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Azobenzene
CASRN 103-33-3
Contents
0351
Azobenzene; CASRN 103-33-3
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 Azobenzene
File On-Line 09/07/1988
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) no data
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 07/01/1993
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Azobenzene
CASRN -- 103-33-3
Not available at this time.
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Azobenzene
CASRN -- 103-33-3
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Azobenzene
CASRN -- 103-33-3
Last Revised -- 07/01/1993
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 -- Azobenzene induced invasive sarcomas in the spleen and other
abdominal organs in male and female F344 rats following dietary
administration. It is genotoxic and may be converted to benzidine, a known
human carcinogen, under the acidic conditions in the stomach.
___II.A.2. HUMAN CARCINOGENICITY DATA
None.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Sufficient. In an NCI study (1979), azobenzene was administered in the
diet to F344 rats and B6C3F1 mice (50 animals/sex/dose) for 106 weeks and 105
weeks, respectively. Control groups consisted of 50 untreated animals of
each sex. The dietary concentrations were 200 and 400 ppm for rats. For
male mice the dietary concentrations were 200 and 400. Because of lowered
body weights after 38 weeks, the initial 400 and 800 ppm concentrations for
female mice were reduced, to give time-weighted concentrations of 208 and 505
ppm. In rats sarcomas of various types, including fibrosarcomas,
hemangiosarcomas and osteosarcomas, were observed in the spleen and other
abdominal organs at incidences that were dose-related in each sex and that
were statistically significantly higher in the high-dose group than in
controls in each sex. In mice no tumors were observed at any site at
significantly higher incidence than in the controls for either sex.
In a carcinogenesis screening assay (Innes, 1968; Innes et al., 1969) in
two hybrid strains of mice (B6C3F1 and B6AKFl) azobenzene was administered
either by a single subcutaneous injection or in the diet at a concentration
of 56 ppm continuously until termination of the test at 18 months. No
response was observed in the subcutaneous injection study and of the four
groups (including males and females of these strains) only male B6C3F1 mice
responded. The incidence of hepatomas was 8/18 in the treated group compared
with 8/73 in controls. These results were considered by the authors as
"requiring additional evaluation".
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Azobenzene was positive in a reverse mutation plate incorporation assay
in Salmonella (Ames test) upon addition of hepatic extracts for metabolism.
Azobenzene causes DNA single strand breaks with <30% cytotoxicity by the
alkaline elution/rat hepatocyte assay (Sina et al., 1983) and produces
unscheduled DNA synthesis in human lymphocytes (Gaudin et al., 1971). It
should be noted that azobenzene may be converted non-enzymatically under the
acidic conditions in the stomach to the known human carcinogen benzidine.
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
___II.B.1. SUMMARY OF RISK ESTIMATES
Oral Slope Factor -- 1.1E-1 per (mg/kg)/day
Drinking Water Unit Risk -- 3.1E-6 per (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+1 ug/L
E-5 (1 in 100,000) 3E+0 ug/L
E-6 (1 in 1,000,000) 3E-1 ug/L
___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE)
Tumor Type -- abdominal cavity sarcomas
Test Animals -- rats/F344, female
Route -- diet
Reference -- NCI, 1979
Administered Human Equivalent Tumor
Dose (ppm) Dose (mg/kg)/day Incidence
------------ ---------------- ---------
0 0 0/20
200 1.53 5/50
400 3.06 21/50
___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE)
The slope factor calculated from data on male rats is 7.3E-2 per
(mg/kg)/day using 0.375 kg for the rat body weight. A body weight of 0.25 kg
was used for female rats.
The unit risk should not be used if the water concentration exceeds 3E+3
ug/L, since above this concentration the unit risk may not be appropriate.
___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE)
This study is of adequate design. A sufficient number of animals were
treated at the maximum tolerated dose by an appropriate route for a period
approximating their natural lifespan. The response did not vary markedly
between sexes.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
___II.C.1. SUMMARY OF RISK ESTIMATES
Inhalation Unit Risk -- 3.1E-5 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) 3 ug/cu.m
E-5 (1 in 100,000) 3E-1 ug/cu.m
E-6 (1 in 1,000,000) 3E-2 ug/cu.m
___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE
Calculated from oral data in Section II.B.2.
___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE)
The unit risk should not be used if the air concentration exceeds 3E+2
ug/cu.m, since above this concentration the unit risk may not be appropriate.
___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE)
While the study design is adequate for a feeding bioassay, these data are
less than optimal for the assessment risk related to exposure by inhalation
in the absence of route-comparative pharmacokinetic information.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1985
The 1985 Health and Environmental Effects Profile for Azobenzene received OHEA
review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 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 -- Azobenzene
CASRN -- 103-33-3
Last Revised -- 08/01/1989
__VI.A. ORAL RfD REFERENCES
None
__VI.B. INHALATION RfD REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Gaudin, D., R.S. Gregg and K.L. Yielding. 1971. DNA repair inhibition: A
possible mechanism of action of co-carcinogens. Biochem. Biophys. Res.
Commun. 45(3): 630-636.
Innes, J.R.M. 1968. Evaluation of carcinogenic, teratogenic and mutagenic
activities of selected pesticides and industrial chemicals. Vol. 1,
Carcinogenic study. Bionetics Research Labs, Inc., Bethesda Natl. Tech. Info.
Service, U.S. Department of Commerce.
Innes, J.R.M., B.M. Ulland, M.G. Valerio, et al. 1969. Bioassay of
pesticides and industrial chemicals for tumorigenicity in mice: A preliminary
note. J. Natl. Cancer Inst. 43: 1101-1114.
NCI (National Cancer institute). 1979. Bioassay of azobenzene for possible
carcinogenicity. NCI Carcinogenesis Technical Report Series. No. 154.
p. 112.
Sina, J.F., C.L. Bean, G.R. Dysart, V.I. Taylor ad M.O. Bradley. 1983.
Evaluation of the alkaline elution/rat hepatocyte assay as a predictor of
carcinogenic/mutagenic potential. Mutat. Res. 113(5): 357-391.
U.S. EPA. 1985. Health and Environmental Effects Profile for Azobenzene,
Final Draft. Prepared by the Office of Health and Environmental Health and
the Environmental Criteria and Assessment Office, Cincinnati, OH for the
Office of Solid Waste and Emergency Response, Washington, DC. EPA/600/X-
86/082.
_VII. REVISION HISTORY
Substance Name -- Azobenzene
CASRN -- 103-33-3
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
09/07/1988 II. Carcinogen summary on-line
08/01/1989 VI. Bibliography on-line
01/01/1991 II. Text edited
01/01/1991 II.C.1. Inhalation slope factor removed (global change)
07/01/1993 II.D.3. Secondary contact's phone number changed
VIII. SYNONYMS
Substance Name -- Azobenzene
CASRN -- 103-33-3
Last Revised -- 09/07/1988
103-33-3
AZOBENZEEN
Azobenzene
AZOBENZIDE
AZOBENZOL
AZOBISBENZENE
AZODIBENZENE
AZODIBENZENEAZOFUME
AZOFUME
BENZENEAZOBENZENE
BENZENE, AZODI
BENZOFUME
DIAZOBENZENE
DIPHENYLDIAZENE
1,2-DIPHENYLDIAZENE
DIPHENYLDIIMIDE
ENT 14,611
NCI-C02926
USAF EK-704
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0351.HTM
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