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1,4-Dioxane
CASRN 123-91-1
Contents
0326
1,4-Dioxane; CASRN 123-91-1
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 1,4-Dioxane
File On-Line 08/22/1988
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) no data
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 09/01/1990
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- 1,4-Dioxane
CASRN -- 123-91-1
Not available at this time.
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- 1,4-Dioxane
CASRN -- 123-91-1
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- 1,4-Dioxane
CASRN -- 123-91-1
Last Revised -- 09/01/1990
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 -- Induction of nasal cavity and liver carcinomas in multiple strains
of rats, liver carcinomas in mice, and gall bladder carcinomas in guinea pigs.
___II.A.2. HUMAN CARCINOGENICITY DATA
Inadequate. Three epidemiologic studies on workers exposed to 1,4-dioxane
are available. Theiss et al. (1976) reported 12 deaths among 74 workers
exposed to dioxane. Two of the deaths were due to cancer: one lamellar
epithelial carcinoma in a 66-year-old man and one myelofibrotic leukemia in a
71-year-old man. No statistically significant increase was noted based on
these few cases of cancer. Among 165 production and processing workers
exposed to dioxane (as well as vinyl chloride, perchloroethylene, methylene
chloride, trichloroethylene and carbon tetrachloride), 12 deaths were reported
(Buffler et al., 1976, cited in U.S. EPA, 1986b). Three of these deaths were
due to cancer: one stomach cancer, one alveolar carcinoma, and one
mediastinal malignancy. These deaths were not different from the expected
numbers. In an unpublished report to NIOSH by Dernehl (1976, cited in U.S.
EPA, 1986b), four cancers were reported among 80 dioxane workers. The cancers
included a colonic cancer, a pulmonary cancer, a lymphosarcoma, and a
glioblastoma. Again, the observed number of cancer cases was not different
from the expected cancer deaths.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Sufficient. The NCI (1978) administered 1,4-dioxane (greater than or
equal to 99.9% pure) in the drinking water to Osborne-Mendel rats (35
rats/sex/dose) and mice (50 mice/sex/dose) for a significant portion of their
lifespan (110 weeks, rats; 90 weeks, mice). Male and female rats were given
530, 240, or 0 mg/kg/day and 640, 350, or 0 mg/kg/day, respectively. High-
dose and matched control male rats were placed in the study 1 year after the
study began to replace two original groups of male rats that had died during
an air-conditioning failure. Male and female treated rats had a statistically
significant elevated incidence of nasal cavity squamous cell carcinomas and
treated female rats had a statistically significant elevated incidence of
liver adenomas, both dose-related. Male and female mice treated with 830, 720
or 0 mg/kg/day and 860, 380, or 0 mg/kg/day, respectively, developed a
statistically significant elevated incidence of liver carcinomas and liver
carcinomas or adenomas, both dose-related. Although the survival rate of
treated rats and female mice was decreased compared with controls, the NCI
concluded that sufficient numbers of treated animals survived.
Kociba et al. (1974) administered 1%, 0.1%, 0.01% or 0% 1,4-dioxane in the
drinking water to male and female Sherman rats for up to 716 days (60
rats/sex/treatment group). The incidences of hepatocellular carcinomas, liver
cholangiomas, and nasal cavity squamous cell carcinomas showed a significant
increase in the high-dose rats of both sexes. Similar administration of 0.5%
to 2% 1,4-dioxane to male guinea pigs for 23 months induced gall bladder
carcinomas (2/22) and liver hepatomas (3/22) (Hoch-Ligeti and Argus, 1970).
Hoch-Ligeti et al. (1970) and Argus et al. (1973) treated male Sprague-Dawley
rats with 1.8, 1.4, 1.0, 0.75, or 0% 1,4-dioxane in the drinking water for 13
months, followed by a 3-month observation period. Treatment-related
hepatocellular carcinomas and nasal cavity carcinomas were observed at 1.8%
and 1.4% 1,4-dioxane, and treatment-related nasal cavity carcinomas were
observed at 1.0% and 0.75% 1,4-dioxane. Liver tumors (7/26) were induced in
male Wistar rats after oral administration of 1% 1,4-dioxane in the drinking
water for 63 weeks (Argus et al., 1965). One kidney transitional cell
carcinoma and one myeloid leukemia were also observed in the treated animals.
A lymphoid tissue lymphosarcoma was observed in 1 of 9 control rats.
In a 2-year inhalation study (Torkelson et al., 1974), male and female
Wistar rats were exposed to 111 ppm or 0 ppm 1,4-dioxane vapor. Three
replicate groups of 288 rats/sex served as the treated and control groups.
Comprehensive gross and microscopic examination of the major organs and
tissues revealed no treatment-related lesions.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
1,4-Dioxane was found to be a promoter in a two-stage skin carcinogenesis
study in mice (King et al., 1973). A single dermal application of 50 ug of
7,12-dimethylbenzoanthracene (DMBA) was followed 1 week later by thrice-weekly
paintings of 1,4-dioxane (unspecified concentration in acetone) for 60 weeks.
Similar applications of 1,4-dioxane without DMBA initiation did not result in
a significantly increased incidence of subcutaneous carcinomas.
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
___II.B.1. SUMMARY OF RISK ESTIMATES
Oral Slope Factor -- 1.1E-2/mg/kg/day
Drinking Water Unit Risk -- 3.1E-7/ug/L
Extrapolation Method -- Linearized multistage procedure, extra risk
Drinking Water Concentrations at Specified Risk Levels:
Risk Level Concentration
-------------------- -------------
E-4 (1 in 10,000) 3E+2 ug/L
E-5 (1 in 100,000) 3E+1 ug/L
E-6 (1 in 1,000,000) 3 ug/L
___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE)
Tumor Type -- squamous cell carcinoma of the nasal turbinates
Test Animals -- rat/Osborne-Mendel, male
Route -- drinking water
Reference -- NCI, 1978
Administered Dose Human Equivalent Tumor
(%) (mg/kg)/day Dose (mg/kg)/day Incidence
--- ------------ ---------------- ---------
0 0 0 0/33
0.5 240 48 12/25
1.0 530 106 16/33
___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE)
Transformed doses in mg/kg/day were provided by the study's author. NCI
(1978) determined average daily doses from the mean consumption of dioxane
solution per week at intervals during the second year of treatment. The
length of exposure, experiment, and lifespan was 110 weeks for treated and
control animals. The weight of the animals was assumed to be 0.55 kg from the
study. The human weight was assumed to be 70 kg.
The unit risk should not be used if the water concentration exceeds 3E+4
ug/L, since above this concentration the slope factor may differ from that
stated.
___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE)
The compound was administered at multiple dose levels by a relevant route
of exposure. The animals were exposed for a significant portion of their
lifespan, and comprehensive histologic examinations were performed. Although
survival was affected by treatment, adequate numbers of rats were at risk for
development of late-appearing tumors.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
Not available.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1986a,b
The values in the 1986 Reportable Quantities Document for 1,4-dioxane have
received limited Agency review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 05/13/1987, 02/03/1988
Verification Date -- 02/03/1988
___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 -- 1,4-Dioxane
CASRN -- 123-91-1
Last Revised -- 08/01/1991
__VI.A. ORAL RfD REFERENCES
None
__VI.B. INHALATION RfD REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Argus, M.F., J.C. Arcos and C. Hoch-Ligeti. 1965. Studies on the
carcinogenic activity of protein-denaturing agents: Hepatocarcinogenicity of
dioxane. J. Natl. Cancer Inst. 35(6): 949-958.
Argus, M.F., R.S. Sohal, G.M. Bryant, C. Hoch-Ligeti and J.C. Arcos. 1973.
Dose-response and ultrastructural alterations in dioxane carcinogenesis.
Influence of methylcholanthrene on acute toxicity. Europ. J. Cancer. 9:
237-243.
Buffler, P.A., S.M. Wood, L. Suarez and D.J. Kilian. 1976. Mortality follow-
up among workers exposed to 1,4-dioxane in the chemical industry. Unpublished
report submitted to NIOSH by the Epidemiology Program, Dept. of Preventive
Medicine and Community Health, The University of Texas Medical Branch,
Galveston, Texas. December 17, 1976. (Cited in U.S. EPA, 1986b)
Dernehl, C.U. 1976. Epidemiology study of dioxane workers. Written
communication to NIOSH. April, 1976. (Cited in U.S. EPA, 1986b)
Hoch-Ligeti, C. and M.F. Argus. 1970. Effects of carcinogens on the lung of
guinea pigs. In: Conference on the Morphology of Experimental Respiratory
Carcinogenesis, Gatlinburg, Tennessee, P. Nettesheim, M.G. Hanna, Jr. and J.W.
Deatherage Jr., Ed. AEC Symposium Series No. 21, Springfield, VA, NTIS.
p. 267-279.
Hoch-Ligeti, C., M.F. Argus and J.C. Arcos. 1970. Induction of carcinomas in
the nasal cavity of rats by dioxane. Br. J. Cancer. 24: 164-167.
King, M.E., A.M. Shefner and R.R. Bates. 1973. Carcinogenesis bioassay of
chlorinated dibenzodioxins and related chemicals. Environ. Health Perspect.
5: 163-170.
Kociba, R.J., S.B. McCollister, C. Park, T.R. Torkelson and P.J. Gehring.
1974. 1,4-Dioxane. I. Results of a 2-year ingestion study in rats. Toxicol.
Appl. Pharmacol. 30: 275-286.
NCI (National Cancer Insitute). 1978. Bioassay of 1,4-Dioxane for Possible
Carcinogenicity, CAS No. 123-91-1. NCI Carcinogenesis Tech. Rep. Ser. No. 80.
DHEW Publication No. (NIH) PB-285-711.
Theiss, A.M., E. Tress and I. Fleig. 1976. Industrial-medical investigation
results in the case of workers exposed to dioxane. Arbeitsmed. Sozialmed.
Preventivmed. 11: 35-46.
Torkelson, T.R., B.K.J. Leong, R.J. Kociba, W.A. Richter and P.J. Gehring.
1974. 1,4-Dioxane. II. Results of a 2-year inhalation study in rats.
Toxicol. Appl. Pharmacol. 30: 287-289.
U.S. EPA. 1986a. Reportable Quantities Document for 1,4-Dioxane (review
draft). Prepared by the Carcinogen Assessment Group, Office of Health and
Environmental Assessment, Washington, D.C. for the Office of Emergency and
Remedial Response and Office of Solid Waste and Emergency Response,
Cincinnati, OH.
U.S. EPA. 1986b. Evaluation of the Potential Carcinogenicity of 1,4-Dioxane
(123-91-1) (review draft). Prepared by the Carcinogen Assessment Group,
Office of Health and Environmental Assessment, Washington DC for the Office of
Emergency and Remedial Response and Office of Solid Waste and Emergency
Response, Cincinnati, OH. OHEA-C-073-97.
_VII. REVISION HISTORY
Substance Name -- 1,4-Dioxane
CASRN -- 123-91-1
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
08/22/1988 II. Carcinogen summary on-line
06/01/1989 II.D.3. Primary and secondary contacts changed
02/01/1990 VI. Bibliography on-line
09/01/1990 II. Text edited
09/01/1990 III.A. Health Advisory on-line
09/01/1990 VI.D. Health Advisory references added
08/01/1991 VI.C. Citations clarified
01/01/1992 IV. Regulatory Action section on-line
VIII. SYNONYMS
Substance Name -- 1,4-Dioxane
CASRN -- 123-91-1
Last Revised -- 08/22/1988
123-91-1
diethylene dioxide
diethylene oxide
1,4-Dioxane
Dioxane, 1,4-
p-dioxane
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0326.HTM
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