United States
Environmental Protection ' tlAU-l IN-b IU J
Agency March, 1991
Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR 2-NITROANILINE
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE
j
NOTICE
i 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 Is being circulated for comments
on Its technical accuracy and policy Implications.
HEADQUARTERS LIBRARY
ENVIRONMENTAL PROTECTION AGEKtf
WASHINGTON, D.C. 20460
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DISCLAIMER
This report Is 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
Is 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,
environmental effects of hazardous waste constituents
searched for in this document and the dates searched
aquatic life and
The literature
are Included 1n
"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
(RfOs) 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 lifespan. 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 RfOs is 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 noncarcino-
genlc health effects of compounds that are also carcinogenic.
Reportable quantities (RQs) based on both chronic toxlclty and
carclnogenldty are derived. The RQ Is used to determine the quantity of a
hazardous substance for which notification Is required in the event of a
release as specified under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). These two RQs (chronic toxlclty
and carclnogenldty) represent two of six scores developed, (the remaining
four reflect ignltabllHy, reactivity, aquatic toxlclty, and acute mammalian
toxlclty). Chemical-specific RQs reflect the lowest of these six primary
criteria. The methodology for chronic toxlclty and cancer based RQs are
defined in U.S. EPA, 1984 and 1986a, respectively.
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EXECUTIVE SUMMARY
^ When released to the atmosphere, 2-nHroanlllne will degrade rapidly by
reaction with photochemically produced hydroxyl radicals. The estimated
half-life for this reaction In air Is -11 hours (Atkinson, 1988). By
analogy to the aromatic amlne chemical class (Parris, 1980), ?-n1troan1-
llne may undergo covalent binding to humlc materials In soil and water.
This covalent binding process may represent a mechanism by which 2-nltro-
anlllne may be converted to a latent form In the biosphere. If covalent
binding does not occur, 2-n1troan1l1ne may leach readily In soil, based on
estimated K values of 53-79 {lyman, 1982; Swann et al., 1983). The
results of various biological screening studies Indicate that 2-nHroanlllne
resists blodegradatlon or Is only slowly blodegraded (KHano, 1978; Urano
and Kato, 1986; Young and Affleck, 1974; PHter, 1976; Malaney, 1960; Hallas
and Alexander, 1983; Alexander and Lustlgman, 1966; Zeyer and Kearney,
1983). Aquatic hydrolysis and volatilization are not significant breakdown
processes.
The National Occupational Exposure Survey (NOES) estimated that 1611
U.S. workers are potentially exposed to 2-nHroanlllne (NIOSH, 1989).
Occupational exposure to 2-n1troan1l1ne U possible during Its production
and use as a chemical Intermediate. The most likely route of exposure In
occupational settings Is by dermal contact. Exposure from Inhalation 1s
probably low because nltroanlllne Is a solid at room temperatures and has
low vapor pressure (NCI, 1985). The use of 2-nltroanlllne In dye synthesis
suggests that It may be released to the environment 1n wastewater effluents
from dye production (Steadman et al., 1977). 2-NHroanlllne may also occur
In the environment as a mlcroblal decomposition product of dlnltrobenzene
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(Hallas and Alexander, 1983). Pertinent monitoring data regarding food.
Inhalation and dermal exposure of 2-n1troan1l1ne were not located In the
available literature cited In Appendix A.
The lack of adequate freshwater and saltwater toxlclty and bloconcentra-
tlon data for flora and fauna precludes the development of criteria for
2-nltroanlllne. The larval sea lamprey was not affected when exposed to 5.0
mg/2. for 24 hours (Applegate et a I., 1957); 9.8 mg/i was the 14-day
LC5Q for gupples (Oeneer et al., 1987). Carp that were force-fed 2-nitro-
anlUne at a dose <189 mg/kg suffered no observed adverse effects (Loeb and
Kelly, 1963). The dilate bacteria, Tetrahyjnena pyrlformls. had a 60-hour
IGC50 of 115.55 mg/B. (Schultz and Applehans, 1985). LD s for the
redwing blackbird, starling, coturnlx and house sparrow were 750, >1000, 750
and 750 mg/kg, respectively (Schafer et al., 1983).
Five hours after IntraperHoneal administration of 2-n1troan1l1ne at 100
ymol/kg (13.8 mg/kg) to male Wlstar rats, unspecified dlazo-poslUve
metabolites were Identified in the urine (Uatanabe et al., 1976). Although
there are few data relevant to the absorption of 2-n1troan1l1ne (Moskalenko,
1966; Vasllenko et al., 1974), the similarity of Us properties to those of
the 4-1somer, which Is known to be rapidly absorbed when administered
orally, 1ntraper1toneally or dermally (U.S. EPA, 1985), suggests that
2-nHroan1l1ne may also be readily absorbed when given by these routes. If
the o-lsomer behaves similarly to the p-1somer, a substantial fraction of an
Intraperltoneally administered dose of 2-nltroanlllne or Its metabolites may
be excreted In the urine (Mate et al., 1967).
Two studies by Bio/Dynamics reported effects In rats that were exposed
by Inhalation to vapor/aerosols of 2-n1troan1l1ne 6 hours/day, 5 days/week
for 4 weeks. In the first (Bio/Dynamics, 1983a), 2-n1troan1l1ne at 0, 10,
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28 or 73 mg/m3 mixed with 2000 mg/m3 cellosolve was given to both sexes;
in the second study {B1o/Dynamics, 1983b), rats were exposed to 0, 9.8 or 93
mg/m3 in the absence of cellosolve. Secretory effects (nasal discharge
and lacrlmatlon) were reported In the first study at >28 mg/m3 and in the
second study at 9.8 mg/m3. At 73 and 93 mg/m3, males had decreased
leukocyte counts. Females showed decreased erythrocyte and hemoglobin
values and higher relative liver weights at 73 mg/m3. Both sexes showed
altered erythrocyte morphology and slight, but not significantly, elevated
methemoglobin levels at 73 mg/m3. At 93 mg/m3, methemoglobin and
hematocrU Increased significantly. Vasllenko et al., (1974) reported hemo-
toxlc effects from 5 mg/m3 2-n1troan1l1ne given 5 hours/day for 4 months,
but experimental details were lacking. Moskalenko (1966) and Vasllenko et
al. (1972) also reported Increased hemotoxlc effects from short-term oral
intoxication. Pertinent data regarding chronic exposure to 2-nUroanlline
by any route were not located.
Acute Intraperitoneal or oral administration of 2-nHroaniline caused
hemotoxlc effects (Watanabe et al., 1976; Moskalenko, 1966). Other effects
of acute oral administration were spasms, enlarged livers and altered
oxidatlve phosphorylation (Moskalenko, 1966; Vasllenko et al., 1974; Kolodub
and Vasllenko, 1976). Topically applied as a paste In water, 2-nHroaniline
was transiently Irritating to the skin and eyes of rabbits (Younger Labora-
tories, 1977). Acute inhalation exposure to 7.5-11.7 mg/l 2-nHroanlllne
aerosol/vapor for 4 hours led to mortalities In rats, witti no consistent
dose-response trend (Haskell Laboratories, 1981). The oral LD_Q values
for rats, mice and guinea pigs were 635-3520 mg/kg (Younger Laboratories,
1977; Toxic Substances List, 1974; RTECS, 1975; Vasllenko et al., 1974;
Moskalenko, 1966). The dermal LD for rats was 7940 mg/kg (Younger
Laboratories, 1977).
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Pertinent data regarding the cardnogenlctty of 2-n1troan1l1ne adminis-
tered orally or by Inhalation or other routes of exposure were not located
1n the literature surveyed. The compound was predominantly nonmutagenlc
(see Section 6.3.). In developmental toxlclty studies, 2-n1troan1l1ne
caused maternal toxldty (plloerectlon, pale or cold extremities, depressed
weight gain and food consumption, hypoactlvlty, convulsions, salivation,
prostration, shallow respiration, loss of muscle coordination, and mortali-
ties) when mated rats were given 300-1200 mg/kg by gavage on gestation days
6-15 (Monsanto, 1984, 1985). Mean fetal body weights were depressed at 800
and 1200 mg/kg. One fetus 1n each of 2 of 25 litters of dams dosed with 600
mg/kg had situs Inversus syndrome. No fetal effects were reported at dose
levels below those associated with maternal toxlclty.
2-N1troan1l1ne was placed 1n EPA welght-of-evidence Group D because data
were not located regarding Its cardnogenlcHy In humans or animals.
Neither potency slope factors nor a cancer-based RQ were derived.
An RfC of 0.002 mg/m3 for subchronU Inhalation exposure was derived
from the NOAEL of 9.8 mg/m3 1n the 4-week Intermittent exposure Inhalation
study by Bio/Dynamics (1983b). A NOAELucr of 1.8 mg/m3 was estimated
Ht L
and an uncertainty factor of 1000 was applied. An RfC for chronic
Inhalation exposure may be extrapolated from these data by dividing the
subchronlc RfC by an additional uncertainty factor of 10, giving a value of
0.0002 mg/m3. However, confidence 1n this RfC Is low.
Oral data were not sufficient to derive RfDs for subchronlc or chronic
oral exposure to 2-nltroanlllne. In the absence of adequate oral data, a
provisional RfD of 0.0006 mg/kg/day for subchronlc oral exposure was derived
from the Inhalation study that served as the basis for the subchronlc
Inhalation RfC. The provisional status reflects low confidence because of
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route-to-route extrapolation. An RfD for chronic oral exposure may be
extrapolated Prom these data by dividing the subchronic RfD by an additional
uncertainty factor of 10, giving a value of 0.00006 mg/kg/day. Confidence
in both the subchronic and chronic oral RfD is low.
Because data for 2-nitroanlline were Inadequate for derivation of an RO,
for chronic toxicity, the RQ of 100 derived by U.S. EPA (1985) for 4-nitro-
aniline was adopted for 2-nitroaniline. Short-term exposure data indicate
that both isomers have similar (hemotoxic) effects in animals.
vlii
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1
1.1. S1RUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 3
1.5. SUMMARY 3
2. ENVIRONMENTAL FATE AND TRANSPORT 4
2.1. AIR 4
2.2. WATER 4
2.2.1. Hydrolysis 4
2.2.2. Oxidation 4
2.2.3. Mlcrobial Degradation 5
2.2.4. Volatilization 5
2.2.5. Adsorption 5
2.3. SOIL 6
2.3.1. Mlcrobial Degradation 6
2.3.2. Adsorption 6
2.4. SUMMARY 7
3. EXPOSURE 8
3.1. WATER 8
3.2. FOOD 9
3.3. INHALATION 9
3.4. DERMAL 9
3.5. SUMMARY 9
4. ENVIRONMENTAL TOXICOLOGY 11
4.1. AQUATIC TOXICOLOGY 11
4.1.1. Acute Toxic Effects on Fauna . . . . 11
4.1.2. Chronic Effects on Fauna 11
4.1.3. Effects on Flora 11
4.1.4. Effects on Bacteria 12
4.2. TERRESTRIAL TOXICOLOGY 12
4.2.1. Effects on Fauna 12
4.2.2. Effects on Flora 12
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TABLE OF CONTENTS (cont.)
4.3. FIELD STUDIES 12
4.4. AQUATIC RISK ASSESSMENT 12
4.5. SUMMARY 13
5. PHARMACOKINETCS 15
5.1. ABSORPTION 15
5.2. DISTRIBUTION 15
5.3. METABOLISM 15
5.4. EXCRETION 15
5.5. SUMMARY 16
6. EFFECTS 17
6.1. SYSTEMIC TOXICITY 17
6.1.1. Inhalation Exposure 17
6.1.2. Oral Exposure 19
6.1.3. Other Relevant Information 19
6.2. CARCINOGENICITY 21
6.2.1. Inhalation Exposure 21
6.2.2. Oral Exposure 22
6.2.3. Other Relevant Information 22
6.3. GENOTOXICITY 22
6.4. DEVELOPMENTAL TOXICITY 22
6.5. OTHER REPRODUCTIVE EFFECTS 25
6.6. SUMMARY 26
7. EXISTING GUIDELINES AND STANDARDS 28
7.1. HUMAN 28
7.2. AQUATIC 28
8. RISK ASSESSMENT 29
8.1. CARCINOGENICITY 29
8.1.1. Inhalation 29
8.1.2. Oral 29
8.1.3. Other Routes 29
8.1.4. Weight of Evidence 29
8.1.5. Quantitative Risk Estimates 29
8.2. SYSTEMIC TOXICITY 29
8.2.1. Inhalation Exposure 29
8.2.2. Oral Exposure 32
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TABLE OF CONTENTS (cont.)
9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
9.2. BASED ON CARCINOGENICITY .
10. REFERENCES.
APPENDIX A: LITERATURE SEARCHED
APPENDIX B: SUMMARY TABLE FOR 2-NITROANILINE
APPENDIX C: DOSE/DURATION RESPONSE GRAPHS FOR EXPOSURE TO
2-NITROANILINE
35
35
37
49
52
53
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LIST OF TABLES
No. TUIe Page
6-1 1050 Values for 2-NHroanlHne 20
6-2 Genotoxlclty Testing of 2-NHroan1l1ne 23
9-1 2-N1troan1llne: Minimum Effective Dose (MED) and
Reportable Quar>tHy (RQ) 36
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LIST OF ABBREVIATIONS
ADI
AEL
ATP
BCF
BOD
CAS
COO
DNA
PEL
NEC
HID
IGC
Koc
K
ow
LC
50
50
LD
50
LDU
LED
LOAEL
MM AD
NOAEL
PCB
pKa
RDOR
RfD
RQ
RVd
RVe
TWA
Acceptable dally Intake
Adverse-effect level
Adenoslne trlphosphate
Bloconcentratlon factor
Biological oxygen demand
Chemical Abstract Service
Chemical oxygen demand
Deoxyrlbonuclelc add
Frank-effect level
Human equivalent concentration
Highest Ineffective dose
Growth Inhibition concentration
Soil sorptlon coefficient
Octanol/water partition coefficient
Concentration lethal to 50% of recipients
Dose lethal to 50% of recipients
Log dose units
Lowest effective dose
Lowest-observed-adverse-effect level
Mass median aerodynamic diameter
No-observed-adverse-effect level
Polychlorlnated blphenyl
Negative 1og,Q of dissociation constant
Regional deposited dose ratio
Reference dose
Reportable quantity
Dose-rating value
Effect-rating value
Time-weighted average
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
2-NHroan1l1ne 1s the common name for the chemical known as benzenamlne,
2-nltro- by the CAS. It 1s also known by the synonyms o-n1troan1l1ne,
ortho-nltroanlHne, o-amlnonltrobenzene, 2-amlnonltrobenzene and ONA. Trade
names for ?-n1troan1lIne Include Azoene Fast Orange GR base (and salt),
Azoflx Orange GR salt, Azogene Fast Orange GR, Azoic Olazo Component 6,
Brentamlne Fast Orange Gr base (and salt), C.I. Azoic Dlazo Component 6,
C.I. 37025, Devol Orange B (and salt B), Dlazo Fast Orange GR, Fast Orange
Base GR (and JR), Fast Orange 0 base (and salt), Hlltonll Fast Orange GR
base (and salt), Hlndasol Orange GR salt, Natasol Fast Orange GR salt,
Orange Base C1BA IJ, Orange Base 1RGA II and Orange GRS salt (Chemllne.
1989). The structure, molecular weight, empirical formula and CAS number
for 2-n1troan1l1ne are as follows:
Molecular weight: 138.13
Empirical formula: C,H,N000
b D c /-
CAS Registry nur er: 88-74-4
1.2. PHYSICAL AND CHEMICAL PROPERTIES
2-Nltroanlllne Is an orange-yellow, orange-red or gold-yellow crystal-
line compound that Is soluble In alcohol, ether, benzene, acetone and
chloroform {Weast, 1985; Wlndholz, 1983; Hawley, 1981). Selected physical
properties are as follows:
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Melting point;
Boiling point:
Specific gravity:
Vapor pressure:
at 25°C
Water solubility:
at 30°C
Log Kow:
pKa:
Flash point:
Autolgnltlon:
Conversion factor;
(air at 20°C)
71.5°C
284°C
1.442 (15°C)
0.000878 mm Hg
{extrapolated
from 40°C)
1470 ppm
1.85
-0.26 (25°C)
168°C
521°C
1 mg/m3 = 0.174 ppm
1 ppm =5.74 mg/m3
Heast, 1985
Weast, 1985
Weast, 1985
Ferro and
Placente, 1985
Gross et al., 1933
Hansch and Leo, 1985
Perrln, 1964
Hawley, 1981
Hawley, 1981
2-N1troan111ne forms water soluble salts with mineral acids (Wlndholz,
1983).
1.3. PRODUCTION DATA
In 1988, three U.S. manufacturers produced 8.366 million pounds of
2-n1troan1l1ne. These manufacturers Include OuPont, Monsanto and the
Blackman-Ulmer Division of Synalloy Corporation (USI1C, 1989). The 1989
Directory of Chemical Producers cites the Monsanto Company In Sauget, IL, as
a manufacturer of 2-nltroanlllne. The Blackman-Ulmer Division of Synalloy
Corp. Is located In Spartanburg, SC (SRI, 1989). The dye and pigment
division of DuPont 1s located In Deepwater, NJ.
2-N1troan1l1ne Is manufactured by reacting 2-nltrochlorobenzene with
aqua ammonia (Dunlap, 1981; Wooster, 1963).
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1.4. USE DATA
2-N1troanll1ne 1s used as a chemical Intermediate to produce a variety
of dyes, lakes and toners for the dye Industry (Kuney, 1988; Northcott,
1978). It Is also used as a chemical Intermediate to produce sulfaqulnoxa-
line (a cocddlostat), o-phenylenedlamlne, benzotrlazole and photographic
antifogging agents (Kuney, 1988).
1.5. SUMMARY
2-N1troan111ne Is an orange-yellow, orange-red or gold-yellow crystal-
line compound that Is soluble In alcohol, ether, benzene, acetone and
chloroform (Weast, 1985; 'dindholz, 1983; Hawley, 1981). Its solubility In
water at 30°C Is 1470 ppm (Gross et al., 1933). In 1988, three U.S. manu-
facturers produced 8.366 million pounds of 2-nltroanlllne (USITC, 1989).
2-NHroanlllne Is used as a chemical Intermediate to produce a variety of
dyes, lakes and toners for the dye Industry (Kuney, 1988; Northcott, 1978).
It Is also used as a chemical Intermediate to produce sulfaqulnoxallne (a
coccldiostat), o-phenylenedlamlne, benzotrlazole and photographic anti-
fogging agents (Kuney, 1988).
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Based on a vapor pressure of 0.000878 mm Hg at 25°C (Ferro and Placente,
1985), 2-n1troan1l1ne is expected to exist In the atmosphere predominantly
In the solid phase {Elsenrelch et al.t 1981). The dominant environmental
fate process In air Is probably the gas-phase reaction with sunlight-formed
hydroxyl radicals. Using the method of Atkinson (1988), the rate constant
for the gas-phase reaction between 2-nitroan1line and hydroxyl radicals Is
an estimated 34.3xlO~lz cmVmolecule-sec at 25°C. Assuming an average
atmospheric hydroxyl radical concentration of 5xl05 molecules/cm3, the
half-life for this reaction Is -11 hours.
2.2. HATER
2.2.1. Hydrolysis. Pertinent data regarding the hydrolysis of 2-n1tro-
anlllne were not located In the available literature cited in Appendix A.
However, aromatic nitro compounds and aromatic amines generally resist
aqueous environmental hydrolysis (Harris, 1982). Therefore, hydrolysis of
2-nitroanlline Is not expected to be significant In the environment.
2.2.2. Oxidation. Aromatic amines in natural water react with photo-
chemlcally produced oxidants such as hydroxyl radicals and peroxy radicals
(Mill and Mabey, 1985). For unsubstltuted aniline, the half-lives for
reaction with hydroxyl and peroxy radicals are -30 and 19 hours of sunlight.
respectively (Mill and Mabey, 1985). These half-lives pertain specifically
to photo-oxidation at the water's surface under constant, full-intensity
sunlight. Reaction data specific to 2-n1troanil1ne were not located.
Compared with aniline, the reaction of hydroxyl and peroxy radicals with
2-nltroaniline is probably slower because of the nitro presence. Although
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specific experlinental or estimated rate data are not available. U 1s
possible that photo-oxidation of 2-nltroanlllne 1n shallow, brightly sunlit
natural water has some environmental significance.
2.2.3. Mlcroblal Degradation. The results of several biological screen-
Ing studies Indicate that 2-n1troanlUne either resists blodegradatlon or Is
only slowly blodegraded (KHano, 1978; Urano and Kato, 1986; Young and
Affleck, 1974; PHter, 1976; Halaney, 1960). For example, <30%
bio-oxidation was observed over a 14-day Incubation period using the
Japanese M1TI protocol (KHano, 1978). LHtle or zero degradation was found
using electrolytic resplrometers (Urano and Kato, 1986; Young and Affleck,
1974). A theoretl- cal BOD of only 16% was measured In a Warburg
resplrometer using activated sludge that had been acclimated to aniline
(Halaney, 1960). Removal was 0% (based upon COD) In a batch system using
activated sludge and a 5-day Incubation period (PHter, 1976).
Aerobic Incubation of 2-nltroanlllne In a rotary shaker using sewage
Inocula for 52 days resulted In a maximum loss of 15%, as measured by UV
absorbance (Hallas and Alexander, 1983). Incubation In an anaerobic
Incubator for 52 days resulted 1n a loss of -70 percent. A lag period of
-17 days occurred before anaerobic loss was measurable (Hallas and
Alexander, 1983).
2.2.4. Volatilization. Based upon a water solubility of 1470 ppm at 30°C
and a vapor pressure of 0.000878 mm Hg at 25°C (see Section 1.2.), the
Henry's Law constant for 2-nHroanlllne is an estimated 1.09xlO"7
atm-m3/mol. A Henry's Law constant of this magnitude Indicates that
volatilization from water 1s not significant (Thomas, 1982).
2.2.5. Adsorption. Based upon the discussion In Section 2.3.2., 2-n1tro-
anlUne may undergo strong covalent binding with humlc materials In natural
water, resulting In chemical conversion of 2-nltroanlllne to a latent form.
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The covalent binding reaction is not readily reversible. In the absence of
covalent binding, adsorption to sediment and suspended material in water is
not expected to be significant.
2.3. SOIL
2.3.1. Mlcroblal Degradation. Using 14C-radiolabeled 2-nltroaniline, a
20-day 14C-carbon dioxide evolution of 1.9% was measured from a laboratory
flask system containing a silt loam soil medium (Zeyer and Kearney, 1983).
From the same soil system that had been sterilized with sodium azlde,
14C-carbon dioxide evolution was <0.3%. Although the rate of degradation
is slow, these results suggest that 2-nHroaniline can biodegrade in soil.
Degradation of 2-nitroanlline in a soil mineral salts suspension
occurred in >64 days, as determined by 100% loss of UV absorbance (Alexander
and Lustigman, 1966).
2.3.2. Adsorption. The K of an organic compound can be estimated
from the following regression-derived equations (Lyman, 1982):
Log KQC -- -0.55 log (water solubility in ppm) f 3.64
Log KQC = 0.937 log KQW - 0.006
Based upon a water solubility of 1470 ppm and a log K of 1.85 (see
Section 1.2.). the KQC for 2-n1troan1l1ne is estimated at 53-79, Indicat-
ing high soil mobility {Swann et al., 1983). Although high soil mobility Is
predicted, 2-nitroanillne undergoes strong covalent binding with humlc
materials. Aromatic amines (such as the chloro- and methylanlUnes) undergo
covalent binding with humates (Parris, 1980). An initial rapid (and revers-
ible) binding phase is followed by a slow reaction (that is not readily
reversible), in which the amlne compound is chemically altered to yield an
amino-substltuted quinone. This covalent binding process represents a
mechanism In which aromatic amines may be converted to latent forms in the
biosphere (Parris, 1980).
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If 2-nHroanl 1 Ine undergoes covalent binding 1n the terrestrial environ-
ment, leaching will not be significant. However, In the absence of covalent
binding, significant leaching may be possible,
2.4. SUMMARY
When released to the atmosphere, 2-n1troan1l1ne will degrade rapidly by
reaction with photochemically produced hydroxyl radicals. The estimated
half-life for this reaction In average air Is -11 hours (Atkinson, 1988).
By analogy to the aromatic amlne chemical class (Parrls, 1980), 2-n1tro-
anlUne may undergo covalent binding to humlc materials 1n soil and water.
This covalent binding process may represent a mechanism by which 2-nltro-
anlUne may be converted to a latent form In the biosphere. If covalent
binding does not occur, 2-n1troan1l1ne may leach readily in soil, based on
estimated KQC values of 53-79 (Lyman, 1982; Swann et al., 1983). The
results of various biological screening studies Indicate that 2-n1troan1l1ne
either resists blodegradatlon or Is only slowly blodegraded (KHano, 1978;
Urano and Kato, 1986; Young and Affleck, 1974; PHter, 1976; Malaney, 1960;
Hallas and Alexander, 1983; Alexander and Lustlgman, 1966; Zeyer and
Kearney, 1983). Aquatic hydrolysis and volatilization are not significant
fate processes.
0318d -7- 05/21/90
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3. EXPOSURE
The National Occupational Exposure Survey (NOES) estimated that 1611
U.S. workers are potentially exposed to 2-n1troan1line (NIOSH, 1989). The
NOES estimate 1s based upon NIOSH surveys of U.S. industry conducted between
1981 and 1983.
Occupational exposure to 2-nltroan1l1ne is possible during Its produc-
tion and use as a chemical Intermediate. The most likely route of exposure
In occupational settings Is by dermal contact (NCI, 1985). Exposure by
inhalation Is probably low because nltroanlHne Is a solid at room tempera-
tures with a low vapor pressure (NCI, 1985).
2-NHroanlllne can be produced during both the aerobic and anaerobic
Incubation of 1,2-dlnltrobenzene in sewage (Hallas and Alexander, 1983).
This suggests that 2-n1troan1l1ne may be present in some environmental
samples as a result of dlnHrobenzene blodegradatlon, rather than direct
anthropogenic release.
3.1. HATER
Published monitoring data pertaining to the detection of 2-nltroanlllne
1n environmental waters are very limited. 2-NHroan1l1ne was qualitatively
detected 1n the River Waal at Brakel in the Netherlands during monitoring
between 1972 and 1974 (Meiers and Van Der Leer, 1976). A 2-nHroan1l1ne
concentration of 1 ppb was detected In the Rhine River at Loblth, Nether-
lands In 3uly, 1979 (Zoeteman et al., 1980). A compilation of chemicals
Identified in municipal landfill leachates reported a 2-n1troan1l1ne
concentration of 180 mg/i (Brown and Donnelly, 1988).
0318d -8- 05/21/90
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The U.S. EPA (1989) STORET Data Base contains 30 positive detections of
2-nHroanlllne 1n surface waters. The maximum, minimum and mean concentra-
tions for these positive detections reported by STORE! are 1.70, 0.09 and
0.55 pg/l, respectively.
Chemical Intermediates used in the synthesis of dyes and pigments can be
emitted to the environment In wastewater streams generated at production
sites (Steadman et al., 1977). Since 2-n1troan1line 1s widely used In dye
synthesis (see Section 1.4.), 1t may be released to the environment through
wastewater effluents.
3.2. FOOD
Pertinent monitoring data regarding levels of 2-n1troan1l1ne 1n food
were not located 1n the available literature cited In Appendix A.
3.3. INHALATION
Pertinent monitoring data regarding Inhalation exposure of 2-nHro-
anlllne were not located In the available literature cited In Appendix A.
3.4. DERMAL
Pertinent monitoring data regarding dermal exposure of 2-n1troan1l1ne
were not located In the available literature cited In Appendix A.
3.5. SUMMARY
The National Occupational Exposure Survey (NOES) estimated that 1611
U.S. workers are potentially exposed to 2-nltroanlllne (NIOSH, 1989).
Occupational exposure to 2-nltroanlllne is possible during Its production
and use as a chemical Intermediate. The most likely route.of exposure In
occupational settings Is by dermal contact. Inhalation exposure Is probably
low because n1troan1l1ne Is a solid at room temperatures with a low vapor
pressure (NCI, 1985). The use of 2-nHroan1l1ne In dye synthesis
0318d -9- 05/21/90
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suggests that it may be released to the environment in wastewater effluents
From dye production (Steadman et al., 1977). 2-NHroaniline may also occur
in the environment as a microblal decomposition product of dinitrobenzene
(Hallas and Alexander, 1983). Pertinent monitoring data regarding food,
Inhalation and dermal exposure of 2-n1troanil1rie were not located in the
available literature cited in Appendix A.
0318d
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4. ENVIRONMENTAL TOXICOLOGY
4.1. AQUATIC TOXICOLOGY
4.1.1. Acute Toxic Effects on Fauna. Pertinent data regarding the
effects of acute exposure of saltwater fauna to 2-n1troan1l1ne were not
located In the available literature cited In Appendix A. Studies with
freshwater fauna Include a 14-day study with the guppy, Poecllla retlculata.
which resulted 1n an LC5Q of 70.79 pmol/i (9.8 rng/a) (Deneer et al.,
1987). Loeb and Kelly (1963) reported no effect 1n carp, Cyprlnus carplo.
that were force-fed the test article at 163, 177 and 189 mg/kg for 22 hours.
Applegate et al. (1957) found no effects In larval sea lampreys, Petromyzan
marlnus, exposed to 5.0 mg/i for 24 hours.
4.1.2. Chronic Effects on Fauna.
4.1.2.1. TOXICITY Pertinent data regarding the effects of chronic
exposure of aquatic fauna to 2-n1troan1l1ne were not located In the
available literature cited In Appendix A.
4.1.2.2. BIOACCUMULATION/BIOCONCENTRATION Sasaki (1978) reported
that 2-n1troan1l1ne Is nonaccumulatlve or Is slightly b1oaccumu1at1ve.
Tests were conducted with carp exposed to the test article under flowthrough
conditions at 25DC for ~8 weeks. In evaluating the results of bloaccumula-
tlon tests, an 8-week BCF exceeding "a few hundred times" Is typically
considered to be highly bloaccumulatlve, whereas criteria for judging a
chemical to be of low bloaccumulatlon potential were not described.
4.1.3. Effects on Flora.
4.1.3.1. TOXICITY Pertinent data regarding the toxic effects of
exposure of aquatic flora to 2-nltroanlllne were not located In the
available literature cited 1n Appendix A.
0318d -11- 05/21/90
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4.1.3.2. BIOCONCENTRATION Pertinent data regarding the bloconcen-
tratlon potential of 2-nitroan1l1ne In aquaUc flora were not located In the
available literature cited In Appendix A.
4.1.4. Effects on Bacteria. Ihe effects of 2-nltroanlUne on growth of
the dilate, Tetrahymena pyrlformls. were Investigated by Schultz and
Applehans (1985). Cultures of the dilates were grown at 28° under static
conditions, and cultures were tested with 50 ms. of the test substance at
five different concentrations. The 60-hour IGC5Q was 115.55 mg/8, (0.837
mmol/l).
4.2. TERRESTRIAL TOXICOLOGY
4.2.1. Effects on Fauna. Schafer et al. (1983) examined the acute oral
toxldty of 2-nltroanillne to birds. The LD s for redwing blackbirds,
Aegelaius phoenlceus. starlings, Sturn Is vulgar Is. the Coturnlx quail,
Coturn1x coturnlx, and the house sparrow, Passer domestlcus. were 750,
>1000, 750 and 750 mg/kg, respectively.
4.2.2. Effects on Flora. Pertinent data regarding the effects of
exposure of terrestrial flora to 2-n1troan1lIne were not located in the
available literature dted in Appendix A.
4.3. FIELD STUDIES
Pertinent data regarding the effects of 2-n1troan1line on flora and
fauna in the field were not located in the available literature dted 1n
Appendix A.
4.4. AQUATIC RISK ASSESSMENT
The lack of pertinent data regarding the effects of exposure of aquatic
fauna and flora to 2-n1troan1l1ne precluded the development of a freshwater
criterion by the method of U.S. EPA/OWRS (1986). Additional data required
for the development of a freshwater criterion include the results of acute
0318d
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assays with a salmonld fish species, a warm water fish species, a third fish
species or an amphibian, planktonlc and benthlc crustaceans, an Insect, a
nonarthropod and nonchordate species and an Insect or species from a phylum
not previously represented. The development of a freshwater criterion will
also require data from chronic toxUHy tests with two species of fauna and
one species of alga or vascular plant and at least one bloconcentratlon
study.
The lack of pertinent data regarding the effects of exposure of aquatic
fauna and flora to 2-nltroanlllne precluded the development of a saltwater
criterion by the method of U.S. EPA/OWRS (1986). Additional data required
for the development of a saltwater criterion Include the results of acute
assays with two chordate species a nonarthropod and nonchordate species, .a
mysld or panaeld crustacean, two additional nonchordate species and one
other species of marine fauna. The development of a saltwater criterion
also requires data from chronic toxlclty tests with two species of fauna and
one species of algae or vascular plant and at least one bloconcentratlon
study.
4.5. SUMMARY
The lack of adequate freshwater and saltwater toxlclty and bloconcentra-
tlon data with both flora and fauna precludes the development of criteria
for 2-nltroanlllne. The larval sea lamprey was not affected when exposed at
5.0 mg/a. for 24 hours (Applegate et a!., 1957); 9.8 mg/s, was the 14-day
1C for gupples (Deneer et al., 1987). Carp that were force-fed 2-nltro-
anlllne at a dose <189 mg/kg suffered no observed adverse effects (Loeb and
Kelly, 1963). The dilate bacteria, Tetrahymena pyrlformls. had a 60-hour
IGC5Q of 115.55 mg/i (Schultz and Applehans, 1985). 2-NHroanallne
0318d -13- 05/21/90
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LDggS for the redwing blackbird, starling, coturnlx and house sparrow were
750, >1000, 750 and 750 mg/kg, respectively (Schafer et al., 1983).
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5. PHARMACOKINETICS
5.1. ABSORPTION
A Pertinent data regarding the absorption of 2-nHroaniline were not
located In the available literature cited In Appendix A. However, Its
Isomer, 4-n1troan1l1ne, Is readily absorbed from the gastrointestinal tract,
from the peritoneal cavity and through skin (U.S. EPA, 1985). Since the two
compounds have similar K s (Index of hydrophoblclty} and pK values <1,
OW a
It Is likely that 2-n1troan1l1ne Is also readily absorbed. In an English
abstract of a Russian study of permissible concentrations of nltroamlno
compounds In reservoir waters, Mostcalenko (1966) reported that all three
(presumably orally administered) Isomers of nltroanlllne affected hematology
parameters 1n acute and subacute protocols with guinea pigs, rats and mice.
Indicating that absorption from the gastrointestinal tract had occurred. In
a similar abstract, Vasllenko et al. (1974) reported "a skln-resorptlve
effect" for all three Isomers In rats.
5.2. DISTRIBUTION
Pertinent data regarding the distribution of 2-nltroanlllne were not
located In the available literature cited In Appendix A.
5.3. METABOLISM
Five hours after IntraperHoneal administration of 2-n1troan1l1ne at TOO
nmol/kg (13.8 mg/kg) to male Wlstar rats, unspecified d1azo-pos1tive
metabolites were identified In the urine (Watanabe et al., 1976).
5.4. EXCRETION
When Mate et al. (1967) treated male rats IntraperHoneally with 10 mg
[l4C]p-n1troan1line per animal, 76.5% of the dose was excreted In the
urine within 24 hours. If the o-lsomer behaves similarly to the p-lsomer,
It can be Inferred that a large fraction of IntraperHoneally administered
2-nltroanlllne or Its metabolites Is excreted In the urine.
0318d -15- 05/21/90
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5.5. SUMMARY
Five hours after intraperHoneal administration of 2-n1troan1l1ne at 100
>imol/kg (13.8 mg/kg) to male Wlstar rats, unspecified dlazo-posltlve
metabolites were Identified In the urine (Watanabe et al., 1976). Although
there are few data relevant to the absorption of 2-nHroan1Hne (Moskalenko,
1966; Vasllenko et al., 1974), the similarity of Us properties to those of
the 4-1somer, which Is known to be rapidly absorbed when administered
orally, IntraperHoneal ly or dermally (U.S. EPA, 1985), suggests that
2-nltroanlltne may also be readily absorbed when given by these routes. If
the o-isomer behaves similarly to the p-lsomer, a substantial fraction of an
1ntraper1toneally administered dose of 2-n1troan1l1ne or Its metabolites may
be excreted 1n the urine (Mate et al., 1967).
0318d
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposure.
6.1.1.1. SUBCHRONIC According to Bio/Dynamics (1983a), aerosols of
0 (vehicle) 10, 28 or 73 mg/m3 2-nltroanlllne In cellosolve vehicle were
given to groups of 10 Sprague-Dawley rats per sex, 6 hours/day, 5 days/week
for 4 weeks In Inhalation chambers. The concentration of cellosolve In the
air was -2000 mg/m3 \n all groups. Particle size was determined for
samples taken from four to six of the exposures, and the count median
diameter was 0.5-0.9 vm with standard deviations of 1.1-2.2 and no
concentration-related trend. There was no treatment-related mortality. All
exposed groups had yellow fur. The 28 and 73 mg/m3 groups had Increased
Incidence of dried red nasal discharge; lacrlmatlon was reported for the
latter group. There was no effect on body weight or ophthalmoscoplc
findings. At 73 mg/m3, males showed a significant dose-related decrease
^ In leukocyte count, and females showed decreased erythrocyte and hemoglobin
values. Both sexes of this dose group showed variations In erythrocyte
morphology, Including polychromla, anlsocytosls and polkllocytosls. Methe-
moglobln values showed slight, but not significant, Increases at the high
dose. Serum calcium concentration Increased significantly above concurrent,
but not historical, controls In mid- and high-dose males. Microscopic
examination of a wide range of tissues from rats In the control and
high-dose groups, Including the eyes and nasal turblnates, revealed no
compound-related adverse effects, except on the testes. The testes of
high-dose males had lower absolute and relative weights with degeneration of
germinal epHhella. The testes of rats In the other exposed groups
exhibited no effects of treatment. High-dose females had higher relative
liver weights (B1o/0ynam1cs, 1983a).
0318d -17- 05/21/90
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Subsequently, Monsanto (1983) reported finding new data 1n the litera-
ture on effects of cellosolve on the reproductive system; therefore, a
second study was performed. Ten male Sprague-Dawley rats/group were exposed
In chambers to vapor/aerosols of 0, 9.8 and 93 mg/m3 2-n1troan1l1ne 6
hours/day, 5 days/week for 4 weeks (B1o/Dynam1cs, 1983b). The atmospheres
were generated by passing warmed nitrogen over heated 2-n1troan1l1ne In the
absence of cellosolve at controlled rates. Controls were subjected to
atmospheres containing warmed nitrogen without passage over 2-n1troan1l1ne.
The mean count median diameters for the particles In the air In the control
and low-dose groups were 0.53 and 0.55 ym with standard deviations of 1.9
and 2.1, respectively, In chambers maintained at 26°C. Monsanto (1983}
Interpreted the similarity In particle size 1n the control and low-dose
chambers to suggest that virtually all the 2-nltroanlllne present In the
low-dose chamber existed as a vapor. In the high-dose group, the average
mass median diameter and standard deviation were reported as 3.5 and 2.7
iim, respectively. No mortalities were reported. The exposed groups had
yellow fur and secretory responses such as Iacr1mat1on, mucold or dried red
nasal discharge, especially 1n the later weeks. In the high-dose group,
methemoglobtn and hematocrlt were Increased and leukocyte counts (segmented
neutrophlls) were decreased relative to concurrent controls. Only methemo-
globln was outside the range of historical controls. There were no effects
on body weight, organ weights or the gross appearance of a wide range of
tissues, Including the testes. Hlstopathologlcal examination, limited to
the testes and epldldymus, revealed no compound-related changes.
Vasllenko et al. (1974) reported that hemotoxlc effects of 2-n1troan1-
llne were less pronounced than were the decreases In hemoglobin concentra-
tion and erythrocyte count In rats exposed to 5 mg/m3 4-n1troan1l1ne, 5
hours/day for 4 months.
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6.1.1.2. CHRONIC Pertinent data regarding the systemic toxlclty of
chronic Inhalation exposure to 2-n1troan1l1ne were not located In the
available literature cited In Appendix A.
6.1.2. Oral Exposure.
6.1.2.1. SUBCHRONIC Moskalenko (1966) reported that subacute
(presumably oral) Intoxication of mice and guinea pigs with 2-n1troan1lIne
was associated with Increased hemoglobin, erythrocytes and retlculocytes,
along with the presence of Heinz bodies, and that these effects were accen-
tuated relative to acute Intoxication. Dose and duration of exposure were
not reported. Vasllenko et al. (1972} reported that oral administration of
2-n1troan1l1ne to rats at 0.1-0.2 LD for 30 days caused transformation
of hemoglobin to methemoglobln, nltrosylhemoglobin and sulfhemoglobln. The
Increased levels of methemoglobln and sulfhemoglobln were associated with
decreased oxyhemoglobln, but total hemoglobin was unaffected.
6.1.2.2. CHRONIC Pertinent data regarding the systemic toxldty of
chronic oral exposure to 2-n1troan1l1ne were not located In the available
literature cited In Appendix A.
6.1.3. Other Relevant Information. Younger Laboratories (1977) found
transient Irritation to the eyes and no Irritation to the skin of New
Zealand white rabbits from topical applications of 50 and 500 mg finely
ground 2-nltroanlline moistened with water to the eyes and skin, respec-
tively. Oral and dermal LD.._ values are summarized 1n Table 6-1. The
DU
oral L05 for rats were 535-3520 mg/kg. The limited data do not suggest
major differences In the acute toxldty of 2-nltroanlllne to rats, mice and
guinea pigs.
0318d -19- 05/21/90
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TABLE 6-1
LD50 Values for 2-NHroan1Hne
Species/Strain Sex Route of L05p Value
Administration (mg/kg)
Reference
Rats/
Sprague-Dawley
Rats/
Sprague-Dawley
Rats/NR
Rats/NR
Mice/NR
Guinea pigs/NR
M,F
M,F
NR
NR
NR
NR
dermal
oral
oral
oral
oral
oral
7940
2050
535
3520
1246.1
2350
Younger Laboratories,
1977
Younger Laboratories,
1977
loxlc Substances List,
1974; RTECS, 1975
Vasllenko et al.. 1974
Moskalenko, 1966
Moskalenko, 1966
NR = Not reported
0318d
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Haskell Laboratories (1981) exposed groups of 10 male CM:CD rats (head
only) for 4 hours to 1.1-12.02 mg/i 2-nltroan1lIne aerosols/vapor con-
talning mlcrocrystalllne particles with MHAD ranging from 4-11 vm and
geometric standard deviations ranging from 1.16-1.84. There were no
mortalities at concentrations <6.6 mg/i; however, at concentrations of
7.55-11.66 mg/i, 1/10-6/10 rats died with In 2-4 hours of Initial
exposure. This effect was not considered dose-related. Lack of dose-
related mortality precluded determination of an LC , and the approximate
lethal concentration was estimated to be >12 mg/a. Clinical signs, other
than mortality, were bright orange urine, slight corneal opacif1cat1on 24
hours after exposure that cleared in 2-3 days and 2-5% weight loss In the
first 24 hours with normal gains afterward. Necropsies showed slightly
enlarged livers and congested, mottled lungs.
A single Intraperltoneal Injection of 100 pmol/kg (13.8 rug/kg) or in
vUro Incubation of 0.5 ymol 2-n1troanlline with 0.1 v^ol hemoglobin
resulted In methemoglobln formation in the blood of male rats (Watanabe et
al., 1976). Hoskalenko (1966) reported that acute (presumably oral) Intoxi-
cation of mice and guinea pigs at the LD5Q for 2-nltroanlllne resulted In
spasms and Increased hemoglobin, erythrocytes and retlculocytes, along with
Heinz bodies, leukocytosls, neutrophils and lymphopenla. Vasllenko et al.
(1974) reported that 2-n1troan1lIne showed hepatotroplc properties when
orally administered to rats at half the L0|-n- Kolodub and Vasllenko
(1976) reported that 20% of the oral LD5Q for 2-nltroanlllne inhibited
electron transfer and decreased ATP synthesis In livers of rats.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carcinogenicity of
inhaled 2-n1troan1l1ne were not located in the available literature dted
1n Appendix A.
0318d -21- 05/21/90
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6.2.2. Oral. Pertinent data regarding the carclnogenlcity of orally
administered 2-nHroannine were not located In the available literature
cited In Appendix A.
6.2.3. Other Relevant Information. Pertinent data regarding the carclno-
genlcHy of 2-n1troan1l1ne administered by other routes were not located 1n
the available literature cHed In Appendix A.
6.3. GENOTQXICITY
Relevant genotoxldty data for 2-nHroan1l1ne are presented \r\ Table
6-2. The data are mainly negative. In prokaryotes, 2-n1troan1l1ne Induced
reverse mutations In tester strains 1A98 and 1A1598 of Salmonella typjij-
murlain, both of which are sensitive to frameshift mutations, but not In
strains TA100 or TA1535, both of which are sensitive to base-pair substitu-
tions (Garner and Nutman, 1977; Chlu et al., 1978; Thompson et a!., 1983;
Shlmizu and Takemura, 1983; Le et al., 1985; Shlmizu and Yano, 1986). A
recent publication confirmed the low mutagenic potential of 2-n1troan1l1ne
1n Salmonella ty^hjmurium (strains TA98 and TA100) {Dellarco and Prival,
1989). This study was done under conditions allowing for the reduction of
the nitro group. Revertants were not Induced In Escherlchla coll (Thompson
et al., 1983), but 2-nitroaniline was positive In the differential toxidty
test in Bacillus subtllis (Shimizu and Yano, 1986). In mammalian systems,
results were entirely negative. Iji vitro. 2-nltroaniline failed to Induce
unscheduled DNA repair 1n rat hepatocytes (Yoshimi et al., 1988; Thompson et
al., 1983); in y_1_y_o. It failed to Induce strand breaks detectable by
alkaline elution in Swiss mice (Cesarone et al., 1982).
6.4. DEVELOPMENTAL TOXICITY
In a range-finding study, groups of six mated Crl:CO rats were given 0,
50, 200, 400, 800 or 1200 mg/kg 2-n1troan1l1ne in corn oil by gavage on
0318d
-22-
02/15/91
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gestation days 6-15 (Monsanto, 1984). Four dams died In the highest dose
group; mean maternal body weight gains and food consumption were reduced In
the two highest dose groups. Clinical signs exhibited by dams In the two
highest groups Included hypoactlvlty, convulsions, salivation, prostration,
piloerectlon, shallow respiration and loss of muscle coordination. All
treated dams had yellow stains on their fur. No effects were seen on the
mean number of viable fetuses, total Implantations or resorptlons. Mean
fetal body weights were depressed only at the two higher doses. No external
malformations were found (Monsanto, 1984).
Based on the Monsanto (1984) range-finding study, groups of 25 mated
Charles River CD rats were given 0, 100, 300 and 600 mg/kg/day 2-nltro-
anlUne In corn oil by gavage on gestation days 6-15 (Monsanto, 1985).
There were no treatment-related mortalities In the dams. Transient maternal
toxldty In the 300 and 600 mg/kg/day groups was Indicated by plloerectlon
and pale or cold extremities. Maternal weight gains were depressed In the
600 mg/kg/day group. Food consumption was reduced In the 300 and 600
mg/kg/day groups, especially during treatment. There were no chemical-
related effects on pregnancy rates, fetal resorptlons, fetal viability,
postlmplantatlon losses, total Implantations or mean litter weights. One
fetus In each of two Utters of high-dose dams had situs Inversus syndrome.
6.5. OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding other reproductive effects of 2-n1troan1l1ne
were not located 1n the available literature dted In Appendix A. Recall,
however, the Bio/Dynamics study (1983a) referred to In Section 6.1.1.1.
where absolute and relative testlcular weight was reduced In rats exposed to
73 mg/m3 2-n1troan1l1ne In cellosolve vehicle.
0318d -25- 02/15/91
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6.6. SUMMARY
Two studies by Bio/Dynamics reported effects In rats that were exposed
by Inhalation to vapor/aerosols of 2-n1troan1l1ne 6 hours/day, 5 days/week
for 4 weeks. In the first (B1o/Dynam1cst 1983a), 2-nltroan1l1ne at 0, 10,
28 or 73 mg/m3 mixed with 2000 mg/m3 cellosolve was given to both sexes;
In the second study (Bio/Dynamics, 1983b), rats were exposed to 0, 9.8 or 93
mg/m3 In the absence of cellosolve. Secretory effects (nasal discharge
and lacrlmatlon) were reported In the first study at >28 mg/m3 and In the
second study at 9.8 mg/m3. At 73 or 93 mg/m3, males had decreased
leukocyte counts. Females showed decreased erythrocyte and hemoglobin
values and higher relative liver weights at 73 mg/m3. Both sexes showed
altered erythrocyte morphology and slight, but not significantly elevated
methemoglobln levels at 73 mg/m3. At 93 mg/m3, methemoglobln and
hematocrit Increased significantly. Vasllenko et al. (1974) reported hemo-
toxlc effects from 5 mg/m3 2-n1troan1l1ne given 5 hours/day for 4 months,
but experimental details were lacking. Moskalenko (1966) and Vasllenko et
al. (1972) also reported Increased hemotoxlc effects from subacute oral
Intoxication. Pertinent data regarding chronic exposure to 2-n1troan1l1ne
by any route were not located.
Acute 1ntraper1toneal or oral administration of 2-nltroanlllne caused
hemotoxlc effects (Watanabe et al., 1976; Moskalenko, 1966). Other effects
of acute oral administration were spasms, enlarged livers and altered
oxldatlve phosphorylatlon (Moskalenko, 1966; Vasllenko et al., 1974; Kolodub
and Vasllenko, 1976). Topically applied as a paste 1n water, 2-n1troan1l1ne
was transiently Irritating to the skin and eyes of rabbits (Younger Labora-
tories, 1977). Acute Inhalation exposure to 7.5-11.7 mg/i 2-nltroanlHne
aerosol/vapor for 4 hours led to mortalities In rats, with no consistent
0318d -26- 02/15/91
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dose-response trend (Haskell Laboratories, 1981). The oral LDrQ values
A for rats, mice and guinea pigs were 535-3520 mg/kg (Younger Laboratories,
1977; Toxic Substances List, 1974; RTECS, 1975; Vasllenko et al.t 1974;
Moskalenko, 1966). The dermal LD5 for rats was 7940 mg/kg (Younger
Laboratories, 1977).
Pertinent data regarding the carcinogeniclty of 2-nltroanillne adminis-
tered orally or by Inhalation or other routes of exposure were not located.
The compound was predominantly nonmutagenlc (see Section 6.3.). In develop-
mental toxldty studies, 2-n1troan1l1ne caused maternal toxlclty (plloerec-
tlon, pale or cold extremities, depressed weight gain and food consumption,
hypoactlvlty, convulsions, salivation, prostration, shallow respiration,
loss of muscle coordination or mortalities) when mated rats were given 800
or 1200 mg/kg by gavage on gestation days 6-15 (Monsanto, 1984; 1985). Mean
fetal body weights were depressed at 800 and 1200 mg/kg. One fetus in each
^. of 2 of 25 litters of dams dosed with 600 mg/kg had situs Inversus syndrome.
No fetal effects were reported at dose levels below those associated with
maternal toxlclty.
0318d -27- 02/15/91
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
Pertinent guidelines and standards for 2-n1troan1l1nef Including EPA
ambient water and air quality criteria, drinking water standards, FAO/HHO
ADIs, EPA or FDA tolerances for raw agricultural commodities or foods and
ACGIH, N10SH or OSHA occupational exposure limits, were not located In the
available literature cited In Appendix A.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic life from
exposure to 2-nHroan1l1ne were not located In the available "literature
cited 1n Appendix A.
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the cardnogenldty of
Inhaled 2-n1troan1llne to humans or to animals were not located 1n the
available literature dted In Appendix A.
8.1.2. Oral. Pertinent data regarding the carclnogenldty of orally
administered 2-n1troan1l1ne to humans or to animals were not located In the
available literature cited In Appendix A.
8.1.3. Other Routes. Pertinent data regarding the carclnogenldty of
2-n1troan1l1ne administered by other routes to humans or to animals were not
located In the available literature cited 1n Appendix A.
8.1.4. Weight of the Evidence. Because there are no data available
regarding carclnogenldty of 2-n1troan1l1ne to humans or to animals, this
chemical 1s placed In EPA we1ght-of-ev1dence Group D -- Not Classifiable as
to Human Carclnogenldty, according to guidelines established by the U.S.
EPA (1986b).
8.1.5. Quantitative Risk Estimates. Because 2-n1troan1l1ne Is classified
In EPA we1ght-of-ev1dence Group D and quantitative dose-response data are
not available, quantitative risk assessment cannot be performed.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME (SUBCHRONIC) Two unpublished studies
reported effects In rats exposed In Inhalation chambers to vapor/aerosols of
2-n1troan1l1ne 6 hours/day, 5 days/week for 4 weeks. In the first
(Bio/Dynamics, 1983a), 2-n1troan1l1ne at 0, 10, 28 or 73 mg/m3 was mixed
with 2000 mg/m3 cellosolve and administered to both sexes. In the second
study (81o/Dynam1cs, 1983b), only males were exposed to 0, 9.8 or 93 mg/m3
0318d -29- 08/16/90
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1n the absence of cellosolve. Signs of local Irritation (nasal discharge
and lacrlmatlon) were reported In the first study at >28 mg/m3 (Rec. #4,
Appendix C.2.1.) and In the second study at >9.8 mg/m3 (Rec. #1, Appendix
C.2.1.). Rats In the control and high-dose groups 1n the first study were
subjected to a comprehensive hlstopathologlcal examination that Included the
eyes and nasal turblnates. There were no treatment-related hlstopathologl-
cal alterations 1n the eyes or nasal epithelium. The lacMmatlon and nasal
discharges are considered to be the result of local Irritation, since they
were not accompanied by evidence of hlstopathologlcal damage.
In the first study at 73 mg/m3 {Rec. #3, Appendix C.2.1.), and 1n the
second at 93 mg/m3 (Rec. #2, Appendix C.2.1.), males had decreased leuko-
cyte counts. Females showed decreased erythrocyte and hemoglobin values and
higher relative liver weights at 73 mg/m3. Both sexes showed altered
erythrocyte morphology and slight, but not significantly elevated methemo-
globln levels at 73 mg/m3. At 93 mg/m3 {Rec. #2, Appendix C.2.1.),
methemoglobln and hematocrlt were Increased significantly. These data
Indicate that the critical effect of Inhalation exposure to 2-n1troan1l1ne
Is altered hematology. Including decreased leukocyte count, altered erythro-
cyte morphology, hematocrlt and blood hemoglobin concentration and methemo-
globlnemla {B1o/Dynam1cs, 1983a,b). Vasllenko et al. (1974) reported
hemotoxlc effects 1n rats at 5 mg/m3 2-n1troan1l1ne given 5 hours/day for
4 months, but experimental details were lacking; therefore, this study Is
not considered adequate for quantitative risk assessment.
In the first study (Bio/Dynamics, 1983a), Intermittent exposure to 28
mg/m3 was a LOAEL for nasal and eye Irritation (Rec. #4, Appendix C.2.1.),
and Intermittent exposure to 73 mg/m3 was a LOAEL (Rec. #3, Appendix
C.2.1.) for hemotoxlclty. Intermittent exposure to 9.8 mg/m3 was a NOAEL
0318d
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(Rec. #1, Appendix C.2.1.) and Intermittent exposure to 93 mg/m3 was a
LOAEL (Rec. #2, Appendix C.2.1.) for hemotoxlclty (B1o/Dynamics, 1983b).
Since 9.8 mg/m3 did produce Irritant effects In the Bio/Dynamics (1983b)
study (Rec. #1, Appendix C.2.I.), however, 1t Is considered a LOAEL for
Inhalation exposure to 2-n1troanalIne.
As Indicated by Bio/Dynamics (1983b) and Monsanto (1983), particle size
1n the control and low-dose groups was virtually Identical. Monsanto (1983)
Interpreted this observation to Indicate that virtually all the 2-n1tro-
anlllne present 1n the air at the low dose was present In the vapor form. A
LOAELHEC can be estimated from the LOAEL of 9.8 mg/m3 (Rec. #1, Appendix
C.2.1.) In the Bio/Dynamics (1983b) study. The Intermittent exposure level
of 9.8 mg/m3 1s multiplied by 6 hours of exposure per 24-hour day and 5
days of exposure per 7-day week to estimate an adjusted equivalent con-
tinuous exposure concentration of 1.8 mg/m3. The adjusted concentration
of 1.8 mg 2-nltroanlllne/m3, therefore, 1s the LOAELucr {B1o/Dynam1cs,
Mt L
1983b).
An adjusted equivalent continuous exposure concentration of 5.0 mg/m3
Is estimated by multiplying the 28 mg/m3 Intermittent exposure level by 6
hours of exposure per 24-hour day and by 5 days of exposure per 7-day week.
An RfC for subchronlc Inhalation exposure can be estimated by applying
an uncertainty factor of 1000 (10 to reflect the uncertainties In the
methodology for estimating a HEC from animal exposure data, 10 to provide
additional protection for unusually sensitive Individuals, and 10 for use of
a LOAEL for RfD derivation) to the LOAELUC_ of 1.8 mg/m3. The resulting
net
RfC for subchronlc Inhalation exposure of 0.002 mg/m3 1s recommended for
exposure to vapors of 2-n1troan1l1ne.
O
0318d -31- 03/11/91
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Confidence In the study, based on observations restricted to 10 male
animals per exposure level and a 4-week exposure duration, 1s low.
Confidence 1n the data base Is low because the Bio/Dynamics (1983a) study
supports the NOAEL In the key study, because other data support hematologlc
toxUHy as the critical effect, and because a developmental toxldty study
did not report fetal effects at levels below those associated with maternal
toxlclty. Confidence In the RfC, therefore, 1s medium.
8.2.1.2. CHRONIC Pertinent data regarding the systemic toxlclty of
chronic Inhalation exposure to 2-n1troan1"!1ne were not located In the
available literature cited In Appendix A. A chronic Inhalation RfC may be
calculated by dividing the subchronlc RfC by an additional uncertainty
factor of 10, giving a value of 0.0002 mg/m3.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME (SUBCHRONIC) ~ Abstracts of Russian
studies were not compiled Into data records In Appendix C.2.2., because data
that associated hemotoxlc effects with subacute oral Intoxication with
2-nltroanllIne were Inadequately reported (Moskalenko, 1966; Vasllenko et
a!., 1972). Watanabe et al. (1976) showed that IntraperHoneal Injection of
rats with 2-n1troan1l1ne also resulted In hemotoxlclty.
In developmental toxlclty studies, 2-n1troan1l1ne caused maternal
toxlclty (Recs. #1, 2, 4, 5, Appendix C.2.2.) when mated rats were given
300-1200 mg/kg/day by gavage on gestation days 6-15 (Monsanto, 1984; 1985).
Mean fetal body weights were depressed at 800 and 1200 mg/kg/day (Recs. #1,
2, Appendix C.2.2.). One fetus In each of 2 of 25 Utters of dams dosed at
600 mg/kg/day had situs Inversus syndrome (Rec. #4, Appendix C.2.2.). No
fetal or reproductive effects were reported at dose levels not associated
with maternal toxlclty (Recs. #3, 5, 6, Appendix C.2.2.). Since studies of
0318d
-32-
03/11/91
-------
oral exposures of sufficient detail and duration are lacking, an RfO for
subchronlc oral exposure to 2-nltroanlllne cannot be derived from route-
specific data. Data regarding other nltroanlUnes administered orally were
also Insufficient (U.S. EPA, 1985), precluding adoption of an RfD for oral
exposure to 2-nHroanlllne by analogy to other nltroanlllnes. In the
absence of adequate route-specific data, It 1s appropriate to consider
deriving an RfD for oral exposure from Inhalation data. As Indicated above,
hemotoxldty appears to be the critical effect of exposure to 2-nltroanlllne
by any route of exposure.
Since the local Irritant effects seen with Inhalation exposure to
2-nltroanaline would not be expected with oral exposure, the NOAEL of 9.8
mg/m3 for hemotoxldty in the B1o/Dynamics (1983b) 4-week Inhalation study
can also serve as the basis for a provisional subchronlc oral RfD. As
described in Section 8.2.1.1., the 9.8 mg/m3 Intermittent exposure
concentration can be expanded to an equivalent continuous exposure concen-
tration of 1.8 mg/m3. In the absence of pharmacoklnetlc data. It 1s
appropriate to assume that steady state may have been reached during each
exposure Interval. Since experimental blood:a1r partition coefficients for
2-nltroanlllne 1n humans and animals are unavailable, It Is appropriate to
assume an equivalent value for both species. Multiplying this concentration
by the reference Inhalation rate for rats of 0.223 mVday (U.S. EPA, 1980}
and dividing by the TWA body weight for rats In this group of 0.350 kg
results in an estimated Inhaled dose of 1.15 mg/kg/day. In the absence of
adequate pharmacoklnetU data, it Is appropriate to assume absorption of 50%
of an Inhaled dose and 100% of an Ingested dose. An equivalent oral dose of
0.58 mg/kg/day Is estimated by multiplying the Inhaled dose by the ratio of
percent Inhalation to percent gastrointestinal absorption. Applying an
0318d -33- 08/16/90
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uncertainty factor of 1000 (10 to extrapolate from animals to humans, 10 to
provide additional protection for unusually sensitive humans, and 10 to
reflect the uncertainties arising from lack of sufficient reproductive and
oral exposure data) results in an RfD for subchronic oral exposure to
2-nitroaniline of 0.0006 mg/kg/day.
Confidence in the key study, based on observations In 10 male rats per
exposure level and a 4-week duration of exposure, is low. Confidence in the
data base Is low, primarily because of the lack of sufficient oral exposure
data. Confidence in the RfO, therefore, is low.
8.2.2.2, CHRONIC Pertinent data regarding the systemic toxicity of
chronic oral exposure to 2-nltroanlline were not located in the available
literature cited in Appendix A. Therefore the chronic RfD for
2-nitroanallne must be calculated by dividing the above subchronic oral RfD
by an additional uncertainty factor of 10 to account for the use of a
short-term study for chronic RfD derivation, giving a value of 0.00006
mg/kg/day.
0318d
-34-
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
There were no chronic or subchronlc studies of sufficient detail and
duration that could be used to derive an RQ ranking for 2-n1troan1l1ne. The
U.S. EPA (1985) derived an RQ of 100 for 4-nHroan1l1ne based on an abstract
of a 90-day study by Houser et al. (1983) In which 3 mg/kg/day administered
to rats by gavage decreased the oxygen-carrying capacity of the blood and
caused splenic hlstopathology. 2-N1troan1l1ne administration by several
routes for a shorter duration also has hemotoxlc effects, Including methe-
moglobln formation, which could decrease oxygen-carrying capacity (Bio/
Dynamics, 1983a,b; Vasllenko et al., 1972, 1974; Moskalenko, 1966; Watanabe
et al., 1976), suggesting that p- and 2-n1troan1l1ne cause similar effects.
Therefore, the RQ of 100 for the 4-1somer Is adopted for 2-n1troan1l1ne
(Table 9-1).
9.2. BASED ON CARCINOGENICITY
Pertinent data regarding the carclnogenldty of 2-nltroanlllne to humans
or animals by any route were not located in the available literature cited
1n Appendix A. Therefore, this chemical was placed In EPA we1ght-of-
evldence Group D (U.S. EPA, 1986b) -- Not Classifiable as to Human Carclno-
genldty. No hazard ranking Is possible for substances 1n Group D, and
therefore, a carcinogenlcity-based RQ cannot be derived.
0318d -35- 08/16/90
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TABLE 9-1
2-N1troan1l1ne
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Species/Sex:
Dose3:
Duration:
Effect:
RVd:
RVe:
CS:
RQb:
Reference:
oral
rats/NR
4.7 mg/day
90 days
reduced oxygen-carrying capacity of blood
4.7
7
32.9
100
Houser et al., 1983
Equivalent human dose
bThe RQ for 4-n1troan1l1ne was adopted for 2-nHroan1l1ne by analogy.
NR = Not reported
0318d
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Northcott, J. 1978. Amines, aromatic (anilines). In: Klrk-Othmer Encyclo-
pedia of Chemical Technology, Vol. 2, 3rd ed., M. Grayson and D. Eckroth,
Ed. John Wiley and Sons, Inc., New York. p. 319.
0318d
-42-
08/16/90
-------
Parrls, G.E. 1980. Covalent binding of aromatic amines to humates. 1.
Reactions wHh carbonyls and qulnones. Environ. Sd. Technol . 14(9):
1099-1106.
Perrin, D.D. 1964. The effect of temperature of PK values of organic
bases. Aust. J. Chem. 17: 484-488.
PHter, P. 1976. Determination of biological degradablllty of organic
substances. Water Res. 10: 231-235.
RTECS (Registry of Toxk Effects of Chemical Substances). 1975. H.E.
Chrlstenson, T.T. Luglnbyhl, Ed. U.S. Department of Health, Education and
Welfare, Rockvllle, MD. (Cited 1n Watanabe et al., 1976)
Sasaki, S. 1978. The scientific aspects of the chemical substances control
law 1n Japan. ITK Aquatic Pollutants. Transformation and Biological
Effects, 0. Hutzlnger, L.H. Von Letyueld and B.C.J. Zoetemazn, Ed. Pergamon
Press, Oxford, p. 283-298.
Schafer, E.W., Jr., W.A. Bowles, Jr. and J. Hurlbut. 1983. The acute oral
toxlclty, repel lency and hazard potential of 998 chemicals to one or more
species of wild and domestic birds. Arch. Environ. Contam. Toxlcol. 12(3):
355-382.
Schultz, T.W. and F.M. Applehans. 1985. Correlations for the acute
toxlclty of multiple nitrogen substituted aromatic molecules. Ecotoxlcol.
Environ. Saf. 10: 75-85.
0318d -43- 08/16/90
-------
Shlmlzu, H. and N. Takemura. 1983. Mutagenlclty of some anallne deriva-
tives. In.: Occupational Health 1n the Chemical Industry, R.R, Orford, J.W.
Cowell, G.G. Jamison and G.3. Love, Ed. MEDICHEM, Edmonton, p. 497-506.
Shlmlzu, M. and E. Yano. 1986. Mutagenlclty of mononltrobenzene deriva-
tives In the Ames test and rec assay. Hutat. Res. 170(1-2): 11-22.
SRI (Stanford Research Institute). 1983. Evaluation of the Potential of
o-N1troan111ne to Induce Unscheduled DNA Synthesis In Primary Rat Hepatocyte
Cultures, with cover memo and sheet. EPA 878214903. Flche No. OTS0206696.
SRI (Stanford Research Institute). 1989. 1989 Directory of Chemical
Producers: United States of America. SRI International, Menlo Park, CA.
p. 370, 805.
Steadman, T.R., E.W. Helper, T. Parsons, G.E. W1lk1ns and N.P. Phillips.
1977. Industrial Process Profiles for Environmental Use. Organic Dyes and
Pigments Industry. EPA 600/2-77-023g. NTIS PB281-479. p. 68-69.
Swann, R.L., D.A. Laskowskl, P.J. McCall, K. Vanderkuy and H.J. Olshburger.
1983. A rapid method for the estimation of the environmental parameters
octanol/water partition coefficient, soil sorptlon constant, water to air
ratio, and water solubility. Res. Rev. 85: 17-28.
Thomas, R.G. 1982. Volatilization from water. In.: Handbook of Chemical
Property Estimation Methods, W.J. Lyman, W.F. Reehl and O.K. Rosenblatt, Ed.
McGraw-Hill Book Co., New York. p. 15-1 to 15-34.
0318d
-44-
08/16/90
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Thompson, C.2., L.E. Hill, J.K. Epp and G.S. Probst. 1983. The Induction
of bacterial mutation and hepatocyte unscheduled DNA synthesis by mono-
substituted anilines. Environ. Mutagen. 5(6): 803-811.
Toxic Substances List. 1974. H.E. ChMstensen, T.T. Luglnbyhl, Ed. U.S.
Department of Health, Education and Welfare, Rockvllle, MD. (Cited 1n
Watanabe et al., 1976)
Urano, K. and Z. Kato. 1986. Evaluation of blodegradatlon ranks of
priority organic compounds. J. Hazard. Mat. 13: 147-159.
U.S. EPA. 1980. Guidelines and Methodology Used 1n the Preparatalon of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 79347-79357.
U.S. EPA. 1984. Methodology and Guidelines for Ranking Chemicals Based on
Chronic Toxlclty Data. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1985. Health and Environmental Effects Profile for NHroanlllne.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste
and Emergency Response. EPA/600/X-85/115. MTIS PB88-180443/AS.
0318d -45- 08/16/90
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U.S. EPA. 1986a. Methodology for Evaluation Reportable Quantity Adjust-
ments Pursuant to CERCLA Section 102. Prepared by the Carcinogen Assessment
Group, Office of Health and Environmental Assessment for the Office of
Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1986b. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1989. STORE! Water Quality Database. Online: July, 1989.
U.S. EPA/OWRS (U.S. Environmental Protection Agency/Office of Water Regula-
tions and Standards). 1986. Guidelines for Deriving Numerical National
Water Quality for the Protection of Aquatic Organisms and Their Uses.
Washington, DC. GRAI8522.
USITC (U.S. International Trade Commission). 1989. Synthetic Organic
Chemicals: United States Production and Sales, 1988. USI1C Publ. 2219,
Washington, DC. p. 3-2, 3-11.
Vasllenko, N.M., V.I. Zvezdal and I.I. Kovalenko. 1972. Inaction of the
blood respiratory pigment under the effect of aromatic nltro and amlno
compounds from the benzene series. Sovrem. Prob. Blokhlm. Dyhanlya Klin.,
Mater. Vses. Knof. 1: 411-413. '
Vasllenko, N.M., V.I. Zvezdal and F.A. Kolodub. 1974. Toxic action of
raonon1troan1l1ne Isomers. Gig. SanH. 8: 103-104.
0318d
-46-
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Watanabe, T., N. Ishlhara and M. Ikeda. 1976. ToxIcHy of and biological
monitoring for 1,3-d1am1no-2,4-6-trInltrobenzene and other nltroamlno
derivatives of benzene and chlorobenzene. Int. Arch. Occup. Environ.
Health. 37(3): 157-168.
Weast, R.C., Ed. 1985. CRC Handbook of Chemistry and Physics, 66th ed.
CRC Press, Inc., Boca Raton, FL. p. C-73.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co., Rahway,
NJ. p. 944-945.
Wooster, C.B. 1963. Ammonolysls. lr\: Klrk-Othmer Encyclopedia of Chemical
Technology, Vol. 2, 2nd ed., A. Standen, Ed. John Wiley and Sons, Inc., New
York. p. 352-353.
Yoshlml, N., S. Sugle, H. Iwata, et al. 1988. The genotoxUHy of a
variety of aniline derivatives In a DNA repair test with primary cultured
rat hepatocytes. Mutat. Res. 206(2): 183-191.
Young, J.C. and S.B. Affleck. 1974. Long-term blodegradablHty tests on
organic Industrial wastes. Eng. Bull Purdue Univ., Eng. Ext. Ser. 1:
154-164.
Younger Laboratories. 1977. Toxlclty Study of o-N1troanH1ne. EPA
878211624. Flche #206222.
0318d -47- 08/16/90
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Zeyer, J. and P.C. Kearney. 1983. Mlcroblal metabolism of [14C]n1tro-
annines to [i4C]carbon dioxide. J. Agrlc. Food Chem. 31: 304-308.
Zoeteman, B.C.J., K. Harmsen, J.B.H.J. Unders, C.F.H. Morra and W. Slooff.
1980. Persistent organic pollutants In river water and ground water of the
Netherlands. Chemospfiere. 9: 231-249.
0318d
-48-
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APPENDIX A
LITERATURE SEARCHED
This HEED is based on data Identified by computerized literature
searches of the following:
CHEMLINE
TSCATS
CASK online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TQXltT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSD8
SCISEARCH
Federal Research In Progress
These searches were conducted In July, 1989, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hygienists).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hygienists).
1987. TLVs: Threshold Limit Values for Chemical Substances in the
Work Environment adopted by ACGIH wUh Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.O. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 28. John Wiley and
Sons, NY. p. 2879-3816.
0318(1 -49- 08/16/90
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Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.t Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
Grayson, M. and D. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John WITey and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC {International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, WHO, Lyons, France.
Oaber, H.M., W.R. Mabey, A.T. Lieu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo
Park, CA.
NTP (National Toxicology Program). 1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report In the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call 1n Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
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In addition, approximately 30 compendia of aquatic toxlclty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute ToxIcHy
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
ToxIcHy Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0318d -51- 08/16/90
-------
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APPENDIX C
DOSE/DURATION RESPONSE GRAPHS FOR EXPOSURE TO 2-NITROANALINE
C.I. DISCUSSION
Dose/duration-response graphs for Inhalation and oral exposure to
2-nltroanlllne, generated by the method of Crockett et al. (1985) using the
computer software by Durkln and Meylan (1989) developed under contract to
ECAO-C1nc1nnat1, are presented In Figures C-l through C-4. Data used to
generate these graphs are presented in Section C.2. In the generation of
these figures, all responses are classified as adverse (PEL, AEL or LOAEL)
or nonadverse (NOEL or NOAEL) for plotting. The ordlnate expresses
Inhalation exposure In either of two ways. In Figure C-l, the experimental
concentration, expressed as mg/m3, was multiplied by the time parameters
of the exposure protocol (e.g. hours/day and days/week) and Is presented as
expanded experimental concentration [expanded exp cone (mg/m3)]. In
Figure C-2, the expanded experimental concentration was multiplied by the
animal Inhalation rate 1n mVday and divided by the animal body weight 1n
kg to calculate a dally dose In mg/kg/day. The dally dose was then
multiplied by the cube root of the ratio of the animalihuman body weight to
adjust for species differences In metabolic rate (Mantel and Schnelderman,
1975). The result was multiplied by an absorption coefficient of 0.5 to
adjust to an equivalent absorbed dose and then multiplied by 70 kg, the
reference human body weight, to express the human equivalent dose as mg/day
for a 70 kg human [human equivalent dose (mg/day}]. For oral exposure, the
ordlnate expresses dose as human equivalent dose. The animal dose In
mg/kg/day Is multiplied by the cube root of the ratio of the animal:human
body weight to adjust for species differences In basal metabolic rate
0318d -53- 08/16/90
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10000
I
*
*
V
M
I
X
ill
A
*
z
0.001
(Inhalation Exposure)
HUMRN EQUIU DUBflTION (fraction lifespan)
ENUELOP METHOD
Key: L - LOAEL
n « NOAEL
Solid Une » Adverse Effects Boundary
Dashed line » No Adverse Effects Boundary
FIGURE C-l
Dose/Duration-Response Graph for Inhalation Exposure to 2-NUroan1l1ne:
Envelope Method (Expanded Experimental Concentration)
0318d
-54-
08/16/90
-------
f
£
v
111
I
to
1008 r
L
160 r
fc
10 t
i.
1
X..
! 1 1
e.eei
(Inhalation Exposure)
1 1 I t
~\r
F>4
nl
0.01
HUMflN EQUIU DURRTION (fraction lifespan)
ENUELOP METHOD
0.1
Key: L LOAEL
n » NOAEL
Solid line « Adverse Effects Boundary
Dashed line « No Adverse Effects Boundary
FIGURE C-2
Dose/Duration-Response Graph for Inhalation Exposure to 2-NHroanlllne:
Envelope Method (Human Equivalent Dose)
0318d
-55-
08/16/90
-------
V
c
A
8.0001
(Oral Exposure)
Fl
fl2
F4
43
iti6
0.001 6.01
HUhRN EOUIU DURRTION (fraction lifespan)
ENUELOP METHOD
0.1
Key: F
A « AEL
L - LOAEL
n . NOAEL
Solid line » Adverse Effects Boundary
Dashed line - No Adverse Effects Boundary
FIGURE C-3
Dose/Duration-Response Graph for Inhalation Exposure to 2-NUroanlllne:
Envelope Method
0318d
-56-
08/16/90
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\
9
r.'
M
18888 ^
1088
Oral Exposure)
1 I I 1 1 i I 1
Fl
R2
F4
--t5-
1 i 1
i 1 1
-p6
j I
0.801 0.01
HUflflN EQUIU DURflTION (fraction lifespan)
CENSORED DRIfl METHOD
0.1
Key: F » FEL
A - AEL
L - LOAEL
n « NOAEL
Solid line - Adverse Effects Boundary
Dashed line No Adverse Effects Boundary
FIGURE C-4
Dose/Duration-Response Graph for Inhalation Exposure to 2-N1troan1l1ne:
Censored Method
0318d
-57-
08/16/90
-------
(Mantel and Schnelderman, 1975). The result Is then multiplied by 70 kg,
the reference human body weight, to express the human equivalent dose as
mg/day for a 70 kg human [human equlv dose (mg/day)].
The adverse effects boundary (solid line) Is drawn by Identifying the
lowest adverse effect dose or concentration at the shortest duration of
exposure at which an adverse effect occurred. From this starting point, an
Infinite line Is extended upward parallel to the dose axis. The starting
point 1s then connected to the lowest adverse effect dose or concentration
at the next longer duration of exposure that has an adverse effect dose or
concentration equal to or lower than the previous one. This process Is
continued to the lowest adverse effect dose or concentration. From this
point a line parallel to the duration axis 1s extended Infinitely to the
right. The adverse effects region lies above the adverse effects boundary.
Using the envelope method, the no adverse effects boundary (dashed line)
1s drawn starting with the point representing the highest no adverse effects
dose or concentration. From this point, a line parallel to the duration
axis 1s extended to the dose or concentration axis. The starting point Is
then connected to the next equal or lower no adverse effect dose or concen-
tration at a longer duration of exposure. When this process can no longer
be continued, a line parallel to the dose or concentration axis Is dropped
to the duration axis. The no adverse effects region lies below the no
adverse effects boundary. At either ends of the graph between the adverse
effects and no adverse effects boundaries are regions of ambiguity. The
area (If any) resulting from Intersections of the adverse effects and no
adverse effects boundaries Is defined as the region of contradiction.
In the censored data method, all no adverse effect points located 1n the
region of contradiction are dropped from consideration and the no adverse
0318d
-58-
08/16/90
-------
effects boundary Is redrawn so that It does not Intersect the adverse
effects boundary and no region of contradiction Is generated. This method
results In the most conservative definition of the no adverse effects region.
figure C-l represents the (lose/duration-response graph of Inhalation
data expressed as expanded concentrations and generated by the envelope
method. The boundary for adverse effects 1s defined by two points (B1o/
Dynamics, 1983a): LOAELs In rats for transient corneal opaclf1cat1on In a
single 4-hour exposure (Rec. #6, Section C.2.1.) and for hemotoxIcHy In
rats exposed for 4 weeks (Rec. #3, Section C.2.I.). Rec. #5 (Section
C.2.I.), a PEL for lethality In rats exposed for 4 hours was not displayed
because It would obscure Rec. #6 (Section C.2.I.). The boundary for no
adverse effects 1s defined by a NOAEL (Rec. #4, Section C.2.1.) for nemo-
toxlclty In the same study. The large region of ambiguity results from the
paucity of the database. Figure C-2 represents the graph for the same data
set expressed as the human equivalent dose and graphed by the envelope
method.
Figure C-3 represents the dose/duration-response graph of oral data
generated by the envelope method. The boundary for adverse effects Is
defined by FELs for LD values In guinea pigs (Rec. #11, Section C.2.2.)
and rats (Rec. #8, Section C.2.2.), and a LOAEL for transient signs of
maternal toxlclty In a gavage study In rats (Rec. #5, Section C.2.2.). Rec.
#10 (Section C.2.2.), an LD5Q 1n mice, was not plotted because It would
obscure rec. #11 (Section C.2.2.). The boundary for no adverse effects
passes through two points, both of which are NOAEls for fetotoxlclty and
maternal toxlclty In pregnant rats (Recs. #3 and 6, Section C.2.2.). The
small region of contradiction probably arises from the choice of doses In
the two developmental toxlclty studies In rats (Monsanto, 1984, 1985). The
0318d
-59-
08/16/90
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region of contradiction Is eliminated using the censored data method In
Figure C-4, In which the no adverse effects boundary passes only the NQAEL
of Rec. #6 (Section C.2.2.) (Monsanto, 1985). None of these records are
derived from exposures of sufficient duration and presented \n sufficient
detail to be the basis for an RfD; therefore, a subchronlc oral RfD was
derived from Inhalation data (Rec. #1, Section C.2.I.).
C.2. DATA USED TO GENERATE DOSE/DURATION-RESPONSE GRAPHS
C.2.1. Inhalation Exposure.
Chemical Name: 2-N1troan1lIne
CAS Number: 88-74-4
Document Title: Health and Environmental Effects Document on 2-NHroanll1ne
Document Number: Pending
Document Date: Pending
Document Type: HEED
RECORD #1: Species: Rats
Sex: Male
Effect: LOAEL
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
10
5
IRRIT
NASAL
2
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
# Inhal . Exp. days:
0.35 kg
9.8 mg/m3
1 .75 mg/m3
4 weeks
4 weeks
6.00
5.00
Comment:
Citation:
Exposed to 0, 9.8, 93 mg/m3 aerosol/vapor 6 hours/day, 5
days/week. Nasal Irritation, lacrlmatlon; this value 1s also
a NOAEL for hemotoxldty (see next record). Basis for
subchronlc Inhalation and oral RfDs.
B1o/Dyanamics, 1963b
03180
-60-
08/16/90
-------
RECORD #2;
Species:
Sex:
Effect:
Route:
Rats
Hale
LOAEL
Inhalation
Body Weight: 0.35 kg
Reported Dose: 93 mg/m3
Converted Dose: 16,6 mg/m;
Exposure Period: 4 weeks
Duration Observation: 4 weeks
Molecular Weight:
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
# Inhal. Exp. days:
Comment :
Citation:
RECORD #3:
Comment:
Citation:
Number Exposed: 10
Number Responses: 5
Type of Effect: IRRIT
Site of Effect: NASAL
Severity Effect: 2
10
NR
HEMAT
BLOOD
7
See previous record; methemogloblnemla.
Blo/Dyanamlcs, 1983b
Species: Rats
Sex: Both
Effect: LOAEL
Route: Inhalation
Number Exposed: 20
Number Responses: NR
Type of Effect: IRRIT
Site of Effect: NASAL
Severity Effect: 2
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
Inhal. Exp. days:
20
NR
HEMAT
BLOOD
7
Exposed to 0, 10, 28, 73 mg/m3 aerosol/vapor 6
days/week. Nasal Irritation, lacrlmatlon,
testlcular effects 1n males attributed to
(vehicle).
B1o/Dynam1cs, 1983a
0.2721 kg
73 mg/m3
13 mg/m3
4 weeks
4 weeks
6.00
5.00
hours/day, 5
hemotoxldty;
cellosolve
0318d
-61-
08/16/90
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RECORD #4;
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Both
NOAEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
Inhal. Exp. days:
0.2721 kg
28 mg/rn3
mg/m3
weeks
weeks
00
.00
Number Exposed: 20
Number Responses: NR
Type of Effect: IRRIT
Site of Effect: NASAL
Severity Effect: 2
See previous record; nasal Irritation, lacrlmatlon; this value
1s also a NOAEL for hemotoxidty In this study. At 10
mg/m3, only effect was yellow discoloration of fur.
Bio/Dynamics, 1983a
RECORD #5: Species: Rats
Sex: Male
Effect: PEL
Route: Inhalat
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
1on
10
3
DEATH
BODY
10
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
# Inhal . Exp. days:
10 10 10
NR NR NR
0.245 kg
7.55 mg/i
7550 mg/m3
1 days
14 days
4.00
1.00
WGTIN WGTIN DEGEN
LIVER LUNG EYE
445
Comment: Exposed to 1.1, 6.53, 6.61,
mg/i vapor and aerosol. Not
Lowest lethal concentration.
Citation: Haskell Laboratories, 1981
7.55, 8.66, 8.96, 11.66, 12.02
expanded to continuous exposure.
0318d
-62-
08/16/90
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RECORD #6;
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Male
LOAEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
0.245 kg
6.61 mg/2.
6610 mg/m3
1 days
14 days
4.00
1.00
Number Exposed: 10
Number Responses: NR
Type of Effect: DEGEN
SHe of Effect: EYE
Severity Effect: 5
Details 1n previous record. Transient corneal opadfIcatlon.
Haskell Laboratories, 1981
C.2.2. Oral Exposure.
Chemical Name: 2-NHroanlllne
CAS Number: 88-74-4
Document Title: Health and Environmental Effects Document on 2-NHroan1l1ne
Document Number: Pending
Document Date: Pending
Document Type: HEED
RECORD #1: Species:
Sex:
Effect:
Route:
Rats
Female
FEL
Gavage
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
0.2755 kg
1200 mg/kg/day
1200 mg/kg/day
10 days
16 days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
6666
45 NR NR
DEATH NEUR8 WGTDC WGTDC
BODY CNS FETUS BODY
10 9 8 4
Comment:
CHatlon:
Dosed 0, 50, 200, 400, 800, 1200
6-15. Maternal death, CNS signs.
probably from maternal toxlclty.
Monsanto, 1984
mg/kg/day gestation days
Reduced fetal body weight
0318d
-63-
08/16/90
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RECORD #2;
Comment:
Species:
Sex:
Effect:
Route:
Rats
F ema1e
AEL
Gavage
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
0.2852 kg
800 mg/kg/day
800 mg/kg/day
10 days
Duration Observation: 16 days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
666
1 NR NR
NEURB WGTOC MGTOC
CNS FETUS BODY
7 8 4
Protocol 1n
gasping for
Reduced mean
previous record. Dams lethargic, unsteady,
air, decreased weight gain, food consumption.
fetal weight probably due to maternal toxldty.
Citation:
RECORD #3:
Monsanto,
Species:
Sex:
Effect:
Route:
1984
Rats
F ema 1 e
NOAEL
Gavage
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
0.2897 kg
400 mg/kg/day
400 mg/kg/day
10 days
16 days
Number Exposed: 6
Number Responses: 6
Type of Effect: PIGMN
Site of Effect: SKIN
Severity Effect: 1
Comment:
Citation:
Details In previous record; discolored fur reported 1n all
exposed groups.
Monsanto, 1984
RECORD #4: Species: Rats
Sex: Female
Effect: FEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
25
NR
WGTDC
BODY
4
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
0
2
TERAS
FETUS
9
0.2897 kg
600 mg/kg/day
600 mg/kg/day
11 days
16 days
Comment: Dosed 0, 100, 300, 600 mg/kg/day gestation days 6-15.
Decreased maternal body weight gain, food consumption Situs
Inversus 1n one fetus 1n each of two litters.
Citation: Monsanto, 1985
0318d
-64-
08/16/90
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RECORD #5:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
F ema1e
LOAEL
Gavage
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
0.28232 kg
300 mg/kg/day
300 mg/kg/day
11 days
Duration Observation: 16 days
Number Exposed: 25
Number Responses: NR
Type of Effect: 70XSL
Site of Effect: OTHER
Severity Effect: 4
Protocols In previous record. Transient plloerectlon, pale,
cold extremities. Reduced food consumption. Yellow-orange
stains body, urine. No fetal effects.
Monsanto, 1985
RECORD #6:
Comment :
Citation:
RECORD #7:
Comment:
Citation:
Species: Rats
Sex: Female
Effect: NOAEL
Route: Gavage
Number Exposed: 25
Number Responses: 25
Type of Effect: PIGMN
SHe of Effect: OTHER
Severity Effect: 1
Details previous record.
Monsanto, 1985
Species: Rats
Sex: Both
Effect: PEL
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 10
1050 study.
Younger Laboratories, 1977
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
0.28108 kg
100 mg/kg/day
100 mg/kg/day
11 days
16 days
0.35 kg
2050 mg/kg/day
2050 mg/kg/day
1 day
1 day
0318d
-65-
08/16/90
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RECORD #8:
Comment:
Citation:
RECORD #9:
Comment:
Citation:
RECORD #10:
Comment:
Citation:
Species: Rats
Sex: NR
Effect: PEL
Route: Oral
Number Exposed:
Number Responses
Type of Effect:
Site of Effect:
Severity Effect:
LDso study.
Toxic Substances
Species: Rats
Sex: NR
Effect: PEL
Route: Oral
Number Exposed:
Number Responses
Type of Effect:
SHe of Effect:
Severity Effect:
LDso study.
Vasllenko et al.
Species: Mice
Sex: NR
Effect: PEL
Route: Oral
Number Exposed:
Number Responses
Type of Effect:
Site of Effect:
Severity Effect:
LDso study.
Moskalenko, 1966
Body Weight:
Reported Dose:
Converted Dose:
(NOS) Exposure Period:
Duration Observation:
NR
: NR
DEATH
BODY
10
List, 1974; RTECS, 1975
Body Weight:
Reported Dose:
Converted Dose:
(NOS) Exposure Period:
Duration Observation:
NR
: NR
DEATH
BODY
10
, 1974
Body Weight: 0
Reported Dose: 1
Converted Dose: 1
(NOS) Exposure Period: 1
Duration Observation: 1
NR NR NR
: NR NR NR
DEATH NEURB SUBCC
BODY MSKEL RBC
10 7 2
0.35 kg
535 mg/kg/day
535 mg/kg/day
1 day
1 day
0.35 kg
3520 mg/kg/day
3520 mg/kg/day
1 day
1 day
.03 kg
246.1 mg/kg/day
250 mg/kg/day
day
day
NR
NR
HEMAT
LYM
6
0318d
-66-
08/16/90
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RECORD #11: Species: Guinea pigs Body Weight: 0.84 kg
Sex: NR Reported Dose: 2350 mg/kg/day
Effect: PEL Converted Dose: 2350 mg/kg/day
Route: Oral {NOS} Exposure Period: 1 day
Duration Observation: 1 day
Number Exposed: NR NR NR NR
Number Responses: NR NR NR NR
Type of Effect: DEATH NEURB SUBCC HEHA1
Site of Effect: BODY MSKEL RBC LYM
Severity Effect: 10 7 2 6
Comment: 1059 study.
Citation: Moskalenko, 1966
NR = Not reported
0318d -67- 08/16/90
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