Un,,ed States 500ECAOCING021
Environmental Protection
Agency
f/EPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR 1.3-BUTADIENE
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DRAFT: DO NOT CITE OR QUOTE
NOTICE
This document Is a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It 1s being circulated for comments
on Its technical accuracy and policy Implications.
U.S. Environmental Protection Agency
Region 5, Library (5PL-16)
830 S. Dearborn Street, Room 1670
Chicago, IL 60604
-------
DISCLAIMER
This report Is an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
-------
PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). 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 from Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for 1n this document
and the dates searched are Included 1n "Appendix: Literature Searched."
Literature search material 1s 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 Is 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, for example, one that does
not constitute a significant portion of the Hfespan. This type of exposure
estimate has not been extensively used, or rigorously defined as previous
risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for 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. A
carcinogenic potency factor, or q-|* (U.S. EPA, 1980), Is provided Instead.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxldty and cardno-
gsnldty are derived. The RQ 1s used to determine the quantity of a hazar-
dous substance for which notification 1s required 1n the event of a release
as specified under the CERCLA. These two RQs (chronic toxldty and cardno-
genlclty) represent two of six scores developed (the remaining four reflect
1gn1tab1l1ty, reactivity, aquatic toxldty, and acute mammalian toxldty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxldty and cancer-based RQs are defined 1n U.S.
EPA, 1984 and 1986c, respectively.
111
-------
EXECUTIVE SUMMARY
1,3-Butad1ene Is a colorless gas with a mild aromatic odor at ambient
temperatures (Hawley, 1981). It Is soluble 1n most common organic solvents,
but Is almost Insoluble 1n water (Klrshenbaum, 1978; McAullffe, 1966). In
1985, 10 U.S. manufacturers produced 2.3 billion pounds of rubber-grade
1,3-butadlene (USITC, 1986). U.S. production of all grades of butadiene In
both 1985 and 1986 was estimated to be -2.5 billion pounds (C8.E News,
1986). 1,3-Butad1ene Is used predominantly 1n the production of synthetic
rubbers and elastomers (CMR, 1985).
1,3-Butadlene 1s not expected to be a persistent environmental compound.
When released to the atmosphere, It will oxidize rapidly with several
oxldant species. The dominant atmospheric removal process will be reaction
with hydroxyl radicals, which has an estimated half-life of 2.6 hours 1n a"
normal atmosphere. If released to the aquatic environment, volatilization
and oxidation (by singlet oxygen) are expected to be the significant
environmental fate processes. The estimated volatilization half-life of
1,3-butad1ene from a river 1 m deep flowing 1 m/sec 1s -2.2 hours. The
estimated half-life of the reaction with singlet oxygen In sunlit natural
water Is -1 day. Aquatic hydrolysis, direct photolysis, adsorption to sedi-
ment and bloconcentratlon are not expected to be significant; 1f released to
soil, significant evaporation 1s likely to occur. Based on estimated K
values (116-288), any residual 1,3-butad1ene In soil Is susceptible to
significant leaching.
Atmospheric emission sources of 1,3-butadlene Include Industrial
effluent and fugitive emissions, forest fires and exhausts from automobiles,
dlesel engines and jet turbines (Graedel, 1978; Hayano et al., 1985; Hughes
1v
-------
et al., 1979; Katzman and Ubby, 1975). Based on available monitoring data
(see Table 3-1), a typical ambient air concentration of 1,3-butadlene In a
U.S. urban/suburban area Is -1-2 ppb. Assuming an ambient air concentration
of 1.5 ppb, an average dally Inhalation Intake of 66 yg has been estimated
for the U.S. ur4>an/suburban population. An NIOHS conducted between 1972 and
1974 estimated that -65,000 U.S. workers are potentially exposed to
l,3-butad1ene (NIOSH, 1984).
The only available Information concerning the toxldty of 1,3-butad1ene
to aquatic biota was a 24-hour LC of 71.5 mg/l for plnperch, Lagodon
rhomboldes (Daugherty and Garret, 1951).
1,3-Butad1ene Is absorbed after Inhalation by B6C3F1 mice and Sprague-
Oawley rats (Bond et al., 1986). Estimates of absorption were >4-20% of
Inhaled dose for mice and >1.5-17% for rats exposed to very high concen-
trations.
Following Inhalation, 1,3-butad1ene 1s distributed to the brain, liver,
kidney and spleen of rats at nearly equivalent levels, and very high levels
are found In the perlnephMc fat (Shugaev, 1969). 1,3-Butad1ene was also
found to distribute to the mouse brain and the central nervous system of the
cat following Inhalation exposure (Shugaev, 1969).
The primary In vivo metabolites of 1,3-butad1ene 1n the blood of rats
and mice following Inhalation exposure appear to be 1,2-epoxy-3-butene and
butadiene dlepoxlde (Bond et al., 1986). Saturation of the metabolic elimi-
nation mechanism for 1,3-butad1ene was approached at Inhalation exposure
levels >1000 ppm (2200 mg/m3) 1n both Sprague-Dawley rats and B6C3F1 mice
(Krelllng et al., 1986a,b; FUser and Bolt, 1984). The maximal metabolic
rate of elimination of 1,3-butadlene (V ), however, was found to be
ffla X
approximately twice as high In mice as 1n rats. Exhalation of 1,3-butad1ene
-------
monoxide and acetone has been demonstrated In rats exposed to 1,3-butad1ene
by Inhalation (Fllser and Bolt, 1984). The primary in vitro metabolites of
1,3-butad1ene(us1ng rat liver mlcrosomes) are 1,3-epoxybutene-3, 3-butene-
1,2-dlol, dlepoxybutene and 3,4-epoxy-l,2-butaned1ol (Malvolsln and
Roberfrold, 1982).
Excretion of radioactivity derived from Inhaled radlolabeled 1,3-buta-
dlene was determined to be primarily In the urine and exhaled air of
1,3-butad1ene-exposed Sprague-Dawley rats and B6C3F1 mice (Bond et al.,
1986). These routes of elimination accounted for -75-85% of the total 14C
eliminated.
The toxlclty of 1,3-butad1ene following Inhalation exposure appears to
depend on the species of animal. Adverse effects attributable to 1,3-buta-
dlene exposure were practically nonexistent except for Increased salivation
observed 1n female Sprague-Dawley rats exposed to 8000 ppm (17,698 mg/m3);
6 hours/day, 5 days/week for 13 weeks (Crouch and PulUnger, 1978; Crouch et
al., 1979) and In rabbits and dogs exposed to 6700 mg/m3, 7.5 hours/day, 6
days/week for 8 months (Carpenter et al., 1944). The bone marrow appears to
be a target site for 1,3-butadlene toxlclty In B6C3F1 and NIH mice (Irons et
al., 1986a,b; Lelderman et al., 1986). A 1,3-butad1ene-1nduced macrocytlc-
megaloblastlc anemia was observed In B6C3F1 and NIH mice exposed to 1250 ppm
(2765 mg/m3), 6 hours/day, 5-6 days/week for as few as 6 weeks (Irons et
al, 1986a,b; Lelderman et al., 1986). Chronic Inhalation exposure to
l,3-butad1ene at >625 ppm (1383 mg/m3), 6 hours/day, 5 days/week for 60
weeks caused gonadal atrophy In both sexes of B6C3F1 mice (NTP, 1984).
Nonneoplastlc lesions of the nasal cavity of male mice occurred at 1250 ppm
(2765 mg/m3) (NTP, 1984).
v1
-------
Several ep1dem1olog1ca1 studies (HcHUhael et al., 1974; Andjelkovlch et
al., 1976; Hatanoskl et al.. 1982) associate work 1n the SBR Industry with
excess risk of cancers of the hematopoletlc and lymphatic systems, but
concurrent exposure to potential carcinogens other than 1,3-butad1ene also
occurred. Long-term Inhalation cardnogenlclty studies performed with
B6C3F1 mice (NTP, 1984) and Sprague-Dawley rats (Hazleton Laboratories.
1981a) confirmed that 1,3-butad1ene 1s carcinogenic 1n these species. Rats
exhibited an Increased Incidence of the following tumors: Leydlg cell
adenomas, exocrlne adenomas of the pancreas, multiple mammary gland tumors,
folllcular cell adenomas and carcinomas of the thyroid, and stromal sarcomas
of the uterus-cervix. The most prevalent tumor types 1n B6C3F1 mice were
malignant lymphomas associated with the hematopoletlc system, and hemanglo-
sarcomas. This mouse strain 1s not only much more sensitive In terms of a
carcinogenic response than 1s the Sprague-Dawley rat, but the tumor sites
also differ 1n the two species. Several hypotheses for these differences
have been postulated, Including a faster rate of 1,3-butad1ene metabolism by
the mouse (KrelUng et al., 1986a,b); limited detoxification by the mouse
leading to greater accumulation of the primary reactive metabolite,
1,2-epoxybutene-3 (KrelUng et al., 1987); a lower absorption rate In the
rat vs. the mouse (Bond et al., 1986); and the presence of an endogenous
virus (HuLV) In the B6C3F1 mouse strain, which may act 1n combination with
butadiene to yield Increased luekemla-lymphoma response (Irons et al.,
4. . '
1986a).
1,3-Butadlene Is mutagenlc In bacteria with activation (DeMeester et
al., 1980) and Induces chromosomal aberrations and SCE 1n mice (Tlce et al.,
1987). Data from Hazleton Laboratories (1981b) Indicate that 1,3-butad1ene
1s a teratogen when pregnant female rats are exposed by Inhalation at 8000
ppm (17,698 mg/m'), 6 hours/day during organogenesls.
-------
1,3-Butad1ene has been classified as an EPA Group 82 compound, probable
human carcinogen. A q * of 2.4x10"* (ppm)"1 or 1.8 (mg/kg/day)"1
expressed as Internal dosage [or 9.0 (mg/kg/day)'1 assuming 20% absorption
via Inhalation and 100% absorption from the gut] was derived as the geo-
metric mean of q *s developed from the data In male and female nice 1n the
HTP (1984) Inhalation study. An RQ of 1000 was derived for systemic
toxUUy from a chronic Inhalation rat study (Hazleton Laboratories, 1981a).
An RQ of 10 was based on cardnogenldty 1n male mice (NIP, 1984).
-------
TABLE OF CONTENTS
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. Reaction with Hydroxyl Radicals 4
2.1.2. Reaction with Ozone 4
2.1.3. Reaction with Atomic Oxygen 4
2.1.4. Reaction with NHrate Radical 5
2.2. WATER 5
2.2.1. Hydrolysis 5
2.2.2. Photolys1s/Photoox1dat1on 5
2.3.3. Mlcroblal Degradation 5
2.2.4. Volatilization 6
2.2.5. Adsorption 6
2.2.6. B1oconcentrat1on 6
2.3. SOIL 6
2.3.1. Adsorption 6
2.3.2. Volatilization 7
2.4. SUMMARY 7
3. EXPOSURE 8
3.1. WATER 8
3.2. FOOD 8
3.3. INHALATION 8
3.4. DERMAL 10
3.5. SUMMARY 10
4. AQUATIC TOXICITY 11
4.1. ACUTE TOXICITY 11
4.2. CHRONIC EFFECTS 11
4.3. PLANT EFFECTS 11
4.4. SUMMARY 11
1x
-------
TABLE OF CONTENTS (cont.)
Page
5. PHARMACOKINETCS 12
5.1. ABSORPTION 12
5.2. DISTRIBUTION 13
5.3. METABOLISM 14
5.4. EXCRETION 18
5.5. SUMMARY 19
6. EFFECTS 20
6.1. SYSTEMIC TOXICITY 20
6.1.1. Inhalation Exposures 20
6.1.2. Oral Exposures 23
6.1.3. Other Relevant Information 24
6.2. CARCINOGENICITY 24
6.2.1. Inhalation 24
6.2.2. Oral 32
6.2.3. Other Relevant Information 32
6.3. MUTAGENICITY 33
6.4. TERATOGENICITY 33
6.5. OTHER REPRODUCTIVE EFFECTS 37
6.6. SUMMARY 37
7. EXISTING GUIDELINES AND STANDARDS 39
7.1. HUMAN 39
7.2. AQUATIC 39
8. RISK ASSESSMENT 40
8.1. CARCINOGENICITY 40
8.1.1. Inhalation 40
8.1.2. Ingestlon 40
8.1.3. Other Routes 40
8.1.4. Weight of Evidence 40
8.1.5. Quantitative Risk Estimates 41
8.2. SYSTEMIC TOXICITY 44
-------
TABLE OF CONTENTS (cont.)
Page
9. REPORTABLE QUANTITIES 45
9.1. BASED ON SYSTEMIC TOXICITY 45
9.2. BASED ON CARCINOGENICITY 49
10. REFERENCES 52
APPENDIX A: LITERATURE SEARCHED 68
APPENDIX B: SUMMARY TABLE FOR 1,3-BUTADIENE 71
-------
LIST OF TABLES
No. Title Page
3-1 Ambient A1r Monitoring Data for 1,3-Butad1ene 9
6-1 Inhalation Cardnogenldty of Butadiene (98.9-100%
purity) After 60-61 Weeks of Exposure (6 hours/day,
5 days/week) 1n B6C3F1 Mice 26
6-2 Inhalation Cardnogenldty of Butadiene (unknown purity)
In Sprague-Dawley Rats Exposed 6 hours/day, 5 days/week ... 30
6-3 Mutagenldty Testing of 1,3-Butad1ene 34
9-1 Inhalation Toxldty Summary for 1,3-Butad1ene 46
9-2 Inhalation Composite Scores for 1,3-Butadlene 47
9-3 l,3-Butad1ene: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 48
9-4 Derivation of Potency Factor (F) for Butadiene 50
-------
LIST OF ABBREVIATIONS
ADP
ATP
BCF
CS
DNA
LD50
MED
MTD
NADPH
NOAEL
NOHS
PEL
ppb
ppm
RfD
RQ
RVd
RVe
SBR
SCE
TLV
UDS
v/v
Adenoslne 5'-dlphosphate
Adenoslne 5'-trlphosphate
B1oconcentrat1on factor
Composite score
Deoxyrlbonuclelc acid
Soil sorptlon coefficient standardized
with respect to organic carbon
Octanol/water partition coefficient
Concentration lethal to 50% of recipients
(and all other subscripted dose levels)
Dose lethal to 50% of recipients
Minimum effective dose
Maximum tolerated dose
N1cot1nam1de adenlne dlnucleotlde phosphate
(reduced form)
No-observed-adverse-effect level
National Occupational Hazard Survey
Permissible exposure level
Parts per billion
Parts per million
Reference dose
Reportable quantity
Dose-rating value
Effect-rating value
Styrene-butadlene rubber
Slster-chromatld exchange
Threshold limit value
Unscheduled DNA synthesis
Volume per volume
-------
1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
1,3,-Butadiene Is the common name for the chemical also known as
butadiene, blethylene, blvlnyl, dlvlnyl, trans-butadiene, erythrene,
pyrrolylene, vVnylethylene and buta-1,l-d1ene (SANSS, 1987). The structure,
molecular weight, empirical formula and CAS Registry number for 1,3-buta-
dlene are as follows:
CH2=CH-CH=CH2
Molecular weight: 54.09
Empirical formula: C.H,
CAS Registry Number: 106-99-0
1.2. PHYSICAL AND CHEMICAL PROPERTIES
1,3-Butadlene 1s a colorless gas with a mild aromatic odor at ambient
temperatures (Hawley, 1981). It Is soluble In ethanol and methanol and
readily soluble In most other common organic solvents (Klrshenbaum, 1978).
Selected physical properties of 1,3-butadlene are listed below:
Melting point: -108.9°C Klrshenbaum, 1978
Boiling point: -4.41°C Klrshenbaum, 1978
Specific gravity:
(liquid at 20°C) 0.6211 Hawley, 1981
Vapor pressure, atm:
at -4.5°C 1 Perry and Green, 1984
at 14.5°C 2 Perry and Green, 1984
at 47.0°C 5 Perry and Green, 1984
Water solubility:
at 25°C 735 ppm McAullffe, 1966
Log Kow: 1.99 Hansch and Leo, 1981
A1r odor threshold: 1.6 ppm Amoore and Hautala,
1983
0068d -1- 09/14/87
-------
Flash point: -76°C Hawley, 1981
A1r conversion factors 1 mg/m3 = 0.445
at 20°C: 1 ppm = 2.212 mg/m3
Although 1,3-butadlene Is a gas at normal temperatures and pressures, H
Is easily Hcpjlfled (Hawley, 1981). The liquid material polymerizes
readily, particularly 1n the presence of oxygen, and the commercial material
usually contains an Inhibitor to prevent spontaneous polymerIzaton during
shipping and handling (Hawley, 1981; Klrshenbaum, 1978). Butadiene under-
goes addition, substitution, oxidation and 01els-Alder reactions and can be
hydrogenated to butene and butane (Klrshenbaum, 1978).
1.3. PRODUCTION DATA
In 1985, 10 U.S. manufacturers produced 2.3 billion pounds of rubber-
grade l,3-butad1ene (USITC, 1986). U.S. production of all grades of buta-
diene 1n both 1985 and 1986 was estimated to be -2.5 billion pounds (C&E
News, 1986). 1,3-Butadlene Is produced by the following manufacturers, with
a combined annual capacity of 3.755 billion pounds (SRI, 1986):
Company Location
Amoco Corp. Chocolate Bayou, TX
Atlantic Richfield Channelvlew, TX
Dow Chemical Freeport, TX
DuPont Chocolate Bayou, TX
El Paso Products Corpus Chrlstl, TX
Exxon Corp. Baton Rouge, LA
Exxon Corp. Baytown, TX
Mobil Corp. Beaumont, TX
Shell 011 Deer Park, TX
Shell 011 Norco, LA
Texaco Port Neches, TX
Texas Oleflns Houston, TX
Current exports of 1,3-butadlene total -125 million pounds/year, with
Imports totaling -500 million pounds/year (CiE News, 1986).
0068d -2- 09/14/87
-------
1,3-Butad1ene 1s manufactured by steam cracking of naphtha and gas oil
fractions, which produce butadiene and ethylene as co-products, or by the
catalytic dehydrogenatlon of n-butene and n-butane (Klrshenbaum, 1978). The
steam cracking process Is the predominant U.S. production process (SRI,
1986). The IsomeMc 1,2-butad1ene 1s sometimes found as a contaminant of
1,3-butadlene {Klrshenbaum, 1978).
1.4. USE DATA
The use pattern for 1,3-butadlene was estimated 1n CMR (1985) as
follows: styrene-butadlene rubber, 37%; polybutadlene rubber, 22%; adlpo-
nltrlle/HMDA (hexamethylened1am1ne), 11%; styrene-butadlene latexes, 9%;
neoprene, 7%; ABS resins, 5%; exports, 4%; nltrlle rubber, 3% and other, 2%.
The dominant use Is the production of synthetic rubbers and elastomers; the
miscellaneous uses Include use as a chemical Intermediate for the production
of 1,4-hexad1ene and 1,5,9-cyclodecatrlene (Klrshenbaum, 1978).
1.5. SUMMARY
l,3-Butad1ene Is a colorless gas with a mild aromatic odor at ambient
temperatures (Hawley, 1981). It Is soluble In most common organic solvents,
but 1s almost Insoluble In water (Klrshenbaum, 1978; McAullffe, 1966). In
1985, 10 U.S. manufacturers produced 2.3 billion pounds of rubber-grade
1,3-butadlene (USITC, 1986). U.S. production of all grades of butadiene In
both 1985 and 1986 was estimated to be -2.5 billion pounds (CiE News,
1986). 1,3-Butad1ene 1s used predominantly In the production of synthetic
rubbers and elastomers (CMR, 1985).
0068d -3- 09/14/87
-------
2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Because of Us very high vapor pressure, 1,3-butad1ene win exist
entirely 1n the vapor phase 1n the atmosphere. It 1s extremely reactive
with various atmospheric oxldants and, therefore, does not persist In the
atmosphere. Although 1,3-butadlene Is transformed rapidly In the atmo-
sphere, It has been detected as a commonly occurring atmospheric contaminant
(Section 3.3.), probably because of Us continual emission to the atmosphere
from automobile exhaust, dlesel exhaust and other sources.
2.1.1. Reaction with Hydroxyl Radicals. The recommended rate constant
for the vapor-phase reaction of 1,3-butad1ene with photochemlcally produced
hydroxyl radicals In the atmosphere Is 6.68X10"11 cm3/molecule-sec at
25°C (Atkinson, 1985). Assuming an average atmospheric hydroxyl radical
concentration of 8xl05 molecules/cm3 (U.S. EPA, 1987), the estimated
half-life Is 3.6 hours, which Indicates that reaction with hydroxyl radicals
will be the dominant atmospheric removal process.
2.1.2. Reaction with Ozone. The recommended rate constant for the vapor-
phase reaction of 1,3-butadlene with ozone 1n the atmosphere 1s 8.1xlO~18
cma/molecule-sec at 25°C (Atkinson and Carter, 1984). Assuming an average
atmospheric ozone concentration of SxlO11 molecules/cm3 (U.S. EPA,
1987), the estimated half-life 1s -40 hours. Acroleln has been Identified
as one of the products of the reaction of 1,3-butad1ene with ozone (N1k1 et
al., 1983).
2.1.3. Reaction with Atomic Oxygen. The rate constant for the vapor-
phase reaction of 1,3-butadlene with atomic oxygen (03P) 1n the atmosphere
Is 19.4xlO"12 cm3/molecule-sec at 24°C (Atkinson and Pitts, 1977).
Assuming an average atmospheric atomic oxygen concentration of 2.5x10*
molecules/cm3 (Graedel, 1978), the estimated half-life Is -16.5 days.
0068d -4- 09/14/87
-------
2.1.4. Reaction with Nitrate Radical. The reaction with nitrate radicals
has been recognized as a potentially Important n1ght-t1me environmental sink
for some chemicals. The rate constant for the vapor-phase reaction of
1,3-butadlene In the atmosphere Is 5.34xlO~14 cma/molecule-sec at 22°C
(Atkinson et a-}., 1984). Assuming an average atmospheric nitrate radical
concentration of 2.4x10* molecules/cm3 (Atkinson et al., 1984), the
estimated half-life 1s -15 hours.
2.2. WATER
2.2.1. Hydrolysis. 1,3-Butad1ene does not contain hydrolyzable func-
tional groups; therefore, It 1s considered Inert to environmental hydrolysis
(Jaber et al., 1984).
2.2.2. Photolys1s/Photoox1dat1on. Direct photolysis Is not environ-
mentally significant with respect to 1,3-butadlene (Jaber et al., 1984).
Jaber et al. (1984) estimated the aquatic oxidation rate constants for.
the reaction of 1,3-butad1ene with peroxy radicals and singlet oxygen to be
2/M-sec and IxlO7 M-sec, respectively. Assuming that the concentrations
of peroxy radicals and singlet oxygen In sunlit natural water are 10~9 M
and 10~12 M, respectively (Mabey et al., 1981), the corresponding half-
lives for 1,3-butad1ene are 11 years and 1 day. Therefore, reaction with
singlet oxygen Is a potentially significant removal mechanism.
2.2.3. M1crob1al Degradation. Limited data are available pertaining to
the environmental blodegradatlon of 1,3-butad1ene. Thorn and Agg (1975)
listed 1,3-butadlene as biodegradable under typical biological sewage treat-
ment conditions as long as suitable acclimation Is achieved. A Nocardla
species Isolated from soil has been found to use 1,3-butad1ene as a sole
carbon and energy source (Watklnson and Sommervllle, 1976).
0068d -5- 09/14/87
-------
2.2.4. Volatilization. Based on measured water-to-alr equilibria data
(H1ne and Mookerjee, 1975), the Henry's Law constant for 1,3-butad1ene at
25eC Is 0.0617 atm-mVmole. This value of Henry's Law constant Indicates
that volatilization from water will be rapid. Using the method outlined In
Lyman et al. (1982), the estimated volatilization half-life of 1,3-butadlene
from a river 1 m deep flowing at 1 m/sec with a wind velocity of 3 m/sec Is
-2.2 hours. The volatilization rate from deeper or less rapidly moving
bodies of water will be slower.
2.2.5. Adsorption. Based on the estimated K values from Section
2.3., 1,3-butad1ene Is not expected to partition significantly from the
water column to sediment or suspended participate matter.
2.2.6. B1oconcentrat1on. The BCF values of an organic chemical can be
estimated from the following regression equations (Lyman et al., 1982):
log BCF = 0.76 log K - 0.23 (2-1)
log BCF = 2.791 - 0.564 log WS (In ppm) (2-2)
For 1,3-butad1ene, the BCF values calculated from Equations 2-1 and 2-2
are -19 and 17, respectively, based on a log K of 1.99 and a water
solubility of 735 ppm. These BCF values Indicate that 1,3-butadlene Is not
expected to bloconcentrate significantly 1n aquatic organisms.
2.3. SOIL
Pertinent data regarding the chemical or mlcroblal degradation of
1,3-butad1ene In son could not be located 1n the available literature as
cited 1n Appendix A.
2.3.1. Adsorption. The K of an organic chemical can be estimated
from the following regression equations (Lyman et al., 1982):
log K = 3.64 - 0.55 log WS (In ppm) (2-3)
log K = 0.544 log K f 1.377 (2-4)
0068d -6- 06/23/87
-------
For 1,3-butad1ene, the K values calculated from Equations 2-3 and 2-4
are 116 and 288, respectively, based on a water solubility of 735 ppm and a
log K of 1.99. These K values Indicate high to medium soil mobility
(Swann et al., 1983); 1,3-butadlene 1s susceptible to significant leaching
In most soils. ~
2.3.2. Volatilization. Because 1,3-butad1ene Is a gas at normal tempera-
tures and pressures, rapid evaporation from dry surfaces can be expected.
In addition, 1,3-butad1ene volatilizes rapidly from water (see Section
2.2.4.), which suggests significant evaporation from moist soil surfaces.
2.4. SUMMARY
1,3-Butadlene 1s not expected to be a persistent environmental compound.
When released to the atmosphere, 1t will oxidize rapidly with several
oxldant species. The dominant atmospheric removal process will be reaction
with hydroxyl radicals, which has an estimated half-life of 2.6 hours 1n a-
normal atmosphere. If released to the aquatic environment, volatilization
and oxidation (by singlet oxygen) are expected to be the significant
environmental fate processes. The estimated volatilization half-life of
1,3-butadlene from a river 1 m deep flowing 1 m/sec Is -2.2 hours. The
estimated half-life of the reaction with singlet oxygen In sunlit natural
water Is -1 day. Aquatic hydrolysis, direct photolysis, adsorption to sedi-
ment and bloconcentratlon are not expected to be significant; 1f released to
soil, significant evaporation Is likely. Based on estimated K values
(116-288), any residual 1,3-butad1ene 1n soil Is susceptible to significant
leaching.
0068d -7- 09/14/87
-------
3. EXPOSURE
An NOHS conducted between 1972 and 1974 estimated that -65,000 U.S.
workers may be exposed to 1,3-butad1ene (NIOSH, 1984). Surveys conducted by
NIOSH at six user facilities found worker exposure levels of 0.06-39 ppm
(0.13-86 mg/m3), significantly below the OSHA standard of 1000 ppm (2200
mg/m3) (OSHA, 1985).
3.1. HATER
Ewlng et al. (1977) collected surface water samples from 204 sites near
heavily Industrialized areas across the United States and analyzed the
samples for a wide variety of contaminants. 1,3-Butad1ene was Identified 1n
only one sample. The U.S. EPA STORET data base contained only one reporting
station for 1,3-butadlene; the reported level of 1,3-butadlene was 3 ppb.
3.2. FOOD
Pertinent food monitoring data could not be located In the available
literature as cited In Appendix A.
3.3. INHALATION
Ambient air monitoring data for 1,3-butad1ene are presented 1n Table
3-1. These data Indicate that the general population 1n urban/suburban
areas 1s typically exposed to an ambient air concentration of 1.5 ppb (3.3
vg/m3) and an average Intake of 20 m3 of air/day, resulting In an
average dally Inhalation Intake of -66 ^g.
1,3-Butad1ene 1s emitted to the atmosphere In automobile and dlesel
exhaust, In Incomplete combustion products from forest fires, from effluents
and fugitive emissions from Industrial manufacturing processes and 1n jet
turbine exhausts (Graedel, 1978; Hayano et al., 1985; Hughes et al., 1979;
Katzman -and L1bby, 1975). It has also been Identified 1n tobacco smoke
(Graedel, 1978).
0068d -8- 06/23/87
-------
41
C
«
a
03
-"
£
v
a
c
t»
o
I
c
41
i
0)
u
!
i
SI*
ac
-
w>
**
e
I
*^
§
15 >
u .O
4)
u
§
A)
a
e
1
1
u
0
^,-n-
O
' *^ y
Iff*
^B ll» &
"S m vl **
a o
\s *~ & t*
C 41 ** i"~
C 0 4)
C 41 >
«« 9 i 4)
S-"5~
^ ^3 b» flf
u e
CO
CM
ri
{»
i
o
en
?
i
«
2
41
X
C
o
^J
i
a
c
*>
CM
i"S
c
o c
CD
^*
J
^3
'O
a.
at
u
w
^
v a>
k. a
o 4>
"3» cu
e
u ««
u
2J
5 'a
p- 4)
<§£
^ CM
I* ,
a c 4i
U ^
*- «fl U
e o -o
*O C ** 4»
^lls
i i« -O
r*
f"
d
Q.
n
2
&
41
C
VI
41
^
u
>o
W
Jfl >
II
r*
JD
e en
" .
g g
2 *-
2
O
+*
e
i
«/i
^
iq
w«
V
e
c
u.
o
*
i
?
i
"
<
41
a
**
4>
>
ae
CM
<£
*~
c
^B
z
*/»
i
^
a
*v
w
e
41
u
e
41
C
e
^
Ul-'
c u
8"t"
^J ^
41
>
9
8|>
O
O
i.
|
i
3
3
<
«*
4<
O»
C
*
^
0
^
g
«p>
e c
41
" 41
2*
Q
ic«>
i -o c
x a «.
5 o -o
«^
C A
i/» 4) t
w a
4) A >-
fVS
*- tte
c u
_e -o
C Q.
4) 4) 4)
C i
" >J!J
1
O
.0
a
a
c
w
w
X
41
Jtf
W
^
41
K
o
C
^a
r> o
o o
CD
r-
j
&
>
3
c
5
c
a
o£
>»
4>
= 1
m &>
~
TO
0 41
ae o
01
01
^
«
"S
So.
4, 4)
C "
o > ja
~
o
w
1
o
03
r»
>*
s
e
K
*
k* O
0)
U £
o
*** o
&» e
£2?
It **
£3
§S5
*^ ^^
^
*
41
CD
(/> ?
?
O
C
c
o
^
(Q
u
o
X
t/t
o
«
*rf
Q
*
§
A
u
o
o'
en
en
1
^
CD
41
«
^
*;
o
^
L»
3
oe
F"*
nj
4)
C
I
C 1
2 2
*
en
o
o
r^
^"
fi
^
^>_i
3
5 *
4, ^
a? *»
u
41
I/) uu
0068d
-9-
09/14/87
-------
3.4. DERMAL
Pertinent dermal monitoring data could not be located 1n the available
literature as cited 1n Appendix A.
3.5. SUMMARY
Atmospheric" emission sources of 1,3-butad1ene Include Industrial
effluent and fugitive emissions, forest fires and exhausts from automobiles,
dlesel engines and jet turbines (Graedel, 1978; Hayano et a!., 1985; Hughes
et al., 1979; Katzman and Llbby, 1975). Based on available monitoring data
(see Table 3-1), a typical ambient air concentration of 1,3-butad1ene 1n a
U.S. urban/suburban area 1s -1-2 ppb. Assuming an ambient air concentration
of 1.5 ppb, an average dally Inhalation Intake of 66 yg has been estimated
for the U.S. urban/suburban population. An NOHS conducted between 1972 and
1974 estimated that ~65,000 U.S. workers are potentially exposed to
l,3-butad1ene (NIOSH, 1984).
0068d -10- 06/23/87
-------
4. AQUATIC TOXICITY
4.1. ACUTE TOXICITY
The only available Information regarding the toxldty of 1,3-butad1ene
to aquatic biota was a 24-hour LC5Q of 71.5 mg/8, for pin perch, Laqodon
rhomboldes. a marine fish species (Daugherty and Garrett, 1951).
4.2. CHRONIC EFFECTS
Pertinent data regarding the chronic toxldty of 1,3-butad1ene to
aquatic organisms could not be located In the available literature as cited
In Appendix A.
4.3. PLANT EFFECTS
Pertinent data regarding the effects of 1,3-butad1ene on aquatic plants
could not be located 1n the available literature as cited In Appendix A.
4.4. SUMMARY
The only available Information concerning the toxldty of 1,3-butadlene,
to aquatic biota was a 24-hour LC5Q of 71.5 mg/l for plnperch, Laqodon
rhomboldes {Daugherty and Garret, 1951).
0068d -11- 06/23/87
-------
5. PHARMACOKINETICS
5.1. ABSORPTION
In preliminary experiments, NTP (1985a) Investigated the Inhalation
absorption of 14C-1,3-butad1ene In rats and mice exposed nose-only to
concentrations jof 7-7100 ppm (15.45-15,675 mg/m3) for 6 hours. Following
exposure the animals were placed 1n metabolism cages for measurement of
excreted radioactivity. Based on the excretion of radioactivity and
plethysmographlc data obtained from other animals similarly exposed, the
Investigators estimated respiratory retention of 7.1, 3.1 and 1.5% of the
Inhaled dosage 1n rats exposed to 70, 930 and 7100 ppm (154.5, 2053 and
15,675 mg/m3} and 54, 9.6 and 4.7X 1n mice exposed to 7, 80 and 1040 ppm
(15.45, 176.6 and 2296 mg/m3), respectively.
In a published version of these and additional Inhalation absorption
studies, Bond et al. (1986) exposed Sprague-Dawley rats and B6C3F1 mice for.
6 hours to various concentrations of 14C-1,3-butad1ene (four to six
animals at each concentration) by nose only Inhalation. The concentrations
of l,3-butad1ene for rats were 0.14, 1.4, 12.1, 134, 1720 and 12,700
mg/m3. Exposure concentrations for mice were 0.14, 1.4, 12.1, 145 and
1870 mg/m3. At the end of the exposure period, the rats and mice were
sacrificed and placed Individually 1n a desiccator containing enough
tetraethyl ammonium hydroxide to digest the carcass. Volatile radioactivity
liberated during the digestion process was measured 1n the atmosphere of the
desiccator, and samples of the digest were taken to measure radioactivity
remaining 1n the carcass. Total 14C retained In the animals at the end of
the 6-hour exposure period was estimated as the sum of the volatile radio-
activity and the radioactivity 1n the digest. This method [of measuring the
absorption and retention of 14C-labeled 1,3-butad1ene and unidentified
0068d -12- 01/21/88
-------
metabolites] Indicated that the percentage of Inhaled 1,3-butad1ene retained
1n the animals as [14C]-1,3-butadlene equivalents [at the end of the
6-hour exposure] ranged from 4-20% 1n mice and from 1.5-17X 1n rats. These
figures are measurements of radioactivity retained by the animal at the end
of the 6-hour _exposure period and do not Include any 1,3-butadlene or
metabolites absorbed and exhaled during the exposure period. When these
data were normalized to body weight for each species, the amount of
1,3-butad1ene and metabolites accumulated at the end of the 6-hour exposure
period (1n terms of wmol [14C]-1,3-butad1ene equivalent/kg) was signifi-
cantly larger In mice (0.2-650 ymol/kg) than 1n rats (0.08-160 ymol/kg)
over the range of 1,3-butad1ene concentrations used (0.14-1800 mg/m3).
Data were not located regarding the absorption of 1,3-butadlene from the
gastrointestinal tract. In the absence of data to the contrary 1t 1s
prudently conservative to assume 100X absorption for purposes of risk.
assessment.
5.2. DISTRIBUTION
The distribution of 1,3-butadlene In various organs of the rat, 1n the
brain of the mouse and 1n the central nervous system of the cat was studied
by Shugaev (1969). Animals were exposed for 2 or 4 hours to concentrations
approximating the 2- or 4-hour LC,-n. Animals that died were not used to
determine 1,3-butad1ene 1n organs. Following Inhalation exposure to
1,3-butadlene, the organs were removed and homogenized, and extracted with
ether, benzene or 1so-octane. The extracts were then analyzed for butadiene
1n the brain, liver, kidney and spleen of the rat at essentially equivalent
levels (36.3-51.4 mg X), and higher levels of butadiene were found 1n the
perlnephrlc fat (152 mg X). 1,3-Butad1ene was found In the brain of the
0068d -13- 01/21/88
-------
mouse following Inhalation exposure and was fairly evenly distributed
throughout the central nervous system of the cat. In this study (Shugaev,
1969), the elimination of butadiene from the brain and liver of the rat was
examined by exposing animals to butadiene by Inhalation for 1 hour, and then
sacrificing the-anlmals and determining the tissue concentrations of buta-
diene at various times (0.1, 15, 30, 60 and 90 minutes) after termination of
exposure. Butadiene concentrations decreased steadily 1n the brain and
liver; 1n rats sacrificed 90 minutes after termination of exposure, only
trace amounts of butadiene were found In the liver and brain.
5.3. METABOLISM
In a study by Bond et al. (1986) (see Section 5.1.), B6C3F1 mice and
Sprague-Oawley rats were exposed by nose only Inhalation to 14C-1,3-buta-
dlene, labeled In the number 1 carbon atom. Concentrations of 1,3-butadlene
used for rats were 134 and 1720 mg/m3 for rats, and 14.2, 145 and 1870'
mg/m3 for mice. After 2, 4 or 6 hours of exposure, groups of three
animals were withdrawn from the Inhalation chamber and blood samples were
Immediately taken and analyzed for 1,3-butad1ene and metabolites. Ninety
percent of the total 14C measured 1n the blood consisted of volatile
butadiene metabolites (1,2-epoxy-3-butene and butadiene dlepoxlde) and
nonvolatile metabolites (unidentified). The parent compound 1,3-butad1ene
and radioactive 14CO , derived from 1,3-butad1ene, were also found.
Species differences 1n metabolism were found at Inhaled 1,3-butad1ene
concentrations of -130 and 1800 mg/m3. Mice had significantly higher
blood concentrations of 1,2-epoxy-3-butene than did rats, and rats had
significantly higher concentrations of 14C02 In the blood than did
mice. 1,3-Butadlene and dlepoxybutene concentrations were similar.
0068d -14- 10/14/87
-------
A study of the rate of metabolism of 1 ,3-butad1ene 1n male B6C3F1 mice
was performed by KrelUng et al. (1986a,b) using a gas uptake method. This
method Involved placing a group of mice (usually eight) In a desiccator
containing Initial butadiene concentrations of between 10 ppm (22 mg/m3)
and 5000 ppm (T1.061 mg/m3) and following the disappearance of 1,3-buta-
dlene (by gas chromatography) from the desiccator atmosphere over time.
That disappearance of 1 ,3-butad1ene from the desiccator atmosphere 1s a
measure of the metabolic elimination rate of butadiene 1n the mice 1s
supported by the observation that pretreatment with dlthlocarb, a metabolic
Inhibitor, decreases the rate of disappearance of 1 ,3-butadlene. The
metabolic elimination rate constants determined for mice were compared with
those determined for rats using a similar gas uptake technique (Bolt et al.,
1984). At all exposure concentrations, mice metabolized 1 ,3-butad1ene
faster than did rats. The metabolic elimination rate for butadiene In mice'
was proportional to exposure concentrations up to 1000 ppm (2212 mg/m3).
At exposure concentrations >1000 ppm, metabolic elimination of 1 ,3-butad1ene
In mice approached saturation, and a V for the 1 ,3-butad1ene el1m1na-
indx
tlon rate was calculated to be 400 ymol-h^kg'1. In rats (Bolt et
al., 1984), the metabolic elimination rate was also proportional to exposure
concentrations up to -1000 ppm (2212 mg/m3). Above 1000 ppm, the
metabolic elimination of 1 ,3-butad1ene In rats approached saturation, but
the calculated V for rats (220 vrool'h^kg"1) was well below
that calculated for mice. Bolt et al. (1984) also observed that pretreat-
ment of rats with Aroclor 1254 to Induce the 1 ,3-butad1ene metabolizing
enzyme (presumably cytochrome P-450) Increased the V of the 1,3-buta-
fflo X
dlene elimination mechanism. In the Aroclor-pretreated rats, saturation of
this elimination mechanism was not observed up to exposure concentrations of
12,000 (26,547 mg/m3) 1 ,3-butad1ene.
0068d -15- 10/14/87
-------
When Sprague-Dawley rats were exposed In an Inhalation chamber (desic-
cator) to concentrations of 1,3-butadlene (>2000 ppm or 4425 mg/m3), which
are much larger than those required to achieve saturation of the 1,3-buta-
dlene metabolism mechanism, the exhalation of butadiene monoxide by the rats
was demonstrated (FUser and Bolt, 1984).
l£ vitro experiments using liver mlcrosomal preparations from rats and
an NADPH-generatlng system demonstrated that 1,3-butad1ene 1s metabolized to
l,2-epoxybutene-3 (Malvolsln et al., 1979). Pretreatment of rats with
phenobarbltal before preparation of liver mlcrosomes Increased the rate of
oxidation of 1,3-butad1ene to 1,2-epoxybutene-3 by the mlcrosomal prepara-
tion, and treatment of mlcrosomal preparation with SkF 525A Inhibited the
butadiene epoxldase activity and strengthened the case for the Involvement
of cytochrome P-450 1n the mlcrosomal epoxldatlon of 1,3-butadlene.
1,3-Epoxybutene-3 undergoes further metabolism J£ vitro and reacts with
mlcrosomal epoxlde hydratase to form 3-butene-l,2-d1ol (Malvolsln and
Roberfrold, 1982; Malvolsln et al., 1982) or 1,2-epoxybutene-3 may undergo a
second oxidation reaction to form dlepoxybutene (Malvolsln and Roberfrold,
1982). 3-Butene-l,2-d1ol may also undergo a second oxidation reaction to
form 3,4-epoxy-l,2-butaned1ol. The metabolic pathway of 1,3-butad1ene 1s
shown 1n Figure 5-1.
Species differences were also noted 1n the ability of liver homogenates
to produce butadiene monoxide when Incubated with 1,3-butad1ene (Schmidt and
Loeser, 1985, 1986). B6C3F1 mouse liver preparations were found to have a
much greater butadiene monoxide-producing activity when Incubated with
1,3-butad1ene than did human liver preparations, which suggests that the
mouse may not be a good model for studying the metabolism of 1,3-butad1ene
(Schmidt and Loeser, 1986).
0068d -16- 01/21/88
-------
CHE=CH-CH=CHg 1,3-butadi
NROPH
«fe «
CH2=CH-CH-CH2
V
(Epoxlde hydratase)
CHE=CH-CH-CHe
E I I *
OH OH
3-butene-l,e dlol
NROPH
4
icresoacs
CH2-CH-CH-CH,
\ / « !
OH OH
diol
Cboih siercoisoacrs product^)
NOOPH, Oc, icrocoiac
A
CHe-CH-CH-^CHe
dlepoxybutone
(both sttr«ois«iirs produced)
FIGURE 5-1
HUrosomal Metabolic Pathway of l,3-Butad1cne
Source: BalvoUIn and Roberfrold, 1982
-17-
06/23/87
-------
5.4. EXCRETION
The excreUon of an Inhaled dose of radlolabeled 1,3-butadlene was
measured 1n Sprague-Dawley rats and B6C3F1 mice by Bond et al. (1986).
Groups of mice were exposed to 1,3-butad1ene concentrations of 14.2, 145 and
1870 mg/m3 (four animals at each concentration), and rats (four animals at
each concentration level) were exposed to 1,3-butad1ene concentrations of
134, 1720 and 12,700 mg/m3. At the end of the exposure period, the
animals were placed 1n metabolism cages. Urine and feces samples (collected
separately) were taken at various times after the end of exposure and
expired air was collected In a series of traps designed to collect 1,3-buta-
dlene and Us volatile metabolites. The traps for expired air were sampled
for radioactivity at the same time that urine and fecal samples were taken,
and this sampling was continued for 65 hours following the termination of
exposure. At all concentrations of 1,3-butad1ene tested, urine and exhaled.
air were the major routes of excretion of 14C for both rats and mice, and
these routes accounted for -75-85% of the total 14C eliminated. The
relative Importance of the different pathways for the excretion of 1,3-buta-
dlene and Its metabolites varied with the concentration of 1,3-butad1ene to
which the animals were exposed. At higher concentrations of Inhaled
1,3-butadlene, exhalation of 14C02 became a major pathway for urinary
excretion of 14C. In mice, the half-time for urinary excretion of 14C
was 4.6 hours and the half-time for fecal excretion of 14C was 8.6 hours.
In rats, the half-time for excretion of 14C In feces and urine were 22 and
5.6 hours, respectively.
0068d -18- 10/14/87
-------
5.5. SUMMARY
l,3-Butad1ene 1s absorbed after Inhalation by B6C3F1 mice and Sprague-
Dawley rats (Bond et al., 1986). Estimates of absorption were >4-20% of
Inhaled dose for mice and >1.5-17% for rats exposed to very high concen-
trations.
Following Inhalation, 1,3-butad1ene 1s distributed to the brain, liver,
kidney and spleen of rats at nearly equivalent levels, and very high levels
are found In the perlnephrlc fat (Shugaev, 1969). 1,3-Butadlene was also
found to distribute to the mouse brain and the central nervous system of the
cat following Inhalation exposure (Shugaev, 1969).
The primary jm vivo metabolites of 1,3-butad1ene In the blood of rats
and mice following Inhalation exposure appear to be 1,2-epoxy-3-butene and
butadiene dlepoxlde (Bond et al., 1986). Saturation of the metabolic elimi-
nation mechanism for 1,3-butadlene was approached at Inhalation exposure.
levels >1000 ppm (2200 mg/m3) In both Sprague-Dawley rats and B6C3F1 mice
(KrelUng et al., 1986a,b; Fllser and Bolt, 1984). The maximal metabolic
rate of elimination of 1,3-butad1ene (V ), however, was found to be
approximately twice as high In mice as In rats. Exhalation of 1,3-butad1ene
monoxide and acetone has been demonstrated 1n rats exposed to 1,3-butad1ene
by Inhalation (Fllser and Bolt, 1984). The primary In vitro metabolites of
1,3-butadlene (using rat liver mlcrosomes) are 1,3-epoxybutene-3, 3-butene-
l,2-d1ol, dlepoxybutene and 3,4-epoxy-l,2-butaned1ol (Malvolsln and
Roberfrold, 1982).
Excretion of radioactivity that Is derived from Inhaled radlolabeled
1,3-butad1ene was determined to be primarily In the urine and exhaled air of
1,3-butad1ene-exposed Sprague-Dawley rats and B6C3F1 mice (Bond et al.,
1986). These routes of elimination accounted for -75-85% of the total 14C
eliminated.
0068d -19- 10/14/87
-------
6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposures.
6.1.1.1. SUBCHRONIC ~ A 3-month Inhalation toxlclty study of
1,3-butadlene was conducted by Crouch and Pulllnger (1978) and Crouch et al.
(1979). Five groups of Sprague-Dawley rats (40 male and 40 female animals
In each group) were exposed to 0, 1000 ppm (2212 mg/m3), 2000 ppm (4425
mg/m3), 4000 ppm (8849 mg/m3) and 8000 ppm (17,698 mg/m3)
(concentrations 1n mg/m3 as reported by authors), 6 hours/day, 5 days/week
for 13 weeks. The parameters examined 1n the exposed rats Included growth
rate, food consumption, hematology and blood biochemistry, urine analysis,
erythrocyte and brain chollnesterase activity, erythrocyte osmotic fragil-
ity, neuromuscular function and neutrophll phagocytosis. Macroscopic and
hlstopathologlc examinations were also conducted. No effects attributable
to l,3-butad1ene exposure were observed In any of these parameters and the
only adverse affect reported was Increased salivation In female animals that
were exposed to higher concentrations of 1,3-butadlene.
Carpenter et al. (1944) exposed groups of 24 albino rats, 12 guinea
pigs, 4 rabbits and 1 dog to 1,3-butad1ene by Inhalation. Animals were
equally distributed by sex except for the dogs, which were all females. The
concentrations used were 600 ppm (1327 mg/m3), 2300 ppm (5088 mg/m3) and
6700 ppm (14,822 mg/m3). Exposure was for 7 1/2 hours/day, 6 days/week
for 8 months. Chamber-exposed controls were maintained. Biological param-
eters examined were body weight, blood cytology, fertility (rats, rabbits
and guinea pigs), blood and urine chemistry, kidney and liver weights (rats
only), ocular examination of rabbits and dogs, and general organ gross and
microscopic pathology. The only adverse effect noted was a decrease 1n body
0068d -20- 09/14/87
-------
weight gain 1n exposed rats and male guinea pigs. Body weight gain In rats
was <90X of controls only at >2300 ppm. Quantitative data were not provided
for guinea pigs. Carpenter et al. (1944) concluded that 1,3-butadlene Is a
relatively Innocuous substance.
Several statjles have Indicated that stem cells In the bone marrow of
mice are a target site for 1,3-butad1ene-1nduced toxldty. Irons et al.
(1986a) exposed male B6C3F1 mice to 1,3-butadlene by Inhalation to 1250 ppm
(2765 mg/m3), 6 hours/day, 6 days/week for 6-24 weeks. Blood and bone
marrow were examined, and treated mice were found to have a 1,3-butad1ene-
Induced macrocytlc-megaloblastlc anemia. Lelderman et al. (1986) also
exposed male B6C3F1 mice to 1,3-butad1ene by Inhalation to 1250 ppm (2765
mg/m3). The exposure schedule used was 6 hours/day, 5 days/week for 6 or
30-31 weeks. in. vivo and in vitro assays were used to Investigate the
proliferation and differentiation of bone marrow cells. After 6 weeks of
exposure to 1,3-butad1ene, Lelderman et al. (1986) concluded that there were
alterations In bone marrow stem cell development.
Studies of 1,3-butadlene toxldty using B6C3F1 mice are complicated by
the presence of an endogenous type C retrovlrus (MuLV) present 1n this
strain. Irons et al. (1986b) exposed eight male NIH Swiss mice, which do
not possess this virus, to 1,3-butadlene by Inhalation at a concentration of
1250 ppm (2763 mg/m3), 6 hours/day, 5 days/week for 6 weeks. At the end
of the exposure period, peripheral blood was drawn and analyzed and the
cellularlty of bone marrow from the femur was determined. Irons et al.
(1986b) concluded that 1,3-butad1ene exposure caused alterations In bone
marrow precursor cell activity and that the changes In the bone marrow and
peripheral blood were Indicative of a 1,3-butad1ene-1nduced macrocytlc-
0068d -21- 09/14/87
-------
megaloblastlc anemia. It was also concluded from this study that the bone
marrow toxIcHy Induced by exposure to 1,3-butad1ene Is Independent of the
presence of the muMne MuLV virus.
The effects of Inhalation exposure to 1,3-butad1ene on the Immune system
were examined b~y Thurmond et al. (1986). B6C3F1 mice were exposed to a
1,3-butad1ene concentration of 1250 ppm (2765 mg/m3), 6 hours/day, 5
days/week for 6 or 12 weeks. Lymphold organ hlstopathology was examined and
Immune function assays were performed to evaluate specific humoral and
cell-mediated Immunity; no significant 1mmunolog1cal defects were detected
1n the 1,3-butadlene-exposed mice.
A number of Russian studies, available only as brief abstracts, have
been performed on the subchronlc Inhalation toxldty of 1,3-butad1ene. Rats
exposed for 81 days (exposure schedule unknown) to 1,3-butad1ene (30
mg/m3) developed dystrophlc processes In the tissue structures of the'
kidneys and heart (N1k1forova et al., 1969) and structural changes In the
spleen (Molodyuk et al., 1969). Rats exposed for 81 days to 1,3-butadlene
(30 mg/m3 and 300 mg/m3) developed erythrocytosls and leukocytosls (R1pp
and Lyutlkova, 1966), and rabbits exposed to 1,3-butad1ene (200 mg/i;
exposure schedule not given) showed an Increased ratio of erythroblasts to
granulocytes (Pokrovskll and Volchkova, 1968). Experimental animals
(species not reported) exposed to 1,3-butad1ene by Inhalation (1.0, 3.0 and
30 mg/m3) had morphological changes In the liver and kidneys, disturbances
of the central nervous system, and changes In the Immune system (R1pp,
1969). Rats exposed by Inhalation to 1,3-butad1ene (100 mg/l), 6 hours/
day, 6 days/week for 4.5 months had alterations In the bronchial epithelium
of the lung and a hypersecretory state In the connective tissue structures
of the lungs (Kuz'mln, 1969). These studies were not available 1n suffi-
cient detail to assess their reliability.
0068d -22- 06/23/87
-------
6.1.1.2. CHROMIC In an Inhalation study of the toxldty of
l,3-butad1ene 1n male and female B6C3F1 mice (NTP, 1984), exposure to
1,3-butadlene, 6 hours/day, 5 days/week for 60-61 weeks at concentrations of
0, 625 ppm (1383 mg/m3) or 1250 ppm (2765 mg/m3) caused gonadal atrophy
In both sexes -at both concentrations. Male B6C3F1 mice exposed to 2765
mg/m3 had nonneoplastlc lesions of the nasal cavity; the details of this
study are presented In Section 6.2.1.
Chronic toxlclty data were obtained from the 105- to 111-week cancer
study by Hazleton Laboratories (1981a) (also reported 1n Owen et al., 1987)
(Section 6.2.1.). In this experiment, Sprague-Dawley rats of both sexes
were exposed to 1000 or 8000 ppm (2212 or 17,698 mg/m3), 6 hours/day, 5
days/week. There were no effects on overall body weight gain, hematology,
blood biochemistry, urlnalysls, neuromuscular tests or gross pathology.
Survival was significantly reduced In both sexes at 8000 ppm, and rats at-
this level exhibited ataxla and ocular and nasal discharge. Increased
absolute and relative liver weights were observed In 8000 ppm rats of both
sexes and In 1000 ppm females, but hlstopathologlc changes 1n the liver were
not observed at either concentration, and the elevated liver weights were
attributed to enzyme Induction, an adaptatlve rather than a toxic response.
Increased absolute and relative heart, lung and kidney weights were observed
1n 8000 ppm males. Hales at 8000 ppm had an Increased Incidence of nephro-
pathy that was considered partially responsible for the decreased survival
observed 1n this group.
6.1.2. Oral Exposures.
6.1.2.1. SUBCHRONIC Rats (strain not specified) were given
1,3-butad1ene orally at 100 mg/kg/day for 2.5 months (Donetskaya and
Schvartsapel, 1970). Granular and hydropic dystrophy, cytolysls and dis-
turbances of permeability were found In the cells of the brain, sympathetic
0068d -23- 01/13/88
-------
ganglia, heart, liver and kidneys. Lymphoh1st1ocyt1c Infiltration was found
1n the lungs, heart, liver, kidneys and gastrointestinal tract. A thicken-
ing of the Interalveolar septa was also found 1n the lungs.
6.1.2.2. CHRONIC Pertinent data regarding chronic oral exposure to
l,3-butad1ene could not be located In the available literature as cited In
Appendix A.
6.1.3. Other Relevant Information. The oral LD5Q for 1,3-butad1ene 1s
5480 mg/kg In the rat and 3210 mg/kg 1n the mouse (Sax, 1984). Humans
exposed to 2000 ppm (4425 mg/m3), 4000 ppm (8849 mg/m3) or 8000 ppm
(17,698 mg/m3) 1,3-butad1ene for 6-8 hours experienced a slight Irritation
of the eyes (Carpenter et al., 1944). Inhalation of 1,3-butadlene (exposure
schedule and concentration not reported) by mice Increased liver content of
ATP and Increased the ratio of ATP to ADP (Oura et al., 1967). Direct
dermal contact with l,3-butad1ene caused burns and frostbite (Sandmeyer,
1981).
6.2. CARCINOGENICITY
6.2.1. Inhalation. Human epldemlologlc data regarding the cardnogenlc-
1ty of l,3-butad1ene are restricted to several studies of workers exposed In
the production of SBR. SBR usually 1s made up of 26% 1,3-butad1ene and 9%
styrene (U.S. EPA, 1985). Exposure to many other chemicals Including
toluene and benzene also occurred; exposures usually were not quantified and
the effects of 1,3-butadlene Independent from other chemicals could not be
evaluated. Some of these epldemlologlc studies (McMlchael et al., 1974;
Andjelkovlch et al., 1976; Melnhardt et al., 1982) suggested a correlation
between SBR production and excess cancer risk; others (Checkoway and
Williams. 1982; Matanoskl et al., 1982) did not. The strengths and weak-
nesses of these studies have been reviewed extensively by the U.S. EPA
(1985). [It 1s beyond the scope of this task to repeat that effort here].
0068d -24- 02/06/89
-------
Two long-term Inhalation cardnogenlclty studies, one using B6C3F1 mice
(NTP, 1984} and one using Sprague-Dawley rats (Hazleton Laboratories, 1981a;
Owen et al., 1987) established 1,3-butadlene as a carcinogen In both
species. NTP (1984) exposed groups of 50 male and 50 female mice to 0, 625
or 1250 ppm (0,- 1383 or 2765 mg/m3), 6 hours/day, 5 days/week for 60 weeks
(males) or 61 weeks (females). The experiment was designed with a 103- to
104-week exposure period, which was shortened because of high mortality pri-
marily associated with neoplasla. Incidences of statistically significant
tumors are summarized 1n Table 6-1. The tumor type with the highest overall
Incidence 1n both sexes was a lymphoma associated with the hematopoletlc
system. Other tumors with statistically Increased Incidences In both sexes
Included alveolar or bronchlolar adenomas or carcinomas, hemanglosarcoma of
the heart and squamous cell neoplasm of the forestomach. The Increased
Incidence of hemanglosarcoma of the heart following 1,3-butad1ene exposure
Is significant because this 1s a rare tumor type 1n this strain of mouse
(Wooder, 1986). 1,3-Butad1ene-exposed female B6C3F1 mice also had Increased
Incidences of hepatocellular adenoma and carcinoma, aclnar cell carcinoma of
the mammary gland and granulosa cell neoplasm of the ovary.
In the Hazleton Laboratory (1981a) study, groups of 110 male and 110
female Sprague-Dawley rats were exposed to 1,3-butad1ene at concentrations
of 1000 ppm (2212 mg/m3) or 8000 ppm (17,698 mg/m3) for 111 weeks
(males) or 105 weeks (females). Ten rats/sex/group were sacrificed at 52
weeks for gross and hlstopathologlcal examination. Male rats had an
Increased Incidence of Leydlg cell adenomas and carcinomas of the testes and
an Increased Incidence of exocrlne adenoma of the pancreas (Table 6-2).
Female rats had an Increased Incidence of multiple mammary gland tumors, fo
llcular cell adenomas and carcinomas of the thyroid, and stromal sarcomas of
the uterus-cervix.
0068d -25- 01/13/88
-------
4)
U
^»
^£
*~
">>O
* U
1 »«^
^ MM
3
Q, e
O -X
r- 4)
1 4)
-x.
00 vi
^^ CQ
o
4)
C W>
4>
«^ »
o >»
* -o
3 >.
CD VI
U- 3
O O
^^
' vO
W
4>
Ct
bv
4) 3
O* wi
O O
C Q.
X
U LU
U
w o
C i/i
o .*
4)
* 41
*9 3
""B
C I
- O
L.
4>
4-1
^
^ W
O C
*» o
t/1 MM
*~ <^
M«* M
(Q
*~
X
4)
CO
S"s
O CL
O A
r** ^» (^ C^ fwM
O O CO ^ O
O O O CO O
»
o o o o o
V V II il V
0. Q. Q. Q. CL
C3 C3 C3 C^ cn
w» un «i * *
CM 0 00 *
r
u « i_ «
,2 § ,2 §
o e i_ o c
0
u i_ S i/> o i-
C ^9 O ^3 C ^9
o u us o u
U U O L.
£L W ^3 ^~ VI ^3 ^
>» O u* P- g -^ O
O O J= C Q. O O
41 C Q. 3 O 4> C
>4I S S > b. >4>
^ ^ i* £ '"OU ''Q*^
W
i^
4^ ^S
^^ u
o S
& 5
OS *-
4^ 4) 4^ VI
CT »O ** I- 4> CT
C S v» ifl t_ C
3 4) >» 4» O 3
* £ V» £ U- r-
J^ ^^
n
E
O ui CT
CM g
sO
03
CO
r f- CO ,
O O O O
o o o o
* * *
o o o o
V V II V
Q. a. CL a.
O CFI O CTi
ir> «* * ^
co so p«» ui
CM ^- r-
u 2
r- O
u o e
o *- -
§£ U
I/I U U
03 C 13
WE O U
& O w
o c i S
£ e a. o o
a, « u 4) e
S S r I- > 41
r- JC ifl U ro fO
W
t^
^^ ^S
41 U
"o §
^L Q
0 E
«< 4) 4-> vi
g * i_ 41 en
4> >, 4) O 3
£ VI £ <*- r-
^c
n
E
O CT
u-i 1
«M
> CO
A
^^
CM
^_
O
O
o
V
Q.
O
LO
On
CM
1
§
r?
U
«^
4^
41
"o
CL
15
41 >>
£ VI
vO
O
O
O
II
a.
on
*
j^
w
^
^
»l
o
c
1
c.
^
V
4)
^
0068d
-26-
06/23/87
-------
-.
0
u
r
1
vO
LU
OD
rg u
u C
«* u
<- «
n en
00 »-
CO
Tumor
Incidence
a*
a.
«
h-
C
en
0
0)
b.
X
CO
8?
o a.
Q^k
^k
I^OOOOi O O r OO
^oooooooooo
ooooooooooa
II V II V V II U V il ,i V
0.0.0.0.0.0.0.0.0.0.0.
u
^ en o o en o o en oo en oo
^ *f vn u"i ^ m u^ ^ ^ ^ ^
X-s.V.X'VX.XV.X'x'v
r n i OOOOO(VlO<
L. m u S
L. o c u o e
o o
£ u g £ u 3) o *^ e& uE^S^> g o
cwo>gge <^o.ou oot/iigge ^
>gCr~S O enigc O UCr-rgi g O Cn
O. O O JZ C O. »> fO 3r OOJE C
u a> c a. Q u>g c u c o. a* c a. 3
r b. > O) S S ^~ U O. <^U rgO >4> S 5
("* fg r^ *O >^ 4; r^ tg 4^ w *g W 4> r0* ^ >% CU
u 5 ^ u
W ^ W C O ^" ^
§*O E T3 "o
a. o > o,
*- o E -^ t.1- OE
i/i HJ a* - ^ t- fo 2 ** *-> a> «-'
U* C B^^3b> > B *Q C Bl/lig
O 3 4> >» O O "- t. 5 > 3 O > 4)
U- r fl/l£Vh. r OS O > UEl^^
n n
e s
^v ^x
^3 ^^ ^^ (^^ Bf)
(VI sO
*" >« 00
r» «
rw p-
0068d
-27-
09/H/87
-------
-7
0
u
^^
I
*o
UJ
_J
00
re W
u c
*^ re
<- W
«- Vb
** «^
re e
CO
4>
u
i- C
O 4>
3 »-
r- U
e
Qf
^^
i
I
^B
e
O»
re
h
X
0)
01
vi E
0 Q.
Q«»
^L
OO O«J c a,
r- U Qt 4) rgo > 4) S
r^ rg 4> ^ (j ^4) r** ^ >>
o o
e
J£ rg ^^
UP 4»
g "o
^ ^ rts >» +* Q)
Q) C} B ^ C7) *5 ^^
t. > 5 rrj e S vi
O «- 2 > 3 4» >»
Ifc* r"^ B O * ^ VI
Ilk kU
n a
^. ^+
^^ O) C? C7
Oj E u*i £
^ CM
c*5 r*
r^ p^ r1^
O O (\i
O O O
0 C> 0*
V V il
a. a. a.
v> o^ ^
* * ^
00 O U1
P"- p«"
i
o
u c
o
§u
VI W ^
u i » 3
- Q. O U fa
91 rg c OS
G a - o
rg u re e
8 f «- O. 41
jC rg u £ I/I t-
< 4) 4J
4» O -
>
!
1
§
^_
o
o
o
V
ex
ft
CO
*^
^_
^"
u
3s
O vi
p pg
3 P-
e ex
pg o
{^n ^£
>,
re
o
0068d
-28-
09/14/8
-------
9
Ol
» Qj
Wl >» A
0>
o
o
u
ro ^
0)
o»
a*
o
u.
o»
re
ft*
a
o
u
o>
u
c
0>
^
>
X U
ft)
u
o
o£ ,-
** «0
U. I
00 O
0) ^
re
^
4>
»* E
U X "^
re ft> wn 00
W re
O u. c __
"«, "2
*5 *.-
C u .
** u- fa j/>
O B
*O ** =
41
U
0)
i
»
*
>»
o
«- o>
C J=
o
u
o
tn u,
o> en
u
c -o
o> &
*<
to
I/I
x:
<->
en
e
a*
cr
u. &>
0 3
i/i
i/» f~
Ol f
C "0
O
" a> £ o>
o j:
i_ - ;r t. v
O U ' O 0*
u- C Q.
» ft» £
§ u Su S-
_ o .Z « *
51" 3S -
^ a> «
O
C/>
fO
0068d
HJ I/I «^
O) > Ol O
£ I ^ C
f (X h-
O U
-29-
o
u
02/06/89
-------
.°.
^|PQ
^^ ^^
o>
L. 4)
VI
C >>
o o
c
.K un
e
3 *
"^ ^^
IV
^ ^3
c *v
4> VI
O 3
IV O
'tj *
03 ^
U- -O
O 4>
(^
>i O
^^ CL
*- X
O UJ
O) TO
o oe
c
^ 9*^
/« rti
0 *
o
C 1
O 4)
«- 3
«-> 0»
f t-
IV O.
f» */*
JH w»
c
1-1 C
0
rg o
U C
« O
1/1 «
»- U.
^^ t^
»
^"
l_
*~
C
O
^^
4)
O>
fQ
H-
X
3
o> "i"
vi Q.
O Q.
a
CO
o
o
o
V
a.
0
o
f
o
o
c
(B
c
o
rg
U E
O
0) C
i^ **
o u
>» u.
4) IV
_J U
VI
4)
v<
^
O
01
o
o
ll
Q.
O
0
V.
n
i
4>
e
u
u
o
X
4)
VI
^
41
^
^
e
&
CM
^«
O
H
a.
o
0
eo
Q
C
'g
c
4>
O
IV
^
'a) ra
U C
o
^ «^
o u
>. L.
41 05
_l U
VI
4>
^^
VI
^J
n
S
ol
o
O CM
fBW ^
CM
CM
Ol r1*1
r- o
CO O
o o
II V
a. a.
o o
o o
f- CO
^
c
OB
c o
U f *-
u -o u
O >» t_
X Qj ^
4* JO
t/1
^3
4^ trt
1- 4>
C vi
t) 4)
a. *->
X
n
E
o>
o E
o
O CO
00 ^^
«o
jr
r~* ^~
^f ^D
O 0
* *
0 O
II V
CL a.
o o
0 0
o o
r- LO
o
e
P*
o>
<3 >»
E t-
o s
C e
4) S
E *»
VI
o
c
I/I
l
!~ U S g
U T3 U 5
C U g
Jg ^ vi
r VI 4)
U E IV CL VI
^^ O B *^ ^
^^ C O ^* O
r^ 4) w ^~ E
O -O »- 33
u_ ro vi E *
wo
x -o
c
4) Ol
U
O 1 >»
*^ VI t~
O 3 5
L" t ff
^^ 4) B
5^1
k.b
n
E
oi"
O
O CM
r ^
CM
CM
vO
O
O
11
a.
o
o
>^
VI
*v
c
O
C
u
u
r U
U O
C
ig ^
fM ^f
ul
o
F- c
r- fl>
^ ^0
^3
«^
o
>>
5
0068d
-30-
06/23/87
-------
~*
^__
c
Q
U
C\4
LA
*O
"^
CQ
^^
^j
r- Ol
TO
4-» O
» u-
TO C
en
CO
u
O>
u
l_ C
o o
E x>
t 0
^^
Oi
a.
r-
k.
g5
3
^B
C
C7*
^
o
a;
en
u
TO
^^
X
0)
^/o
^»»
at E
in a.
o ex
C3 ^^
CO
o
II
CX
o
o
^^
^^
1
o
u
k.
TO
1/1
^^
1
o
u
I/I
X
^
^
k.
a>
u
i
in
3
k.
O>
4->
3
u-
^^
B
E
en
0 E
0
0 CM
CM
CM
-1_|-
O
0
o
V
ex
o
o
^^
qf
CO
^^
fc.
E
m
£
o
^«
ex
^^
f"*
3
E
V)
XJ
C m
TO k.
"en E
3
k.
TO XJ
tgj
TO
^C ^"*
E O>
u-
^^
ft
E
"V
en
o E
0
0 00
CO en
»
r»
^»
*~~
0
0
o
V
CX
o
o
^^
^i
p-»
fcrt
rg
E
o
e
u
k.
"ai "
U X)
c
k. TO
TO
9 ffl
o
P- C
'o X!
U. TO
x»
o
k.
^2
44
0
o
II
CX
0
o
^^
IT)
1
O
k.
TO
"
|^
^
^^
W
X
^^
^
k.
a>
i
3
k.
^pj
3
U.
O
Of
E
?
^
Q>
^^
t3
9
^
«V
*
t/t
^»
Oi
a>
Oj
5i
o
XJ
o
Jp
**
^rf
TO
f*
flj
o &
§» ^
"C £ *"
5 Is
*^ ^
4^ «»
^* ^r^
^ 4fe>
4? X» 0
^B ^ flj
5 5^
^9 dK
^> ^1 w
- k.
C
E TO
x; k.
TO 3
TO
TO C
_ CX
C =
w ^^
^? MB
r^^
^
^^
U m
e
Ol
JC C
r- TO
«
>»
3
^0
(J^
O
1/1
JC
4-*
en
c
k.
4^
^}
O)
TO
**
X)
*
a> XJ
XJ Ol
3 JC
r- u
U TO
C Q)
k.
4-> C
O O>
C Ol
I/I
^u ^^
o >
XJ TO
4^
k. +-
0 0
a. c
Oi
(» ^^
XJ 1
0)
JC 0
^ ^^
"* £
^»
ja oi
3 JC
exi
c
3
0) 1/1
JC C
4- 0
XJ 4^
C TO
TO 3
X» TO
o> >
J= 0>
in
** p
r- TO
ja u
3 «-
ex en
0
C i
o> o
Ol JC
ja 4-i
TO
4-> ex
0 0
C 4^
^ i^
fQ f
!
>» TO
XJ 3 Ol
3-0 4-
4-> »- TO
m > 3
o-
^U T3 ^^
JC C XJ
r- <
*
x» >»
3 k)
4- TO
00 3
er
U- 01
O XJ
I/I
I/I 1
4U P
C TO
J* k.
TO O>
C) ^
z o
in
j^
Oi
o>
y
ID
O
k.
0
^o
I/I
o
ex
X
Oi
0>
k.
o*
in
O)
*5
g
u.
in
^^
Oi
Ol
*
p^
pM
^»
k.
O
XJ
o
ex
X
Oi
o>
k.
O)
J
i/>
^"1 <^
00 ^0
en u
f**
^^
* &
< *
c^ 3
uj TO
O
|
(/> Ol
3
TO
k.
CX
U
^B ^J
3 r-
O TO
^O SI
TO ja
XJ
c
TO
X
o>
&
k.
O)
^
c
TO
in
j^
O?
o>
^
CM
tn
A
k.
O
cw
^
O)
i^
^
k.
3
l«
CX
0
k.
en
x.
X
o>
I/I
"s.
1/1
4^
TO
k.
O
O
4->
TO
JC
^^
C
o
CX
3
1/1
in
TO
O)
C
^rf
«/l
^^
u
&
^"
4^,
Oi
k.
k.
o >.
4^ ^
TO f
C TO
0
d "o*
c o
Ol i
XJ 0
Oi m
JC "^
H- JC
U
Ol
JC
r-
.
^
fll
L_
^^
U
c
c
r~
^
o
*^
S *
t^ ^^
^ fcfl
O
0) t
C7>
TO 4->
4J U
"- TO
E x
k. UJ
^C
i k.
C Ol
0 JC
k. I/I
JC
U U-
o
^J C*
JC
^»
** *©
*0 r^
3
4-« I/I
i Ol
3 >-
1/1
^> Ol
^ JC
^
JC ,^
*^
I/I
in CX
3
O
JS&
(J
c "°
fll &
-S M
J- *c
Q^
C *~
^ ^^
c
o "~
k> ^n
4- 01
C u
o c
o a,
XJ
k. ^
o u
^M C
^
k>
l2 °
TO
Ol
' 3
^» f~
t3
^^ ^
JC t
r- CX
XJ
00680
-31-
02/06/89
-------
6.2.2. Oral. Pertinent data regarding the carclnogenlclty of 1,3-buta-
dlene by the oral route of exposure could not be located 1n the available
literature as cited 1n Appendix A.
6.2.3. Other Relevant Information. The positive carclnogenlclty studies
In Sprague-Dawley rats (Hazleton Laboratories, 1981a) and In B6C3F1 mice
(Haseman et al., 1984; Huff et al., 1985; NTP, 1984) reveal that mice were
more sensitive than rats regarding carcinogenic response to butadiene.
Several Investigators (Kre1l1ng et al., 1986a,b; Bond et al., 1986) raised
the question of whether differences 1n species metabolism of 1,3-butad1ene
might be responsible for differences 1n species susceptibility to the
carcinogenic properties of 1,3-butadlene. Mice do metabolize 1,3-butadlene
faster than rats (KrelUng et al., 1986a,b) and higher blood levels of the
primary reactive metabolite, 1,2-epoxy-3-butene, have been found 1n
butadiene-exposed mice when compared with similarly exposed rats (Bond et
al., 1986; KrelUng et al., 1987).
Differences 1n species metabolism of 1,3-butad1ene between Sprague-
Dawley rats and B6C3F1 mice may only partially explain the greater sensitiv-
ity of B6C3F1 mice to the carcinogenic properties of 1,3-butad1ene following
Inhalation exposure. Another possibility 1s that an endogenous virus (MuLV)
present 1n the B6C3F1 mouse strain acted 1n combination with 1,3-butad1ene
to produce the high Incidence of lymphoma present 1n this strain of mouse
after 1,3-butadlene exposure. Studies are 1n progress using a mouse strain
(NIH) which 1s free from the MuLV virus to elucidate what role, 1f any, this
virus plays In the development of lymphomas 1n 1,3-butad1ene-exposed B6C3F1
mice (Irons et al., 1986b).
The toxic response to 1,3-butad1ene consisting of a butadiene-Induced
macrocytlc-megaloblastlc anemia 1n mice (Irons et al., 1986a,b) may be
0068d -32- 10/05/88
-------
considered a preneoplastlc response. This 1,3-butad1ene-1nduced anemia 1n
mice Is considered to be similar to human preleukemlc syndrome and may play
a role 1n butadiene-Induced muMne thymus lymphoma/leukemla (Irons et al.,
1986a).
6.3. MUTAGENICJTY
MutagenlcHy data are summarized In Table 6-3. Apparently metabolism of
1,3-butad1ene to a reactive metabolite Is required for butadiene to exert
Its mutagenlc effect 1n certain strains of Salmonella typhlmurlum (Poncelet
et al., 1980; OeMeester et al., 1980; Wooder, 1986), although positive
results without S-9 activation were obtained 1n an earlier study 1n S.
typhlmurlum strain TA1535 at higher concentrations. Similarly, positive
results 1n a forward mutation test 1n mouse lymphoma cells were obtained 1n
the presence but not the absence of S-9 from rats (Sernau et al., 1986).
Positive results were also obtained In ±n yjvo mlcronucleus (Choy et al.,
1986) and SCE tests (Cunningham et al., 1986), 1n .mouse and rat bone marrow
cells and 1n the SCE test 1n rat bone marrow cells (Cunningham et al.,
1986). Results were negative 1n in vivo tests for unscheduled DNA synthesis
1n liver cells from rats and mice (Vincent et al., 1986) and 1n the micro-
nucleus test 1n rat bone marrow cells (Choy et al., 1986; Cunningham et al.,
1986). Recently, T1ce et al. (1987) reported Increases In chromosome
aberrations and SCE (with depressed mltotlc activity) 1n bone marrow and
Increased mlcronuclel formation In peripheral blood.
6.4. TERATOGENICITY
An Inhalation teratogenlclty study of 1,3-butad1ene was performed by
Hazleton Laboratories (1981b). Female Sprague-Dawley rats were exposed to
200, 1000 or 8000 ppm (442, 2212 or 17,698 mg/m3) 6 hours/day on days 6-15
(Inclusive) of gestation. Maternal toxlclty 1n the form of reduced body
0068d -33- 10/05/88
-------
Ol
5
^^
*
9
^
n <4-
1 O
Ol
CO X
^C v*
t- Ol
*"
^^
^^
u
g
Ol
01
t)
3
Ol
e
01
01
01
Of
c
i
u
01
e
e
O.
VI
Ol
oc
c
> VI
V»
U
e
e
X 01
u. o
x a
u O
e
o
e
o
f£
u
Q.
>,
^
a
55
flS "c
-a
O u.
>Q
VI
<
O
co
91
01 *~
VI
41 i
oi *q
^g
01 X
0 01
o,f
91 Ol «- O C
i u, j= -o x a .
k. c/1 a. k. 01 UOI
41 "O ^ ^ x 41 >9 *O k. k.
x oi vi ^ m iq > i o 3
o> 3* k. x o CM 41 k. Q.X x
x iq iq e i 1- 0> "OX
O^-fiXUOl <«^U 4><>«u<»"
W>4I fk. C4I W^UB
k. i*. a, o 3<»- m
OIXO.O > >*- Avlvib.
c u js vi oi e c
- C VI T3 k. XIQ k.41 Ol
3013^010 3 3 vi
A oi «> 8 vi-ooi-o
i^ S'VOI vi Oiq-*«)9
k.*»xooie on -^ a. iq «>
O 3 k. k. O 1 <» X3I-3
u. a a >*- -^ « vik. 1x1^ Q.JB
1 * * 1
_ ^
O r~4i 9l>^10l 9I>'9
1 I «rf 1 » k. -*^ ' « Ol
fcl> !*
1 * OO) * ^ Ol * O k. Ok,
x « 41 x 41
> ifl JS » 19 f
u a. ^. o Q.
X u vi > u vi
pj a x "" 8
CM *O (V ^ ^ «8
C k.
o
VI ** h
4i 0
v* ^
0) t)
Ii
0068d
co
^*
91
41 "~
« r~
^g
41 -^
O 01
g a fcfl ki U1 PM
t> tM -O OICM^ ^-a
91 9i>^4l 91 91 > i 01 91 91 01
l i »* i 1 ^ i >k.x
C/l Vlf^k.'V C/l C/>^k.^ C/^O'Q
1 * O4I 1 * O4l ' ^r*0l
Si- k. - «- « «-
u x o u ** ox
UO4I k.OOI k.01
< a. < a. a.
iv. iv. 41 41
i o e o > >
§0 0
C 41 k. a a
u o oi u o iq IQ
C 41 X
> x oi f <« vi vi
~» ^ a. u i« i«
> k> ^ VI U
S'e x § ' 1 21
01 3 X 01 9 VI <^ VI ^
3 U 3 kl 3 U
O U Ok) O U
Ol 01 x> 01
VI VI VI VI VI VI
^ 41 iq 4> ^i un ui
91 91 91
91 91 91
1
|
^0 «1 Jj
<«
VI
"I
i
13
VI
C k.
- o
I/I rq
3 kl
0 U
01
VI VI
15 01
X
Ul
en
91
^
09/1^
-------
4>
U
e
,
&
QJ
QC
^^
2
B
^^
s
c
o
CL
VI
41
Ol
c
- 1
* w
IB **
> VI
>l
«
c
e
3 41
IB vi
b. e
e
Oi b.
u e
e
o
o
IB
U
a.
a.
>.
b.
3
Ok
^^
^ E
'O C
£3.
"O b.
C 0
>,
TJ
Vi
VI
^(
CO
^
l_ r~
Oi
fcrt
i:
o a*
__
i i
ifi ^
<\*
f- -0
i i ^ **
V> (/> O *V
*Si
b. Ol
o.
U* **
i o e o
u o oi b. o
> «- 4i .c «B
s <« a u
> b. 'O VI u
5 4< "3 .M £
r- o .a "B -o
c u
0
*»
3 W
O u
>C Ol
X
s
00
*
c
Ol O
VI *
u -»
Ol
i |
c b. e
- e
V*
o ~
* iO
Ol
VI
b.
01
>
01
an
o i
a, vi u
vi oi e
Oi b. Ol
L. 3
f cr
O -" «
t> I * Z
§fi
b, IB Ol
~"* Q'
VI ^
3 41
*fc. b. O Ol vi
§"" oi o JS 2 5 8"
4A b> ^3 C7) Ol *B b
c u oi e
11 ^ >>UOI VI VI
iB^aoxs »o i-
bi'Qvl^>viV 9
251 .xi.2 1 5
1> 3 OOX3
O -
oi oi e
o u -
i £
Ol r-
VI Ol VI
3 u i
is 1
S u
O >- 0
n co £. u
to r« a. oi
t -J r-
c e
o -o o
* IB »^
§ b?l §
co eo co
en en S en
~* en .
e c
l 41 r- r
IB U 01
c
o
Oi
VI 4^
iB u
Ol 3
b. ^
U C
c
VI
.<-> 3
C U
Ol >
o u
» O i- i in
i IB IB O- '^E
tM*^TJ «CVl OP'i'^
OCVI3 O IB IB
vl»»b.O VI T3 T5 "O
^~ O i/i ^" 4| ^x
S^ vi >i «} vi i/i e>j
oi en b. IB 8 o b.
VI 3 -O Q. 3 L.
eou-o exoo
> S
u. b. Ol u- vi
8« 018^ n oi i
ou > o 3 <_>ci
b»«A' <^b.iB lOOOl
u. co i u- Q as .a u
VI
3
01
u
3
c
o
b. +*
U VI
0068d
-35-
01/21/88
-------
c
1)
01 r-
U 05
ll I
U 00
4>
VI
C
o
&
VI
0)
0)
t/l
I
V
oc
cr>
= 1
> VI
>»
V U)
U
0) L.
UO
o
u
Ul
fM
X O >. X O >.
0>£>><« 4>£>«i«
_ « "O /O ^
CO O CO O
"Ott*fc <«&*I4.
s
on
o
e
u
O VI
*rf «^
c o
a -a
f
11
C O fO
T) E u
U VI
I £i
n
u
o
z
II
QQ68d
-36-
01/21/88
-------
weight gain was observed at 442 and 2212 mg/m3 and loss of maternal body
weight was observed at 17,698 mg/m3. A teratogenlc effect 1n the form of
major skeletal and cardiovascular-thoracic anomalies was noted 1n fetuses of
dams exposed to 8000 ppm (17,698 mg/m3).
An abstract^ of a Russian study (Serebrennlkov and Ogleznev, 1978)
Indicated that a 4-month Inhalation of 1,3-butad1ene (concentration not
reported) by female rats (strain not specified) caused embryonal mortality
and teratogenesls.
6.5. OTHER REPRODUCTIVE EFFECTS
NTP (1984) performed a cancer study 1n which groups of 50 B6C3F1
mice/sex were exposed to 0, 625 or 1250 ppm (0, 1383 or 2765 mg/m3), 6
hours/day, 5 days/week. The study had to be terminated after 60-61 weeks
because of high cancer-related mortality. Gonadal atrophy was observed 1n
both sexes 1n both treated groups.
6.6. SUMMARY
The toxldty of 1,3-butad1ene following Inhalation exposure appears to
depend on the species of animal. Adverse acute effects attributable to
1,3-butad1ene exposure were practically nonexistent except for Increased
salivation 1n females 1n Sprague-Dawley rats exposed to 8000 ppm (17,698
mg/m3), 6 hours/day, 5 days/week for 13 weeks (Crouch and PulUnger, 1978;
Crouch et al., 1979) and 1n rabbits and dogs exposed to 6700 mg/m3, 7.5
hours/day, 6 days/week for 8 months (Carpenter et al., 1944). Reduced body
weight 1n rats and male guinea pigs was observed at this level. The bone
marrow appears to be a target site for 1,3-butad1ene toxldty 1n B6C3F1 and
NIH mice (Irons et al., 1986a,b; Lelderman et al., 1986). A 1,3-butadlene-
Induced macrocyt1c-megaloblast1c anemia was observed 1n B6C3F1 and NIH mice
exposed to 1250 ppm (2765 mg/m3), 6 hours/day, 5-6 days/week for as few as
0068d -37- 10/05/88
-------
6 weeks (Irons et al., 1986a,b; Leiderman et al., 1986). Chronic Inhalation
exposure to 1,3-butadiene at >625 ppm (1383 mg/m3), 6 hours/day, 5 days/
week for 60 weeks caused gonadal atrophy In both sexes of B6C3F1 mice (NTP,
1984). Nonneoplastlc lesions of the nasal cavity of male mice occurred at
1250 ppm (2765 mg/m3) (NTP, 1984).
Several ep1dem1olog1cal studies (McMichael et al., 1974; Andjelkovlch et
al., 1976; Matanoskl et al., 1982) associate work 1n the SBR Industry with
excess risk of cancers of the hemotopoietic and lymphatic systems, but
concurrent exposure to potential carcinogens other than 1,3-butadiene also
occurred. Long-term inhalation carcinogenicity studies performed with
B6C3F1 mice (NTP, 1984) and Sprague-Dawley rats (Hazleton Laboratories,
1981a; Owen et al., 1987) confirm that 1,3-butad1ene 1s carcinogenic in
these species. Statistically significant (p<0.05) Increased incidences of
primary tumors at multiple sites were observed including lymphomas,
hemangiosarcomas, alveolar/bronchiolar adenomas, acinar cell carcinomas,
granulosa cell tumors or carcinomas, forestomach papillomas and carcinomas,
and hepatocellular adenomas and carcinomas. The most prevalent tumor types
in B6C3F1 mice were lymphomas associated with the hematopoietic system and
hemangiosarcomas. Five other tumor sites also had statistically significant
Increases (p<0.05) in this study, which had to be terminated after 60-61
weeks because of high cancer mortality. This mouse strain was found to be
far more sensitive in terms of a carcinogenic response than was the
Sprague-Dawley rat.
Butadiene is mutagenlc in bacteria only with activation (DeMeester et
al., 1980) and Induces chromosomal aberrations and SCE In mice (Tice et al.,
1987; Wooder, 1986). Data from Hazleton Laboratories (1981b) Indicate that
1,3-butadiene is a teratogen when pregnant female rats are exposed by
inhalation at 8000 ppm (17,698 mg/m3), 6 hours/day during organogenesls.
0068d -38- 01/06/89
-------
7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
A TLV of 10 ppm (22 mg/m3) has been adopted for 1,3-butadlene (ACGIH,
1986a), and this compound has been listed In Appendix A2, Industrial
Substances Suspect of Carcinogenic Potential for Man. This TLV has been
adopted on the basis of positive Inhalation cardnogenlclty studies with
rats and mice and observed teratogenlc effects In rats (ACGIH, 1986b). The
OSHA (1985) PEL Is 1000 ppm (2200 mg/m3).
7.2. AQUATIC
Guidelines and standards for the protection of aquatic organisms from
the effects of 1,3-butadlene could not be located In the available litera-
ture as cited 1n Appendix A.
0068d -39- 09/14/87
-------
8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Two long-term Inhalation cardnogenlclty studies of
1,3-butad1ene have been conducted. In the NTP (1984) study, mice were
exposed to 1,3-Jbutad1ene at concentrations of 625 (1381 mg/m3) or 1250 ppm
(2763 mg/m3). The exposure schedule was 6 hours/day, 5 days/week. The
study was scheduled for 2 years but had to be terminated after 60-61 weeks
because of high cancer mortality. Several tumor types 1n various organs
were observed, but the two most significant were lymphoma arising from the
hematopoletlc system and hemanglosarcomas. In general, cancer response was
both massive and rapid. Male and female Sprague-Dawley rats exposed to 1000
ppm (2212 mg/m3) and 8000 ppm (17,698 mg/m3) 1,3-butad1ene by Inhalation
for 6 hours/day, 5 days/week for 105 or 111 weeks (Hazleton Laboratories,
1981a, subsequently published as Owen et al., 1987) also developed tumors of
various organs (testes, pancreas, mammary gland, thyroid and uterus-cervix).
8.1.2. Ingestlon. Pertinent data regarding the cardnogenlclty of
l,3-butad1ene via Ingestlon could not be located In the available literature
as cited In Appendix A. However, because of the high volatility of
1,3-butadlene and Us low solubility In water, this route 1s not considered
nearly as Important as the Inhalation route.
8.1.3. Other Routes. Pertinent data regarding the cardnogenlclty of
1,3-butad1ene following exposure by other than the Inhalation or Ingestlon
routes could not be located In the available literature as dted 1n
Appendix A.
8.1.4. Weight of Evidence. Based on the positive results from two long-
term Inhalation cardnogenlclty studies (NTP, 1984; Hazleton Laboratories,
1981a) In two spedes (rats and mice) that caused multiple tumor types,
0068d -40- 10/05/88
-------
together with supporting Information about metabolites having genotoxlc and
carcinogenic properties, and Inadequate ep1dem1olog1cal evidence for
1,3-butadlene carclnogenldty In humans, 1,3-butadlene Is classified by EPA
as Group B2, probable human carcinogen.
8.1.5. Quantitative Risk Estimates.
8.1.5.1. INHALATION U.S. EPA (1985) derived q *s for 1,3-buta-
dlene based on the Incidence of tumors 1n the NTP (1984) mouse study and
Hazleton Laboratories (1981a) rat study using the multistage model.
Separate q,*s were developed for males and females of both species. From
the NTP (1984) study, tumor Incidences of 2/50, 43/49 and 40/45 were used
for male mice at 0, 625 and 1250 ppm (0, 1383 and 2765 mg/m3) and tumor
Incidences of 4/48, 31/48 and 45/49 were used for female mice exposed to the
same concentrations. These numerators are the numbers of animals observed
at time of death with tumor types that both occurred at a statistically
Increased Incidence (hemanglosarcomas, lymphomas, lung and forestomach
tumors 1n both sexes, plus mammary, ovarian and liver tumors 1n female mice)
and also tumor types considered unusual In this strain of mouse at 60-61
weeks (preputlal gland squamous-cell carcinomas, brain gllomas and Zymbal
gland carcinomas 1n male mice). The transformed doses were calculated as
Internal or retained doses, based on an evaluation of then unpublished NTP
(1985) mouse absorption data, which showed a substantial reduction, 1n the
percent of the Inhaled dose that was retained, as the exposure concentration
Increased. Retained dose In the NTP (1984) study was estimated from plots
of log vg/kg butadiene retained 1n animals vs. log ppm exposure
concentration 1n the NTP (1985) study (U.S. EPA, 1985). Potency estimates
were then calculated using a correction term to account for the shortened
experiment time of 60-61 weeks. Adjusting to lifetime exposure resulted In
a q.j* of 6.1X10"1 (mg/kg/day)"1 (Internal dose) or 9.2X10"1
0068d -41- 02/06/89
-------
(ppm)"1 (air concentration) based on data from male mice, and S.OxlO"1
(mg/kg/day)"1 (Internal dose) or 4.5xlO~a (ppm)'1 based on data from
female mice. Since the male and female mouse response was so similar, the
results were combined by taking as the final potency estimate the geometric
mean of 6.4X10"1 (ppm)"1. Assuming humans breathe 20 m'/day, weigh 70
kg and absorb 54% of Inhaled l,3-butad1ene (at low exposure concentrations),
this q,* was expressed as 1.8 (mg/kg/day)"1 In terms of Internal dose
(U.S. EPA, 1985). The potency estimates from mouse studies were considered
to be consistent with the human responses; however, there were too many
uncertainties and gaps 1n the human data base to make more definitive
statement (U.S. EPA, 1985).
Subsequent to the NTP (1985) unpublished report, the final data were
published (Bond et al., 1986) and these published data contained differences
1n the low exposure absorption 1n the mouse (but not In the rat) compared
with the unpublished report. The main difference 1s that low exposure
Inhalation absorption of butadiene 1n the mouse (and, by extrapolation,
humans) 1s now estimated to be 20% Instead of 54% (see Section 5.1.). These
new figures lead to a decrease 1n the estimated potency from q * =
6.4X10"1 (ppm)"1 to q-j* = 2.4X10"1 (ppm)"1. The details have
recently "been presented (Bayard, 1988; Cote and Bayard, 1988). These
estimates supersede those of the U.S. EPA (1985) document. The estimate
based on Internal dose remains the same, q,* = 1.8 (mg/kg/day)"1, since
the low exposure absorption fraction 1s assumed the same for mice and humans.
U.S. EPA (1985) also derived q^s of 7.0xlO"» (mg/kg/day)"1
Internal dose or 4.2xlO~a (ppm)"1 from the data on male rats, and
9.4xlO~2 (mg/kg/day)"1 Internal dose or 5.6xlO~2 (ppm)"1 from the
data on female rats from the Hazleton Laboratories (1981a) studies. U.S.
EPA (1985) noted that these data were unpublished and had not been audited.
0068d -42- 02/06/89
-------
In addition, a major concern was that the Individual animal data were not
Included In the report. Subsequently, the data have been published (Owen et
a!., 1987). The published data 1n general support the unpublished report.
However, small differences 1n some Incidence rates are apparent. Because
the primary data are still not available for evaluation and because the U.S.
EPA (1985) analysis demonstrates that a more conservative approach to
carcinogenic risk assessment Is based on the NTP (1984) mouse data, this
document shall adopt the q * of 2.4X10'1 (ppm)"1 from the U.S. EPA
(1985) analysis of the NTP (1984) mouse data as the upper limit estimate of
Incremental carcinogenic potency.
The concentration of butadiene 1n the air associated with an upper limit
Increased lifetime risk of cancer at a risk level of 10~5 was calculated
by dividing 10~5 by the q * of 2.4xlO~1 (ppm)"1 to give a lower
limit concentration of 4.2xlO~5 ppm or 9.3xlO~5 mg/m3. This lower
limit concentration (9.3xlO~5 mg/m3) Is associated with a risk level of
1CT5. The lower limit concentration associated with a risk level of
10"6 1s 4.2xlO~* ppm or 9.3xlO~* mg/m3 and the concentration
associated with a risk level 10"7 1s 4.2xlO~7 ppm or 9.3xlO~7 mg/m3.
8.1.5.2. ORAL -- Based on the NTP (1984) Inhalation study which
showed l,3-butad1ene to be a potent carcinogen at multiple sites, the
assumption 1s made that 1,3-butadlene can also cause cancer via the Inges-
tlon route. Assuming 100% absorption from the gut (see Section 5.1.) and an
Inhalation absorption at low exposures of 20%, an upper limit Incremental
risk estimate of q * = 9.0 (mg/kg/day)"1 1s used. This value supersedes
that of U.S. EPA (1985).
0068d -43- 02/06/89
-------
8.2. SYSTEMIC TOXICITY
Two animal studies, one using mice (NTP, 1984) and one using rats
(Hazleton Laboratories, 1981a; Owen et al., 1987), demonstrated that
1,3-butad1ene Is a carcinogen following exposure by Inhalation. Data
regarding the cardnogenlclty of 1,3-butadlene following exposure by the
oral route could not be located In the available literature as cited 1n
Appendix A. In the absence of evidence to the contrary, 1t was assumed that
1,3-butadlene Is potentially carcinogenic by both routes of exposure (oral
and Inhalation); In addition, Insufficient data for RfD derivation precludes
such a quantitative derivation for systemic toxldty (RfD).
0068d -44- 10/05/88
-------
9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The toxidty of 1,3-butad1ene was discussed In Chapter 6 and dose-
response data relevant for consideration 1n derivation of CSs are summarized
In Table 9-1. _The studies of Irons et al. (1986a,b) and Lelderman et al.
(1986) were not considered suitable for RQ determination because the
responses 1n these studies (macrocyt1c-megaloblast1c anemia and alterations
1n stem cell development) were considered to be preneoplastlc responses 1n
1,3-butad1ene-exposed mice.
The most severe effect In Table 9-1 Is mortality 1n rats at an equiva-
lent human dosage of 340 mg/kg/day. Another severe effect 1s teratogenlclty
with maternal toxidty (Hazleton Laboratories, 1981b). This effect occurred
at an equivalent human dose of 483 mg/kg/day.
The next most severe effect was gonadal atrophy 1n mice (NTP, 1984).
The effect on reproductive dysfunction associated with this atrophy was not
studied. Gonodal atrophy occurred at an equivalent human dose of 24
mg/kg/day In females. Multiplication of this dose by 70 kg gives an MED of
1666 mg/day.
The least severe response, reduced body weight 1n rats (Carpenter et
al., 1944), occurred at an equivalent human dose of 148 mg/kg/day. CSs for
these effects are calculated and presented 1n Table 9-2.
The highest CS, 10, corresponding to the lowest RQ (1000) 1s associated
with mortality In chronically exposed rats In the study by Hazleton Labora-
tories (1981a). This 1s the RQ of choice and 1t 1s presented 1n Table 9-3.
0068d -45- 10/05/88
-------
41
C
4)
T3
3
03
1
to
*
0
F- X
1 k
en g
UJ S
CD ^)
* X
U
X
e
^~
e
o
^
2
«2
e
4l
u
i
41
Ik
OE
41
VI
e
o
ex
vi
Oi
oe
^-j
JJf
flj OJ
> e .*
«- m X,
3 E 71
CT 3 E
T)
T3 41
01 vi X
E 0 IT)
k a TB
o >»
»
en
k F-
41
C
41 F-
ex iv
k
IT) «*
g i 41
4^ ^^
.C VI
OIF-
O
Si
e
x o
v w
o
:O «-
o
1^
4) OO
ee
CO
*~
CO
ft
CO
^^
« t/l
II >l
S3
?~i
09 C
CO >i O
0 TJ S
tfl V
^^ X. OO
VI
e k k
Q. 3 O
CX O u-
f.
O .X
O 10 41
co 41
CM r- a
k
at
w
o
^
CM
o
x. e
VI <**
< J3
oe ID
VI f
o> e co
«- 41 en
«?.":
41 k IT) F-
F- O F- IV
M .n CD
19 IQ en ^^
Z _l 41
,,
F-
IQ
k
5
«>
^M
S
^
r* «
,8 ^
?^
S-v,
tO V M
en 41
£»;*
ex k a
3
SO
f k
O O
09 ^ Ik
«
^
ee
u
CO
0
X >I
1
41
3 >i
VI ITJ F-
-.1-31
ac a
v<
41
si
«* IT)
Oi k .a
F- O -
M J3 O3
Z * F-
U VI
>. U 9f
X> C F- VI
O 01 IT) U 3
O 41 41 k 4l
>«< F- VI O Ik
>|>T) 01 3 f
» k .x ** * e
4) vi 41 ^
U «- Ik k
« k IV VI
x - o e F- 41
O vi T- 3
** vi 5 U **
O E vi vi
F- F- 41 IT) F-
ifl - -- > 15
e «< » F- e E
k j; u 19 k
41 Ol 41 f T3 O
«- S k e
IV Ol ik c iv A
X a oi ia u i«
as
*
41
r»
S
^
"in oi
5 T
l/l F"
09 >i U
en ID e
r~ » e
F- > e>
ex i/i *<
ex k vi
3 41
o o o>
g^-k
OD ^ O
^
«
ee
Tg
CM
r»
CM
C9
CM
1
3 >i
X, Ol 41
I/I IT) F"
ee to o
eo
en
eC
F-
3E
_2>
ex
0
k
F-
Tl
e
p)
CM
4>
O
CO
ai
~>!
VI
CO
09 1/1
^» ^ 4t
S. k o
ex 3 vo
2 * ^
k
V
^
o
1
en
09
an
^
r»
0
o
o
U1
^.
X, hk
oi co
O tj
£
o
r*
VI
^N
T)
o
01
3
VI
O
A
X
41 »
F?CD
41 F-
Is
< .
a=»
IS
^^^^^
i^ Q;
iS
£ VI
41
CM «
II
dllS
a,1^
k £
3 e
VI ~
i*
X "
* k
""it
i-
** o»
^
-^.c
li O*
^w. to
i:
o
c _g
^ r»
21
is
e Oi
§5
U
01^
3 01
vi e
o
x 2
01 >
Ol ^
£ T9
C
Ol '
^ ^^
>l ^
F- .g
J1
^ E
>ȣ
O k
o c
41 0
IT) <
3 F-
0 T)
*""
i
o
r*
**
O>
$
X
T3
e
e
^;
41
U
e
01
Ol
01
k
4)
£
0
«*
01
*
g
°
i
c
01
**
o
o
IT)
k
Ol
*
o
o
o
k
3
U
Ol
J
Ol
VI
O
T3
1
"c
o
T3
i
o
VI
C
*Q
fc.
**
0)
^2
Ol
c
2?
ex
«
3
.a
T3
Ol
IT)
3
W
T)
«
^^
S
CO
en
a.
hU
*
.
Z3
I
**-
*
++
O»
Of
3
i
41
U
C
4i
4)
ee
u
.
o
CD
on
Ok
V)
=3
C
IV
i
k
o
**
4>
£
^
°
C
41
Ol
41
41
o
£ 3
t^ O
41 >V
o* if
I/I
Ol
k
3
U
w T3
k k
en o
ex
1 £
-------
_ .
Ol
o
*~
^
£
CO
1
CO
1
o
o
eg
C/5
O
0>
ae
^
u
LU
o
s
o
U UJ »
-" -C >
CB ^
O C TD
JE § 0>
" z 3.
1/1 >>
O
<£
t/i
01
u
9i
a.
w
^
0) C
« 5^
coo
o >->
01 i_ 03
r O f
M ^ CO
= -"~
o
o
o
r
O
^
a
>,
1*"
^
4^
L.
0
o
CO
o
CM
«»
O
CM
^_,
f^
Of
*
r~ i/i
CO 4>
cn «^
^ CO
O 4-»
r a; i_
U >>
OJ 4->
U- u
0)
X
u o
c
Q\ ^-»
^P ^0
o c
4-> L.
^ ^
U 4-t
o
r~
CO
crT
CO
*
o
CO
+,
t^
ac
CO
en
r~
»
a.
U.--,
^^
o
o
o
^
CO
CO
3^
f
0.
O
5
^
o
I?
1
0
CO
A
~
1.3
CO
Ol
3
O
X
^.
^
en
L. 1
O)
C,
O) i
OB ^3
L.
tj d^
o
o
o
un
^
^^
2
cn
0)
3
o
o
"S
u
3
o
Ol
Q.
sO
CO
0
~
CO
CO
+J
f*J
ac
0)
L.
3
1/1
O
o.
X
0)
u
c
o
u.
J=
0
4->
1
M-»
X
o
o.
o.
0
4«*
o
BW
o
o
£
u-
c
IBM
4-*
c
HI
u
c
3
c
o
o
^
o
3
VI
o
o
0>
^J
^-B
41
0068d
-47-
10/05/88
-------
TABLE 9-3
1,3-BUTADIENE
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: Inhalation
Dose*: 24,080 mg/day
Effect: mortality
Reference: Hazleton Labortorles, 1981a; Owen et al., 1987
RVd: 1
RVe: 10
Composite Score: 10
RQ: 1000
*Equ1valent human dose
0068d -48- 10/05/88
-------
9.2. BASED ON CARCINOGENICITY
Two long-term Inhalation cardnogenldty studies of 1,3-butad1ene have
been performed (Hazleton Laboratories, 1981a; NTP, 1984). These studies
were summarized In Section 6.2. and Tables 6-1 and 6-2. There Is sufficient
evidence from trrese two studies to conclude that 1,3-butad1ene Is a carcino-
gen In animals. There Is, however, Inadequate evidence to demonstrate or
refute the carcinogenic potential 1n humans. Butadiene Is therefore classi-
fied as an EPA Group 82, probable human carcinogen. The available animal
data provide a basis to derive an RQ based on cardnogenlcHy. An F Factor
was calculated from the geometric mean of the tumor Incidence 1n male and
female mice. The data and derivation of the F factor are presented 1n Table
9-4. Because the F factor 1s between 1 and 100, 1,3-butad1ene 1s placed 1n
Potency Group 2. An EPA Group 82 chemical In Potency Group 2 has a MEDIUM
hazard ranking under CERCLA. Therefore, the RQ based on cardnogenlcHy Is
10.
0068d -49- 01/06/89
-------
TABLE 9-4
Derivation of Potency Factor (F)
Agent: Butadiene
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical
state:
Body weight (average):
Duration of treatment:
Duration of study:
Planned duration of study:
Target organ and tumor
type:
NTP, 1984
Inhalation
mouse
B6C3F1
male
air
0.035 kg
60 weeks
60 weeks
104 weeks
Lung-adenoma/carcinoma
Hematopo1et1c system-
NTP, 1984
Inhalation
mouse
B6C3F1
female
air
0.035 kg
61 weeks
61 weeks
104 weeks
Lung-adenoma/car c 1 noma
Hematopoletlc system-
Experimental doses/
exposure:
Transformed doses
(mg/kg/day) Internal:
Tumor Incidence:
Unadjusted 1/EDio:
(mouse)
malignant lymphoma
Heart-hemang1osarcoma
Forestomach-squamous
cell neoplasm
Preputlal gland-squamous
cell carcinomas
Zymbal gland-carcinomas
Brain - glloma
0, 625, 1250 ppm
6 hours/day, 5 days/week
0, 17.6, 28.5
2/50, 43/49, 40/45
0.8955 (mg/kg/day)'1
malignant lymphoma
Heart-hemang1osarcoma
Forestomach-squamous
cell neoplasms liver..
Mammary gland aclner
cell carcinoma.
Ovary-granulosa cell
tumors
Llver-Hepatocellular
tumors
0, 625, 1250 ppm, 6
hours/day, 5 days/week
0, 17.6, 28.5
4/48, 31/48, 45/49
0.1853 (mg/kg/day)'1
0068d
-50-
01/06/89
-------
TABLE 9-4 (cont.)
Species extrapolation
factor:
Adjusted factor for
early sacrifice:
Internal to external
dose:
Adjusted
(external) (F factor):
Geometric mean:
12.6
5.21
0.20
11.8 (mg/kg/day)'
12.6
4.96
0.20
2.3 (mg/kg/day)'
5.2 (mg/kg/day)'
0068d
-51-
01/06/89
-------
10. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986a.
Threshold Limit Values and Biological Exposure Indices for 1986-1987.
Cincinnati, OH. p. 40.
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986b.
Documentation of the Threshold Limit Values and Biological Exposure Indices,
5th ed. Cincinnati, OH. p. 68-69.
Amoore, J.E. and E. Hautala. 1983. Odor as an aid to chemical safety: Odor
thresholds compared ylth threshold limit values and volatilities for 214
Industrial chemicals 1n air and water dilution. J. Appl. Toxlcol. 3:
272-290.
Andjelkovlch, D., J. Taulbeen and M. Symons. 1976. Mortality experience of
a cohort of rubber workers, 1964-1973. J. Occup. Med. 18: 387-394. (Cited
1n U.S. EPA, 1985)
Arnts, R.R. and S.A. Meeks. 1981. Blogenlc hydrocarbon contribution to the
ambient air of selected areas. Atmos. Environ. 15: 1643-1651.
Atkinson, R. 1985. Kinetics and mechanisms of the gas-phase reactions of
hydroxyl radical with organic compounds under atmospheric conditions. Chem.
Rev. 85: 69-201.
0068d -52- 02/06/89
-------
-------
-------
Atkinson, R. and W.P.L. Carter. 1984. Kinetics and mechanisms of gas-phase
reactions of ozone with organic compounds under atmospheric conditions.
Chem. Rev. 84: 437-470.
Atkinson, R. and J.N. Pitts, Jr. 1977. Absolute rate constants for the
reaction of oxygen (3P) atoms with allene, 1,3-butad1ene and vinyl methyl
ether over the temperature range 297-439 K. J. Chem. Phys. 67: 2492-2495.
Atkinson, R., S.M. Aschmann, A.M. Winer and J.N. Pitts, Jr. 1984. Kinetics
of the gas-phase reactions of No. 3 radicals with a series of dlalkenes,
cycloalkenes and monoterpenes at 295 K. Environ. Sc1. Techno!. 18: 370-375.
Bayard, S.P. 1988. Pharmacoklnetlcs In the risk assessment of 1,3-buta-
dlene. Presented at the Inst. Workshop on Biological Data for Pharmaco-
klnetlc Modeling and Risk Assessment, Ashevllle, NC. May.
Bolt, H.M., J.G. Fllser and F. Stoermer. 1984. Inhalation pharmacoklnetlcs
based on gas uptake studies. V. Comparative pharmacoklnetlcs of ethylene
and l,3-butad1ene In rats. Arch. Toxlcol. 55: 213-218.
Bond, J.A., A.R. Dahl, R.F. Henderson, J.S. Dutcher, J.L. Mauderly and L.S.
Blrnbaum. 1986. Species differences In the disposition of Inhaled
butadiene. Toxlcol. Appl. Pharmacol. 84: 617-627.
Brodzlnsky, R. and H.B. Singh. 1982. Volatile organic chemicals In the
atmosphere: An assessment of avlalable data. Atmospheric Science Center,
SRI International, Menlo Park, CA. 198 p. Contract 68-02-3452.
0068d -53- 01/06/89
-------
Carpenter, C.P., C.B. Shaffer, C.S. Well and H.F. Smyth, Jr. 1944. Studies
on the Inhalation of l:3-butad1ene; with a comparison of Us narcotic effect
with benzol, toluol, and styrene, and a note on the elimination of styrene
by the human. J. Ind. Hyg. Toxlcol. 26: 69-78.
C&E News (Chemical and Engineering News). 1986. Key Chemicals. Butadiene.
Chemical and Engineering News, June 9, 1986. p. 15.
Checkoway, H. and T.M. Williams. 1982. A hematology survey of workers at a
styrene-butadlene synthetic rubber manufacturing plant. Am. Ind. Hyg.
Assoc. J. 43: 164-169. (CUed In U.S. EPA, 1985)
Choy, W.N., D.A. Vlachos, H.J. Cunningham, G.T. Arce and A.M. Sarrlf. 1986.
Genotox1c1ty of 1,3-butad1ene Induction of bone marrow mlcronuclel In B6C3F1
mice and Sprague-Dawley rats U» vivo. Environ. Mutagen. 8: 18.
CMR (Chemical Marketing Reporter). 1985. Chemical Profile. Butadiene.
Chemical Marketing Reporter, April 11, 1985.
Cote, I. and S.P. Bayard. 1988. EPA's risk assessment of 1,3-butadlene.
Presented at the National Institute of Environmental Health Sciences'
International Symposium on l,3-Butad1ene, Research Triangle Park, NC. April.
Crouch, C.N. and D.H. PulUnger. 1978. The toxlclty of butadiene to rats
by Inhalation. Toxlcol. Appl. Pharmacol. 45(1): 249-250.
0068d -54- 02/06/89
-------
Crouch, C.N., D.H. PulUnger and I.F. Gaunt. 1979. Inhalation toxlclty
studies with 1,3-butad1ene -- 2. 3-Month toxlclty study 1n rats. Am. Ind.
Hyg. Assoc. J. 40: 796-802.
Cunningham, M.Jr, W.N. Choy, G.T. Arce, et al. 1986. In vivo slster-
chromatld exchange and mlcronucleus Induction studies with 1,3-butad1ene 1n
B6C3F1 mice and Sprague-Dawley rats. Mutagenesls. 1: 449-452.
Daugherty, P.M., Jr. and J.T. Garrett. 1951. Toxlclty levels of hydro-
cyanic add and some Industrial by-products. Texas J. Scl. 3: 391-396.
(Cited In U.S. EPA, 1983)
DeMeester, C., F. Poncelet, M. Roberfrold and M. Merder. 1978. Mutagen-
1c1ty of butadiene and butadiene monoxide. Blochem. Blophys. Res. Commun.
80(2): 298-305.
DeMeester, C., F. Poncelet, M. Roberfrold and M. Mercler. 1980. Mutagen-
Iclty of butadiene towards Salmonella typh1mur1um. Toxlcol. Lett. 6:
125-130.
Donetskaya, E.I. and F.S. Schvartsapel. 1970. Morphological studies of the
organs of white rats under the action of 1,3-butad1ene In subacute experi-
ments. Tr. Permsk Med Inst. 82: 223-225.
Ewlng, B.B., E.S.K. Chlan, J.C. Cook, C.A. Evans, P.K. Hopke and E.G.
Perkins. 1977. Monitoring to detect previously unrecognized pollutants 1n
surface waters. Appendix: Organic Analysis Data. U.S. EPA, Washington, DC.
p. 75. EPA 560/6-77-015. Appendix: EPA 600/6-77-015A.
0068d -55- 01/06/89
-------
Miser, J.G. and H.M. Bolt. 1984. Inhalation pharmacoklnetlcs based on gas
uptake studies. VI. Comparative evaluation of ethylene oxide and butadiene
monoxide as exhaled reactive metabolites of ethylene and 1,3-butad1ene 1n
rats. Arch. Toxlcol. 55: 219-223.
Graedel, I.E. 1978. Chemical Compounds In the Atmosphere. Academic Press,
New York. p. 76.
Hansch, C. and A.3. Leo. 1981. Medchem Project. Issue No. 19. Pomona
College, Claremont, CA.
Haseman, J.K., D.D. Crawford, J.E. Huff, G.A. Boorman and E.E. HcConnell.
1984. Results from 86 two-year carc1nogen1dty studies conducted by the
NTP. J. Toxlcol. Environ. Health. 14: 621-639.
Hawley, G.G. 1981. The Condensed Chemical Dictionary, 10th ed. Van
Nostrand Relnhold Co., New York. p. 156.
Hayano, S., J.H. Lee, K. Furuya and T. Klkuchl. 1985. Formation of
hazardous substances and mutagenldty of PAH produced during the combustion
process 1n a dlesel engine. Atmos. Environ. 19: 1009-1015.
Hazleton Laboratories. 1981a. The toxlclty and carc1nogen1c1ty of buta-
diene gas administered to rats by Inhalation for approximately 24 months.
Prepared for the International Institute of Synthetic Rubber Producers, New
York, NY. Unpublished. (Cited 1n U.S. EPA, 1985; Scala, 1981)
0068d -56- 02/06/89
-------
Hazleton Laboratories. 1981b. 1,3-Butad1ene Inhalation teratogenlclty
study In the rat. Intl. Inst. of Synthetic Rubber. OTS 8e submission.
Flche #OTS0505459. Doc #888200415 (8EhQ-0882-0441).
H1ne, J. and P.K. Mookerjee. 1975. The Intrinsic hydropMHc character of
organic compounds. Correlations 1n terms of structural contributions. J.
Org. Chem. 40: 292-298.
Huff, J.E., R.L. Melnlck, H.A. Solleveld, J.K. Haseman, M. Powers and R.A.
Miller. 1985. Multiple organ cardnogenlclty of 1,3-butad1ene in B6C3F1
mice after 60 weeks of Inhalation exposure. Science. 227: 548-549.
Hughes, T.W., D.R. Tlerney and Z.S. Khan. 1979. Measuring fugitive
emissions from petrochemical plants. Chem. Eng. Prog. 75: 35-39.
Irons, R.D., C.N. Smith, W.S. Stlllman, R.S. Shah, W.H. Stlnhagen and L.J.
Lelderman. 1986a. Macrocytic-megaloblastic anemia in male B6C3F1 mice
following chronic exposure to 1,3-butad1ene. Toxicol. Appl. Pharmacol. 83:
95-100.
Irons, R.O., C.N. Smith, W.S. Stlllman, R.S. Shah, W.H. Stlnhagen and L.J.
Lelderman. 1986b. Macrocytlc-megaloblastlc anemia 1n male NIH Swiss mice
following repeated exposure to 1,3-butadiene. Toxicol. Appl. Pharmacol.
85: 450-455.
0068d -57- 01/06/89
-------
Jaber, H.M., W.R. Mabey, A.T. L1u, T.W. Chou and H.L. Johnson. 1984. Data
acquisition for environmental transport and fate screening. SRI Inter-
national, Menlo Park, CA. p. 105. EPA 600/6-84-009. NTIS PB 84-243906, PB
84-243955.
Katzman, H. and W.F. L1bby. 1975. Hydrocarbon emissions from jet engines
operated at simulated high-altitude supersonic flight conditions. Atmos.
Environ. 9: 839-834.
Klrshenbaum, I. 1978. Butadiene. In.: Klrk-Othmer Encyclopedia of Chemical
Technology, 3rd ed., M. Grayson and D. Eckroth, Ed. John Wiley and Sons,
Inc., New York. p. 313-337.
KrelUng, R., R.J. Lalb and H.M. Bolt. 1986a. Alkylatlon of nuclear
proteins and DNA after exposure of rats and mice to [1,4-14C]l ,3-butad1ene.
Toxlcol. Lett. 30: 131-136.
KreHIng, R., R.J. La1b and H.M. Bolt. 1986b. Species differences 1n
butadiene metabolism between mice and rats evaluated by Inhalation pharmaco-
klnetlcs. Arch. Toxlcol. 58: 235-238.
KrelUng, R., R.J. La1b, J.6. Fllser and H.M. Bolt. 1987. Inhalation
pharmacoklnetlcs of 1,2-epoxybutene-3 reveal species differences between
rats and mice sensitive to butadiene-Induced carclnogenesls. Arch. Toxlcol.
61: 7-11.
0068d -58- 01/06/89
-------
Kuz'mln, V.I. 1969. Pathomorphologlcal changes In the lungs of white rats
under the action of 1,3-butadlene and a-methylstyrene vapors. Nauch. Tr.
Omsk. Med. Inst. 88: 215-219. (CA 75:107749b)
Lelderman, L.J.,~W.S. StUlman, R.S. Shah, W.H. Stelnhagen and R.D. Irons.
1986. Altered hematopoletlc stem cell development in male B6C3F1 mice
following exposure to 1,3-butad1ene, Exp. Mol. Pathol. 44: 50-56.
Lonneman, W.A., R.L. Sella and J.J. Bufal1n1. 1978. Ambient air hydro-
carbon concentrations 1n Florida. Environ. Sd. Technol. 12: 459-463.
Lonneman, W.A., G.R. Namle and J.J. Bufalinl. 1979. Hydrocarcons In
Houston air. U.S. EPA, Research Triangle Park, NC. EPA 600/3-79-018.
Lyman, W.J., W.F. Reehl and O.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Methods. McGraw-Hill Book Co., New York. p. 15-16,
5-4, 5-10, 4-9.
Mabey, W.R., J.H. Smith, R.T. Podoll, et al. 1981. Aquatic fate process
data for organic priority pollutants. Monitoring and Data Support Division
(WH 553), Office of Water Regulations and Standards, U.S. EPA, Washington,
DC. p. 28. EPA 40/4-81-014.
Malvolsln, E. and M. Roberfroid. 1982. Hepatic microsomal metabolism of
1,3-butadiene. Xenob1ot1ca. 12(2): 137-144.
0068d -59- 01/06/89
-------
Halvo1s1n, E., G. Lhoest, F. Poncelet, M. Roberfrold and H. Herder. 1979.
Identification and quantHatlon of l,2-epoxybutene-3 as the primary metabo-
lite of l,3-butad1ene. 3. Chromatogr. 178(2): 419-425.
Malvolsln, E., M. Herder and H. Roberfrold. 1982. Enzymlc hydratlon of
butadiene monoxide and Us Importance 1n the metabolism of butadiene. Adv.
Exp. Hed. Blol. 136A: 437-444.
Hatanoskl, G.H., L. Schwartz, 3. Sperrazza and 3. Tonascla. 1982. Hortal-
1ty of workers 1n the styrene-butadlene rubber polymer manufacturing
Industry. John Hopkins University School of Hygiene and Public Health,
Baltimore, HD. Unpublished. (Cited In U.S. EPA, 1985)
HcAullffe, C. 1966. Solubility 1n water of paraffin. Cycloparaff1n,
olefln, acetylene, cycloolefln and aromatic hydrocarbon. 3. Phys. Chem.
70: 1267-1275.
HcHlchael, A.3., R. Splrtas and L.L. Kupper. 1974. An epldemlologlc study
of mortality within a cohort of rubber workers, 1964-1972. 3. Occup. Med.
16: 458-464. (Cited 1n U.S. EPA, 1985)
Helnhardt, T.3., R.A. Lemen, H.S. Crandall and R.3. Young. 1982. Environ-
mental epldemlologlc Investigation of the styrene-butadlene rubber Industry.
Scand. J. Work Environ. Health. 8: 250-259. (Cited 1n U.S. EPA, 1985)
HUler, D.F. and A.3. Alkezweeny. 1980. Aerosol formation 1n urban plumes
over Lake HUhlgan. Ann. N.Y. Acad. Sc1. 338: 219-232.
0068d -60- 02/06/89
-------
Molodyuk, A.V., V.V. Semchenko and G. R1pp. 1969. Microscopic changes 1n
the spleen of experimental animals during the Inhalation of 1,3-butadlene.
Nauch. Tr. Omsk. Med. Inst. 88: 170-173. (CA 75:107773e)
Nellgan, R.W. 1962. Hydrocarbons 1n the Los Angeles atmosphere. Arch.
Environ. Health. 5: 581-591.
N1k1, H., P.O. Maker, C.M. Savage and L.P. Breltenbach. 1983. Atmospheric
ozone-olefln reactions. Environ. Scl. Techno!. 17: 312A-322A.
N1k1forova, A.A., G. Rlpp and I.I. Taskaev. 1969. Action of 1,3-butadlene
on the structural elements of kidneys and heart. Nauch. Tr. Omsk. Med.
Inst. 88: 166-169.
NIOSH (National Institute for Occupational Safety and Health). 1984.
l,3-Butad1ene. Current Intelligence Bulletin 41. U.S. EPA. Health, Educa-
tion, Welfare, NIOSH, Washington, DC. p. 1-18.
NTP (National Toxicology Program). 1984. Toxicology and Cardnogenesls
Studies of l,3-Butad1ene 1n B6C3F1 Mice. National Toxicology Program,
Research Triangle Park, NC. (Also published as Report No.. NTP-83-071;
NIH/PUB-84-2544)
NTP (National Toxicology Program). 1985. Quarterly report from Lovelace
Research Institute, January 1 through March 31, 1985. Interagency agreement
22-YOI-ES-0092. (L. BUnbaum, NTP Project Officer) (Cited 1n U.S. EPA,
1985)
0068d -61- 02/06/89
-------
OSHA (Occupational Safety and Health Administration). 1985. OSHA Occupa-
tional Standards. Permissible Exposure Limits. 29 CFR 1910.1000.
Oura, E., N.C.R. Raiha and H. Suomalalnen. 1967. Influence of some
alcohols and narcotics on the adenoslne phosphates 1n the liver of the
mouse. Ann. Med. Exp. B1ol. Fenn. 45: 57-62. (CA 006/001290E)
Owen, P.E., J.R. Glalster, I.F. Gaunt and D.H. Pulllnger. 1987. Inhalation
toxlclty studies with 1,3-butad1ene. 3. Two-year tox1cty/carc1nogen1dty
study In rats. Ann. Ind. Hyg. Assoc. J. 48(5): 407-413.
Perry, R.H. and 0. Green. 1984. Perry's Chemical Handbook. Physical and
Chemical Data, 6th ed. McGraw-Hill Book Co., New York. p. 3-62.
PokrovskH, V.A. and R.I. Volchkova. 1968. Effect of some organic poisons
on blood formation processes. Tr. Voronezh. Gos. Med. Inst. 73(4): 61-64.
(CA 74:97300m)
Poncelet, F., C. DeMeester, M. Duverger-van Bogaert, M. Lambotte-Vandepaer,
M. Roberfrold and M. Merder. 1980. - Influence of experimental factors on
the mutagenlclty of vlnyllc monomers. Arch. Toxlcol. 4: 63-66.
R1pp, G.K. 1969. Toxlcohyglenlc characteristics of 1,3-butad1ene. Nauch.
Jr., Omsk. Med. Inst. 88: 10-18. (CA 75:107777j)
R1pp, G.K. and T.M. Lyutlkova. 1966. Some hematologlcal Indexes 1n experi-
mental chronic Intoxication wHh dlvlnyl and cracking gas. Nauch. Tr. Omsk.
Med. Inst. 69: 90-92.
0068d -62- 01/06/89
-------
Sandmeyer, E.E. 1981. Butadiene. in.: Patty's Industrial Hygiene and
Toxicology. John Wiley and Sons, Inc., New York. p. 3207-3208.
SANSS (Structure and Nomenclature Search System). 1987. Chemical Informa-
tion System (CIS-) computer data base. Online.
Sax, N.I. 1984. Dangerous Properties of Industrial Materials, 6th ed. Van
Nostrand Relnhold Company, New York. p. 545.
Scala, R.A. 1981. Status report on butadiene Inhalation study. Annu.
Meet. Proc. - Int. Inst. Synth. Rubber Prod. 22: I1/1-I1/13.
Schmidt, U. and E. Loeser. 1985. Species differences In the formation of
butadiene monoxide from 1,3-butad1ene. Arch. Toxlcol. 57(4): 222-225.
Schmidt, U. and E. Loeser. 1986. Epoxldatlon of 1,3-butad1ene 1n liver and
lung tissue of mouse, rat, monkey and man. Adv. Exp. Med. B1ol. 197:
951-957.
Sella, R.L. 1979. Non-urban hydrocarbon concentrations In ambient air
north of Houston, TX. U.S. EPA, Research Triangle Park, NC. p. 38. EPA
600/3-79-010.
Sella, R.L., R.R. Arnts and J.W. Buchanan. 1984. Atmospheric volatile
hydrocarbon composition at five remote sites In northwestern North Carolina.
U.S. EPA, Research Triangle Park, NC. EPA 600/0-84-092.
0068d -63- 01/06/89
-------
Serebrennikov, O.A. and G.A. Ogleznev. 1978. Developmental anomalies 1n
the mother-fetus system following exposure to petrochemical products.
Deposited Doc. 151-2. (CA 205223A)
Sernau, R., J.-Cavagnaro and P. Kehn. 1986. 1,3-Butad1ene as an S-9
activation-dependent gaseous positive control substance In L-5178Y cell
mutation assays. Environ. Mutagen. 8: 75-76.
Shugaev, B.B. 1969. Concentrations of hydrocarbons 1n tissues as a measure
of toxldty. Arch. Environ. Health. 18: 878-882.
SRI (Stanford Research Institute). 1986. 1986 Directory of Chemical
Producers: United States of America. SRI International, Menlo Park, CA.
p. 514.
Stephens, E.R. and F.R. Burleson. 1967. Analysis of the atmosphere for
light hydrocarbons. J. A1r Pollut. Control Assoc. 17: 147-153.
Swann, R.L., O.A. Laskowskl, P.J. McCall, K. Vander Kuy and H.J. Dlshburger.
1983. A rapid method for the estimation of the environmental parameters
octanol/water partition coefficient, soil sorptlon constant, water to air
ratio and water solubility. Res. Rev. 85: 23.
Thorn, N.S. and A.R. Agg. 1975. The breakdown of synthetic organic com-
pounds 1n biological processes. Proc. R. Soc. Lond. B. 189: 347-357.
0068d -64- 01/06/89
-------
Thurmond, L.M., L.D. Lauer, R.V. House, et al. 1986. Effect of short-term
Inhalation exposure to 1,3-butad1ene on murlne Immune functions. Toxlcol.
Appl. Pharmacol. 86: 170-179.
Tlce, R.R., R. Boucher, C.A. Luke and M.D. Shelby. 1987. Comparative
cytogenetlc analysis of bone marrow damage Induced 1n male B6C3F1 mice by
multiple exposures to gaseous 1,3-butad1ene. Environ. Mutagen. 9: 235-250.
U.S. EPA. 1980. Guidelines and Methodology for the Preparation of Health
Effect Assessment Chapters of the Consent Decree Water Criteria Documents.
Federal Register. 45(231): 79347-79357.
U.S. EPA. 1983. Health and Environmental Effects Profile for 1,3-Butad1ene.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Solid
Waste, Washington, DC.
U.S. EPA. 1984. Methodology and Guidelines for Ranking Chemicals Based on
Chronic Toxldty Data. Prepared by the Office of Health and Environmental
Assessment Office, Cincinnati, OH for the Office of Solid Waste and
Emergency Response, Washington, DC.
U.S. EPA. 1985. Mutagen1c1ty and Carclnogenldty Assessment of
l,3-Butad1ene. Office of Health and Environmental Assessment, Washington,
DC. EPA 600/8-85-004F. NTIS PB 86-125507.
0068d -65- 02/06/89
-------
U.S. EPA. 1986a. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Haste, Washington,
DC.
U.S. EPA. 1986b. Methodology for Evaluating Potential CarclnogenlcHy 1n
Support of Reportable Quantity Adjustments Persuant to CERCLA Section 102.
Prepared by the Office of Health and Environmental Assessment, Carcinogen
Assessment Group for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1986c. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1987. Graphical Exposure Modeling System (GEMS). Fate of Atmo-
spheric Pollutants (FAP) computer data systems. U.S. EPA, Research Triangle
Park, NC.
USITC (U.S. International Trade Commission). 1986. Synthetic Organic
Chemicals. United States Production and Sales. USITC Publ. 1892, Wash-
ington, DC. p. 19, 22.
Vincent, D.R., G. Theall Arce and A.M. Sarrlf. 1986. Genotoxlclty of
l.3-butad1ene assessment by the unscheduled DNA synthesis assay In B6C3F1
mice and Sprague-Dawley rats Jm vivo and ^n vitro. Environ. Mutagen. 8: 88.
Watklnson, R.F. and H.J. Somervllle. 1976. The mlcroblal utilization of
butadiene, in: Proc. 3rd Int. B1odegradat1on Symp. p. 35-42.
0068d -66- 02/06/89
-------
Wooder, M.F. 1986. Butadiene Overview. Annu. Meet. Proc. - Int. Inst.
Synth. Rubber Prod. 27: 18.
0068d -67- 02/06/89
-------
APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXBACK 76
TOXBACK 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
These searches were conducted 1n February, 1987. In addition, hand searches
were made of Chemical Abstracts (Collective Indices 5-9), and the following
secondary sources should be reviewed:
AC6IH (American Conference of Governmental Industrial Hyg1en1sts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986-1987. TLVs: Threshold Limit Values for Chemical Substances 1n
the Work Environment adopted by ACGIH with Intended Changes for
1986-1987. Cincinnati, OH. Ill p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hyc;1ene and Toxicology, 3rd rev. ed., Vol. 2B. John Wiley and
Sons, NY. p. 2879-3816.
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
0068d -68- 02/06/89
-------
Grayson, M. and D. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. WHO, IARC, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. Lieu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
SRI International, Menlo Park, CA. EPA 600/6-84-010. NTIS
PB84-243906.
NTP {National Toxicology Program). 1986. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1986. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report 1n the Special Review
Program, Registration Standards Program and the Data Call 1n
Programs. Registration Standards and the Data Call 1n Programs.
Office of Pesticide Programs, Washington, DC.
U.S. EPA. 1985. CSB Existing Chemical Assessment Tracking System.
Name and CAS Number Ordered Indexes. Office of Toxic Substances,
Washington, DC.
USITC (U.S. International Trade Commission). 1985. Synthetic
Organic Chemicals. U.S. Production and Sales, 1984, USITC Publ.
1422, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
Worthing, C.1*. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
0068d -69- 02/06/89
-------
In addition, approximately 30 compendia of aquatic toxlclty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Hater Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxldty
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxldty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
In addition, the following documents were consulted:
Santodonato, J. 1985. Monograph on human exposure to chemicals In
the workplace: 1,3-butad1ene. National Cancer Inst. p. 53.
U.S. EPA. 1976. Biological effects and environmental aspects of
1,3-butadlene. Office of Toxic Substances, Washington, DC. p. 58.
U.S. EPA. 1978. Investigation of selected potential environmental
contaminants: Butadiene and Us ollgomers. p. 195.
U.S. EPA. 1981. Chemical Hazard Information Profile Draft Report
l,3-Butad1ene. OTS, Washington, DC.
U.S. EPA. 1983. Health and Environmental Effects Profile for
1,3-Butadlene. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Solid Waste, Washington. DC.
U.S. EPA. 1985. The air toxics problem 1n the United States: An
analysis of cancer risks for selected pollutants. Office of Air
Quality Planning and Standards, p. 123.
0068d -70- 02/06/89
-------
01
TS
>e
^^
3
CO
t
r>
k
O
4k
tl
.O
«fl
k»
>»
k
VI
t
«>
u
e
it
u
«
ik
*
OE
«
V
k
O
o
VI
1
^ ^_ ^"" ^^
00 a c o eo
e! o> e « tr
*» *" * 10 !
4» t_ 10
= e
eu & » ^ eo Q.
001- a a j; 522 «
u
£ W
« U *
» 1 A
1 A «
« M >*l
1 "0
S._ -o >
a. >> ^ < ««. Ol
i o> S1-*
o ^ I >>
J£ >. at
MO* i
» i e.~
oi ~" » Pn
a
iu>
at
«
a a u. a a
-, «« w e e*hk
VI VI
ii »
«^ ««
1^ ^* VI *
i. VI 1- V>
§., I*
~"a. "%
VI ~* VI
3 < 3 i
^i ^i
t_ u
aa» »<
t e
CM 3 (M 3
e M. vi e J> vi
k. f U * u JC 4> J*
e 01 o> e A) u
*x! * _*.£ 8
5 .^ * £ . « *
t-> >« r> >»r-
>*-i'o~c<«<0 a e
>> « i >» « i e ^~
aa >o>o o o - CT o o
i O B f * ^i OCU^iO r-
»~
VI VI
ftl Ol
K K
It It
IH 1^
I £ > £
VI * VI **
3 O 3 O
o o o .0 aa OA
n»c « « «
>H
«* >»
» «#
«« i u
UU ft "
» * JE ~ c
a < * < c
M * SOU
ku u i> w a1 u. u
^^ 3 ^* ^S 'O
eu e V o e tww u
O 4" O ~- *> i
e o> ae » me e
w o u o K o u o < o e
«oi.«-e tu i- c i
r-£C»- £ C CX T3 &
>aueu r-ueu o« >
fAuk ivAkk a. vi vi
C3£<« u. 3 £ « uj u u o v> u u ac aa OB
tf
o
i
f»
1
«fe
e
e
«
£
«rf
vt
S
«
«l
>
k
1
a
e
e
«*
a,
u
o
A
«
^
e
^
b.
«rf
VI
l«
o>
g
o
o>
g
VI
VI
o
If
o
«rf
(Q
F"
------- |