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Aniline
CASRN 62-53-3
Contents
0350
Aniline; CASRN 62-53-3
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 Aniline
File On-Line 09/07/1988
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) no data
Inhalation RfC Assessment (I.B.) on-line 12/01/1993
Carcinogenicity Assessment (II.) on-line 02/01/1994
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Aniline
CASRN -- 62-53-3
Not available at this time.
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Aniline
CASRN -- 62-53-3
Last Revised -- 12/01/1993
The inhalation Reference Concentration (RfC) is analogous to the oral RfD and
is likewise based on the assumption that thresholds exist for certain toxic
effects such as cellular necrosis. The inhalation RfC considers toxic effects
for both the respiratory system (portal-of-entry) and for effects peripheral
to the respiratory system (extrarespiratory effects). It is expressed in
units of mg/cu.m. In general, the RfC is an estimate (with uncertainty
spanning perhaps an order of magnitude) of a daily inhalation exposure of the
human population (including sensitive subgroups) that is likely to be without
an appreciable risk of deleterious effects during a lifetime. Inhalation RfCs
were derived according to the Interim Methods for Development of Inhalation
Reference Doses (EPA/600/8-88/066F August 1989) and subsequently, according to
Methods for Derivation of Inhalation Reference Concentrations and Application
of Inhalation Dosimetry (EPA/600/8-90/066F October 1994). RfCs can also be
derived for the noncarcinogenic health effects of substances that are
carcinogens. Therefore, it is essential to refer to other sources of
information concerning the carcinogenicity of this substance. If the U.S. EPA
has evaluated this substance for potential human carcinogenicity, a summary of
that evaluation will be contained in Section II of this file.
___I.B.1. INHALATION RfC SUMMARY
Critical Effect Exposures* UF MF RfC
-------------------- --------------------------- ----- --- ---------
Lack of toxicity NOAEL: 19 mg/cu.m (5 ppm) 3000 1 1E-3
(however, see study 2) NOAEL(ADJ): 3.4 mg/cu.m mg/cu.m
NOAEL(HEC): 3.4 mg/cu.m
20-26 Week Inhalation
Rat, Guinea Pigs and LOAEL: None
Mouse Study
Oberst et al., 1956
Mild spleen toxicity NOAEL: None
2-Week Rat Inhalation LOAEL: 64.7 mg/cu.m (17 ppm)
Study LOAEL(ADJ): 11.6 mg/cu.m
LOAEL(HEC): 11.6 mg/cu.m
duPont deNemours, 1982
*Conversion Factors: MW = 93.12;
Oberst et al., 1956: Assuming 25C and 760 mmHg, NOAEL (mg/cu.m.) = 5 ppm x
93.12/24.45 = 19. NOAEL(ADJ) = NOAEL (mg/cu.m.) x 6 hours/24 hours x 5
days/7 days = 3.4 mg/cu.m. The NOAEL(HEC) was calculated for a gas:extra-
respiratory effect in the rats assuming periodicity was attained. Since the
b:a lambda values are unknown for the experimental species (a) and humans
(h), a default value of 1.0 is used for this ratio. NOAEL(HEC) = 3.4 x (b:a
lambda(a)/b:a lambda(h)) = 3.4 mg/cu.m;
duPont deNemours, 1982: Assuming 25C and 760 mmHg, LOAEL (mg/cu.m.) = 17
ppm x 93.12/24.45 = 64.7. LOAEL(ADJ) = LOAEL (mg/cu.m) x 6 hours/24 hours x
5 days/7 days = 11.6 mg/cu.m. The LOAEL(HEC) was calculated for a
gas:extrarespiratory effect assuming periodicity was attained. Since the
b:a lambda values are unknown for the experimental species (a) and humans
(h), a default value of 1.0 is used for this ratio. LOAEL(HEC) = 11.6 x
(b:a lambda(a)/b:a lambda(h)) = 11.6 mg/cu.m.
___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC)
Oberst F.W., E. Hackley, C. Comstock. 1956. Chronic toxicity of aniline
vapor (5 ppm) by inhalation. Arch. Ind. Health. 13: 379-384.
duPont deNemours and Company, Inc. 1982. Subacute inhalation toxicity study
of aniline in rats. OTS No. 878220240. Fiche No. 0215025. Available from
EPA. Write to FOI, EPA, Washington, DC 20460.
Co-principal studies are chosen to delineate effect levels. The study of
Oberst et al. (1956), which demonstrated a NOAEL, was complemented by the
duPont deNemours (1982) study which provided a LOAEL.
Oberst et al. (1956) exposed (whole body) 9 male Wistar rats and 2 dogs
for 26 weeks, and 20 female albino mice and 10 guinea pigs for 20 weeks, to 5
ppm (19 mg/cu.m) of reagent grade aniline vapor for 6 hours/day, 5 days/week
(duration-adjusted value = 3.4 mg/cu.m.). Analysis of whole blood, serum, and
body weight was carried out on all animals and urinalysis, rectal
temperatures, and blood pressure were determined for the dogs. Pathology and
histopathology including liver, lung, kidney, and spleen (personal
communication with pathologist of the report), was conducted on the dogs and
four of the smaller animals at termination of exposure. Mention is made that
the rats began to lose weight during the last 3 weeks of exposure although no
figures are given. Blood analysis indicated an increase in methemoglobin in
rats only (0.6%, no statistics or control levels given). No organ pathologies
in any species tested were attributable to aniline vapors. Study limitations
include testing at only one dose, statistical reporting, incomplete
histopathology, and autopsy of a small number of animals. Based on the slight
increase of methemoglobin content and the absence of spleen toxicity, 3.4
mg/cu.m may be designated as a free-standing NOAEL.
In a repeated exposure inhalation study, male Crl:CD rats (16/group) were
exposed (head-only) to 0 (air-exposed controls), 17 ppm (64.7 mg/cu.m), 45 ppm
(171.4 mg/cu.m), or 87 ppm (331.3 mg/cu.m) aniline vapors, 6 hours/day, 5
days/week, for 2 weeks (duPont, 1982). Duration-adjusted values for these
exposures are 0, 11.6, 30.6, or 59.2 mg/cu.m. Toxicity was investigated
utilizing urinalysis, hematology (including methemoglobin), organ and body
weights, and gross pathology, and histopathology (including lungs and
trachea), both following the last exposure and after a 13-day recovery period.
Methemoglobin levels were elevated in a dose-dependent manner at 87 ppm (4.2
to 23%) and at 45 ppm (2.2 to 5.4%); but at 17 ppm the levels were not
significantly different from the controls (0 to 2.9%). This increase was
accompanied by clinical symptoms as the animals exposed to 87 ppm were judged
as slightly cyanotic. The animals exposed to 87 or 45 ppm aniline vapors were
anemic with decreases in RBC counts, hemoglobin content, mean corpuscular
hemoglobin concentration (MCHC), and hematocrit, and accompanying increases in
mean relative spleen weight. Also, exposure-dependent increases in
erythropoietin foci, reticuloendothelial (RE) cell hypertrophy, and
hemosiderin deposition were noted within the spleen of these high-exposure
animals. Although judged as minimal or isolated, splenic histopathology was
noted in the low-dose (17 ppm) group. Hemosiderin deposition occurred in 4 of
5 animals vs. 0 of controls, and RE cell hypertrophy and increases in
erythropoietic foci both occurred in 1 of 5 treated, but in 0 of 5 controls.
Based on these mild splenic effects, 17 ppm (HEC = 11.6 mg/cu.m) is designated
as a LOAEL. Although the duration of this study is only 2 weeks, the critical
effects (methemoglobin increase and splenic involvement) were already manifest
(see Section I.B.4.).
___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC)
UF -- Uncertainty factors of 10 are used for the protection of sensitive human
subpopulations, 10 to allow for animal to human variability, 10 for use of a
subchronic study, and 3 for lack of appropriate reproductive studies. A
modifying factor of 1 is used.
MF -- None
___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC)
The study of Kim and Carlson (1986) demonstrates in rats exposed to
aniline that induced formation of methemoglobin occurs quickly after exposure,
that methemoglobin does not accumulate at low doses, and that methemoglobin is
removed from the blood with a measurable half-life. These authors exposed
groups (maximum of 15/group) of male Sprague-Dawley rats to 0, 10, 30, 50, or
150 ppm aniline for 8 hours/day for 5 days or 12 hours/day for 4 days. The
duration-adjusted values were 0, 9, 27, 45, or 136 mg/cu.m for the 5-day
exposure and 0, 11, 33, 54, or 163 mg/cu.m for the 4-day exposures. An
increase in methemoglobin values over control levels was noted at the
beginning of the second day of exposure to 150 and 50 ppm, with methemoglobin
levels tending to cumulate and become at least partially additive. Although a
slight increase in methemoglobin was noted in the 30 ppm groups (HECs = 27 to
33 mg/cu.m and presumably in the 10 ppm groups (HECs = 9 to 11 mg/cu.m), no
cumulative effects were noted. In additional experiments in which rats were
intraperitoneally injected with aniline, the half-life of methemoglobin in
blood was estimated at 177 minutes (almost 3 hours). The rapidity and
reversibility of methemoglobin formation in humans in response to aniline was
shown by Jenkins et al. (1972), who detected maximum levels of methemoglobin
in humans at 2 hours after oral exposure, but normal levels at 3 hours. This
response would indicate that methemoglobin has a longer half-life in rats than
in humans (3 hours vs. <1 hour).
Humans appear to be more sensitive than rats to aniline exposure (as
indicated by formation of methemoglobin). Jenkins et al. (1972) noted that
after oral administration of aniline to volunteers and rats, the dose that
produced increased levels of methemoglobin was much lower for humans than for
rats. After correcting these values for inhalation exposure (assumed 100%
absorption), the concentrations of aniline producing the same plasma levels of
methemoglobin in humans were still less than in rats by a factor of 12 to 90.
Other documentation indicates that this disparity in sensitivity may also
apply to inhalation exposure. Whereas Vasilinko claims "definite" increases
in methemoglobin in workers exposed to 0.5 to 1.0 mg/cu.m. aniline vapors
(duration adjusted), the rat studies of duPont deNemours (1982) and Kim and
Carlson (1986) indicate effects on methemoglobin level at 31 mg/cu.m and 45 to
54 mg/cu.m aniline, respectively. The reason for this increased sensitivity
in humans is not known and does not appear to be related to the half-life of
methemoglobin in the serum, which is three times longer in rats than in
humans.
The occurrence of some non-neoplastic splenic lesions (fibrosis,
mesothelial hyperplasia) in animals exposed to aniline is related to
accumulation of hemosiderin deposits thought to be formed secondarily to
methemoglobin (Goodman et al., 1984). On the other hand, Weinberger et al.
(1985) showed a clear relationship between occurrence of splenic lesions and
the development of splenic sarcomas in animals fed aniline HCl or the aniline-
based food coloring D and C Red No. 9, even though this latter compound is not
reported to produce methemoglobinemia. Thus methemoglobin formation may not
be an obligate precursor to splenic hyperplastic lesions for all aniline
compounds.
An occupational study was conducted on workers in a plant producing
diphenylamine in which aniline was used as the raw material (Vasilenko et al.,
1972). The only harmful chemicals to which workers were exposed were aniline
and hydrogen chloride (present at 5 mg/cu.m) under conditions that excluded
liquid aniline as potential source of exposure to skin. Aniline
concentrations ranged from 1.3 to 2.75 mg/cu.m (occupational adjustment =
concentration x 10 cu.m air/ 20 cu.m air x 5 days/7 days = 0.5 to 1.0
mg/cu.m). (The method or frequency of measurement was not reported.) At the
beginning of the study, the exposed group consisted of 47 men and 11 women
(duration of employment was 3 to 5 years for 65.5% of the workers). The
control group consisted of 67 men and 8 women. On reexamination 1 year later,
33 were evaluated from the exposed group (sex was not given). A "definite"
increase in methemoglobin content was claimed during the first year (no data
presented). A decrease in hemoglobin levels, erthyrocyte number, and
coagulative factors was also reported although no data were presented. Lung
parameters were not examined. No scientific judgment could be made upon the
effects claimed in this study.
The potential for production of developmental and reproductive effects at
10, 30, and 100 mg/kg/day aniline HCl was studied in Fischer 344 rats (24-
27/group) gavaged on gestational days 7 to 20 (CIIT, 1981). A significant
increase in methemoglobin (13.7% vs. 3.5% in controls) and altered
hematological measures (decrease in RBCs and an increase in MCV) were observed
in the dams of the 100 mg/kg group. Compared with controls, a dose-dependent
increase in the relative spleen weight was observed in the dams of all
treatment groups. No histopathology was performed in this study. No
treatment-related alterations were observed in the reproductive parameters
examined (including number of corpora lutea, implantations, resorptions, or
dead fetuses). In the fetuses of the 100 mg/kg group, the relative liver
weight and erythrocyte size were significantly elevated over control values.
The methemoglobin levels in the fetuses were not significantly different from
those of the controls. Aniline produced no other dose-related adverse effects
in the fetuses and dams. In the next phase of this study, development of pups
was observed from parturition to postnatal day 60. An increase in the number
of postnatal deaths occurred in this phase, from 8% in the controls, to 9.6 %
at 10 ppm, 20.8% at 30 ppm, and 12.5% at 100 ppm. The cause of death was not
determined in any of these pups. No embryotoxicity or teratogenicity was
observed at levels of aniline that caused maternal toxicity. Based on the
increases in methemoglobin formation, a NOAEL of 30 mg/kg/day is designated
for maternal effects, with a NOAEL of 100 mg/kg/day for fetal effects.
Feeding studies of aniline hydrochloride also note splenic pathology,
methemoglobin formation, and hemosiderosis as principal non-neoplastic lesions
(U.S. EPA, 1985).
___I.B.5. CONFIDENCE IN THE INHALATION RfC
Study -- Low
Data Base -- Low
RfC -- Low
Although the duration of the Oberst et al (1656) study is longer than 13
weeks and is conducted with several species, it is poorly reported, used a
single exposure concentration and small numbers of animals. Although of short
duration, the study of duPont deNemours (1982) is well conducted and examines
a number of valid endpoints. Confidence in the data base is low as no
appropriate reproductive studies were located. Low confidence in the RfC
follows.
___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC
Source Document -- This assessment is not presented in any existing U.S. EPA
document.
Other EPA Documentation -- U.S. EPA, 1985
Agency Work Group Review -- 09/20/1990
Verification Date -- 09/20/1990
___I.B.7. EPA CONTACTS (INHALATION RfC)
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).
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Aniline
CASRN -- 62-53-3
Last Revised -- 02/01/1994
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 tumors of the spleen and the body cavity in two strains
of rat, and some supporting genetic toxicological evidence.
___II.A.2. HUMAN CARCINOGENICITY DATA
Inadequate. Case et al. (1954) investigated the occurrence of bladder
tumors among British workers in the chemical dye industry. These workers
were generally exposed to a number of different aromatic amines including
aniline, alpha- and beta-napthylamine, benzidine and auramine. Although
little specific exposure information was available, it was the authors'
judgment that there was not sufficient evidence to suggest that aniline
itself is a cause of bladder tumors.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Sufficient. Aniline hydrochloride was administered in the diet for 2
years to CD-F rats (130 rats/sex/group) at levels of 0, 200, 600 and 2000 ppm
(CIIT, 1982). An increased incidence of primary splenic sarcomas was
observed in male rats in the high-dose group. Stromal hyperplasia and
fibrosis of the splenic red pulp, which may represent a precursor lesion of
sarcoma, was also observed in the high-dose males and, to a lesser degree, in
the female rats.
Dietary aniline hydrochoride was administered at 0, 3000 or 6000 ppm to
50 male and 50 female Fischer 344 rats for 103 weeks (NCI, 1978). The
animals were sacrificed at 107-110 weeks. The male rats showed statistically
significant dose-related trends in incidence of hemangiosarcomas and sarcomas
or fibrosarcomas. The males also had statistically significantly increased
incidences of hemangiosarcoma in the spleen, fibrosarcoma and sarcoma (not
otherwise specified) in the body cavity and spleen, and a significant
dose-related trend in incidence of malignant pheochromocytoma. According to
the authors, there was a possible association in the female rats between
aniline hydrochloride treatment and the increased incidence of fibrosarcoma
and sarcoma in multiple organs of the body cavity. None of the pooled
control groups of 249 female and 250 male rats were observed to have
fibrosarcoma or sarcoma in the spleen or multiple organs of the body cavity.
Food containing 0, 6000 or 12,000 ppm aniline hydrochloride was also given to
50 male and 50 female B6C3F1 mice for 103 weeks (NCI, 1978). No
statistically significant increase in any type of tumor in male or female
mice was observed.
Hagiwara et al. (1980) administered 0, 0.03, 0.06 or 0.12% aniline alone
or in combination with the comutagen norharman in the drinking water to 10 to
18 male Wistar rats for 80 weeks. The incidence of forestomach papillomas
was low and did not appear to be dose-related. One pituitary adenoma was
observed in the 0.03% aniline group. No tumors were observed in the
controls. According to the authors, oral administration of aniline and
norharman, separately or in combination, had no cocarcinogenic effect on the
urinary bladder or other organs examined. Druckrey (1950) exposed 50 rats to
a dose of 22 mg/day aniline hydrochloride in the drinking water for their
lifetime. Fifty percent mortality occurred at day 450 and 100% at day 750.
No tumors were observed in the bladder, liver, spleen or kidney, the only
organs evaluated.
Syrian golden hamsters, 15 male and 15 female, received 52 weekly
subcutaneous injections of 0 or 1.9 mmol/kg of aniline 1n peanut oil (Hecht
et al., 1983). No increased incidence of tumors was observed. Mean survival
was reduced in the aniline-treated groups.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Aniline produced generally negative results in reverse mutation assays
using Salmonella typhimurium (Miyata et al., 1981; Simmon, 1979a; DeFlora,
1981; Parodi et al., 1981; McCann et al., 1975; Hecht et al., 1979; Haworth
et al., 1983; Garner and Nutman, 1977). Nagao et al. (1977) and Sugimura et
al. (1982) reported aniline to be mutagenic for S. typhimurium only when
assayed in the presence of the comutagen norharman. Aniline did not induce
mitotic recombination in the presence or absence of metabolic activation in
Saccharomyces cerevisiae (Simmon, 1979b). Aniline was reported to show
positive results in the L5178+/- mouse lymphoma gene mutation assay (Amacher
et al., 1980).
Aniline caused an increased frequency of SCE in vivo in mouse bone marrow
cells (Parodi et al., 1982, 1983) and in two in vitro assays with Don cells
(Abe and Sasaki, 1977) and lung fibroblasts (Kawachi et al., 1980). In
another in vitro assay, only the two metabolites of aniline, 2-aminophenol
and N-phenylhydroxylamine, increased the frequency of SCE in human
fibroblasts (Wilmer et al., 1981).
Aniline transformed the mouse cell line Balb/3T3, but not Syrian hamster
embryo cells or Fischer 344 rat embryo cells infected with murine leukemia
virus (Dunkel et al., 1981). DNA damage assays in E. coli (Mamber et al.,
1983) and B. subtilis (McCarroll et al., 1981) were negative.
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
___II.B.1. SUMMARY OF RISK ESTIMATES
Oral Slope Factor -- 5.7E-3/mg/kg/day
Drinking Water Unit Risk -- 1.6E-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) 6E+2 ug/L
E-5 (1 in 100,000) 6E+1 ug/L
E-6 (1 in 1,000,000) 6 ug/L
___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE)
Tumor Type -- spleen, combined fibrosarcoma, stromal sarcoma, capsular sarcoma
and hemangiosarcoma
Test Animals -- rat/CD-F, male
Route -- diet
Reference -- CIIT, 1982
Administered Human Equivalent Tumor
Dose (ppm) Dose (mg/kg)/day Incidence
------------ ---------------- ---------
0 0 0/64
200 1.23 0/90
600 3.69 1/90
2000 12.29 31/90
___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE)
Calculation of the transformed doses for aniline included a correction
for the difference in molecular weights of aniline and aniline hydrochloride,
the form in which the compound was administered in the NCI and CIIT bioassays.
Using data from the male rats (NCI, 1978), slope factors were derived for
the incidence of hemangiosarcoma in the spleen and body cavity
(2.6E-2/mg/kg/day), and individually for the combined incidence of
fibrosarcoma and sarcoma in the spleen (1.0E-2/mg/kg/day), in the body cavity
(6.2E-3/mg/kg/day), and in the spleen and body cavity combined
(1.1E-2/mg/kg/day). Most of the sarcomas observed in the spleen and body
cavity combined were in the spleen; as a consequence, the slope factors for
sarcoma in the spleen and for the spleen and body cavity are very close.
The unit risk should not be used if the water concentration exceeds 6E+4
ug/L, since above this concentration the slope factor may differ from that
stated.
___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE)
An adequate number of animals were dosed for an adequate length of time.
Slope factors derived from tumor data at other sites were with one exception
within a factor of 2.
Studies in rats by Bus and Sun (1979) have indicated that erythrocytes
preferentially bind aniline, and that at high doses (100 mg/kg), aniline
selectively accumulates in the spleen due to scavenging of damaged
erythrocytes. The deposition of debris from erythrocytes results in
hemosiderosis, which in turn induces a fibrotic response in the spleen that
may be involved in sarcoma production. Robertson et al. (1983) have shown
that aniline accumulation in the spleen is nonlinear; only minimal
accumulation of aniline and no hemosiderosis is observed at doses below 10
mg/kg. Since hemosiderosis may be important in the induction of splenic
sarcoma, the linearized multistage procedure may not be the most appropriate
method for the derivation of the slope factor.
__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, 1985
The 1985 Health and Environmental Effects Profile for Aniline has received
Agency review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 05/13/1987, 06/03/1987
Verification Date -- 06/03/1987
___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 -- Aniline
CASRN -- 62-53-3
Last Revised -- 11/01/1990
__VI.A. ORAL RfD REFERENCES
None
__VI.B. INHALATION RfD REFERENCES
CIIT (Chemical Industry Institute of Toxicology). 1981. Final report:
Teratological and postnatal evaluation of aniline hydrochloride in the Fischer
344 rat. Document No. 40+8376093.
E.I. duPont deNemours and Company, Inc. 1982. Subacute inhalation toxicity
study of aniline in rats. OTS No. 878220240. Fiche No. 0215025.
Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Goodman D.G., J.M. Ward, and W.D. Reichardt. 1984. Splenic fibrosis and
sarcomas in F344 rats fed diets containing aniline hydrochloride, p-
chloroaniline, azobenzene, o-toluidine hydrochloride, 4,4'-sulfonyldianiline,
or D and C Red No. 9. J. Natl. Cancer Inst. 73(1): 265-273.
Jenkins F.P., J.A. Robinson, J.B.M. Gellatly, and G.W.A. Salmond. 1972. The
no-effect dose of aniline in human subjects and a comparison of aniline
toxicity in man and the rat. Cosmet. Toxicol. 10: 671-679.
Kim Y.C. and G.P. Carlson. 1986. The effect of an unusual workshift on
chemical toxicity. II. Studies on the exposure of rats to aniline. Fund.
Appl. Toxicol. 7: 144-152.
Oberst F.W., E. Hackley, and C. Comstock. 1956. Chronic toxicity of aniline
vapor (5 ppm) by inhalation. Arch. Ind. Health. 13: 379-384.
U.S. EPA. 1985. Health and Environmental Effects Profile for Aniline
prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, Ohio for the Office of Solid
Waste and Emergency Response, Washington, DC. EPA 600/X-85/356.
Vasilenko N.M., L.N. Khizhniakova, V.I. Zvezdai, et al. 1972. Clinical
hygienic parallels in the action of aniline on the body. Vrach. Delo. 8:
132-134.
Weinberger M.A., R.H. Albert, and S.B. Montgomery. 1985. Splenotoxicity
associated with splenic sarcomas in rats fed high doses of D and C Red No. 9
or aniline hydrochloride. J. Natl. Cancer Inst. 75(14): 681-690.
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Abe, S. and M. Sasaki. 1977. Chromosome aberrations and sister chromatid
exchanges in Chinese hamster cells exposed to various chemicals. J. Natl.
Cancer Inst. 58: 1635-1641.
Amacher, D.E., S.C. Paillet, G.N. Turner, V.A. Ray and D.S. Salsburg. 1980.
Point mutations at the tymidine kinase locus in L5178Y mouse lymphoma cells.
II. Test validation and interpretation. Mutat. Res. 72(3): 447-474.
Bus, J.S. and J. Sun. 1979. Accumulation of covalent binding of
radioactivity in rat spleen after 14C-aniline HCl administration.
Pharmacologist. 21: 221.
Case, R.A.M., M.E. Hosker, D.B. McDonald and J.T. Pearson. 1954. Tumors of
the urinary bladder in workmen engaged in the manufacture and use of certain
dyestuff intermediates in the British chemical industry. Br. J. Ind. Med.
11: 75-104.
CIIT (Chemical Industry Institute of Toxicology). 1982. 104-Week chronic
toxicity study in rats: Aniline hydrochloride. Final report.
DeFlora, S. 1981. Study of 106 organic and inorganic compounds in the
Salmonella/microsome test. Carcinogenesis (London). 2: 283-298.
Druckrey, H. 1950. Beitrage zur Pharmakologie cancerogener Substanzen.
Versuche mit Anilin. Arch. Exp. Path. Pharmakol. 210: 137-158.
Dunkel, V.C., R.J. Pienta, A. Sivak and K.A. Traul. 1981. Comparative
neoplastic tranformation responses of Balb/3T3 cells, Syrian hamster embryo
cells, and Rauscher murine leukemia virus-infected Fischer 344 rat embryo
cells to chemical carcinogens. J. Natl. Cancer Inst. 67(6): 1303-1315.
Garner, R.C. and C.A. Nutman. 1977. Testing of some azo dyes and their
reduction products for mutagenicity using Salmonella typhimurium TA1558.
Mutat. Res. 44: 9-19.
Hagiwara, A., M. Arai, M. Hirose, J. Nakanowatari, H. Tsuda and N. Ito. 1980.
Carcinogenic effects of norharman in rats treated with aniline. Toxicol.
Lett. 6(2): 71-75.
Haworth, S., T. Lawlor, K. Mortelmans, W. Speck and E. Zeiger. 1983.
Salmonella mutagenicity test results for 250 chemicals. Environ. Mutagen.
(Suppl.) 1: 3-142.
Hecht, S.S., K. El-Bayoumy, L. Tulley and E. LaVoie. 1979. Structure-
mutagenicity relationships of N-oxidized derivatives of aniline, 0-toluidine,
2'-methyl-4-aminobiphenyl and 3,2'-dimethyl-4-aminobyphenyl. J. Med. Chem.
22: 981-987.
Hecht, S.S., K. El-Bayoumy, A. Rivenson and E.S. Fiala. 1983. A study in
chemical carcinogenesis. 58. Bioassay for carcinogenicity of 3,2'-dimethyl-
4-nitrosobiphenyl, O-nitrosotoluene, nitrosobenzene and the corresponding
amines in Syrian golden hamster. Cancer Lett. 20(3): 349-354.
Kawachi, T., T. Yahagi, T. Kada, et al. 1980. Cooperative programme on
short-term assays for carcinogenicity in Japan. In: Molecular and Cellular
Aspects of Carcinogen Screening Tests, R. Montesano, H. Bartsch and L.
Tomatis, Ed. IARC Scientific Publ. No. 27. WHO, Lyon, France. p. 323-330.
Mamber, S.W., V. Bryson and S.E. Katz. 1983. The Escherichia coli WP2/WP100
rec assay for detection of potential chemical carcinogens. Mutat. Res. 119:
135-144.
McCann, J., E. Choi, E. Yamasaki and B.N. Ames. 1975. Detection of
carcinogens as mutagens in the Salmonella/microsome test: Assay of 300
chemicals. Proc. Natl. Acad. Sci. USA. 72: 5135-5139.
McCarroll, N.E., C.E. Piper and B.H. Keech. 1981. An E. coli microsuspension
assay for the detection of DNA damage induced by direct-acting agents and
promutagens. Environ. Mutagen. 3: 429-444.
Miyata, R., T. Nohmi, K. Yoshikawa and M.J. Ishidate. 1981. Metabolic
activation of p-nitrotoluene and trichloroethylene by rat liver S9 or mouse
liver S9 fractions in Salmonella typhimurium strains. Eisei Shikensho Hokoku.
99: 60-65.
Nagao, M., T. Yahagi, M. Honda, Y. Seino, T. Matsushima and T. Sugin. 1977.
Demonstration of mutagenicity of aniline and o-toluene by norharman. Proc.
Jap. Acad., Ser. B. 53(1); 34-37.
NCI (National Cancer Institute). 1978. Bioassay for aniline hydrochloride
for possible carcinogenicity. CAS No. 142-04-1. ITS Carcinogenesis Technical
Report Ser. No. 130. U.S. DHEW, PHS, NIH, Bethesda, MD. DHEW Publ. No. (NIH)
78-1385.
Parodi, S., M. Taningher, P. Russo, M. Pala, M. Tamaro and C. Monti-Bragadin.
1981. DNA-damaging activity in vivo and bacterial mutagenicity of 16 aromatic
amines and azo-derivatives, as related quantitatively to their
carcinogenicity. Carcinogenesis (London). 2(12): 1317-1326.
Parodi, S., M. Pala, P. Russo, et al. 1982. DNA damage in liver, kidney,
bone marrow and spleen of rats and mice treated with commercial and purified
aniline as determined by alkaline elution assay and sister chromatid exchange
induction. Cancer Res. 42: 2277-2283.
Parodi, S., A. Zunino, L. Ottaggio, M. DeFerrari and L. Santi. 1983. Lack of
correlation between the capability of inducing sister-chromatid exchanges in
vivo and carcinogenic potency, for 16 aromatic amines and azo derivatives.
Mutat. Res. 108(1-3): 225-238.
Robertson, O., Jr., M.G. Cox and J.S. Bus. 1983. Response of blood, spleen
and liver to aniline hydrochloride insult in male and female Fischer 344 rats
and in male B6C3F1 mice. In preparation. (Cited in "CIIT Activities"
publication)
Simmon, V.F. 1979a. In vitro mutagenicity assays of chemical carcinogens and
related compounds with Salmonella typhimurium. J. Natl. Cancer Inst. 62(4):
893-899.
Simmon, V.F. 1979b. In vitro assays for recombinogenic activity of chemical
carcinogens and related compounds with Saccharomyces cerevisiae D3. J. Natl.
Cancer Inst. 62(4): 901-909.
Sugimura, T., M. Nagao and K. Wakabayashi. 1982. Metabolic aspects of the
comutagenic action of norharman. Adv. Exp. Med. Biol. 136B: 1011-1025.
U.S. EPA. 1985. Health and Environmental Effects Profile for Aniline.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste,
Washington, DC.
Wilmer, J.L., A.D. Kligerman and G.L. Erexson. 1981. Sister chromatid
exchange induction and cell cycle inhibition by aniline and its metabolites in
human fibroblasts. Environ. Mutagen. 3(6): 627-638.
_VII. REVISION HISTORY
Substance Name -- Aniline
CASRN -- 62-53-3
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
09/07/1988 II. Carcinogen summary on-line
04/01/1989 V. Supplementary data on-line
06/01/1989 II.D.2. Work group review date added
08/01/1989 VI. Bibliography on-line
10/01/1990 I.B. Inhalation RfC now under review
11/01/1990 I.B. Inhalation RfC summary on-line
11/01/1990 VI.B. Inhalation RfC references added
11/01/1991 I.B.6. Source Doc. & Other EPA Documentation corrected
01/01/1992 IV. Regulatory Action section on-line
12/01/1993 I.B.1. Critical effect clarified in study 1
02/01/1994 II.D.3. Secondary contact's phone number changed
VIII. SYNONYMS
Substance Name -- Aniline
CASRN -- 62-53-3
Last Revised -- 09/07/1988
62-53-3
aminobenzene
aminophen
Aniline
aniline-oil
kyanol
phenylamine
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0350.HTM
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