloro-l,3-
butadlene exposure. At the highest exposure concentration (100 ppm), there
was slight growth retardation 1n males; females 1n this exposure group
produced more urine, with decreased creatlnlne content. There was a
statistically significant Increase 1n the relative liver and kidney weights
of both males and females at the 100 ppm exposure level; females also showed
a slight Increase In the relative weight of the adrenal. At the lower
2-chloro-l ,3-butadlene exposure levels (10 and 33 ppm), females showed a
statistically significant, dose-related Increase .1n the relative weight of
the IWer and also an Increase 1n relative kidney weight at 33 ppm. At an
exposure level of 33 ppm 2-chloro-l,3-butad1ene, relatively low body weights
were seen In males. Macroscopic and microscopic pathologic evaluation
revealed no alterations that could be attributed to 2-chloro-l,3-butad1ene
exposure. There were also no biochemical changes attributable to exposure.
White rats (eight males/group) were exposed to 2-chloro-l,3-butad1ene
(purity not reported) by Inhalation at concentrations of 0, 0.051, 0.15 and
1.69 mg/m3 (SanotskU, 1976). The exposure period was 4.5 months, but the
exposure schedule was not given. After 2.5 months exposure to the highest
2-chloro-l,3-butadlene level, there was an Increase in the "summation
threshold Index" (definition of this systemic toxlclty parameter was not
provided). After 4.5 months exposure to the highest level, there was a
0112d -16- 05/05/88
-------
decrease 1n the synthesis of hlppurlc add from sodium benzoate {Quick's
test) and an Inhibition of gas exchange. 2-Chloro-l,3-butad1ene exposure at
the two highest levels (0.15 and 1.69 mg/m3) had a gonadotroplc effect on
male rats, evidenced by functional and morphological changes In spermato-
genesls (I.e., reduced number of normal spermatogonla, Increased number of
dead spermatozoa, an Increased susceptibility of spermatozoa to acid-
mediated 1nact1vat1on and a decrease In their period of motmty). The
lowest 2-chloro-l,3-butad1ene exposure level (0.051 mg/m3) had no effect
on either the reproductive or systemic toxldty parameters that were
measured In rats. In the same report (Sanotskll, 1976), C57BL/6 mice
(eight/group) exposed for 2 months to 2-chloro-l,3-butadlene at concentra-
tions of 0.054, 0.064, 0.13, 0.32, 1.85 and 35 mg/m3 showed no systemic
signs of toxldty. Exposure for 2 months to concentrations of 2-chloro-l ,3-
butadlene at >0.32 mg/m3 affected mouse gonads, as evidenced by adverse
changes 1n spermatogenesls. An exposure concentration of 0.064 mg 2-chloro-
1,3-butadlene/m3 had no gonadotroplc effect In mice.
6.1.1.2. CHRONIC Two long-term Inhalation cardnogenldty studies,
one using hamsters and one using rats, contained Information regarding the
systemic toxldty of 2-chloro-l ,3-butad1ene following chronic Inhalation
exposure. In both studies, the test compound was vaporized Into atmospheres
of pure nitrogen to prevent autooxldatlon and dimerlzation; exposure
atmospheres were analyzed for content of 2-chloro-l,3-butad1ene. In the
first cardnogenldty study using Syrian Golden hamsters exposed to 0, 10 or
50 ppm (0, 36 or 181 mg/m3) 6 hours/day, 5 days/week for 18 months (E.I.
DuPont de Nemours and Co., 1985b), a number of toxldty parameters
(Including observation of condition and behavior, determination of body and
organ weights and extensive pathologic examination) were evaluated. Growth
0112d -17- 03/13/89
-------
retardation and a slight reduction In amygloldosls were observed 1n hamsters
exposed to the highest concentration. No effects were observed at 10 ppm,
the other concentration tested. In the second cardnogenldty study (E.I.
DuPont de Nemours and Co., 1985c), Wlstar rats were exposed to 0, 10 or 50
ppm (0, 36 or 181 mg/m3) 2-chloro-l,3-butad1ene 6 hours/day, 5 days/week,
for 2 years. Rats exposed to 50 ppm 2-chloro-l,3-butadlene {181 mg/m3)
showed growth retardation and an Increased Incidence of alopecia without
hlstopathologlc lesions of the skin. Rats exposed to 10 and 50 ppm
2-chloro-l,3-butadiene (36 and 181 mg/m3) showed a decrease In relative
lung weight, which was not dose-related. Ihe toxlcologlcal significance of
this decrease 1n relative lung weight In 2-chloro-l,3-butadlene-exposed rats
1s difficult to Interpret 1n view of the fact that exposed animals had a
lower Incidence of CRD than did control animals. The Investigators suggest-
ed that 2-chloro-l,3-butad1ene exposure might have prevented, In some way,
Jlfc the development of CRD, which In turn led to decreased relative lung weights
In the exposed animals compared with controls. Some liver effects (I.e., a
nondose-related Increase In relative liver weight In fema.les at 10 and 50
ppm and the presence of foci of mild cellular alteration In both sexes at 50
ppm) were also observed In rats exposed to 2-chloro-l,3-butad1ene. The
Increase 1n relative liver weight 1n female rats, however, was thought by
the investigators to be a fortuitous finding without toxlcologlcal signifi-
cance. Because the foci of cellular alteration in the liver at 50 ppm
resembled lesions commonly related to the process of aging, the investi-
gators stated that "It cannot be ruled out" that they represent a chance
effect rather than the result of 2-chloro-l,3-butadiene exposure. The lower
(10 ppm) exposure level is considered to be a NOAEL In this study. These
3H2d -18- 03/13/89
-------
studies (E.I. DuPont de Nemours and Co., 1985b,c) are further summarized 1n
Section 6.2.1. and are contained in the toxlclty summary table for 2-chloro-
1,3-butadiene presented 1n Chapter 9.
6.1.2. Oral Exposure. Pertinent data regarding the systemic toxlclty of
2-chloro-l,3-butad1ene following subchronic or chronic oral administration
of the compound were not located 1n the available literature cited 1n
Appendix A.
6.1.3. Other Relevant Information. One of the first studies of the
systemic toxlclty of 2-chloro-l,3-butad1ene (von Oettlngen et al., 1936)
Included Information on the lethality of 2-chloro-l,3-butad1ene to mice,
rabbits and cats following 8 hours of Inhalation exposure to various concen-
trations of the compound. It Is difficult to determine LC5Qs for the
various species from these data because of the Inconsistencies of effect
with Increasing concentration (i.e., the percentage of mortality did not
Bm strictly Increase with Increasing 2-chloro-l ,3-butad1ene concentration).
Clary (1977) suggested that the inconsistencies 1n the data of von Oettlngen
et al. (1936) may have been due to Improper handling and storage of the
2-chloro-l,3-butadiene used, so that the experimental animals were not
uniformly exposed to pure 2-chloro-l,3-butad1ene, but were Instead exposed
to unknown mixtures of reaction products of 2-chloro-l,3-butadiene. Despite
the difficulty of determining LC^s for the various species in the study
by von Oettlngen et al. (1936), Sanotskil (1976) has published LC5Q values
from the von Oettlngen et al. (1936) study; these values, along with several
other acute toxlclty- values for 2-chloro-l,3-butadiene, are listed In
Table 6-1.
Acute inhalation exposure to 2-chloro-l,3-butadiene appears to be
capable of causing liver injury in rats. Pasted adult male Sprague-Dawley
OH2d -19- 03/13/89
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rats exposed for 4 hours to 100, 150, 225 or 300 ppm 2-chloro-l,3-butad1ene
(362, 543, 815 and 1086 mg/m3) and killed at 24 hours showed signs of
acute hepatotoxlclty (Plugge and Jaeger, 1979). At all exposure concentra-
tions, the total amount of liver nonproteln sulfhydryl groups (mostly GSH)
was significantly Increased >2-fold after exposure to 300 ppm, and exposure
to 2-chloro-l,3-butadlene concentrations of 225 and 300 ppm resulted 1n
Increased serum sorbltol dehydrogenase activity. Serum lactate dehydrogen-
ase activity was also Increased In rats exposed to 300 ppm 2-chloro-l ,3-
butadlene. The Increase In liver NPSH 1s at first difficult to reconcile
with previous studies that have shown 2-chloro-l,3-butadlene exposure to
result 1n decreased hepatic GSH levels (Summer and Greim, 1980, 1981).
Plugge and Jaeger (1979) postulated that the Increase 1n liver NPSH repre-
sents an overshoot In the amount of liver GSH caused by an Increased rate of
GSH synthesis to replace the amounts that were Initially depleted following
2-chloro-l,3-butad1ene exposure.
The effects of single short-term exposures (I.e., 4 hours) to relatively
high concentrations of 2-chloro-l,3-butad1ene [500, 1000, 2000 and 4600 ppm
(1811, 3621, 7243 and 16,658 mg/m3)] were studied by Jaeger et al.
(19755). Fed or fasted adult male Holtzman rats (five/group) were exposed
to the above concentrations of 2-chloro-l,3-butad1ene, and lethality and
serum AKT were measured. Fasted rats exposed to all concentrations of
2-chloro-l,3-butad1ene had elevated serum AKT levels and up to three animals
In each exposed group died within 24 hours. Concentrations of 2-chloro-l,3-
butadlene <2000 ppm did not produce a change 1n serum AKT activity In fed
rats, and there was no mortality observed at these concentrations. At an
exposure concentration of 4600 ppm, elevated serum AK1 and mortality were
observed In fed rats.
0112d -21- 04/19/88
-------
An acute (I.e., 4-week) 2-chloro-l,3-butad1ene Inhalation toxldty study
was conducted using rats and hamsters as part of a range-finding study
before starting a 2-year Inhalation study (Clary et a!., 1978). Wlstar rats
(10/sex/group) and Syrian golden hamsters (10/sex/group) were exposed 6
hours/day, 5 days/ week to 2-chloro-l,3-butadlene at approximate
concentrations of 0, 39, 162 and 630 ppm (0, 141, 587, 2281 mg/m3). At
the end of the study, hemato logical examination (Including measurements of
hemoglobin and hematocrU, and erythrocyte and leukocyte counts) showed no
effects of 2-chloro-l,3-butad1ene exposure at any level on either rats or
hamsters. In rats there was evidence of concentration-related growth
retardation and statistically significant changes In the relative weights of
the kidneys, liver and lungs. At the highest exposure level (630 ppm), all
of the males and 8/10 of the females showed a slight to severe degree of
centrllobular liver degeneration and necrosis. This effect was not observed
1n rats at the two lower exposure levels. The kidneys of rats exposed to
the highest level of 2-chloro-l,3-butadlene showed slightly enlarged tubular
epithelial cells, whereas no renal effects were seen at the lower
2-chloro-l,3-butadlene exposure levels. In hamsters, the highest
2-chloro-l,3-butad1ene exposure level (630 ppm) was lethal to all of the
animals. At the mid-exposure level (162 ppm), necrosis and degeneration of
the hepatocytes were found, and at the lowest exposure level (39 ppm), there
was some Irritation of the mucous membrane of the nasal cavity.
An acute Inhalation study on the systemic toxldty of 2-chloro-l ,3-buta-
dlene In rats was conducted by E.I. DuPont de Nemours and Co. (1985d).
ChR-CD male rats (15) were exposed to 25 ppm 2-chloro-l ,3-butadiene (91
mg/m3) 4 hours/day for 22 days; there were 10 control animals. Animal
body weights were recorded, and the animals were watched for signs of
0112d -22- 05/05/88
-------
toxlclty. At autopsy, various organs (I.e., lung, heart, liver, kidney,
testls and thymus) were weighed, and an extensive hlstologlcal examination
Involving >20 organs was performed. There were no clinical signs of
toxlclty observed during the test, and weight gain patterns In test animals
were similar to controls. Gross and hlstopathologlc examination revealed no
changes attributable to the test compound.
6.2. CARCINOGENICITY
6.2.1. Inhalation. An 18-month Inhalation cardnogenlclty study of
2-chloro-l,3-butad1ene using Syrian golden hamsters was conducted by E.I.
DuPont de Nemours and Co. (1985b). Three groups of hamsters (100/sex/group)
were exposed to 0, 10 or 50 ppm 2-chloro-l ,3-butad1ene {0, 36 or 181
mg/m3) for 6 hours/day, 5 days/week. Systemic toxlclty was discussed 1n
Section 6.1.1.2. Pathologic evaluation Including microscopic examination
was performed on >30 different organs. At the highest exposure level (50
ppm), growth retardation was observed, along with a slight reduction In
amyloldosls. There were no Indications of cardnogenlclty resulting from
2-chloro-l,3-butadlene exposure at either of the concentrations used 1n this
study.
A 2-year inhalation carc1nogen1dty study was conducted by E.I. DuPont
de Nemours and Co. (1985c), where Wlstar rats (100/sex/group) were exposed
to 2-chloro-l,3-butad1ene at concentrations of 0, 10 or 50 ppm (0, 36 or 181
mg/m3} for 6 hours/day, 5 days/week. At week 72 of the study, an
equipment failure resulted 1n the suffocation deaths of 87 males and 73
females In the low level exposure group. Growth retardation was observed In
the high exposure group. There was no action of 2-chloro-l,3-butadlene in
rats up to an exposure level of 50 ppm. At the 50 ppm dose level, both male
0112d -23- 03/13/89
-------
and female rats showed an Increased incidence of fod of cellular alteration
In the IWers (males, 14/97 In control and 30/96 1n 50 ppm group; females,
13/98 1n control and 27/99 1n 50 ppm group).
Several ep1dem1olog1cal studies have examined whether 2-chloro-l,3-buta-
dlene Is capable of causing cancer in workers exposed to the compound and
Its reaction products. Two Russian articles (Khachatryan, 197?a,b) Indicate
that 2-chloro-l,3-butadlene exposure produces an Increased risk of skin and
lung cancer. In the first (Khachatryan, 1972a), 137 cases of skin cancer
were observed during examination of 24,989 Industrial workers from 1956-1970
In the Yerevan region of Russia; the population was divided Into five
subgroups according to the nature of employment. A subgroup composed of 684
persons with extended work experience 1n 2-chloro-l,3-butad1ene production
(I.e., production of chloroprene and polychloroprene latex and rubber) had a
significantly Increased Incidence of skin cancer compared with three other
subgroups composed of unexposed persons. A subgroup composed of 2250
workers exposed only to 2-chloro-l,3-butad1ene derivatives (I.e., workers
from shoe factories with exposure to polychloroprene cement) also showed an
Increased Incidence of skin cancer. The other three subgroups (termed
control populations) were composed of chemical workers (4780 persons) not
exposed to 2-chloro-l,3-butad1ene but with prolonged exposure to lacquers,
acetone, benzene, gasoline and acids; nonchemlcal workers (8755 persons);
and nonindustrlal workers (8520 persons). The concentrations of 2-chloro-
1,3-butad1ene and any other toxic chemicals to which the workers may have
been exposed were not reported. Khachatryan (1972a) concluded that
2-chloro-l,3-butadlene was a carcinogen or cocarclnogen for human skin and
that 2-chloro-l,3-butadiene-induced skin cancer is preceded by chronic
dystrophic and Inflammatory skin ailments, which are caused by binding of
the compound to free sulfhydryl groups in the skin. This study did not
0112d -24- 03/13/89
-------
report the skin cancer Incidence by sex, provided no Information regarding
prior work history and made no mention of other chemicals to which the
workers were concurrently exposed.
In the second study (Khachatryan, 1972b), the Incidence of lung cancer
was Investigated among 19,979 workers In the same region of Russia during
the period 1956-1970. The population was subdivided Into four subgroups
according to the nature of employment, but there was no distinction made 1n
this study as had been made 1n the previous study (Khachatryan, 1972a)
between workers exposed only to 2-chloro-l ,3-butad1ene and those exposed to
2-chloro-l,3-butad1ene derivatives. The four subgroups were composed of
workers with some occupational exposure to 2-chloro-l,3-butadlene or Us
derivatives (2934 persons), chemical workers with no exposure to 2-chloro-
1,3-butad1ene (4780 persons), nonlndustrlal (I.e., professional) workers
(6045 persons) and nonchemlcal workers (6220 persons). A total of 71 cases
of lung cancer were Identified, but detailed Information regarding the
specific types of lung cancer, the Individual's work experience, concentra-
tions of 2-chloro-l,3-butad1ene and Us derivatives to which the workers
were exposed, and smoking habits were not provided. The Incidence of lung
cancer In workers exposed to 2-chloro-l,3-butad1ene and Us derivatives
(1.24%) was significantly higher than the lung cancer Incidences reported 1n
chemical workers, nonchemlcal workers and nonlndustrlal workers (0.46, 0.8
and 0.06%, respectively). Khachatryan (1972b) concluded that exposure to
2-chloro-l,3-butad1ene and its derivatives led to significant Increases In
the incidence of lung cancer. In their evaluation of this study, NIOSH
(1977) reported that work history, carrier progression, age at beginning of
employment, smoking habit and contagious lung diseases have been considered,
DUt detailed Information has not been provided. The methods for diagnosing
0112d -25- 02/22/89
-------
lung cancer and the specific type of cancer diagnosis were not described;
furthermore, there were Inconsistencies between tables and the text
regarding cancer Incidence.
The finding of an Increased Incidence of lung cancer 1n workers exposed
to 2-chloro-l,3-butad1ene (Khachatryan, 1972b) was not confirmed In a study
by E.I. DuPont de Nemours and Co. (Pell, 1978). In this study (Pell, 1978),
historical prospective mortality studies were made of two cohorts of workers
potentially exposed to 2-chloro-l,3-butadlene In the manufacture of
neoprene. One cohort consisted of 1576 male production workers at the
Louisville works In 1957; the other cohort comprised 270 men {both produc-
tion workers and maintenance mechanics) who had exposure to 2-chloro-l,3-
butadlene at the Chambers works 1n New Jersey between 1931 and 1948.
Control populations consisted of DuPont Company employees and retirees, and
U.S. males. Mortality was analyzed for all cohorts during the period 1957
through 1974. With the exception of maintenance mechanics 1n the Louisville
study, the incidence of lung cancer In the 2-chloro-l,3-butadlene-exposed
cohorts from both the Louisville and the Chambers works was not signifi-
cantly different from that observed in the control cohorts. Maintenance
mechanics in the Louisville study appeared to have an excess risk of lung
cancer, but Pell (1978) felt that this excess risk may be due to the
presence of another chemical carcinogen in the plant, cigarette smoking or a
fortuitously high incidence of cancer cases in this group. Pell (1978)
concluded that 2-chloro-l,3-butadiene exposure does not increase the risk of
lung cancer. The incidence of skin cancer was not considered in this study.
The assessment of carcinogenic risk for humans exposed to 2-chloro-l,3-
butadlene is difficult because of limitations in the epidemiological studies
reported by Pell (1978) and Khachatryan (1972a,b). None of these epidemio-
logical studies adequately considered the Intensity or duration of exposure,
0112d -26- 03/13/89
-------
environmental concentrations or the latency period (NIOSH, 1977). In
addition, neither Pell (1978) nor Khachatryan (1972a,b) attempted to analyze
the data separately for workers Involved 1n 2-chloro-l,3-butad1ene polymeri-
zation and workers Involved In monomer production work only, even though
this distinction has been found to be Important In workers In the vinyl
chloride industry (NIOSH, 1977). Ihe Investigators 1n these epldemlologlcal
studies (Pell, 1978; Khachatryan, 1972a,b) did not mention the criteria for
diagnoses of the various cancers, and the cell types for the various skin
and lung cancers reported were not Indicated. Also, Pell (1978) used a
control population that consisted of Industrial workers exposed to agents
known or suspected to be carcinogenic. The use of such a control population
would tend to underestimate the true carcinogenic risk from exposure to
2-chloro-l,3-butad1ene {NIOSH, 1977).
6.2.2. Oral. A long-term oral cardnogenUHy study of 2-chloro-l,3-
butadlene using rats was conducted by Ponomarkov and Tomatis (1980).
Seventeen pregnant female BD IV rats were given 100 mg
2-chloro-l ,3-butad1ene/kg bw as a single oral dose on day 17 of gestation.
Their progeny (81 males and 64 females) were given an oral dose of 50 mg
2-chloro-l,3-butadlene/kg bw In olive oil, once/week, for their entire life
span beginning from the time of weaning. Controls were 14 pregnant female
BO IV rats, which received 0.3 mi. olive oil on day 17 of pregnancy, and
their offspring, which were given 0.3 ml olive oil weekly for life
beginning at weaning. After 120 weeks, all survivors were killed and
autopsied. Major Internal organs were examined histologically. Several
tumors were observed In 2-chloro-l,3-butadiene-treated males that were not
seen in controls, and subcutaneous flbromas were more numerous 1n
2-chloro-l,3-butadiene-treated males than In controls. Ponomarkov and
0112d -27- 03/13/89
-------
Tomatls (1980) concluded, however, that the total Incidence of tumors was
similar In 2-chloro-l,3-butadlene-treated and control animals.
211'fyan et al. (1975, 1977) administered 2-chloro-l,3-butad1ene (200
mg/kg bw) 1n sunflower oil by gavage to 100 random-bred albino rats. Admin-
istration of the compound was twice weekly for 25 weeks. No tumors were
observed 1n the 40 rats that survived 2 years.
6.2.3. Other Relevant Information. 1,3-Butad1ene, a nonchlorlnated
analog of chloroprene, has been shown to be carcinogenic 1n mice and rats.
This structure-activity relationship and the mutagenlc and cell-transforming
capability of chloroprene suggest that chloroprene could be carcinogenic and
should, therefore, be tested further. Ijn y11ro treatment of an established
line of hamster lung cells with 1-500 pg 2-chloro-l ,3-butadiene/ms.
resulted 1n malignant transformation of the cells (Menezes et al., 1979).
Treatment with 1.0 jjg/mi of the compound resulted In transformation 14
weeks after treatment; higher concentrations of 2-chloro-l,3-butadlene did
not accelerate the transformation process.
ZlVfyan et al. (1975, 1977) applied a 50% solution of 2-chloro-l ,3-
butadlene In benzene to the skin of 100 random bred albino mice. Skin
applications were twice weekly for 25 weeks. A positive control group of
mice received 50 skin applications (2/week for 25 weeks) of a 0.1% solution
of DMBA In benzene. No tumors of the skin or other organs were reported in
the mice treated with 2-chloro-l ,3-butadiene, whereas 92% of the DMBA-
treated mice that survived to the time of appearance of the first skin tumor
developed skin carcinomas.
Intratracheal administration of 2-chloro-l,3-butadiene to rats (200
mg/kg bw 5 times at 20-day intervals) produced no tumors in the lungs of
3112d -28- 03/13/89
-------
animals that died or were killed 6 or 14 months after 2-chloro-l,3-butad1ene
administration (ZU'fyan et al., 1977).
6.3. MUTAGENICITY
2-Chloro-l,3-butad1ene has been shown overall to be mutagenlc 1n a
variety of bacterial strains by a number of Investigators (Table 6-2}.
2-Chloro-l,3-butadiene fed to male Drosophlla melanogaster (5.7-34.3 mM for
3 days) Induced recessive lethal mutations (Vogel, 1979). Mutagenlcity was
not detected In 8-azaguan1ne and ouabaln-reslstant V79 Chinese hamster cells
exposed to vapors of 2-chloro-l ,3-butadiene. {<10X v/v) for 5 hours In the
presence of rat liver mlcrosomes (Drevon and Kuroki, 1979). However, this
negative result should be confirmed or refuted by additional testing, since
this test was performed In the presence of 10% serum, which can act as a
sink In absorbing reactive chemical species. Reports from the Russian
literature (Katosova and Pavlenko, 1985; Katosova, 1973) Indicate the
presence of chromosomal aberrations In the lymphocytes and somatic cells of
occupationally exposed humans. Another Russian study (Sanotskli, 1976)
Indicated that rats and mice, exposed by inhalation to various concentrations
of chloroprene showed chromosomal aberrations and dominant lethal effects at
>0,32 and >1.85 mg/m3, respectively. The author suggested 0.15 mg/m3 as
the threshold for embryotoxlc and mutagenlc effects. 2-Chloro-l,3-butad1ene
was not mutagenlc In a mlcronucleus test conducted by E.I. DuPont de Nemours
and Co. (1985e). In this study, two groups of rats (five/sex/group) were
exposed to atmospheres containing 0 or 100 ppm 2-chloro-l,3-butadiene (0 or
361.8 mg/m3). Exposure was 6 hours/day for 4 consecutive days. Following
exposure, the animals were killed and bone marrow preparations were made.
The ratio of poly- and normochromatlc erythrocytes, and the incidence of
tilcronucleated cells/2000 erythrocytes were then recorded. The above
0112d -29- 02/22/89
-------
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mentioned ratio and Incidence were not significantly different between
2-chloro-l,3-butad1ene-treated and control animals.
6.4. TERATOGENICITY
A teratogenlcHy and fetotoxldty study using rats was conducted at the
Haskell Laboratory for Toxicology and Industrial Medicine (E.I. DuPont de
Nemours and Co., 1985J; Cullk et al., 1978). In both studies, the
concentration of 2-chloro-l,3-butad1ene In the test atmosphere was closely
monitored. In the teratology study, pregnant female ChR-CD rats were
exposed by Inhalation to four concentrations of 2-chloro-l,3-butadiene [0,
1, 10 and 25 ppm (0, 3.6, 36 91 mg/m3)]. There were 25 rats/dose level
and exposure was 4 hours/day from day 2 or 3 of pregnancy to day 20 of
gestation. After exposure, autopsies were performed on dams and fetuses
were examined for abnormalities. In the fetotoxldty study, pregnant female
ChR-CD rats were exposed to the same concentrations of 2-chloro-l,3-buta-
dlene vapors that were used In the teratology study, but there were 50 rats/
dose level. Exposure was 4 hours/day on days 1-12 of gestation. The dams
were sacrificed on day 17 of gestation and gross autopsies were performed.
There were no clinical signs of 2-chloro-l,3-butad1ene-1nduced toxlcity In
the dams either during or postexposure at any Inhaled level of 2-chloro-
1,3-butad1ene in either study. Gross pathological changes were not observed
In any organ system, and 2-chloro-l,3-butad1ene exposure did not affect
maternal body weight. 2-Chloro-l,3-butadlene was not fetotoxlc In this
study. Pre- and postlmplantatlon losses of fertilized ova, the number of
live fetuses/Utter and the weight and size of the fetuses were not signifi-
cantly different between exposed and control groups. No major external,
skeletal or soft tissue malformations were found.
0112d -32- 03/13/89
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Another 2-chloro-l ,3-butad1ene fetotoxlci ty/teratogenlcHy study that
used exposure levels high enough to produce signs of maternal and fetotoxlc-
Hy was conducted by E.I. DuPont de Nemours and Co. (1985k). Pregnant rats
(36/dose level) were exposed by Inhalation to chloroprene levels of 0, 10,
25, 75 and 175 ppm (0, 36, 91, 272 and 634 mg/m3}. Exposure was 6 hours/
day on days 4-16 of gestation. The highest exposure level {175 ppm)
produced focal alopecia In the mothers and decreased fetal weight and slight
retardation In bone development. A lower empty uterus weight and lower
fetal weights were seen at the two highest dose levels (75 and 175 ppm); at
the three highest exposure levels {25, 75 and 175 ppm), there was diminished
maternal food consumption'and weight gain. The NOEL for maternal toxlclty
was 10 ppm. Despite signs of fetotoxldty at 75 and 175 ppm, there were no
signs of teratogenlclty at any 2-chloro-l,3-butad1ene exposure level, and
the NOAEL for developmental toxlclty In this study appears to be 25 ppm.
Comparing the Russian literature with other reports reveals some
discrepancy concerning the teratogenlclty/fetotoxlclty of 2-chloro-l,3-
butadlene. Briefly reported Russian studies (Salnlkova and Fomenko, 1973,
1975; Sanotskli, 1976) Indicated that 2-chloro-l,3-butad1ene Is fetotoxlc
and teratogenk In rats at an exposure level of -1 ppm {4 mg/m3). Subse-
quent studies summarized above {E.I. DuPont de Nemours and Co. 1985J,k;
Cullk et al., 1978) Indicated that 2-chloro-l,3-butadlene 1s not fetotoxlc/
teratogenk at exposure levels -100-200 times higher than the levels used In
the Russian studies. In a conference between Soviet scientists and
scientists from DuPont, no resolution was reached as to the cause of this
discrepancy (E.I. DuPont de Nemours and Co., 19851), but It has been sug-
gested that because of the chemical instability of 2-chloro-l,3-butadlene,
the Russian investigators may have inadvertently exposed their animals to
oxidation reaction products of 2-chloro-l,3-butadlene (Cullk et al., 1978).
0112d -33- 02/22/89
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6.5. OTHER REPRODUCTIVE EFFECTS
Male ChR-CO rats (five) were exposed to 25 ppm 2-chloro-l,3-butadlene
(91 mg/m3) 4 hours/day for 22 days {E.I. DuPont de Nemours and Co., 1985d;
Cullk et al., 1978); there were five control animals. After the last
Inhalation exposure, each male was caged with three untreated virgin females
for 7 days. Following mating, the males were autopsled and the reproductive
organs were examined h1stolog1cally. The litters were examined for the
number of pups/Utter and the average body weight at weaning. There was no
effect of 2-chloro-l,3-butad1ene exposure on any of the reproductive
parameters examined.
A 2-generatlon Inhalation study on the effects of 2-chloro-l,3-butadiene
exposure In rats was conducted by E.I. DuPont de Nemours and Co. (1985m).
The vapor of test compound was generated In nitrogen, and concentrations In
the test atmosphere were monitored closely as described above. Fn genera-
tion males and females (25/sex/group) were exposed to atmospheres containing
0, 10, 33 or 100 ppm 2-chloro-l,3-butadiene (0, 36, 120 or 362 mg/m3).
The exposure schedule was 6 hours/day, 5 days/week for 13 weeks. Following
exposure, the chloroprene-exposed animals were mated with untreated males
and females. From the progeny of this mating (F, generation), 320 were
selected randomly, divided into four groups (40/sex/group) and exposed by
Inhalation to the same concentrations of 2-chloro-l,3-butadiene that were
used for the FQ generation. The F-, generation rats were exposed 6
lours/day, 5 days/week for 10 weeks. Parameters evaluated In the FQ
generation included general condition and behavior, body weight, reproduc-
tive performance, hematology and organ pathology. F generation animals
were evaluated for the same parameters wHh the exception of reproductive
performance. At the highest concentration, growth retardation was observed
in members of the FQ generation. There was, however, no effect of
0112d -34- 02/22/89
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2-chloro-l,3-butad1ene exposure at any level on the reproductive performance
of this generation. In the F, generation, the mid- and high concentra-
tions of 2-chloro-l,3-butadlene produced growth retardation In both sexes
compared with controls, but there was no effect of 2-chloro-l,3-butadlene
exposure on any of the other parameters measured. The Investigators
suggested that the growth retardation observed at 100 ppm but not at 33 ppm
in the F- generation and at both 33 and 100 ppm in the F, generation may
have resulted from different diets fed to the different generations.
Reproductive effects following 2-chloro-l,3-butadiene exposure in male
rats have been reported in the Russian literature. Sanotskil (1976) exposed
C57B1/6 mice (number not reported) to 0.017, 0.1 or 1 ppm 2-chloro-l,3-buta-
diene (0.062, 0.36 or 3.6 mg/m3) for 2 months. At the two highest dose
levels, adverse effects on spermatogenesis were noted consisting of an
Increase in the number of tubules with desquamating germinal epithelium. No
effect was noted at the 0.017 ppm exposure level. In a study by Oavtyan
(1972), 100 male rats were exposed to 0, 0.014, 0.042 or 0.47 ppm 2-chloro-
1,3-butadiene (0, 0.051, 0.15 or 1.7 mg/m3) 4 hours/day for 5.5 months.
At the two highest dose levels, there were significant reductions In sperm
motility, viability and acid resistance. There was also testHular atrophy
and a reduction In the number of spermatogonla In some males. No effects
were reported at 0.014 ppm 2-chloro-l,3-butadlene. These findings by
Oavtyan (1972) and Sanotskii (1976) are questionable 1n that they do not
appear to be reproducible. The results were not reproduced In a second
paper by Davtyan et al. (1973) and in a reproduction study by E.I. DuPont de
Nemours and Co. (1985e), although both of these studies used higher exposure
levels of 2-chloro-l,3-butadlene. Ihe method of handling 2-chloro-l,3-
butadlene and the purity of the compound were not reported in the Russian
studies (E.I. DuPont de Nemours and Co., 1985d), and this again raises the
0112d -35- 02/22/89
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possibility that 2-chloro-l,3-butadlene oxidation and dlmerlzatlon products
may have been present 1n the Russian exposure mixture.
6.6. SUMMARY
Acute, subchronlc and chronic Inhalation exposure to 2-chloro-1,3-buta-
dlene has been reported to result 1n growth retardation {Nystrom, 1948; E.I.
DuPont de Nemours and Co., 1985a,b,c; Clary et al., 1978). In addition to
this decrease 1n body weight, changes In the relative weights of a variety
of organs were noted. Significant changes were reported 1n the weights of
the liver, kidney, adrenals and lungs of rats following Inhalation exposure
to 2-chloro-l,3-butad1ene (E.I. DuPont de Nemours and Co., 1985a,c; Clary et
al., 1978). Effects o'f 2-chloro-l ,3-butadlene exposure on the reproductive
system were reported 1n a Russian study that noted a gonadotroplc effect of
2-chloro-l,3-butadlene exposure 1n male rats and mice (Sanotsk11, 1976).
Some toxUlty studies of 2-chloro-l,3-butad1ene, particularly the early
studies and the Russian studies, are difficult to Interpret because the
method of storage and handling of the compound are not reported. 2-Chloro-
1,3-butad1ene appears to be a particularly unstable compound, subject to
oxidation and dlmerlzatlon, and Nystrom (1948) has demonstrated that these
reaction products of 2-chloro-l,3-butadlene are several times more toxic
than the pure compound.
Fasted rats, probably because of a reduction In liver GSH content,
appear to be particularly susceptible to liver Injury following acute
Inhalation exposure to 2-chloro-l,3-butadlene {Plugge and Jaeger, 1979;
Jaeger et al., 1975b).
Long-term 2-chloro-l ,3-butad1ene Inhalation carclnogenldty studies
using rats and hamsters have been conducted. An 18-month hamster study
{E.I. DuPont de Nemours and Co., 1985b) and a 2-year rat study (E.I. DuPont
de Nemours and Co., 1985a) failed to show a carcinogenic effect of 2-chloro-
0112d -36- 03/13/89
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l,3-butad1ene at exposure levels <50 ppm. Two Russian studies (Khachatryan,
1972a,b) have suggested that 2-chloro-l,3-butadlene exposure produces an
Increased risk of skin and lung cancer 1n occupatlonally-exposed persons.
These findings were not confirmed In studies done In the United States
(Pell, 1978). 2-Chloro-l,3-butad1ene also failed to produce a significant
Increase In tumor Incidence In rats exposed to the compound orally over the
course of a lifetime (Ponomarkov and Tomatls, 1980). Also, 2-chloro-l,3-
butadlene was not carcinogenic following application to the skin (Zll'fyan
et al.. 1975, 1977).
2-Chloro-l,3-butad1ene has been demonstrated to be mutagenlc to bacteria
(see Table 6-2) and caused dominant lethal effects In rodents and
chromosomal aberrations In humans {Sanotskll, 1976); and this apparent
Inconsistency between the mutagenlclty of 2-chloro-l,3-butadlene and Us
lack of a carcinogenic effect \t\ vivo has been suggested to be due to
metabolic Inactlvatlon of any carcinogenic Intermediates by glutathlone
(Summer and Grelm, 1980). The U.S. EPA (1986c) study, based on the limited
data available, suggested 2-chloro-l,3-butad1ene 1s a mutagen and a
clastogen.
In studies by E.I. DuPont de Nemours and Co. (1985J,k) and by Cullk et
al. (1978), 2-chloro-l,3-butad1ene was found not to be fetotoxU or terato-
genlc In rats. Fetotoxlclty/teratogenlclty has been reported 1n the Russian
literature (Salnlkova and Fomenko, 1973, 1975; Sanotskll, 1976) 1n rats
exposed to 2-chloro-l,3-butadlene. Once again, the nature of the material
used In the Russian exposures has been questioned (Cullk et al., 1978).
Reproductive effects 1n male mUe and rats following exposure to 2-chloro-
1,3-butadlene have been reported In the Russian literature (Sanotskll, 1976;
Davtyan, 1972). These reproductive effects were not confirmed In studies by
E.I. DuPont de Nemours and Co. (1985d,m).
0112d -37- 04/18/89
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
The TLV-TWA for 2-chloro-l,3-butad1ene Is 10 ppm (35 mg/m3) (ACGIH,
1987). This value represents a reduction from the previous TLV of 25 ppm,
and this reduction stems 1n part from minimal systemic toxlclty effects seen
1n rats and hamsters exposed repeatedly to 39 ppm 2-chloro-l,3-butad1ene
over the course of 4 weeks {ACGIH, 1986; Clary et al., 1978). The PEL for
2-chloro-l,3-butadlene 1s 25 ppm (90 mg/m3) (OSHA, 1985). NIOSH (1977)
recommends a 15-mlnute celling concentration of 1 ppm (3.6 mg/m3) as a
workplace standard. An ADI of 0.13 mg/day for a 70 kg man has been derived
1n an earlier U.S. EPA (1984a) analysis.
7.2. AQUATIC
Data regarding guidelines and standards for 2-chloro-l,3-butad1ene In
aquatic organisms .were not located 1n the available literature cited In
Appendix A.
0112d -38- 04/18/89
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Studies regarding the carclnogenlcHy of 2-chloro-
1,3-butad1ene by Inhalation exposure 1n hamster and rats were conducted by
E.I. DuPont de Nemours and Co. (1985b,c). An 18-month Inhalation study
using Syrian Golden Hamsters (E.I. DuPont de Nemours and Co., 1985b) and a
2-year Inhalation study using Hlstar rats {E.I. DuPont de Nemours and Co.,
1985c) at 2-chloro-l,3-butadlene exposure levels of <50 ppm (181 mg/m3}
failed to produce any evidence of cardnogenldty associated with exposure
to the compound. Two Russian studies (Khachatryan, 1972a,b) reported an
Increased Incidence of lung and skin cancer 1n persons
occupatlonally-exposed to 2-chloro-l,3-butad1ene. These findings have not
been confirmed In epldemlologlcal studies conducted In the United States
(Pell, 1978).
8.1.2. Oral. Male and female BD IV rats given a weekly oral dose of 50
mg 2-chloro-l,3-butad1ene/kg bw over the course of a lifetime starting at
the time of weaning did not have a significantly Increased Incidence of
cancer over that observed In rats given only the corn oil vehicle
(Ponomarkov and TomaUs, 1980). Oral administration of 2-chloro-l ,3-
butadlene (200 mg/kg bw) twice/week for 25 weeks failed to produce tumors In
rats (Zll'fyan et al.. 1975, 1977).
8.1.3. Other Routes. A 50% solution of 2-chloro-l,3-butad1ene 1n benzene
applied to the skin of mice (twice/week for 25 weeks) failed to Induce
tumors of the skin or any other organs (ZH'fyan et al., 1975, 1977).
Intratracheal administration of 2-chloro-l,3-butadlene (200 mg/kg bw) b
times at 20-day Intervals did not produce tumors in the lungs of rats
(Z11'fyan et al., 1977).
0112d -39- 03/13/89
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8.1.4. Weight of Evidence. The epldemlologlcal data concerning the
possible cardnogenlclty of 2-chloro-l,3-butad1ene 1n humans (Khachatryan,
1972a,b; Pell, 1978) yielded results suggestive of lung cancer. Because of
gross Inadequacies 1n all three studies, collectively the human data 1s,
however, appropriately classified as "Inadequate" using the criteria
described by the U.S. EPA (1986b). The animal bloassay data, which shows
both negative and suggestive positive responses (liver foci In both sexes of
rat by Inhalation with dose response), 1s judged Inadequate albeit
suggestive. The mutagenlc data, mammalian cell transforming capability and
structural relationship to 1,3-butad1ene suggests that chloroprene has a
potential to be carcinogenic. The metabolism of chloroprene 1s likewise
thought to Include an epoxlde at least 1n one pathway. Nevertheless, with
some negative studies, the reasons for concern are not quite strong enough
to give a Group C classification and thus the compound Is considered to be
In Group D with a note of concern that unnecessary exposure should be
avoided until additional research 1s conducted.
8.1.5. Quantitative Risk Estimates. Because the animal and human studies
are judges Inadequate to assess the cardnogenlclty, no Inhalation or oral
q,* 1s derived.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) Nystrom (1948)
exposed rats to 2-chloro-l ,3-butadlene at two exposure levels [56 and 334
ppm (203 and 1210 mg/m3)] 8 hours/day for 5 months. The higher exposure
level produced death 1n half of the rats by the end of the week 13, and
decreases in body weight and blood changes 1n the surviving animals. This
study {Nystrom, 1948) was not considered further for risk assessment because
0112d -40- 02/22/89
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of quality factors. Details of the study were obtained from a secondary
source (NIOSH, 1977), and Information regarding the existence and nature of
a control group of animals, and whether other parameters of toxldty were
evaluated (Including hlstopathologlcal examination) were not provided.
The second study considered for RfD development 1s a subchronlc (I.e.,
26-week) 2-chloro-l ,3-butad1ene Inhalation study by E.I. DuPont de Nemours
and Co. (1985a) where rats were exposed to 2-chloro-l ,3-butad1ene at three
exposure levels [10, 33 or 100 ppm (36, 120, 362 mg/m3)] 6 hours/day for 5
days/week. Effects were noted at all exposure levels; the lowest exposure
level (I.e., 36 mg/m3) was associated only with an Increase In relative
liver weight In females. This exposure level corresponds to a transformed
animal dose of 5.0 mg/kg/day [I.e., 36 mg/m3 x 0.152 m3/day (rat
Inhalation rate) [U.S. EPA, 1980] x 1/0.196 (one/rat body weight) x 6
hours/24 hours x 5 days/7days]. Because there were no lesions associated
with the Increase. In relative liver weight, elevated liver weight was
considered an adaptive rather than adverse effect and this exposure level
(10 ppm) was considered a NOAEL for this study.
The third study considered for subchronlc RfD development Is a reproduc-
tion study by E.I. DuPont de Nemours and Co. (1985m) (see Section 6.5.}. In
this study, male rats of the FQ generation exposed to 100 ppm and both
sexes of rats In the F generation exposed to 33 ppm 2-chloro-l ,3-buta-
dlene 6 hours/day, 5 days/week for 13 weeks showed signs of growth retarda-
tion. There were no effects on reproduction at any exposure level. The
lowest exposure level [10 ppm (36 mg/m3)] constitutes a NOEL for this
study and corresponds to a transformed animal dose of 4.6 mg/kg/day [36
mg/m3 x 0.176 m3/day (rat Inhalation rate) x 1/0.245 kg (one/rat body
weight) x 6 hours/24 hours x 5 days/7 days].
-41- 03/13/89
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The Russian subchronlc Inhalation study by SanotskH (1976) was not
considered for RfD development because the exposure schedule was not given
and because gonadotroplc effects were reported In mice and rats at levels
(0.15-1.69 mg 2-chloro-l,3-butadlene/m3) that were well below the exposure
levels (36.2-90.4 mg 2-chloro-l,3-butad1ene/m3) at which no gonadotroplc
effects were reported 1n reproduction rat studies by E.I. DuPont de Nemours
and Co. (1985d,m>.
The appropriate choice of the study for subchronlc Inhalation RfD
development Is that by E.I. DuPont de Nemours and Co. (1985a), In which a
transformed animal dose of 5.0 mg/kg/day was associated with Increased liver
weight 1n female rats. This value constitutes the highest NOAEL In all of
the subchronlc Inhalation studies summarized, below which there is no LQAEL.
A subchronlc Inhalation RfD derived from this NOAEL, however, would be only
slightly larger than the chronic Inhalation RfD of 0.04 mg/kg/day [3 mg/day
(0.1 mg/m3)] derived In Section 8.2.1.2. Because, 1n general, more confi-
dence is placed 1n a chronic toxicHy study and because the data base for
2-chloro-l,3-butadlene strongly Indicates Uttle difference 1n toxic potency
or effects between subchronlc and chronic exposure, It seems appropriate to
adopt the chronic RfD as the subchronlc RfD for this chemical.
Confidence 1n the subchronlc Inhalation RfD 1s high (Section 8.2.1.2.).
8.2.1.2. CHRONIC EXPOSURE Chronic Inhalation toxlclty Information
was found 1n two cardnogenldty studies by E.I. DuPont de Nemours and Co.
(1985b,c) (see Sections 6.1.1.2. and 6.2.1.) and In a fetotoxldty/terato-
genlclty study by E.I. DuPont de Nemours and Co. (1985k) (see Section 6.4.).
Exposure of hamsters to 50 ppm 2-chloro-l,3-butadlene (181 mg/m3) 6
hours/day, 5 days/week for 18 months resulted In growth retardation (E.I.
DuPont de Nemours and Co., 1985b). This exposure level represents a LOAEL,
associated with a transformed animal dose of 30.7 mg/kg/day [i.e., 181
OH2d -42- 02/22/89
-------
mg/m3 x 0.093 mVday (hamster Inhalation rate [U.S. EPA, 1986dJ) x
1/0.098 kg (one/hamster body weight) x 6 hours/24 hours x 5 days/7 days].
There were no effects observed at the lowest exposure level used 1n this
study [10 ppm (36 mg/m3)], and thU therefore constitutes a NOAEL. This
NOAEL corresponds to an animal transformed dose of 6.0 mg/kg/day [36 mg/m3
x 0.102 mVday (hamster Inhalation rate [U.S. EPA, 1986d]) x 1/0.109 kg
(one/hamster body weight) x 6 hours/24 hours x 5 days/7 days].
In the second long-term cardnogenldty study (E.I. OuPont de Nemours
and Co., 1985c) considered for chronic Inhalation RfD development, rats were
exposed to 2-chloro-l ,3-butad1ene [10 and 50 ppm (36. and 181 mg/m3)] 6
hours/day, 5 days/week for 2 years. The higher concentration (50 ppm) was
associated with alopecia, retarded growth and mild hepatocellular lesions of
uncertain biological significance. Decreased relative lung weight 1n both
sexes and elevated relative liver weight In females were observed at both
exposure concentrations. In the absence of histopathologic lesions at 10
ppm, however, these observations are considered nonadverse and 10 ppm 1s
considered a NOAEL. This concentration 1s associated with a transformed
animal dose of 4.0 mg/kg/day [average of male and female rats; I.e., 36
mg/m3 x 0.229 mVday (average rat male/female Inhalation rate [U.S. EPA,
1986d]) x 1/0.364 kg (one/average rat male/female body weight) x 6 hours/24
hours x 5 days/7 days],
A fetotoxldty/teratogenlclty study by E.I. DuPont de Nemours and Co.
(1985k) was considered, along with other chronic Inhalation toxldty data,
In the development of a chronic Inhalation RfD for 2-chloro-l,3-butad1ene.
In this study, there were Indications of fetotoxUHy (i.e., decrease 1n
fetal weight) In pregnant rats exposed to 75 ppm 2-chloro-l,3-butadiene (272
mg/m3) 6 hours/day on days 4-16 of gestation. This exposure corresponds
to a transformed animal dose of 53.2 mg/kg/day [I.e., 272 mg/m3 x 0.147
0112d -43- 04/18/89
-------
mVday (rat Inhalation rate [U.S. EPA, 1986d]) x 1/0.188 (one/rat body
weight) x 6 hours/24 hours]. The next lower 2-chloro-l,3-butad1ene exposure
level (I.e., 25 ppm or 90.5 mg/m3) represents a NOAEL for the fetus and
corresponds to a transformed animal dose of 17.5 mg/kg/day [90.5 mg/m3 x
0.152 mVday (rat Inhalation rate [U.S. EPA, 1986d)]) x 1/0.197 kg
(one/rat body weight) x 6 hours/24 hours].
Two chronic NOAELS, 6.0 mg/kg/day In hamsters and 4.0 mg/kg/day 1n rats,
are available from studies of equal quality for consideration 1n deriving a
chronic Inhalation RfD (selection of either value over the other). In this
case, the NOAEL of 4.0 mg/kg/day 1n rats Is- chosen as the basis for the RfD
because rats may be slightly more sensitive than hamsters and there Is no
assurance that a LOAEL for rats may not occur below the NOAEL for hamsters.
Division of this transformed dose by an uncertainty factor of 100 (10 for
Interspedes extrapolation and 10 for sensitive human populations) results
1n a chronic Inhalation RfD for 2-chloro-l,3-butadlene of 0.04 mg/kg/day, or
3 mg/day for a 70 kg human. Dividing this RfD by a human 24-hour ventlla-
tory volume of 20 mVday (U.S. EPA, 1986d) results 1n a chronic Inhalation
RfD of 0.1 mg/m3.
Confidence In the chronic Inhalation RfD 1s high. Data In hamsters and
rats Indicate that the compound 1s not carcinogenic. The key study was a
well-designed and executed Investigation that Involved comprehensive gross
and microscopic examination of sufficient numbers of rats of both sexes.
Developmental toxlclty, reproduction and chronic and subchronlc toxlclty
studies using rats and hamsters support the NOAEL 1n rats.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURE (SUBCHRONIC) ~ Pertinent data
regarding the systemic toxlclty of 2-chloro-l,3-butadiene following
subchronlc oral administration were not located In the available literature
0112d -44- 04/18/89
-------
cHed In Appendix A. It 1s possible, however, to calculate a subchronlc
oral RfD for 2-chloro-l,3-butad1ene based on the subchronlc Inhalation RfO
for the compound and using appropriate absorption factors for the various
exposure routes. Assuming 50% absorption of 2-chloro-l,3-butad1ene by the
Inhalation route and 10054 absorption of the compound by the oral route the
subchronlc Inhalation RfD of 0.04 rog/kg/day 1s multiplied by 0.5 to give a
subchronlc oral RfD of 0.02 mg/kg/day. Multiplication by the reference
human body weight [70 kg (U.S. EPA, 1986d)] gives a subchronlc oral RfD of
1.0 mg/day.
Confidence In the subchronlc oral RfD for 2-chloro-l,3-butadlene 1s low.
Although confidence In the 1nhalat16n toxlclty data base Is high, there Is
considerable uncertainty associated with route-to-route extrapolation.
8.2.2.2. CHRONIC EXPOSURE Pertinent data regarding the systemic
toxlclty of 2-chloro-l,3-butad1ene following chronic oral exposure were not
located 1n the available literature cited In Appendix A. A chronic oral RfD
can be derived for 2-chloro-l ,3-butadlene using the same approach as was
used for deriving a subchronlc oral RfD. Multiplying the chronic Inhalation
RfD (0.04 mg/kg/day) by an Inhalation absorption factor of 0.5 gives a
chronic oral RfD of 0.02 mg/kg/day. Multiplying the chronic oral RfD by the
reference human body weight [70 kg (U.S. EPA, 1986d)] gives a chronic oral
RfD of 1 mg/day. Confidence In the chronic oral RfD Is low (see Section
8.2.2.1.}. The above systemic toxlclty risk assessment Is based on results
obtained from studies using pure 2-chloro-l,3-butad1ene. This may not
reflect the "real world" risk of exposure to 2-chloro-l,3-butad1ene In the
sense that oxidation products (which may be more toxic than the parent
compound) may be a factor In actual exposures to 2-chloro-l,3-butadlene.
0112d -45- 04/18/89
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9. REPORTA6LE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The systemic toxlclty of 2-chloro-l,3-butadlene was discussed 1n Chapter
6 and Is summarized 1n Table 9-1. Several chronic toxldty studies on
2-chloro-l,3-butadlene were found 1n the available literature that were
considered adequate for RQ development.
The most severe effect In Table 9-1 1s fetotoxHIty (I.e., decrease 1n
fetal weight) observed 1n the fetotox1dty/teratogen1c1ty study by E.I.
DuPont de Nemours and Co. (1985k). This effect occurred at an equivalent
human dose of 7.4 mg/kg/day. Multiplication of this dose by the reference
human body weight (70 kg) gives a MED of 518 mg/day, which corresponds to an
RV, of 1.4. The RV associated with the effect of decreased fetal
d e
weight Is 8 and multiplication of this RVg by the RVrf yields a CS of
11.2 (Table 9-2). This CS Is associated with an RQ of 1000.
The next most severe effect observed was growth retardation, which
occurred In rats exposed to 100 ppm for 26 weeks (E.I. DuPont de Nemours and
Co., 1985a), hamsters and rats exposed to 50 ppm for 18 months and 2 years,
respectively (E.I. DuPont de Nemours and Co., 1985b,c), and In the second
(F ) generation of rats exposed to 33 ppm for 10 weeks (E.I. DuPont de
Nemours and Co., 1985m). Growth retardation rates an RV of 4. An RV
of 2.2 was estimated from the human equivalent dosage of 2.3 mg/kg/day
(MED = 161 mg/day) for rats exposed for 10 weeks In the reproduction study.
No uncertainty factor was applied to expand from subchronlc to chronic
exposure because the toxic potency of 2-chloro-l,3-butad1ene does not appear
to Increase 1n chronic exposure. A CS of 8.8 results (see Table 9-2).
0112d -46- 05/05/88
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Other effects summarized 1n Table 9-1, altered organ weights, mild
Mstopathologlc lesions 1n the liver and alopecia, were not more severe than
those for which CSs have been calculated; hence, CSs are not calculated for
these effects.
The effect chosen for RQ determination for 2-chloro-l,3-butad1ene 1s
decreased fetal weight observed In the developmental toxldty rat study by
E.I. DuPont de Nemours and Co. (1985k). This effect yielded the highest CS
(11.2) of the two considered for RQ determination, and this CS 1s asso-
ciated with an RQ of 1000 (Table 9-3).
9.2. BASED ON CARCINOGENICITY
Data from several studies (E.I. DuPont de Nemours and Co., 1985b,c;
Ponomarkov and Tomatls, 1980; Zll'fyan et al., 1975, 1977) Indicated that
2-chloro-l,3-butad1ene was not carcinogenic In animals following exposure
either by the oral or Inhalation route. Data from human epidemiologies!
studies have been ambiguous 1n the sense that a slgnlfIcantTy Increased
Incidence of skin and lung cancer was reported 1n workers exposed to
2-chloro-l,3-butadlene In Russian studies (Khachatryan, 1972a,b), but the
finding of Increased lung cancer was not confirmed In a study of occupa-
tlonally-exposed Individuals by- Pell (1978). In addition, these epldemlo-
loglcal studies, for reasons pointed out In Section 6.2.1., were not con-
sidered adequate to determine whether 2-chloro-l,3-butad1ene exposure Is
associated with an Increased risk of cancer 1n humans. Because there 1s
evidence that 2-chloro-l,3-butad1ene 1s not carcinogenic In animals, and
Inadequate evidence for cardnogen1c1ty In humans, neither an Inhalation nor
an oral q,* was derived for the compound. The lack of either an Inhala-
tion or oral q * for 2-chloro-l ,3-butadlene and an Inability to assign the
0112d -50- 05/05/88
-------
TABLE 9-3
2-Chloro-l,3-butad1ene
Minimum Effective Dose (HED) and Reportable Quantity (RQ)
Route: Inhalation
Dose*: 518 mg/day
Effect: decreased fetal body weight
Reference: E.I. DuPont de Nemours Co., Inc., 1985k
RVd: 1.4
RVe: 8
Composite Score: 11.2
RQ: 1000
*Equ1valent human dose
0112d -51- 04/19/88
-------
compound to any potency group precludes a hazard ranking for 2-chloro-l,3-
butadlene. Because a hazard ranking Is not available. U Is not possible to
derive an RQ based on cardnogenldty for 2-chloro-l ,3-butadlene.
0112d -52- 04/19/88
-------
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quality of drinking water. Sci. Total Environ. 47: 27-44.
SRI (Stanford Research Institute). 1987. 1987 Directory of Chemical
Producers: United States Of America. SRI International, Menlo Park, CA.
Summer, K-H and H. Grelm. 1980. Detoxlfocatlon of chloroprene (2-chloro-
1,3-butadlene) with glutathione In the rat. Blochem. Blophys. Res. Commun.
96(2): 566-573.
Summer, K-H. and H. Grelm. 1981. Metabolism of chloroprene 2-chloro-l,3-
butadlene depletion of hepatic glutathione In the rat. l_n: 22nd Spring
Meet. German Pharmacol. Soc., Mainz, West Germany, March, 10-13. Naunyn-
Schmledeberg's Arch Pharmacol. 316: R18. (Taken from HEEP/82/07690)
Swann, R.L., O.A. Laskowski, P.J. McCall, K Vander Kuy and H.J. Dishburger.
1983. A rapid method for the estimation of the environmental parameters
octanol/water partition coefficient, soil sorpUon constant, water to air
ratio and water solubility. Res. Rev. 85: 17-28.
3112d -62- 04/19/88
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U.S. EPA. 1980. Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 79347-79357.
U.S. EPA. 1984a. Health and Environmental Effects Profile for 2-Chloro-
1,3-butadlene. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Solid Waste, Washington, DC. EPA/600/X-84-112. NTIS
P888-107511.
U.S. EPA 1984b. Methodology and Guidelines for Ranking Chemicals Based on
Chronic Toxlcity Data. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
J.S. EPA. 1986a. Methodology for Evaluating Carclnogenlclty 1n Support of
^portable Quantity Adjustment Pursuant to CERCLA Section 102. Prepared by
the Office of Health and Environmental Assessment, Carcinogen Assessment
Group, Washington, -DC for the Office of Solid and Emergency Response,
Washington, DC.
U.S. EPA. 1986b. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
0112d -63- 04/18/89
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U.S. EPA. 1986c. Summary Overview of Health Effects Associated with
Chloroprene: Health Issue Assessment. Prepared by the Office of Health and
Environmental Assessment, Environmental Criteria and Assessment Office,
Research Triangle Park. NC for the Office of Air Quality Planning and
Standards, Research Triangle Park, NC. EPA/600-8-85/01 IF. NTJS PB86-197662.
U.S. EPA. 1986d. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment, Cincinnati, OH for the Office of Solid Waste, Washington, DC.
J.S. EPA. 1987a. Graphical Exposure Modeling System (GEMS). Personal
computer version. CLOGP computer program. April 1987. U.S. EPA, Research
Triangle Park, NC.
U.S. EPA, 1987b. Graphical Exposure Modeling System (GEMS). Personal
computer version. PC Chemistry computer program. April 1987. U.S. EPA,
Research Triangle Park, NC.
L.S. EPA. 1987c. Graphical Exposure Modeling System (GEMS). Personal
computer version. Fate of Atmospheric Pollutants (FAP). April 1987. U.S.
EPA, Research Triangle Park. NC.
U.S. EPA. 1988. STORE1 Water Quality Database. On-line: January 1988.
Vogel, E. 1979. Mutagenlcity of chloroprene, 1 -chloro-1,3-trans-butadiene,
1 ,3-dichlorobutene-2 and 1,4-dichloro-2,3-epoxybutane in Drosophila melano-
Caster. Mutat. Res. 67: 377-381.
0112d -64- 04/18/89
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von OetUngen, W.F., W.C. Hueper, W. Delchmann-Gruebler and F.H. Wiley.
1936. 2-Chlorobutad1ene (chloroprene): Its toxlcity and pathology and the
mechanism of Us action. J. Ind. Hyg. Toxlcol. 18: 240-270.
Zll'fyan, V.N., B.S. Flchldzhyan and A.M. Pogosova. 1975. Results of
testing chloroprene for carclnogenlcity. Zh. Eksp. Klin. Hed. 15: 54-57.
(Rus.) {CHed 1n IARC, 1979)
Zll'fyan, V.N., B.S. Flchldzhyan, O.K. GaMbyan and A.M. Pogosova. 1977.
Experimental study of chloroprene for carclnogenlcity. Vop. Onkol. 23:
*
61-65. (Rus.) (CHed In IARC, 1979)
0112d -65- 02/22/89
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APPENDIX A
LITERATURE SEARCHED
This HEED 1s based on data Identified by computerized literature
searches of the following:
CHEMLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHH TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
These searches were conducted 1n October 1987, and the following secondary
sources were 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).
1987. TLVs: Threshold Limit Values for Chemical Substances In the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.O. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2B. John WHey 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.
0112d -66- 04/19/88
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Grayson, M. and D. Eckroth, Ed. 1978-1984. K1rk-0thmer 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. IARC, WHO, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. Lieu, T.W. Chou and H.L. Johnson.
19B4. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo
Park, CA.
NTP (National Toxicology Program). 1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report In the Special Review
Program, Registration Standards Program and the Data Call 1n
Programs. Registration Standards and the Data Call In Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
Windholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
3112d -67- 04/19/88
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In addition, approximately 30 compendia of aquatic toxlclty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. 'Prepared for the
U.S. EPA under Contract No. 68-01-0007. -Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxlclty
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, 3.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. P8-269605.
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.
0112d -68- 04/19/88
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