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1,3-Butadiene
CASRN 106-99-0
Contents
0139
1,3-Butadiene; CASRN 106-99-0
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR 1,3-Butadiene
File On-Line 03/31/1987
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) no data
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 02/01/1991
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- 1,3-Butadiene
CASRN -- 106-99-0
Not available at this time.
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- 1,3-Butadiene
CASRN -- 106-99-0
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- 1,3-Butadiene
CASRN -- 106-99-0
Last Revised -- 02/01/1991
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1
in 1,000,000. The rationale and methods used to develop the carcinogenicity
information in IRIS are described in The Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to
Section I of this IRIS file for information on long-term toxic effects other
than carcinogenicity.
__II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- B2; probable human carcinogen
Basis -- Inadequate human data and sufficient rodent (mouse and rat) studies
in which exposure to airborne concentrations of 1,3-butadiene caused multiple
tumors and tumor types form the basis for this classification. Related
compounds are carcinogenic and mutagenic.
___II.A.2. HUMAN CARCINOGENICITY DATA
Inadequate. Of the three studies on workers specifically identified as
being exposed to 1,3-butadiene, two were cohort studies while one was a cross-
sectional study designed to look at certain hematologic parameters. One of
the cohort studies was a mortality study of 14,000 workers at eight plants,
and it found none of the Standard Mortality Ratios (SMR) for cancer to be
significantly elevated (Matanoski et al., 1982). The second cohort study
found an increase of borderline significance in the SMR for lymphatic and
hematopoietic cancer in a subpopulation (Meinhardt et al., 1982). The cross-
sectional study found no evidence of hematologic effects (Checkoway and
Williams, 1982). Two studies found an association between employment in the
synthetic rubber industry and an elevated risk of cancer. Synthetic rubber is
manufactured from styrene and butadiene. In one case-control study, synthetic
rubber plant workers were found to have an increased risk ratio for deaths
from lymphatic and hematopoietic cancer (McMichael et al., 1976). The second,
a cohort mortality study, found excess lung cancer deaths among workers in a
synthetic rubber area of a plant. This latter finding was based on three
deaths with no control for smoking (Andjelkovich et al., 1977). Given the
inconsistency of results, the methodological limitations of the different
studies, and the confounding effects of exposure to various solvents, styrene,
and possibly other chemicals, the epidemiologic evidence is considered
inadequate.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Sufficient. Two lifetime inhalation studies of 1,3-butadiene in rodents
were initiated. B6C3F1 mice (50/sex/group) were exposed to 625 or 1250 ppm
for 6 hours/day, 5 days/week. Exposure began at 8-9 weeks of age, and all
mice were killed after weeks 60-61 because of excessive deaths among treated
mice. Increases were observed in the number of mice with primary tumors and
in the number of mice with multiple primary tumors. Tumors occurring
throughout the body included hemangiosarcomas of the heart, lymphomas and
alveolar/bronchiolar adenomas/carcinomas (NTP, 1984).
Charles River CD rats (110/sex/group) were exposed to 1000 or 8000 ppm
1,3-butadiene for 6 hours/day, 5 days/week for 111 weeks (males) or 105 weeks
(females). There was a treatment-related increase in mortality, some of which
was attributed to nephropathies in males. Significant increases occurred in
incidence in both common and uncommon tumors including mammary gland
tumors, thyroid follicular adenomas and carcinomas, and Leydig cell adenomas
and carcinomas (Hazleton Laboratories Ltd, 1981). Because of problems with
reporting of this study and because pharmacokinetic analysis indicated that
the effective doses were the same for both treatment groups, this study was
not considered adequate for the estimation of risk.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Three studies have shown 1,3-butadiene to be mutagenic for Salmonella
typhimurium upon addition of mammalian hepatic homogenates for metabolism
(de Meester et al., 1978, 1980; Poncelet et al., 1980). Pharmacokinetic and
various types of toxicity studies indicate that the carcinogenic effect of
1,3-butadiene can be attributed to the metabolites 3,4-epoxybutane and/or
1,2,3,4-diepoxybutane. These metabolites, which are potent alkylating
agents, have been shown to be mutagenic and carcinogenic (Lawley and Brookes,
1967; de Meester et al., 1978; Dean and Hodson-Walker, 1979; Perry and
Evans, 1975; Wade et al., 1979; Voogd et al., 1981; Ehrenberg and Hussain,
1981; Conner et al., 1983; U.S. EPA, 1985). 1,3-Butadiene is structurally
related to known carcinogens.
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
None. 1,3-Butadiene is a gas at room temperature and pressure, making
oral exposure unlikely.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
___II.C.1. SUMMARY OF RISK ESTIMATES
Inhalation Unit Risk -- 2.8E-4 per (ug/cu.m)
Extrapolation Method -- Linearized multistage procedure, extra risk
Air Concentrations at Specified Risk Levels:
Risk Level Concentration
-------------------- ---------------
E-4 (1 in 10,000) 4E-1 ug/cu.m
E-5 (1 in 100,000) 4E-2 ug/cu.m
E-6 (1 in 1,000,000) 4E-3 ug/cu.m
___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE
Species/Strain Dose Tumor Reference
Tumor Type Administered Internal Dose Incidence
Mouse/B6C3F1; Route: Inhalation NTP, 1984
several tumor
types ppm mg/kg/day male female
0 0 2/50 4/48
625 18.4 43/49 31/48
1250 27.8 40/45 45/49
___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE)
Animals dying before onset of first tumor (20 weeks) were eliminated. An
adjustment was made for early sacrifice in the calculation. The
concentration in ppm is assumed to be equivalent for the experimental animals
and humans.
In determining the animal-to-equivalent-human dose, an adjustment was made
to account for the lack of proportionality to external concentration at high
levels. The function for the incremental cancer risk to the animals was based
on a calculated internal dose (in mg/kg) and converted back to risk for low-
dose ppm equivalents in the animal.
Animal upper-limit slope factors of 6.1E-1 per (mg/kg)/day for males, and
3.0E-1 per (mg/kg)/day for females were reconverted to air concentration units
of 9.2E-1 per ppm and 4.5E-1 per ppm by assuming a 20% absorption rate at low
exposures. Data from Bond et al. (1986) support the assumption that in mice
and rats exposed to 13 ug 1,3-butadiene/L air or less, absorption will be 20%.
The quantitative estimates of 1.8E+0 per (mg/kg)/day or 6.4E-1 per ppm is a
geometric mean of slope factors derived from the male and female mouse data
sets. This is a correction from U.S. EPA (1985) in which preliminary data was
used to calculate the unit risk (Cote and Bayard, 1990).
The unit risk should not be used if the air concentration exceeds 16
ug/cu.m, since above this concentration the unit risk may not be appropriate.
___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE)
Unit risks of 3.4E-1 and 1.9E-1 per (ppm) were calculated from male and
female rat data, which were highly limited from a modeling standpoint, having
only one effective dose, confusion over animal accounting, and other
drawbacks.
Adequate numbers of mice were treated. Risk estimates derived from data
on mice and rats differ by a factor of 3 for females (1.9E-1 per (ppm) vs.
5.6E-2 per (ppm) and 80 for males (3.4E-1 per (ppm) vs. 4.2E-3 per (ppm). The
relatively close agreement of quantitative estimates across species for
females supports the confidence in the unit risk. An alternate analysis using
life-table adjustment for both genders of mice shows results within a factor
of 2. Confidence is rated low. Estimates of human risk based on sketchy
epidemiologic data indicate that the unit risk extrapolation from animal to
human is consistent.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1985
The 1985 Mutagenicity and Carcinogenicity Document received both Agency
and external review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 01/07/1987
Verification Date -- 01/07/1987
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_VI. BIBLIOGRAPHY
Substance Name -- 1,3-Butadiene
CASRN -- 106-99-0
Last Revised -- 01/01/1991
__VI.A. ORAL RfD REFERENCES
None
__VI.B. INHALATION RfD REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Andjelkovich, D., J. Taulbee, M. Symons and T. Williams. 1977. Mortality of
rubber workers with reference to work experience. J. Occup. Med. 18: 387-394.
Bond, J.A., A.R. Dahl, R.F. Henderson, G.S. Dutcher, J.L. Mauderly and L.S.
Birnbaum. 1986. Species differences in the disposition of inhaled butadiene.
Toxicol. Appl. Pharmacol. 84: 617-627.
Checkoway, H. and T.M. Williams. 1982. A hematology survey of workers at a
styrene-butadiene synthetic rubber manufacturing plant. Am. Ind. Hyg. Assoc.
J. 43: 164-169.
Conner, M., J. Lou and O. Gutierrez de Gotera. 1983. Induction and rapid
repair of sister-chromatid exchanges in multiple murine tissues in vitro by
diepoxybutane. Mutat. Res. 108: 251-263.
Cote, I.L. and S.P. Bayard. 1990. Cancer risk assessment of 1,3-butadiene.
Environ. Health Perspect. 86: 149-153.
Dean, B.J. and G. Hodson-Walker. 1979. An in vitro chromosome assay using
cultured rat-liver cells. Mutat. Res. 64: 329-337.
de Meester, C., F. Poncelet, F. Roberfroid and M. Mercier. 1978.
Mutagenicity of butadiene and butadiene monoxide. Biochem. Biophys. Res.
Commun. 80: 298-305.
de Meester, C., F. Poncelet, F. Roberfroid and M. Mercier. 1980. The
mutagenicity of butadiene towards Salmonella typhimurium. Toxicol. Lett. 6:
125-130.
Ehrenberg, L. and S. Hussain. 1981. Genotoxicity of some important epoxides.
Mutat. Res. 86: 1-113.
Hazelton Laboratories Europe, Ltd. 1981. The toxicity and carcinogenicity of
butadiene gas administered to rats by inhalation for approximately 24 months.
Prepared for the International Institute of Synthetic Rubber Producers, New
York, NY. Unpublished.
Lawley, P.D. and P. Brookes. 1967. Interstrand cross-linking of DNA by
difunctional alkylating agents. J. Mol. Biol. 25: 143-160.
Matanoski, G.M., L. Schwartz, J. Sperrazza and J. Tonascia. 1982. Mortality
of workers in the styrene-butadiene rubber polymer manufacturing industry.
Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD.
Unpublished.
McMichael, A.J., R. Spirtas, J.F. Gamble and P.M. Tousey. 1976. Mortality
among rubber workers: Relationship to specific jobs. J. Occup. Med. 18:
178-185.
Meinhardt, T.J., R.A. Lemen, M.S. Crandall and R.J. Young. 1982.
Environmental epidemiologic investigation of the styrene-butadiene rubber
industry. Scand. J. Work Environ. Health. 8: 250-259.
National Toxicology Program (NTP). 1984. Toxicology and carcinogenesis
studies of 1,3-Butadiene (CAS 106-99-0) in B6C3F1 mice (inhalation studies).
National Toxicology Program.
National Toxicology Program (NTP) 1985. Draft report on the toxicology and
carcinogenesis studies of 4-vinylcyclohexane in F344/N rats and B6C3F1 mice.
NIH Publication No. 85-2559.
Perry, P. and H.J. Evans. 1975. Cytological detection of mutagen-carcinogen
exposure by sister chromatid exchange. Nature. 258: 121-125.
Poncelet, F., C. deMeester, M. Duverger-van Bogaert, M. Lambotte-Vandepaer, M.
Roberfroid and M. Mercier. 1980. Influence of experimental factors on the
mutagenicity of vinylic monomers. Arch. Toxicol. Suppl. 4: 63-66.
U.S. EPA. 1985. Mutagenicity and Carcinogenicity Assessment Document for
1,3-Butadiene. Office of Health and Environmental Assessment, Washington, DC.
EPA 600/8/85-004F.
Voogd, C.E., J.J. van de Stel and J.A. Jacobs. 1981. The mutagenic action of
aliphatic epoxides. Mutat. Res. 89:269-282.
Wade, M.J., J.W. Moyer and C.H. Hine. 1979. Mutagenic action of a series of
epoxides. Mutat. Res. 66: 367-371.
_VII. REVISION HISTORY
Substance Name -- 1,3-Butadiene
CASRN -- 106-99-0
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
03/01/1988 II.A.2. Text revised
03/01/1988 II.C.4. Confidence statement revised
06/01/1989 II.D.3. Primary contact changed
07/01/1989 II.A.2. Correct Meinhardt citation
07/01/1989 II.A.4. Correct citations
07/01/1989 VI. Bibliography on-line
06/01/1990 IV.A.1. Area code for EPA contact corrected
01/01/1991 II. Text edited
01/01/1991 II.C.1. Inhalation slope factor removed (global change)
01/01/1991 VI.C. Bond et al., 1986 and Cote and Bayard, 1990 refs added
02/01/1991 II.C.3. Information on extrapolation process included
01/01/1992 IV. Regulatory actions updated
04/01/1992 VI. Regulatory action section withdrawn
VIII. SYNONYMS
Substance Name -- 1,3-Butadiene
CASRN -- 106-99-0
Last Revised -- 03/31/1987
106-99-0
BIETHYLENE
BIVINYL
BUTADIEEN
BUTA-1,3-DIEEN
BUTADIEN
BUTA-1,3-DIEN
BUTADIENE
1,3-Butadiene
Butadiene, 1,3-
alpha,gamma-BUTADIENE
DIVINYL
ERYTHRENE
NCI-C50602
PYRROLYLENE
VINYLETHYLENE
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0139.HTM
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