United States
Environmental Protection
Agency
FINAL DRAFT
ECAO-CIN-G112
January, 1991
Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR 3-NITROANILINE
Prepared for
OFFICE OF SOLID HASTE AND
EMERGENCY RESPONSE
CO
CM
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati,
ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
DRAFT: DO NOT CITE OR QUOTE
NOTICE
This document 1s 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 Us technical accuracy and policy Implications.
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DISCLAIMER
This report 1s 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
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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
emergency and remedial actions under the Comprehensive Environmental
Response, Compensation and Liability Act (CERCLA). Both published
literature and Information obtained for 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 In this document and the dates searched are Included In
"Appendix: Literature Searched." Literature search material Is 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, Is an estimate of an
exposure level which would not be expected to cause adverse effects when
exposure occurs during a limited time Interval I.e., for an Interval which
does not constitute a significant portion of the llfespan. 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, a carcinogenic potency factor, or
q]* (U.S. EPA, 1980), Is provided. 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. An RfD may also be derived for the noncardno-
genlc health effects of compounds that are also carcinogenic.
Reportable quantities (RQs) based on both chronic toxlclty nd
cardnogenlclty are derived. The RQ Is used to determine the quantity of a
hazardous substance for which notification 1s required 1n the event of a
release as specified under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). These two RQs (chronic toxldty
and cardnogenlclty) 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 1986b, respectively.
111
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EXECUTIVE SUHMARY
3-NHroanlline Is a synthetic chemical that has the appearance of yellow
rhombic needles 1n Its purified form. It Is slightly soluble 1'n water and
readily soluble 1n organic solvents such as ethanol, ether and methanol.
3-N1troan1!1ne Is used as an Intermediate 1n the synthesis of dyestuffs and
other organlcs. There are no data on producers or volume of production.
The available data Indicate that the environmental fate of 3-n1troan1-
Une 1s controlled largely by Its water solubility, low vapor pressure,
susceptibility to photodegradatlon, and by Its affinity to bind with humlc
substances In soil and sediments. Thus, 3-nltroanlllne Is not expected to
be a major atmospheric contaminant. It may be present In aqueous media, but
probably only near point sources. Although It Is not readily susceptible to
blodegradatlon, Us binding with humlc substances 1n soils and sediments
will probably limit Us bloavallablllty. It has been reported In only a few
monitoring studies, and exposure levels to the general public are probably
minimal.
Information on the environmental toxicology of 3-n1troan1l1ne Is quite
limited. In one study the acute LC to one species of freshwater fish
was reported to be 51 mg/l. There 1s no Information on acute toxlclty to
saltwater species, or on chronic effects to either marine or freshwater
organisms. The partition coefficient for 3-nltroanlllne and experimentally
derived and calculated bloconcentratlon factors Indicate a low potential for
bloaccumulatlon. Data for terrestrial vertebrates (birds and mice) Indicate
a relatively low acute toxlclty of 3-n1troan1l1ne, the oral LDcn values
DU
being >100 mg/kg.
1v
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Sufficient Information Is not available for a quantitative environmental
risk assessment for 3-nltroanlllne. Data are Inadequate for deriving water
quality criteria. There 1s only one specific data point for acute toxlclty
and no Information on which to derive a Criterion Continuous Concentration.
From a qualitative point of view, the available data on environmental
persistence, toxlclty, and bloaccumulatlon potential of 3-n1troan1l1ne
suggest that the chemical represents only a low level of environmental risk.
Releases to the environment would be subject to physical and chemical
degradation, and binding with soil and sediments 1s likely to limit Us
transport and b1oava11abH1ty.
Data concerning health effects of 3-nltroanlllne In mammalian systems
are also limited. Pharmacoklnetlcs data showed that 3-nltroanlllne Is
readily absorbed through the lungs and from Intact skin. Data regarding
absorption from the gastrointestinal tract and tissue distribution were not
found. One report suggested that 3-nHroanHlne Is excreted Into urine as a
conjugated or unconjugated form of the parent molecule (Wells et a!.,
1920-1921), and another report presented evidence that d1azo-posH1ve
substances (Indicators for the presence of nltro-amlno derivatives) are
excreted Into urine of animals Injected 1.p. with 3-n1troan1l1ne (Watanabe
et al., 1976). The evidence also suggested that 3-nltroanlllne, which 1s
formed as a metabolite of 1,3-dlnHrobenzene, Is In turn metabolized to
4-am1no-2-n1trophenol, 2-am1no-4-n1trophenol, 1,3-d1am1nobenzene, and
2,4-d1am1nophenol (Rlckert, 1987). Another study showed that 3-nltroanlllne
can be metabolized to N-oxIdatlon products 1n a cell-free system (Corbett
and Corbett, 1985).
With the exception of genotoxlclty data, almost all toxlclty data were
limited to acute exposure. Lethality data for 3-n1troan1l1ne show LDcns
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of 308 mg/kg for mice, 450 mg/kg for guinea pigs, and 535-900 mg/kg for rats
(Vasllenko et al., 1974; Vernot et al., 1977; RTECS, 1989). Other data
showed that dogs can be killed by a single l.p. Injection of 70 mg/kg,
guinea pigs by 212 mg/kg, cats by 218 mg/kg, and rabbits by 294-346 mg/kg.
A single 1.p. Injection of 200 mg/kg causes no toxic effects In the rabbit
(Hells et al., 1920-1921).
Clinical effects from acute exposure to 3-nHroanlllne Include dyspnea
and convulsions before death, with postmortem signs of asphyxia (Wells et
al., 1920-1921). 3-N1troan111ne Is a met hemoglobin and a sulfhemogloben
former (DeBruln. 1976; Beard and Noe, 1981; Hatanabe et al., 1976; Vasllenko
et al., 1974; Vasllenko and Zveydal, 1974). Other toxic effects may Include
decreases In red and white blood cell counts, bone marrow changes Indicative
of anemia, pulmonary edema, and damage to the kidney, spleen, liver and
heart (Hells et al., 1920-1921). Serum GOT and GPT activities In rats were
not affected by l.p. doses of 100 vmol/kg (Hatanabe et al., 1976).
No data were available regarding subchronlc or chronic toxldty,
carclnogenlclty, developmental toxldty or reproductive toxlclty of
3-n1troan1l1ne.
GenotoxUHy data showed that 3-n1troan1l1ne 1s mutagenlc In Salmonella
typhlmuMum under various conditions. It has produced positive results 1n
strains capable of detecting both base-pair substitutions (TA100 and TA1535)
and frameshlft mutations (TA98, TA1537 and TA1538). In general, concentra-
tions >500 vg/plate are required to Induce mutations In the absence of S9
(Chlu et al., 1978; Shahln, 1985; Shlmlzu and Yano, 1986). Lower concentra-
tions (30-250 yg/plate) of 3-n1troan1l1ne can Induce mutations In the
presence of S9 (Garner and Nutman, 1977; Thompson et al., 1983). 3-N1tro-
anlllne prelncubated with FMN In the presence of hamster or rat liver S9 can
vl
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Induce mutations at concentrations as low as 6.9-27.6 tig/plate (Oellarco
and Prlval 1989). This study Indicates that nHroreductlon may Indeed be a
factor 1n the activation of 3-n1troannine. Other genotoxldty tests showed
that 3-n1troan1lIne Induced a weak positive response In the Kada rec assay
(Shlmlzu and Yano, 1986) and a negative response In the test for unscheduled
DNA synthesis using rat hepatocytes (Thompson et al., 1983).
Data were not available for evaluating the toxldty of 3-nUroan1l1ne
based on carclnogenldty, subchronlc exposure, or chronic exposure.
SubchronU and chronic RfDs (Inhalation and oral) and cancer and chronic RQs
could not be calculated.
3-NHroan1 line Is placed In we1ght-of-ev1dence group D, not classifiable
as to human carclnogenldty. Qualitative evaluations of the potential
cardnogenlclty of compounds can sometimes be based on evidence for
structural analogues or metabolites. Several possible metabolites of
3-nltroanlllne were Identified. 4-Am1no-2-n1trophenol and 2-am1no-4-n1tro-
phenol were carcinogenic 1n male rats, but not In male and female mice.
4-Am1no-2-n1trophenol was possibly carcinogenic In female rats and 2-amlno-
4-n1trophenol was not carcinogenic In female rats. Data were Inadequate for
evaluating the carclnogenldty of 1,3-d1am1nobenzene. All three compounds
were mutagenlc 1n Salmonella 1n the presence or absence of S9. Data
regarding these compounds were not sufficient for altering the evaluation of
3-n1troan1l1ne, because definitive evidence that these compounds are
metabolites of 3-n1troan1l1ne was not available and evidence for potential
carclnogenldty was only "limited," that 1s, positive 1n only one sex of one
species.
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Literature on possible metabolites was also examined for evidence of
developmental or reproductive toxldty. 1,3-D1am1nobenzene was fetotoxlc
and demonstrated significant developmental toxlclty when female rats were
gWen 90 mg/kg bw/day during days 6-15 of gestation (Hruby et a!., 1981).
V111
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TABLE OF CONTENTS (cont.)
4.3. FIELD STUDIES 13
4.4. AQUATIC RISK ASSESSMENT 13
4.5. SUMMARY 14
5. PHARMACOKINETCS 15
5.1. ABSORPTION 15
5.2. DISTRIBUTION 15
5.3. METABOLISM 15
5.4. EXCRETION 16
5.5. SUMMARY 16
6. EFFECTS 17
6.1. SYSTEMIC TOXICITY 17
6.1.1. Subchronlc Exposure 17
6.1.2. Chronic Exposure 17
6.1.3. Other Relevant Information 17
6.2. CARCINOGENICITY 19
6.2.1. Inhalation 19
6.2.2. Oral 19
6.2.3. Other Relevant Information 19
6.3. GENOTOXICITY 21
6.4. DEVELOPMENTAL TOXICITY 26
6.5. OTHER REPRODUCTIVE EFFECTS 27
6.6. SUMMARY 28
7. EXISTING GUIDELINES AND STANDARDS 30
7.1. HUMAN 30
7.2. AQUATIC 30
8. RISK ASSESSMENT 31
8.1. CARCINOGENICITY 31
8.1.1. Weight of Evidence 31
8.1.2. Quantitative Risk Estimates 32
8.2. SYSTEMIC TOXICITY 32
9. REPORTABLE QUANTITIES 33
9.1. BASED ON SYSTEMIC TOXICITY 33
9.2. BASED ON CARCINOGENICITY 33
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TABLE OF CONTENTS (cont.)
10. REFERENCES.
APPENDIX A: LITERATURE SEARCHED 45
APPENDIX B: SUHMARY TABLE FOR 3-NITROANILINE 49
APPENDIX C: DOSE/DURATION RESPONSE GRAPH{S) FOR EXPOSURE TO
3-NITROANILINE 50
xl
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LIST OF ABBREVIATIONS
BCF
bw
FMN
GOT
GPT
l.p.
*d
Koc
LD50
M
om
PO
RfD
RQ
S.E.M.
tl/2
TL
m
81oconcentrat1on factor
Body weight
Median effective concentration
Flavin mononucleotlde
Glutamlc oxaloacetlc transamlnase
Glutamlc pyruvlc transamlnase
Intraperltoneal
Soil adsorption coefficient
Soil organic carbon/water partition coefficient
Soil organic matter/water partition coefficient
Octanol/water partition coefficient
Concentration lethal to 50% of recipients
Dose lethal to 50% of recipients
Molar concentration
Organic matter
Saturation vapor pressure
Reference dose
Reportable quantity
Standard error of the mean
Half-life
Median tolerance limit
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Synonyms for 3-nltroanlllne are as follows: benzenamlne, 3-n1tro (9CI);
3-n1tro- aniline; 3-n1trobenzenam1ne; l-am1no-3-n1trobenzene;
m-n1trophenylam1ne; Amarthol fast orange R base; and C.I. azoic dlazo
component 7. Its Colour Index number 1s C.I. 37030 (CHEMLINE computer
printout, 1989). The struc- tural formula, CAS number, empirical formula,
and molecular weight are as follows:
NH,
CAS No.: 99-09-2
Empirical formula: C,H,NnO«
o b i c
Molecular weight: 138.14
1.2. PHYSICAL AND CHEMICAL PROPERTIES
3-n1troan1l1ne Is a solid that has the appearance of yellow rhombic
needles In Us purified form (Beard and Noe, 1981; Hlndholz et al., 1983;
Weast et al., 1988). It has a burning sweet taste (Beard and Noe. 1981).
It 1s soluble In aqueous solvents (1 g In 880 mi of water), ethanol (1 g
In 20 mi), ether (1 g In 18 rni), and methanol (1 g 1n 11.5 mi)
(Wlndholz et al., 1983). Other chemical and physical properties of 3-n1tro-
anlHne are presented below (Wlndholz et al., 1983; Dean, 1987; Weast et
al.. 1988):
Melting point:
Boiling point:
Density:
Vapor pressure:
114°C
305.7°C
1.43 (20/4°C); 1.1747 (160/4°C); 0.9011 (25/4eC)
1 mm at 119.3°C
0408d
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Log K
ow
Conversion factor:
1.37
2.46
1 mg/m3 =0.17 ppm at 20°C
1.3. PRODUCTION DATA
No producers or production data for 3-n1troan1l1ne were found 1n the
sources available; 167,000 pounds of 3-n1troan1line was Imported in 1976
(USITC, 1976). Aceto Chemical Co. Inc., Flushing, NY stopped importing
3-nltroanlllne after April 1980; Us Inventory as of March 1983 was sold off
at a rate of 10,000 Ib/year (Koeppe, 1983).
1.4. USE DATA
3-N1troan1l1ne 1s used primarily as an Intermediate for the synthesis of
dyestuffs and other organlcs (Beard and Noe, 1981; Wlndholz et al., 1983).
1.5. SUMMARY
3-N1troan1l1ne has the appearance of yellow rhombic needles In Us
purified form. It Is slightly soluble In water and readily soluble In
organic solvents, such as ethanol, ether, and methanol. 3-NHroan1l1ne 1s
used as an Intermediate 1n the synthesis of dyestuffs and other organlcs.
No data on producers or volume of production were found.
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
No comprehensive study on the fate and transport of n1troan1!1nes In the
atmosphere was found In the literature. However, some projections have been
made based on chemical structure and fate of these compounds In aquatic
media {U.S. EPA, 1985).
2.1.1. Physical and Chemical Processes. MononltroanlUnes are likely to
undergo oxidation reactions In the atmosphere. The amlno group may be
especially susceptible to oxidation. Oxidation may occur through reactions
with hydroxyl radicals or molecular oxygen (U.S. EPA, 1985). The half-life
for the reaction of 3-n1troan1l1ne with hydroxyl radicals 1n a typical
ambient atmosphere was calculated by SRC (1989) to be about 14 hours based
on an estimated reaction rate constant of l.TxlO'11 cmVmolecule-sec at
25°C (GEMS, 1987). Direct photodegradatlon of 3-n1troan1l1ne 1s also likely
to occur, but kinetic data are not available to calculate photolytlc rates
1n natural environments (U.S. EPA, 1985).
2.1.2. Transport. Organlcs present In the atmosphere can exist In the
vapor phase or be adsorbed onto partlculate matter. From theoretical
considerations, the partitioning of these compounds between the vapor and
aerosol phases depends on the saturation vapor pressure {Pfl) of the
compound and the size, surface area, and organic content of the particles
(Junge, 1977). Generally, adsorption onto partlculate matter occurs with
compounds having P_ values <10~4 mm Hg, and compounds with P_ values
<1Q~8 mm Hg should occur almost entirely 1n the partlculate phase
(Elsenrelch et al., 1981). The vapor pressure of 3-n1troan1l1ne has been
reported to be 0.000036 mm Hg; therefore, only limited adsorption onto atmo-
spheric particles and dry deposition will occur (SRC, 1989). In contrast,
0408d -3- 05/08/90
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because of the high water solubility of nUroanlllnes, transport of
3-nHroanlllne from the atmosphere to surface waters and soil through wet
deposition Is expected to be significant (U.S. EPA, 1985).
2.2. WATER
2.2.1. Physical and Chemical Processes. The water solubility of
3-n1troan1ltne has been reported to be 910 ppm at 25°C (Seldell, 1941),
Indicating that aqueous environmental media would be subject to contamina-
tion by this compound. There 1s no Information available on the reaction of
3-n1troan1l1ne with free radicals or singlet oxygen In aqueous media.
Laboratory studies with 2-n1troan1l1ne suggest that, In natural aquatic
environments, hydrolysis would not be a significant reaction pathway (U.S.
EPA, 1985). A similar conclusion can probably be made for 3-nltroanlllne.
Ultraviolet absorption maxima for 3-nltroanlllne have been reported to
be 236, 275 (shoulder) and 374 nm (Weast and Astle, 1979). Consequently, In
surface waters, 3-nHroan1l1ne would be susceptible to direct photolysis and
photooxldatlon (SRC, 1989). Laboratory studies have demonstrated that
2- and 4-n1troan1l1ne undergo photolysis, and 3-n1troan1l1ne can be expected
to undergo the same fate. From monitoring data, Zoetman et al. (1980) esti-
mated that the half-life of 3-n1troan1l1ne In the Rhine River was 1.0 days.
2.2.2. B1odegradat1on. There are conflicting data on the susceptibility
of 3-n1troan1l1ne to mlcroblal blodegradatlon In aqueous media. Malaney
(1960) reported some oxidation of all three Isomers of nltroanlUne by
aniline-acclimated activated sludge (as measured In a standard Warburg
resplrometer). In tests conducted with an electrolytic resplrometer, Urano
and Kato (1986a,b) found that a 100 mg/a. concentration of 3-n1tro- aniline
was not blodegraded by unaccllmatlzed activated sludge (30 mg/i) after 240
hours at 20°C. Similarly, PHter (1976) and KHano (1978)
0408d -4- 05/08/90
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reported no degradation of this compound, or of 2- and 4-nltroanlllne, when
Incubated 1n the presence of adapted activated sludge. Partial degradation
of 3-n1troan1l1ne was reported by Chambers et al. (1963) 1n tests using
phenol-adapted bacteria and by Young and Affleck (1974) In tests using a
4-n1troan1l1ne-adapted sewage Inoculum. Park et al. (1988) reported that
3-nltroanllIne was one of a number of aromatic amines that could be used as
a sole source of carbon by Pseudomonas put Ida cultures Isolated from
activated sludge. Paris and Wolfe (1987) reported that bacterial Isolates
obtained from river water were also capable of degrading 3-nltroanlHne.
For a bacterial concentration of TO13 organlsms/i, the disappearance
rate constant for the reaction was 1 .2;t0.8xlO~ls «. (organism)'1
hour"1, and the calculated t,/2 was 58.0 hours. for field samples
obtained from three localities and containing estimated bacterial levels of
only 108 organisms per liter, the average !,. was reported to be 1.7
years. The data Indicated that the primary transformation pathway Involved
the oxldatlve deamlnatlon of the nltroanlllne. Other studies on 2- and
4-nltroanlllne have produced conflicting results, some Indicating a small
level of blodegradatlon and others none at all. The pathway of blodegrada-
tlon of 4-n1troan1l1ne by Pseudomonas and Bacillus was reported to occur
through the formation of 4-phenylened1am1ne and 4-am1nophenol Intermediate
products.
2.2.3. Transport. Based on the water solubility of 910 ppm at 25°C, and
an estimated vapor pressure of 0.0000362 mm Hg at 25° (Ferro and Plancente,
1985), the Henry's Law constant for 3-n1troan1l1ne was estimated by SRC
(1989) to be 7.2xlO~9. This low value Indicates that volatilization of
3-nltroanlllne from aqueous media would be minimal.
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When released In natural waters, 3-n1troan1llne Is likely to undergo
covalent chemical bonding with humlc materials In the water column and
sediments (SRC, 1989). Information on the kinetics of this reaction Is not
available.
2.3. SOIL
2.3.1. Physical and Chemical Processes. On soil surfaces and when
exposed to sunlight, 3-n1troan1l1ne Is expected to be susceptible to photo-
degradation (SRC, 1989}. Data on the kinetics and degradation products of
the reaction, however, are not available.
There Is evidence that aromatic amines such as 3-nltroan1llne bind to
humlc substances (SRC, 1989). Laboratory studies Indicate that the reaction
Involves a chemical covalent bonding that Is achieved through an Initial
rapid reversible step Involving the formation of Imlne linkages with humate
carbonyls, followed by a slower less reversible reaction possibly Involving
1,4- addition to qulnone rings and then tautomerlcatlon and oxidation to
give an amlno-substltuted qulnone (Parrls, 1980). After the second step Is
reached, leaching of 3-n1troanll1ne from the soil Is not expected to be
significant (SRC, 1989).
Brlggs (1981) evaluated the soil/water distribution pattern of various
organic chemicals In four types of silt-loam soils using Initial chemical
concentrations of 5, 10, 15 and 20 ppm. Because the soil adsorption of
nonlonU chemicals Involves the partitioning of the substance between an
organic phase and a water phase, the soil adsorption coefficient (K.) can
be correlated to the partitioning coefficient for soil organic matter and
water (Kom):
K * TOOK ./(% om)
om a
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where % om Is the percent organic matter In the soil (BMggs, 1981). The
average log K for 3-n1troan11lne was reported to be 1.49. This Is
equivalent to a log K of 1.72 assuming a conversion factor of 1.724 as
reported by Brlggs (1981).
2.3.2. Blodegradatlon. Most studies have shown that 3-n1troan1l1ne 1s
not readily degraded by soil microorganisms. Bordeleau and Bartha (1972)
reported that nitroanlllnes, Including 3-n1troan1l1nef were not susceptible
to transformation by partially purified extracts of the soil fungus
Geotrlchum candldum. Alexander and Lustlgman (1966) reported no degradation
of a 10 yg/ma. solution of 3-n1troan1l1ne by a soil Inoculum even after
64 days of Incubation 1n the dark at 25°C. Zeyer and Kearney (1983)
reported that 3-n1troan1l1ne, when used as a sole carbon source, was not
degraded by a strain of Pseudomonas Isolated from soil. Similar results
were seen with 2-n1troan1l1ne, but 4-n1troan1l1ne was degraded by the
bacteria. The only study to demonstrate a potential blodegradatlon of
3-n1troan1l1ne 1s that by HcCormlck et al. (1976). In this study, nltro
reduction of 3-n1troan1l1ne was achieved with cell-free extracts of the
bacterial anaerobe Veil!one11a alkalescens.
2.3.3. Transport. There 1s little Information available on the transport
of 3-n1troan1l1ne 1n soils. Based on a log K of 1.49 (as reported by
Brlggs, 1981), It has been suggested that this compound should be moderately
mobile In soil (U.S. EPA, 1985). However, binding of the compound with
humlc substances 1s expected to substantially reduce translocatlon within
the soil column.
2.4. SUMMARY
The available data Indicate that the environmental fate of 3-n1troan1-
llne 1s controlled largely by Us water solubility, low vapor pressure.
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01/16/91
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susceptibility to photodegradatlon, and by Us affinity to bind with humlc
substances 1n soil and sediments. Thus, 3-nltroanlllne is not expected to
be a major atmospheric contaminant. In may be present 1n aqueous media, but
probably only near point sources. Although 1t Is not readily susceptible to
blodegradatlon, Its binding with humlc substances 1n soils and sediments
will probably limit Us bloavallabUHy.
0408d -8- 03/06/90
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3. EXPOSURE
3-N1troan1l1ne may be released to the environment through process and
waste emissions resulting from Us production or use as a chemical Inter-
mediate (SRC, 1989). Humans are most likely to come Into contact with this
substance In occupational exposure settings. Information on occupational
exposure Is limited. No 3-n1troan1l1ne Is manufactured 1n the United States
but 167,000 pounds Is Imported (USITC, 1976). Occupational exposure will
occur primarily through dermal absorption and Inhalation of vapors (Beard
and Noet 1981).
3.1. HATER
Limited monitoring data for this compound are available. Zoeteman et
al. (1980) detected 3-n1troan1l1ne at a concentration of 0.1 yg/l In
samples taken from the Rhine RWer near LobHh In the Netherlands.
3.2. HASTEHATER EFFLUENTS
Specific Information on the occurrence of 3-nltroanlllne In wastewaters
Is limited to one report Indicating that the compound was present at a
concentration of 259.55 mg/8. 1n an effluent from an organic chemical plant
(U.S. EPA, 1987). Unspecified Isomers of nltroanlllne, at a concentration
of 270 yg/l, were also reported to be present 1n the raw wastewater of a
dye manufacturing plant (Games and HHes, 1977). After treatment, the
effluent contained no detectlble levels of nUroanlUne. 4-N1troan111ne In
the wastewater from a dye manufacturing plant was reported to be oxidized
97.3X during 2 hours of chlorlnatlon (Endyus'kln and F1l1ppov, 1980). A
similar oxidation reaction could be expected with 3-n1troan1l1ne.
0408d -9- 01/16/91
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3.3. SOIL
Soil monitoring data for 3-n1troan1l1ne were not found In the available
literature as listed In Appendix A.
3.4. FOOD
Monitoring data for 3-n1troan1l1ne In food products were not found 1n
the available literature as listed In Appendix A.
3.5. SUMMARY
In the absence of adequate monitoring data, few conclusions can be
reached concerning levels of exposure of the general public to 3-n1troan1-
llne. However, Information provided 1n the previous section would suggest
that exposure levels will probably be minimal except possibly In occupa-
tional exposure situations.
0408d
-10-
01/16/91
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4. ENVIRONMENTAL TOXICOLOGY
4.1. AQUATIC TOXICOLOGY
4.1.1. Acute Toxic Effects on Freshwater Fauna. Oeneer et al. (1987)
evaluated the toxlclty and bloaccumulation potential of various nitrobenzene
derivatives Including 3-n1troan1l1ne, on the guppy, Poecllla retlculata.
The tests were conducted under static water conditions using a standard
water with a hardness of 25 mg/i as CaCOg. The log of the 14-day LC5Q
for 3-n1troan1l1ne was reported to be 2.57. The corresponding LC5Q would
therefore be 371.5 jimol/s, (51 mg/a). Deneer et al. (1987) reported
that the relationship between the acute toxldty and the partition coeffi-
cient for n1troanH1nes could best be described by the following equation:
-log LC = 0.88 log P - 3.83 (r = 0.959)
Toxlclty studies on 4-n1troan1l1ne Indicate that the LC5Q for several
species of fish falls In the range of 10-100 ppm {U.S. EPA, 1985). For this
same Isomer, the LC for Daphnla maqna U 24 ppm, and the EC5Q for
immobilization 1s 2.5 ppm (Bringmann and Kuhn, 1977). The toxlclty
threshold has been reported to be 3.1 ppm as measured by effects on a
population of the protozoan Uronema parducl (Bringmann and Kuhn, 1980).
4.1.2. Acute Toxic Effects on Saltwater Fauna. No pertinent Information
on the acute toxic effects of 3-n1troan1l1ne to marine organisms was found
In the literature listed In Appendix A.
4.1.3. Chronic Effects on Fauna.
4.1.3.1. TOXICITY No pertinent Information on the long term toxic
effects of 3-n1troan1l1ne was found In the literature listed 1n Appendix A.
4.1.3.2. BIOACCUMULATION AND BIOCONCENTRATION Saklya et al. (1988)
studied the uptake of several benzene derivatives, Including 3-n1troan1l1ne,
through the body surface and gill membranes of goldfish. In tests conducted
0408d -11 - 03/06/90
-------
with a 1.0 mM concentration at pH 6.0 and 25°C, the mean absorption rate
constant [(m1n~J g'MxIO4] for 3-nltroanlllne was found to be 1.570
(S.E.M. 0.286) for the body surface and 1.577 (S.E.H. 0.234) for the gills.
In other studies conducted on carp, Sasaki (1978) found that 3-n1troan1l1ne
had a low potential for bloaccumulatlon. The bloconcentratlon factor was
less than 200 after 8 weeks of exposure to concentrations ranging from
0.0001-0.01 of the 48-hour TL .
m
The bloconcentratlon factor (BCF) for 3-nltroanlllne can be estimated
using log K and the regression equation derived by BMggs (1981):
log BCF = 0.87 log K - 0.62
* ow
BMggs (1981) reported a log K of 1.39; therefore, the log BCF would be
0.589, and the BCF 3.89. Howard et al. (1976) calculated a BCF of 8 for
3-nltro- aniline, 12 for 4-n1troan1l1ne, and 6 for 2-nltroanlllne. These
values Indicate that In general nHroanlUne has a low potential for
bloaccumu- latlon.
4.1.4. Effects on Flora. Kramer et al. (1986) evaluated the effect of
various monosubstltuted nltrobenzenes on the autotrophlc growth of synchro-
nous cultures of the green alga Chlorella vulgaMs. The Isoactlve Inhibi-
tory value {pc = -logEC50> where EC,.,, In mol/i, Is the concentra-
tion causing a 50% reduction 1n growth) for 3-n1troan1l1ne was reported to
be 3.14 and 3.10 for measurements made at wavelengths of 680 and 750 nm
respectively. These values are equivalent to EC,,, concentrations of 0.724
mmol/s. (100 mg/i) and 0.794 mmol/a. (110 mg/i), respectively.
4.2. TERRESTRIAL TOXICOLOGY
4.2.1. Effects on Fauna. Limited data are available on the toxldty of
3-n1troan1Hne to terrestrial animals. Schafer et al. (1983) reported that
the acute oral LO Qs for the redwlnged blackbird (Agelalus phoenlceui),
0408d
-12-
05/08/90
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starling (Sturnus vulgar IsJ. Japanese quail (Coturnlx coturnix Japonlca),
and house sparrow (Passer domestlcus) were 133 mg/kg, >1000 mg/kg, 562
mg/kg, and >1000 mg/kg, respectively. In another study, Schafer and Bowles
(1985) evaluated the acute oral toxldty and repellency of various chemicals
to house and deer mice. In a 3-day feeding study with 3-n1troan1l1ne, less
than 50% mortality of deer mice was recorded following an estimated dally
oral dose >375 mg/kg. The compound was applied as a 2% solution to white
wheat seeds Included In the diet of the mice.
4.2.2. Effects on Flora. No pertinent data on the effects of 3-nHro-
anlUne on plants were found In the literature listed In Appendix A.
4.3. FIELD STUDIES
No pertinent field data on the effects of 3-nltroanlllne could be found
In the literature cited 1n Appendix A.
4.4. AQUATIC RISK ASSESSMENT
Sufficient information is not available for a quantitative environmental
risk assessment for 3-n1troanll1ne. Data are Inadequate for deriving water
quality criteria. Water Quality Criteria are based on a Criterion Maximum
Concentration and a Criterion Continuous Concentration. The first value 1s
equal to one-half of the Final Acute Value. The second criterion 1s equal
to the lowest of the Final Chronic Value, the Final Plant Value, or the
Final Residue Value. For 3-n1troan1l1ne there 1s only one specific data
point for acute toxlclty and no Information on which to derive a Criterion
Continuous Concentration.
From a qualitative point of view, the available data on environmental
persistence, toxlclty, and bloaccumulatlon potential of 3-n1troan1l1ne would
suggest that the chemical represents only a low level of environmental risk.
0408d -13- 05/08/90
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Releases to the environment would be subject to physical and chemical
degradation. Although rates of blodegradatlon are probably low, binding of
the chemical with humlc substances In soil and sediments Is likely to limit
Its transport and b1oava1lab1Hty.
4.5. SUMMARY
Information on the environmental toxicology of 3-nltroanllIne Is
limited. The available data for this Isomer as well as for 4-nltroanlllne
Indicate that acute median lethality to freshwater fish falls 1n the range
of 10-100 mg/8.. There Is no Information on acute toxldty to saltwater
species, or on chronic effects to either marine or freshwater organisms.
The partition coefficient for 3-n1troan1line and experimentally derived and
calculated bloconcentratlon factors Indicate a low potential for bloaccumu-
latlon. Data for terrestrial vertebrates (birds and mice) Indicate a
relatively low acute toxlclty of 3-n1troan1l1ne, the oral L05Q values
being above 100 mg/kg\
Sufficient Information 1s not available for a quantitative environmental
risk assessment for 3-n1troan1l1ne. From a qualitative point of view, the
available data on environmental persistence, toxIcHy, and bloaccumulatlon
potential of 3-n1troan1l1ne would suggest that the chemical represents only
a low level of environmental risk.
0408d -14- 05/08/90
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5. PHARMACOKINETICS
5.1. ABSORPTION
Beard and Noe (1981) reported that 3-n1troan1llne Is readily absorbed
through the lungs and also through Intact skin. Other pertinent data
regarding the absorption of 3-nltroanlllne were not located In the sources
searched (see Appendix A).
5.2. DISTRIBUTION
Pertinent data on the tissue distribution of 3-n1troan1l1ne were not
located 1n the sources searched (see Appendix A).
5.3. METABOLISM
3-N1troan1l1ne Injected l.p. Into rabbits or dogs appears 1n the urine
as both conjugated and unconjugated forms of the parent molecule. The uri-
nary substances were Identified by the melting points of crystals obtained
from ether extracts of urine before and after sulfurlc acid hydrolysis
(Hells et al., 1920-1921). Corbett and Corbett (1985) demonstrated that
3-n1troan1l1ne undergoes N-ox1dat1on to hydroxylamlne and nltroso metabo-
lites In the presence of hydrogen peroxide and chloroperoxldase using a
cell-free system. Greater quantities of the hydroxylamlne metabolite was
formed than the nltroso metabolite. No C-ox1dat1on products were found.
The reaction was first order at substrate concentrations ranging from
0.05-0.20 mM, and the rate constant was 0.19 mi-tig"1 proteln-mln'1.
Corbett and Corbett (1985) also demonstrated that 4-n1troan1l1ne and
4-chloroanlllne undergo N-ox1dat1on under the same conditions. Rlckert
(1987) reported that 3-n1troan1l1ne may be an Intermediate for ~ 66% of the
metabolites excreted Into the urine of rabbits dosed with 1,3-dlmethyl-
benzene, suggesting that 3-n1troan1l1ne can be metabolized. These possible
metabolites were Identified as 4-am1no-2~n1trophenol, 2-am1no-4-n1trophenol,
0408d -15- 01/22/91
-------
1,3-d1am1nobenzene, and 2,4-dlamlnophenol. 3-N1troan111ne also Is a
metabolite of 1,3-dlnltrobenzene In the rat (Bailey et al., 1988).
5.4. EXCRETION
Rabbits (1.87-2.13 kg) Injected l.p. wUh 0.53 g of 3-n1troan1l1ne
excreted 13.7-15.6% of the dose Into urine, 74-93% of which was excreted
within the first 24 hours. 3-N1troan1l1ne was detected In the urine within
3 or 4 hours after Injecting two dogs (6.3 and 10.5 kg) with 0.53 or 1.05 g,
respectively, of 3-nltroanlllne (lethal doses) (Hells et al., 1920-1921).
Watanabe et al. (1976) reported that rats receiving 3-n1troan1l1ne l.p. at
100 iimol/kg excreted d1azo-pos1t1ve metabolites Into their urine within 5
hours after Injection. The presence of dlazo-posltlve substances In urine
Is an Indicator for the presence of n1tro-am1no derivatives of benzene and
to chlorobenzenes.
5.5. SUMMARY
3-N1troan1l1ne 1s readily absorbed through the lung and from Intact
skin. Data regarding absorption from the gastrointestinal tract and tissue
distribution were not found. One report suggested that 3-n1troan1l1ne Is
excreted Into urine as conjugated or unconjugated forms of the parent
molecule (Hells et al., 1920-1921); another report presented evidence that
dlazo-posltlve substances (Indicators for the presence of nltro-amlno
derivatives) are excreted Into urine of animals Injected l.p. with 3-nltro-
anlllne {Watanabe et al., 1976). The evidence also suggested that 3-nltro-
anlUne, which Is formed as a metabolite of !,3-d1n1trobenzene, 1s In turn
metabolized to 4-am1no-2-n1trophenol, 2-am1no-4-n1tropheno1, !,3-d1am1no-
benzene, and 2,4-d1am1nophenol (Rlckert, 1987); another study showed that
3-n1troan1l1ne can be metabolized to N-ox1dat1on products In a cell free
system (Corbett and Corbett, 1985).
0408d -16- 01/16/91
-------
6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Subchronlc Exposure. Pertinent data regarding the toxlcity of
3-nHroanillne administered subchronkally by the Inhalation or oral routes
were not located In the sources searched (see Appendix A).
6.1.2. Chronic Exposure. Pertinent data regarding the toxlcity of
3-nltroanlllne administered chronically by the Inhalation or oral routes
were not located In the sources searched (see Appendix A).
6.1.3. Other Relevant Information. Toxlcity data for 3-n1troan1l1ne are
few. Oral LD5Qs reported for rats are 535 mg/kg (RTECS, 1989), 540 mg/kg
{Vernot et al., 1977), and 900 mg/kg (Vasllenko et al., 1974). The L050
values reported for mice are 308 mg/kg (RTECS, 1989) and 310 mg/kg (Vernot
et al., 1977), and the oral LD5Q reported for guinea pigs Is 450 mg/kg
{Vernot et al., 1977).
Wells et al. (1920-1921) reported that a dog weighing 6.3 kg can be
killed by Injecting 15 ma (l.p.) of a 3.5% solution of 3-n1troan1l1ne In
olive oil (70 mg/kg as reported by the authors). [Using the value reported
by the authors for the weight-normalized dose, the 3.5% solution In olive
oil contained only 29.4 mg of 3-n1troan1l1ne/mi; this concentration was
used to calculate weight-normalized doses not reported by the authors]. In
addition, Wells et al. (1920-1921) reported that rabbits weighing 1.7-2 kg
are usually killed by 20 mi of 3-n1troan1l1ne Injected l.p. (calculated
dose = 294-346 mg/kg), and 30 ml always kills rabbits weighing 1.7-2 kg
(calculated dose = 400-519 mg/kg). A cat weighing 2.025 kg can be killed by
15 ma (calculated dose = 218 mg/kg) Injected l.p., and a guinea pig weigh-
ing 0.97 kg can be killed by 7 ml (calculated dose = 212 mg/kg). A single
0408d -17- 03/06/90
-------
l.p. Injection of 15 mi (200-250 mg/kg as reported by the authors) or 11
dally subcutaneous Injections of 10 ml (calculated dose = 155 mg/kg) did
not cause toxic effects In the rabbits.
The clinical effects of lethal doses of 3-n1troan1l1ne In dogs are
dyspnea and convulsion before death, and postmortem examination may show
signs of asphyxia and dark-colored, slowly coagulating blood (Wells et al.,
1920-1921). Repeated sublethal doses to rabbits cause profound emaciation
and severe secondary anemia. Red and white blood cell counts may be
decreased In rabbits given a single subcutaneous Injection, and a second
Injection given 2 days after the first may cause a greater decrease In red
and white blood cell counts, the appearance of numerous atypical white blood
cells, bone marrow changes Indicative of anemia, and swollen and dark-
colored spleen and kidneys. Microscopically, the renal tubules may be
distended and contain small globules or casts, and fatty degeneration may be
seen In the epithelium of the straight tubules In Henle's loop (rabbits and
dogs). Other microscopic effects reported by Wells et al. (1920-1921) were
necrosis and fatty degeneration 1n the central lobular region 1n the liver,
fatty degeneration In the myocardium, a distended spleen containing blood
pigment, leucocytosls, and pulmonary edema.
3-NHroan111ne (4-n1troan1l1ne also) 1s also a methemoglobln former 1n
dogs and cats, and It causes hemolysls and Heinz body formations 1n dogs
{DeBruIn, 1976; Beard and Noe, 1981). Prolonged or excessive exposure may
cause liver damage (DeBruIn, 1976). The vapors of 3-nHroanlllne are
reported to be highly toxic (Beard and Noe, 1981). Vasllenko et al. (1974)
and Vasllenko and Zvezdal (1974) reported that 3-nltroan1l1ne Is hematotoxlc
and causes significant Increases In methemoglobln and sulfhemoglobln levels
0408d -18- 05/08/90
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In blood of mice and rats, Watanabe et al. (1976) reported that methemo-
globlnemla was seen 5 hours after Wlstar rats were Injected 1.p. with
3-n1troan1l1ne at 100 jimol/kg bw. Serum GOT and GPT activities were
measured and were not found to be altered by treatment.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carclnogenlclty of
3-n1troan1l1ne administered by the Inhalation route were not located In the
sources searched (see Appendix A).
6.2.2. Oral. Pertinent data regarding the carclnogenlclty of 3-n1tro-
anlllne administered by the oral route were not located 1n the sources
searched (see Appendix A).
6.2.3. Other Relevant Information. Although no data regarding the
carclnogenlclty of 3-n1troan1l1ne were found In the literature, a qualita-
tive evaluation of potential carclnogenlclty can sometimes be based on
evidence for structural analogues or metabolites. No data regarding the
effects of long-term exposure to the Isomers, 2- and 4-n1troan1l1ne were
found in the literature. Possible metabolites of 3-nHroanlllne (based on
Indirect evidence) are 2,4-dlamlnophenol, l,3-dlamlnobenzene, 4-am1no-2-
nltrophenol, and 2-am1no-4-n1trophenol (Rlckert, 1987). A brief summary of
data regarding carclnogenlclty and genotoxldty of these metabolites 1s
presented below.
IARC (1987) classified 3-phenylened1am1ne (1,3-dlamlnobenzene) as a
Group 3 carcinogen (not classifiable as to Its carclnogenlclty to humans),
based on no data for humans and Inadequate data for animals. Genotoxldty
tests have shown positive results for 1,3-d1am1nobenzene In Salmonella 1n
the presence of S9 (Garner and Nutman, 1977; Thompson et al., 1983).
0408d
-19-
05/08/90
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In a 2-year feeding bloassay using male and female F344 rats and B6C3F1
mice, 4-am1no-2-n1trophenol was carcinogenic In male rats, Inducing transi-
tional-cell carcinomas of the urinary bladder, possibly carcinogenic in
female rats, but not carcinogenic 1n male and female mice (NCI, 1978).
Commercial-grade 4-am1no-2-nHrophenol Induced mutations In Salmonella
(Garner and Nutman, 1977, Dunkel and Simmon, 1980, Shahln et al., 1982),
whereas a purified preparation (98% pure) did not Induce mutations In Salmo-
nella strains TA98, TA1537, TA1538, TA1535 and TA100 (Shahln et al., 1982;
Shahln, 1985). NTP (1988), however, reported that 4-am1no-2-n1trophenol
(99.6% pure) Induced mutations 1n Salmonella In the absence of S9 and
forward mutations in mouse lymphoma cells. 4-Am1no-2-n1trophenol did not
Induce unscheduled DNA synthesis In rat hepatocytes (Williams et al., 1982)
and did not Induce dominant lethal mutations (species not specified)
(Burnett et al., 1977).
2-Am1no-4-n1trophenol showed "some evidence of carclnogenUlty" In male
F344 rats administered the compound by gavage for 2 years (NTP, 1988). The
Incidences of renal cortical (tubular cell) adenomas and renal tubular cell
hyperplasla were Increased. 2-Am1no-4-n1trophenol was not carcinogenic In
female F344 rats or In male and female B6C3F1 mice (NTP, 1988). Shahln
(1985) reported that 2-am1no-4-n1trophenol Induced mutation In Salmonella
strains TA98 and TA1538, but only 1n the absence of S9. According to NTP
(1988), 2-am1no-4-n1trophenol Induced mutations In Salmonella In the
presence of S9, and In mouse lymphoma cells In the absence of S9. NTP
(1988) also reported that 2-am1no-4-n1trophenol Induced sister chromatld
exchanges and chromosomal aberrations In Chinese hamster ovary cells with
and without S9.
0408d -20- 05/08/90
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6.3. GENOTOXICITY
The genotoxlclty data for 3-nltroan1l1ne are summarized In Table 6-1.
Garner and Nutman (1977) tested 3-nHroan1l1ne along with azo dyes and
other nitroanlUne and nitrobenzene compounds for mutagenlc activity 1n
Salmonella typhlmurlum strain 1A1538 using the soft agar overlay method.
3-NKroanlllne was mutagenlc at 50 and 100 pg/plate only in the presence
of rat liver S9. The other Isomers, 2- and 4-n1troan1l1ne, were also
mutagenlc In the presence of S9.
Chlu et al. (1978) showed that 3-nltroanlllne Induced mutations In
Salmonella strain TA98 at a concentration of 10 iimol/plate (1380
ng/plate) 1n the absence of S9, but mutations were not Induced at 0.1 and
1.0 nmol/plate. Under the same conditions, 3-n1troan1l1ne was not
mutagenlc In TA100, and 2-n1troan1l1ne and 4-n1troan1l1ne were not mutagenlc
1n either TA98 or TA100. Chlu et al. (1978) stated that Salmonella strains
TA98 and TA100 have aerobic nltroreductase activity, and the liver nltro-
reductase activity (If present In S9) requires anaerobic conditions.
Therefore, some caution must be exercised In Interpreting these results,
because H Is possible that activation of 3-n1troan1l1ne took place In the
absence of S9. 3-NHroanlllne was mutagenlc In only one of the Salmonella
strains having the nltroreductase activity, and the 2- and 4-1somers were
not mutagenlc 1n either strain. Therefore, under these conditions, 1f the
bacterial nltroreductase activates nltroanlllnes, It only activates the
3-1somer In only one Salmonella strain.
3-NHroan1l1ne was tested for mutagenlc activity In eight Salmonella
strains and In two E.. coll strains using the gradient plate method and for
DNA damaging activity In the unscheduled DNA synthesis assay using rat
hepatocytes (Thompson et al., 1983). 3-NHroanlllne at concentrations
0408d
-21-
03/06/90
-------
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ranging from 30-100 yg/mj. of agar was positive In the presence of S9 1n
strains TA1535, TA98, TA1538 and TA100, but not In strains G46, C3076,
TA1537 and D39S2. 3-N1 troanlUne was negative In all odlmonella strains 1n
the absence of S9, 1n E.. coll strains WP2 and HP2uvrA- under all conditions,
and In the unscheduled DNA synthesis assay. 4-N1troan111ne was positive In
D3052, 1A1538 and TA98 at concentrations ranging from 1-300 yg/mfc of
agar, and 2-n1troan111ne was negative In all strains.
Shahln (1985) tested 3-n1troan1l1ne (98% pure) at 5-1000 yg/plate and
showed positive results In Salmonella strains TA98, TA1538 and TA1535 In the
presence and absence of S9, but not In strains TA1537 and TA100 under the
same conditions. In the absence of S9, mutations were Induced In TA1535 at
500 and 1000 jig/plate, but only at 1000 yg/plate 1n the other positive
strains, whereas In the presence of S9, mutations were Induced at 250-1000
wg/plate 1n strain TA1535 and at 500 and 1000 >ig/plate In the other
positive strains. The number of revertants/Vmol ranged from 8.2 (TA1537
without S9) to 30 (TA98 with S9).
Using the pour-plate method, Shlmlzu and Yano (1986) tested 3-nltro-
anlllne at concentrations ranging from 0.05-10 mg/plate. The compound was
mutagenlc 1n Salmonella strains TA98, TA1538, and TA100 and negative In
TA1537 and TA1535 1n the absence of S9. The compound was not tested 1n the
presence of S9. 3-NHroan1l1ne, at concentrations of 0.5, 1.0, and 5.0
mg/plate Induced 25, 39, and 29 revertants/ymol, respectively. 3-N1tro-
anlUne Induced a slight positive response In the Kada B_. subtnis rec assay
(Shlmlzu and Yano, 1986).
Kawal et al. (1987) tested a series of aliphatic and aromatic nHro
compounds, Including 3-n1troan1l1ne, for mutagenlc activity 1n Salmonella
strains TA100 and TA98 using the prelncubatlon method. 3-N1troan1l1ne was
0408d -24- 01/16/91
-------
positive In strain TA100, Inducing 90 revertants/mg of test compound In the
presence of $9 and 230 revertants/mg In the absence of S9. Using strain
TA98, 3-n1troan1l1ne Induced 1250 revertants/mg 1n the presence of S9 and
270 revertants/mg In the absence of S9. Therefore, 3-n1troan1l1ne had about
the same potency In both strains In the absence of S9, but was significantly
more potent In TA98 In the presence of S9.
Dellarco and PMval (1989) used a prelncubatlon method 1n which FMN was
added to the prelncubatlon mixture along with 59 to promote the reduction of
the nltro group. Salmonella strains TA98 and TA100 were used, and the S9
fraction was obtained from Aroclor !254-1nduced rat or hamster liver.
3-NHroan1l1ne was tested at 0.05-0.2 ymol/plate {6.9-27.6 Mg/plate).
Data were not presented for strain TA100, but the authors reported that the
mutagenlc activity was greater In TA98 than In TA100. 3-N1troan1l1ne was
strongly mutagenlc using the FMN prelncubatlon protocol In the presence of
hamster S9, but was less potent 1n the presence of rat S9. No mutagenlc
activity was observed without FMN 1n the presence of hamster or rat S9. A
rough estimate showed that 3750, 6167, and 8375 revertants/jjtnol of
3-nltroanlllne were Induced at concentrations of 0.1, 0.15, or 0.2 pmol.
respectively, 1n the presence of hamster S9, whereas only 1500, 2167, and
3500 revertants/timol, respectively, were Induced at the same
concentrations In the presence of rat S9. These results showed that
3-nltroanlllne was a more potent mutagen when FMN was Incorporated Into the
assay mixture. Indicating that nltro reduction may Indeed be Involved In the
activation of 3-n1troan1l1ne.
The mutagenlcUy studies discussed above have shown that under condi-
tions 1n which a bacterial nltroreductase could have activated 3-nltroanl-
llne {mutagenlc activity 1n the absence of S9), high concentrations of
0408d -25- 01/16/91
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3-nUroan111ne were generally required to Induce revertants. In one study,
3-n1troan1l1ne at a concentration of 10 ymol or 1380 ^g/plate was
mutagenlc In the absence of S9 (Chlu et al., 1978), and 1n another study, It
was mutagenlc at 500-5000 yg/plate In the absence of S9 (Sh1m1zu and Yano,
1986). 3-N1troan1ltne tested at 10-5000 ug/plate Induced 2.6-fold more
revertants in TA100 1n the absence of S9 than In the presence of S9, whereas
3-n1troan1l1ne was more potent In TA98 In the presence of S9 than In the
absence of S9 (Kawal et al., 1987), Indicating that, If bacterial
nltroreductase Is Involved In activating 3-n1troan1l1ne, some strains have
more activity than others. At very low concentrations of 3-n1troan1l1ne
(6.9-27.6 j»g/plate), FHN, In addition to S9, was required for mutagenlc
activity.
6.4. DEVELOPMENTAL TOXICITY
Pertinent data regarding the developmental toxlclty of 3-n1troan1l1ne
were not located In the sources searched (see Appendix A). Some possible
metabolites of 3-n1troan1l1ne Include 4-am1no-2-n1trophenol, 2-am1no-
4-n1trophenol, 1,3-dlamlnobenzene and 2,4-d1am1nophenol (Rlckert, 1987).
The literature on these metabolites was searched for evidence of
developmental toxIcHy. Two studies of the developmental toxlclty of
1,3-dlamlnobenzene were located. PUclano et al. (1983) treated mature
female Sprague-Dawley rats by gavage with 1,3-d1am1nobenzene at 0 (propylene
glycol vehicle control), 45, 90 or 180 mg/kg bw/day on days 6-15 of
gestation. The day that a vaginal plug or spermatozoa In the vaginal smear
was found was designated day 0 of gestation. Positive controls (vitamin A
and aspirin) were maintained. Pregnant dams (22, 9, 8 and 7 In vehicle
control, 45, 90 and 180 mg/kg bw/day groups, respectively) were killed and
reproductive tracts and contents were examined on gestation day 20. No
0408d -26- 01/22/91
-------
deaths occurred, and no signs of maternal toxlclty were observed, except
that high-dose rats exhibited a significantly (p<0.05) reduced rate of body
weight gain. Parameters of fertility and fetal body weights were unaffected
by treatment. The Incidences of gross external skeletal and visceral
anomalies were not Increased by exposure to 1,3-d1am1nobenzene. Positive
controls responded appropriately.
A German paper reported the results of a developmental toxlclty study of
!,3-d1am1nobenzene (Hruby et al.f 1981). Groups of 25 mated female rats
were treated by gavage with 1,3-dlamlnobenzene at 0 (water control), 10, 30
or 90 ing/kg bw/day on days 6-15 of gestation. In addition, a positive
control group was treated with acetylsallcyllc add. Six high-dose rats
died; no rats 1n the other groups died. Evidence of fetotoxiclty was noted
In high-dose rats; a smaller number of IHters with live fetuses, reduced
placental weight, fewer living fetuses/litter, reduced fetal body weights,
Increased Incidence of fetal resportlon and a greater number of dead fetuses
were observed. Major fetal malformations were not observed In treated rats,
but an Increase 1n the percentage of litters with minor fetal abnormalities
and a greater percentage of fetuses with minor abnormalities were noted In
high-dose rats, compared with negative controls. These signs of
fetotoxiclty and fetal anomalies were not statistically significant In the
10 or 30 mg/kg bw/day dosed groups. Data were unavailable for the remaining
metabolites.
6.5. OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding other reproductive effects of 3-n1troan111ne
were not located In the sources searched (see Appendix A).
0408d -27- 01/22/91
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6.6. SUMMARY
With the exception of genotoxHIty data, almost all toxlclty data were
related to acute exposure. Lethality data for 3-n1troan1l1ne showed LD5Qs
of 308 mg/kg for mice, 450 mg/kg for guinea pigs, and 535-900 mg/kg for rats
(Vernot et al., 1974; Vasllenko et al., 1974; RTECS, 1989). Other data
showed that dogs can be killed by a single 1.p. Injection of 70 mg/kg,
guinea pigs by 212 mg/kg, cats by 218 mg/kg, and rabbits by 294-346 mg/kg
(Wells et al., 1920-1921. A single 1.p. Injection of 200 mg/kg 1s without
toxic effects In the rabbit (Wells et al., 1920-1921).
Clinical effects from acute exposure to 3-n1troan1l1ne Include dyspnea
and convulsions before death, with postmortem signs of asphyxia (Wells et
al., 1920-1921). 3-N1troan111ne Is a methemoglobln and a sulfhemogloben
former (DeBruIn, 1976; Beard and Noe, 1981; Watanabe et al., 1976; Vasllenko
et al., 1974; Vasllenko and Zveydal, 1974). Other toxic effects may Include
decreases In red and white blood cell counts, bone marrow changes Indicative
of anemia, pulmonary edema, and damage to the kidney, spleen, liver, and
heart (Wells et al., 1920-1921). Serum GOT and GPT activities In rats were
not affected by l.p. doses of 100 ymol/kg {Watanabe et al., 1976).
No data were available regarding subchronlc or chronic toxlclty,
cardnogenlclty, teratogenldty, or reproductive toxlclty of 3-n1troan1l1ne.
Genotox1c1ty data showed that 3-nltroanlllne Is mutagenlc In Salmonella
typhlmurlum under various conditions. It has produced positive results In
strains capable of detecting both base-pair substitutions {TA100 and TA1535)
and frameshlft mutations (TA98, TA1537 and TA1538). In general, concentra-
tions >500 yg/plate are required to Induce mutations In the absence of S9
(Chlu et al., 1978; Shahln, 1985; Sh1m1zu and Yano, 1986). Lower concentra-
tions (30-250 vg/plate) of 3-nHroanHlne can Induce mutations In the
0408d -28- 01/16/91
-------
presence of S9 (Garner and Nutman, 1977; Thompson et al., 1983). 3-N1tro-
anlUne prelncubated with FHN In the presence of hamster or rat liver S9 can
induce mutations at concentrations as low as 6.9-27.6 vg/plate (Oellarco
and Prlval 1989). This study Indicates that nltroreductlon may be a factor
In the activation of 3-n1troan1l1ne. Other genotoxldty tests showed that
3-n1troan1l1ne Induced a weak positive response In the Kada rec assay
(Shlmlzu and Yano, 1986) and a negative response In the test for unscheduled
DNA synthesis using rat hepatocytes (Thompson et al., 1983).
Analysis of possible metabolites of 3-n1troan1l1ne showed that data were
Inadequate for evaluating the cardnogenldty of 1,3-dlamlnobenzene;
4-am1no-2-nltrophenol and 2-am1no-4-n1trophenol were carcinogenic In male
rats, but not In male and female mice. 4-Am1no-2-pheno1 was possibly
carcinogenic In female rats and 2-am1no-4-n1trophenol was not carcinogenic
In female rats. All three compounds were mutagenlc 1n Salmonella In the
presence or absence of S9.
Analysis of possible metabolites has shown that 1,3-dlamlnobenzene 1s
fetotoxlc and demonstrates significant developmental toxlclty at 90 mg/kg
bw/day when given during days 6-15 of gestation (Hruby et al., 1981).
0408d -29- 01/16/91
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
There are no U.S. EPA regulatory or verified guidance values currently
available for human exposure to 3-n1troan1l1ne by either oral, Inhalation or
dermal routes.
No occupational exposure standards for 3-nltroanlllne have been
established by OSHA, and no occupational exposure recommendations have been
made by ACGIH or NIOSH. However, OSHA (1989} has established an 8-hour TWA
for 4-nHroan1l1ne of 3 mg/ma (with a skin notation). This level Is
Identical to the TLV» currently recommended by ACGIH (1989).
7.2. AQUATIC
There are no standards or guidelines currently available for the protec-
tion of water resources and aquatic life from exposure to 3-nltroanlllne.
There are also no standards or guidelines currently available for the other
Isomers of nltroanlUne.
0408d -30- 01/16/91
-------
o
8. RISK ASSESSMENT
Statements concerning available literature In this document refer to
published, quotable sources and are In no way meant to Imply that confiden-
tial business Information (CBI), which this document could not address, does
not exist. From examination of the bibliographies of the CBI data, however,
1t was determined that CBI data that would alter the approach to risk
assessment values presented herein do not exist.
8.1. CARCINOGENICITY
Data were not available for a qualitative evaluation of the potential
cardnogenlclty of 3-n1troan1l1ne by any route of exposure.
8.1.1. Height of Evidence. No data were available regarding cardnogen-
IcHy of 3-n1troan1l1ne, and no Inferences can be made regarding the two
Isomerlc forms, 2- or 4-n1troan1l1ne, because long-term studies have not
been conducted. Possible metabolites (based on Indirect evidence) Include
4-am1no-2-nHrophenol, 2-am1no-4-n1trophenol, 1,3-dlamlnobenzene, and
2,4-dlamlnophenol. IARC (1987) classified 1,3-d1amlnobenzene as a Group 3
carcinogen, and NCI (1978) and NTP (1988) concluded that 4-am1no-2-n1tro-
phenol and 2-am1no-4-n1tropheno1 were carcinogenic In male rats, but not In
male and female mice and that 4-am1no-2~n1trophenol was possibly carcino-
genic In female rats and 2-am1no-4-n1trophenol was not carcinogenic In
female rats. All three compounds were mutagenlc In bacteria; 4-am1no-2-
nltrophenol and 2-am1no-4-n1trophenol were mutagenlc 1n mammalian cells; and
2-am1no-4-n1trophenol was also clastogenlc. Because there are no definitive
data showing that these compounds are metabolites of 3-n1troan1l1ne and the
data showed only limited evidence of cardnogenlclty (positive In only one
sex of one species) for these possible metabolites, there Is Insufficient
evidence to modify the over-all-we1ght of evidence group for 3-n1troan1l1ne.
0408d -31- 01/16/91
-------
Therefore, according to EPA methodology for carcinogen risk assessment (U.S.
EPA, 1986a), 3-nltroanlllne Is classified as we1ght-of-ev1dence Group D, not
classifiable as to human carclnogenldty.
8.1.2. Quantitative Risk Estimates. Data were not available for a
quantitative evaluation of the potential carclnogenldty of 3-n1troan1llne.
8.2. SYSTEMIC TOXICITY
Data were not available for assessing the systemic toxlclty of 3-nltro-
anlllne by the Inhalation or oral route for less than lifetime or chronic
exposure.
0408d -32- 01/16/91
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
No data regarding subchronlc or chronic toxlclty of 3-n1troan1l1ne were
found 1n the literature; therefore, a chronic RQ for 3-nHroan1line cannot
be derived.
9.2. BASED ON CARCINOGENICITY
3-NUroan1l1ne was classified as we1ght-of-ev1dence Group D. Based on
EPA methodology for evaluating potential carcinogens for adjusting report-
able quantities (U.S. EPA, 1986b), 3-n1troan1l1ne does not receive a hazard
ranking based on cardnogenlcUy.
0408d -33- 01/16/91
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0408d -34- 01/16/91
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0408d -35- 01/16/91
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0408d -36- 01/16/91
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0408d -37- 01/16/91
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