\I,J
FINAL DRAFT
United States K FTAn TTM
Environmental Protection ' tUMM.l»-
Agency September, 1989
Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR 1.3.5-TRINITROBENZENE
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DRAFT: DO NOT CITE OR QUOTE
NOTICE
CO1
en This document 1s a preliminary draft. It has not been formally released
*by the U.J. Environmental Protection Agency and should not at this stage be
^construed to represent Agency policy. It 1s being circulated for comments
on Us tecinlcal accuracy and policy Implications.
LU U.S. Environmental Protection
Library, Room 2404 FHU-211-A
401 M Street, S.W.
Washington. DC 80460
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DISCLAIMER
This report 1s an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEOs) are prepared for the
Office ol Solid Waste and Emergency Response (OSWER). This document series
Is Interned to support listings under the Resource Conservation and Recovery
Act (RCRn) as well as to provide health-related limits and goals for emer-
gency arvl 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 lo potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for In this document
and the dates searched are Included In "Appendix: Literature Searched."
Literature search material Is current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document Is sent to the Program Officer {OSWER).
Several quantitative estimates are presented provided sufficient data
are aval able. For systemic toxicants, these Include Reference doses (RfDs)
for chrcnlc and subchronlc exposures for both the Inhalation and oral
exposure:. The subchronlc or partial lifetime RfD Is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval I.e., for an Interval that
does not constitute a significant portion of the llfespan. This type of
exposure estimate has not been extensively used, or rigorously defined as
previous risk assessment efforts have focused primarily on lifetime exposure
scenario;. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchron c RfDs Is the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In tie case of suspected carcinogens, RfDs are not estimated. Instead,
a cardrogenlc potency factor, or q-|* (U.S. EPA, 1980a), 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.
Repoi table quantities {RQs) based on both chronic toxldty and carclno-
genldty are derived. The RQ 1s used to determine the quantity of a hazard-
ous substance for which notification 1s required 1n the event of a release
as specified under the Comprehensive Environmental Response, Compensation
and Liability Act (CERCLA). These two RQs (chronic toxlclty and carclno-
genldtyi represent two of six scores developed (the remaining four reflect
IgnHablllty, reactivity, aquatic toxldty, and acute mammalian toxldty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxldty and cancer based RQs are defined In U.S.
EPA, 1984 and 1986a, respectively.
111
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EXECUTIVE SUMMARY
1,3,5-Trlnltrobenzene Is a yellow crystalline solid at room temperature;
It 1s scluble In both polar and nonpolar organic solvents and sparingly
soluble 'n water (Sax and Lewis, 1987; Hlndholz et al., 1983). Information
on curreit methods of production Is lacking 1n the available literature.
Only Eastman Kodak Co. In Rochester, NY, produced this material In 1977
(TSCAPP, 1989). 1,3,5-TMnHrobenzene 1s used mainly 1n explosive composi-
tions {S290 nm (Burllnson et al., 1973; Spanggord et
al., 198d; Capellos and Suryanarayanan, 1973) but the light-Induced trans-
formations of this compound are not well understood. Therefore, the photo-
lytlc destruction of 1,3,5-trlnltrobenzene In the environment cannot be
accurately predicted.
1v
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1,3,f-Tr1n1trobenzene 1s a man-made organic compound that can enter the
environment as a component of wastewater effluent of plants that synthesize,
produce nr demilitarize explosives or munitions. 1,3,5-Trlnltrobenzene may
also entjr the environment through the disposal of solid wastes {Ryon et
al., 1981, Spaldlng and Fulton, 1988; Spanggord et al., 1982a). Limited
monHorUg data are available on the concentration of this compound In the
environment. Sufficient monitoring data are not available to estimate the
exposure of 1,3,5-tr1n1t1robenzene to the general population.
Existing data Indicate that trlnltrobenzene Is highly toxic to aquatic
fauna, tut the compound Is not likely to concentrate In them. Acute
toxlclty data have been reported for four species of fish (fathead minnows,
channel catfish, bluegllls and rainbow trout) and one Invertebrate, the
water fl?a. LC5Q values for fathead minnows range from 0.49-1.1 ppm, and
the other three species displayed sensitivity to trlnltrobenzene at LC
50
levels 0.12 ppm for a period of 32 days. Rainbow trout were
similar!) sensitive to trlnltrobenzene, showing a LOEL of 0.17 ppm for
survival, fry length and fry weight (van der Schalle, 1983). Ventllatory
effects were noted In bluegllls exposed to treatment levels >0.128 ppm for 6
days (vi.n der Schalle et al., 1988). Signs of respiratory distress
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(opercul«r movement Increases, excitability and violent swimming) were noted
*n !• saidvlcensus exposed to >0.1 ppm trlnltrobenzene for short durations
(Hlatt el al.t 1957).
A BC: of 6.36 has been calculated for trlnltrobenzene by Liu et al.
(1983) fiom the estimated log value of 1.36. Bloconcentratlon data reported
by van d;r Schalle (1983) for fathead minnows, rainbow trout and the water
flea support the conclusion that trlnltrobenzene does not significantly
bloaccumilate In aquatic animals.
Toxic effects of trlnltrobenzene In the alga, S. caprlcornutum. was
Investigated by van der Schalle (1983). Significant reduction 1n growth was
noted at all levels tested (0.01-17.32 ppm) after 5 and 14 days exposure,
concentrations of 1.18 ppm were alglddal, and lower concentrations were
alglstatlc.
Data pertinent to the pharmacoklnetlc behavior of 1,3,5-trlnltrobenzene
1n mammalian systems are not available.
Information regarding the chronic or subchronlc toxldty of 1,3,5-trl-
nltrobenzene following Inhalation exposure Is unavailable. Information
regarding oral exposure of chronic cr subchronlc duration 1s limited to an
abstract of a Russian report (Korolev et al., 1977). "Prolonged" oral
administration of 1,3,5-tr1n1trobenzene to mice, rats and guinea pigs
altered .he activities of peroxldase, alkaline phosphatase and ceroplasmln
1n the blood, but further details were unavailable.
Published oral LD^ values for 1,3,5-trlnltrobenzene Include the
following: 600 mg/kg In white mice, 450 mg/kg In white rats, 730 mg/kg In
guinea pigs (Korolev et al., 1977) and 600 mg/kg In mice (Tlmoslevskaya and
Roklonova, 1973).
v1
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Administration of single oral (0.4 ymol/kg) or Intraperltoneal (0.1
doses to rats Increased blood levels of methemoglobln (Senczuk et
al., 1976; Watanabe et al., 1976). Intraperltoneal administration of
Homers of dlnltrobenzene had a similar effect.
Data regarding the carclnogenlcHy of 1,3,5-tr1n1trobenzene were limited
to a sligle study employing dermal and Intraperltoneal administrations.
Single t)p1cal applications of 1,3,5-trlnltrobenzene to the skin of mice
elicited responses (Inflammation, epidermal hyperplasla and cell darkening)
similar to those caused by TPA, a demonstrated promoter of mouse skin
tumors. Direct evidence for the carcinogenic potential of 1,3,5-trlnltro-
benzene .0 cause mouse skin tumors was unavailable (Slaga et al., 1985).
Multiple Intraperltoneal Injections of 1,3,5-trlnltrobenzene (3 times/week
for 8 we;ks) did not cause lung tumors In mice, but neither did benzo(a)-
pyrene, < known carcinogen In the positive controls 1n this study (Slaga et
al., 1985).
l,3,5-Tr1n1trobenzene was mutagenlc In assays for reverse mutations In
i- typhlmurlum strains, and the mutagenlc activity was reduced (but not
abolished) by the presence of a metabolic activating system (McGregor et
al., 1980; Spanggord et al.t 1982b; Kawal et al., 1987).
Data regarding teratogenlc and other reproductive effects of 1,3,5-trl-
nUrobenzene were not available.
As data regarding the carclnogenlclty of 1,3,5-trlnltrobenzene are
Insufficient to assess the carcenogenlc potential In humans, 1,3,5-trlnltro-
benzene ^as assigned to EPA Group D - not classifiable as to human carclno-
genlclty. A subchronlc oral RfD of 5xlO~4 mg/kg/day and a chronic oral
RfD of JxlO~5 mg/kg/day were derived for 1,3,5-trlnltrobenzene, based on
analogy to the RfD for 1,3-dlnltrobenzene. An RQ of 100 for chronic
toxlclty was derived, based on analogy to 1,3-d1n1trobenzene.
vll
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TABLE OF CONTENTS
1. INTR3DUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 3
2. ENVIRONMENTAL FATE AND TRANSPORT 4
2.1. AIR 4
2.1.1. Reaction with Hydroxyl Radicals 4
2.1.2. Reaction with Ozone 4
2.1.3. Photolysis 4
2.1.4. Physical Removal Processes 4
2.2. HATER 5
2.2.1. Hydrolysis 5
2.2.2. Oxidation 5
2.2.3. Photolysis 5
2.2.4. Mlcroblal Degradation 5
2.2.5. Bloconcentratlon 6
2.2.6. Adsorption 6
2.2.7. Volatilization 6
2.3. SOIL 7
2.3.1. Mlcroblal Degradation 7
2.3.2. Adsorption 7
2.3.3. Volatilization 7
2.4. SUMMARY 7
3. EXPOSURE 9
3.1. MATER 9
3.2. FOOD 9
3.3. INHALATION 10
3.4. DERMAL 10
3.5. SUMMARY 10
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 13
4.1.3. Effects on Flora 17
4.1.4. Effects on Bacteria 18
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TABLE OF CONTENTS (cont.)
Page
4,2. TERRESTRIAL TOXICOLOGY 18
4.2.1. Effects on Fauna 18
4.2.2. Effects on Flora 18
4.3. FIELD STUDIES 18
4.4. AQUATIC RISK ASSESSMENT 18
4.5. SUMMARY 20
5. PHAPMACOKINETCS 22
5.1. ABSORPTION 22
5.2. DISTRIBUTION 22
5.3. METABOLISM 22
5.4. EXCRETION 22
6. EFFECTS 23
6.1. SYSTEMIC TOXICITY 23
6.1.1. Inhalation Exposure 23
6.1.2. Oral Exposure 23
6.1.3. Other Relevant Information 23
6.2. CARCINOGENICITY 24
6.2.1. Inhalation 24
6.2.2. Oral 24
6.2.3. Other Relevant Information 24
6.3. MUTAGENICITY 25
6.4. TERATOGENICITY 25
6.5. OTHER REPRODUCTIVE EFFECTS 25
6.6. SUMMARY 25
7. EXISTING GUIDELINES AND STANDARDS 29
7.1. HUMAN 29
7.2. AQUATIC 29
8. RISK ASSESSMENT 30
8.1. CARCINOGENICITY 30
8.1.1. Inhalation 30
8.1.2. Oral 30
8.1.3. Other Routes 30
8.1.4. Weight of Evidence 30
8.1.5. Quantitative Risk Estimates 31
ix
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TABLE OF CONTENTS (cont.)
Page
8.2. SYSTEMIC TOXICITY 31
8.2.1. Inhalation Exposure 31
8.2.2. Oral Exposure 31
9. REPOVTABLE QUANTITIES 34
9.1. BASED ON SYSTEMIC TOXICITY 34
10. REFERENCES 36
APPENDIX \: LITERATURE SEARCHED 45
APPENDIX k SUMMARY TABLE FOR 1,3,5-TRINITROBENZENE 48
APPENDIX :: DOSE/DURATION RESPONSE GRAPH(S) FOR EXPOSURE TO
1,3,5-TRINITROBENZENE 49
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LIST OF ABBREVIATIONS
BCF
CAS
CS
DNA
GMAV
GHCV
Koc
LC50
LD50
MATC
NED
ppm
RQ
RVd
RVe
SD
TLm
TNT
TPA
B1oconcentrat1on factor
Chemical Abstract Service
Composite score
DeoxyMbonuclelc acid
Concentration effective to SOX of recipients
(and all other subscripted concentration levels)
Genus mean acute value
Genus mean chronic value
Soil sorptlon coefficient standardized
with respect to organic carbon
Octanol/water partition coefficient
Concentration lethal to 50% of recipients
(and all other subscripted dose levels)
Dose lethal to SOX of recipients
Maximum acceptable toxicant concentration
Minimum effective dose
Parts per million
Reportable quantity
Dose-rating value
Effect-rating value
Standard deviation
Median tolerance limit
Trinitrotoluene
7J2-d1methylbenz(a)anthracene(DMBA)-12-0-
tetradecanoyl-phorbol-13-acetate
wt/wt
Weight per weight
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
1,3,5 TMnltrobenzene Is also known by the synonyms $-, sym-, symmetric
and syn-t-1n1trobenzene and by the acronym TNB (CAS, 1989; Chemllne. 1989;
SANSS, 1939). The structure, CAS number, empirical formula and molecular
weight an as follows:
O.N
CAS Registry number: 99-35-4
Empirical formula: C,H_N_0.
0 J J 0
Molecular weight: 213.11
1.2. PHYSICAL AND CHEMICAL PROPERTIES
1,3,5-Trlnltrobenzene Is a yellow crystalline solid at room temperature
(Sax and Lewis, 1987). It Is a dimorphous solid; the most common form melts
at 122.5°C and the rare form melts at 61°C (Meast et al., 1988; Wlndholz et
al., 1983). It is soluble In polar organic solvents such as alcohol,
acetone, .»ther and methanol and In nonpolar organic solvents such as
benzene, carbon dlsulflde and petroleum ethers (Sax and Lewis, 1987; Ueast
et al., 1)88; Wlndholz et al., 1983). It Is also moderately soluble In
water (Wlndholz et al., 1983). Selected physical properties for 1,3,5-tr1-
nUrobenzeue are as follows:
Meltlnq point:
Common form
Rare form
Bo111n<| point:
122.5"C
61 "C
315'C
Wlndholz et al., 1983
Weast et al., 1988
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Density:
Water solubility:
at 25«C
at 20*C
Vapor pressure:
at 20°C solid
supercooled liquid
Log Kow:
Conversion factors:
1.688 g/cm3
0.035 g/100 g
0.034 g/100 g
3.2xlO~6 mm Hg
2.2x10""* mm Hg
1.18
1 ppm =8.66 mg/rn3
1 mg/m3 = 0.115 ppm
Sax and Lewis, 1987
Wlndholz et a!., 1983
Spanggord et al., 1980
Spanggord et al., 1980
Spanggord et al., 1980
Hansch and Leo, 1985
1.3. PRODUCTION DATA
Data from the U.S. EPA TSCA production file (TSCAPP, 1989} Indicate that
during l!(77, only Eastman Kodak Co. 1n Rochester, NY, produced 1,3,5-tM-
nitrobenzene. More current United States production data were not located
1n the available literature cited In Appendix A.
Data on the commercial methods used In the production of 1,3,5-tMnltro-
benzene here not located In the available literature. 1,3,5-TrlnHrobenzene
can be synthesized by treating benzene with a mixture of fuming nitric and
fuming sulfuMc acids (Purcell, 1981), by the action of alkali on 2,4,6-trl-
nltrobenzaldehyde or the sequential oxldatlon/decarboxylatlon of 2,4,6-TNT
(Hlndholz et al., 1983). 1,3,5-Tr1n1trobenzene 1s also produced as a
by-product of the production of TNT (Spanggord et al., 1982a; Spaldlng and
Fulton, 1388).
1.4. USE DATA
1,3,5-Trlnltrobenzene 1s used In explosive compositions. It Is less
sensitive to Impact than TNT but more powerful and brlsant (Sax and Lewis,
1987; Wlrdholz et al., 1983). It 1s also used as a vulcanizing agent for
rubber (Barnhart, 1981) and as a pH Indicator (Durst and Bates, 1981).
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1.5. SU1MARY
1,3,5-TrlnHrobenzene 1s a yellow crystalline solid at room temperature;
It Is soluble In both polar and nonpolar organic solvents and sparingly
soluble In water (Sax and Lewis, 1987; Hlndholz et al.t 1983). Information
on currert methods of production Is lacking In the available literature.
Only Eas ,man Kodak Co. In Rochester, NY, produced this material In 1977
(TSCAPP, 1989). 1,3,5-TrlnHrobenzene 1s used mainly In explosive composi-
tions (Sax and Lewis, 1987; Wlndholz et al., 1983). It Is also used 1n the
vulcanization of rubber (Barnhart, 1981) and as a pH Indicator (Durst and
Bates, 1931).
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AJR
Giver the available data on the vapor pressure of 1,3,5-trlnltrobenzene
at 20°C, 2.2xlO~« ram Hg (supercooled liquid) and 3.2x10""* mm Hg (solid),
1t Is expected that this compound will exist both In the vapor phase and In
the partlculate form 1n the ambient atmosphere (E1senr1ch et al., 1981).
2.1.1. Reaction with Hydroxyl Radicals. Using the method of Atkinson
(1985), ii rate constant for the gas phase reaction of 1,3,5-trlnltrobenzene
with photochemically produced hydroxyl radicals 1n the atmosphere can be
estlmatec to be 1.3xlO~15 cmVmolecule-sec. If an average atmospheric
hydroxyl radical concentration Is 5xl05 molecules/cm3, then the
half-lift for the vapor-phase destruction of 1,3,5-trlnHrobenzene In the
atmosphere would be 12,440 days. Consequently, this should not be an
environmentally significant process.
2.1.2. Reaction with Ozone. 1,3,5-TrlnHrobenzene Is not expected to be
susceptible to atmospheric degradation by ozone (Atkinson, 1985; U.S. EPA,
1987).
2.1.3. Photolysis. 1,3,5-TMnltrobenzene Is known to absorb light In the
environmentally significant range of >290 nm (Spanggord et al., 1980;
Capellos and Suryanarayanan, 1973). Sufficient Information does not exist
1n the available literature to accurately predict the photolytlc fate of
1,3,5-trlnltrobenzene In the atmosphere (Section 2.2.3.).
2.1.4. Physical Removal Processes. 1,3,5-TMnltrobenzene In the
atmosphere 1s expected to exist partially In the partlculate form and dry
deposition may partially remove this compound from the atmosphere. The
water so ubHUy of 1,3,5-tMnltrobenzene, 0.035 g/100 g at 25°C (Wlndholz
et al., 1983), suggests that partial removal by wet deposition may also
occur.
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2.2. HATER
2.2.1. iydrolysls. 1,3,5-TMnHrobenzene 1s not expected to hydrolyze
under environmental conditions since 1t contains no hydrolyzable functional
groups (L^man et al., 1982).
2.2.2. )x1dat1on. Oxidation of l,3,5-tr1n1trobenzene In water by
electrophillc alkoxy or akylperoxy radicals 1s not expected to be an
Important fate process.
2.2.3. >hotolys1s. 1,3,5-TrlnHrobenzene Is known to adsorb light 1n the
envlronmeitally significant range >290 nm (Spanggord et al., 1980; Burllnson
et al., 973); however, the photolysis of aqueous 1,3,5-tr1n1trobenzene In
the laboratory produced no reaction after 6 hours {Burllnson et al., 1973).
Capellos ind Suryanarayanan (1973) have shown that 1n the laboratory, photo-
lytlc decomposition of 1,3,5-trlnltrobenzene only occurs 1n the presence of
both oxygen and polar, nucleophlllc reagents, such as methanol. Sunlight
photolysl; of 2,4,6-TNT In river water produced a 10X yield of 1,3,5-trl-
nltrobenzisne after 8 days (Spanggord et al., 1980). Thus, the rate of
photolysl; for !,3,5-tr1-n1trobenzene must be slower than for TNT, otherwise
It would not have been detected In this experiment.
The above data suggest that when 1,3,5-tr1n1trobenzene Is exposed to
light, pfotochemlcal transformations unique to this compound may occur.
Thus, the photolytlc fate of 1,3,5-tr1n1trobenzene based on analogies to
other n1tro-aroroat1c compounds cannot be predicted. More Information Is
necessary to accurately predict what process may occur when l,3,5-tr1n1tro-
benzene 1n water 1s exposed to sunlight.
2.2.4. Hlcroblal Degradation. Insufficient data In the available
lUeraturi; cited In Appendix A preclude the prediction of the mUroblal
degradation of 1,3,5-trlnltrobenzene 1n water. 1,3,5-Tr1n1trobenzene did
not support growth of Nocardla V. cultures (Rodrlguez-Vlllanueva, 1960).
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Cell-fret extracts of Velllonella alkalescens degraded 1,3,5-tr1n1trobenzene
to the amlno compound In the presence of hydrogen at a rate equal to 288
nmol H /mln/mg protein, the most rapid rate obtained for the 40 nitro-
benzene derivatives studied (McCormlck et al., 1976). It 1s not possible to
directly extrapolate from these laboratory studies to the behavior of
l,3,5-tr'n1trobenzene 1n the environment, but It Is possible that anaerobic
blodegracatlon may occur under the proper conditions.
2.2.5. Bloconcentratlon. The BCF for !,3,5-tr1-n1trobenzene can be
calculated to range from 5-23 based on Us water solubility, 0.035 mg/i at
25°C (Wlndholz et al., 1983), and the log K , 1.81 (Hansch and Leo.
1985). The respective regression equations, log BCF = 0.76 log K - 0.23
and log BCF = 2.791 - 0.564 log s, were used In this estimation (Lyman et
al., 198;*). These values suggest that bloconcentratlon In fish and aquatic
organism; Is not an Important fate process.
2.2.6. Adsorption. Using the regression equations log K = 0.544 log
K +1.377 and log KQC = -0.55 log s * 3.64 (Lyman et al.. 1982). the
K for 1,3.5-trlnltrobenzene Is calculated to range from 104-178 based on
the wate- solubility, 340 mg/i at 25°C {Wlndholz et al., 1983), and the
log K ,1.81 (Hansch and Leo, 1985), respectively. These values suggest
that adsorption to sediment and suspended organic matter are not expected to
be Important fate processes.
2.2.7. Volatilization. Using the method of H1ne and HookerJee (1975). an
estlmatec Henry's Law constant of 3.08xlO~» atm m'/mol at 25°C can be
calculated for 1,3,5-tMnHrobenzene. This value suggests that volatiliza-
tion fron water to the atmosphere Is very slow. The volatilization half-
life fron a model river 1 m deep, flowing at 1 m/sec with a wind velocity of
3 m/sec Is 47.5 years (Lyman et al., 1982).
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2.3. SOIL
2.3.1. Hlcroblal Degradation. Sufficient data are not available to
predict Ihe blodegradatlon of 1,3,5-trlnltrobenzene 1n soil. Oxygen uptake
that was not significantly higher than endogenous respiration was obtained
when 1,3,5-trlnltrobenzene was exposed to organisms obtained from soil,
compost or a waste lagoon and enriched using phenol as the carbon source
(Chambers and Kabler, 1964; Chambers et al., 1963; Tabak et al., 1964; Barth
and Buncr, 1979). The results of these studies suggest that Uttle or no
aerobic tlodegradatlon took place; however, anaerobic degradation may occur
In soil uider the proper conditions (see Section 2.2.4.).
2.3.2. \dsorpt1on. K values for 1,3,5-trlnltrobenzene can be esti-
mated to lie In the range from 104-178 (see Section 2.2.6.). These values
suggest tiat 1,3,5-trlnltrobenzene will display moderate to high mobility 1n
soil (Swain et al., 1983).
2.3.3. 'Volatilization. The vapor pressure of 1,3,5-trlnltrobenzene,
3.2x10"* ™n Hg at 20°C (Spanggord et al., 1980), suggests that volatiliza-
tion from soil to the atmosphere 1s not a significant fate process.
2.4. SUIIMARY
Sufficient data do not exist In the available literature to accurately
predict the environmental fate of 1,3,5-trlnltrobenzene but the following
processes are expected to occur 1n the environment: In the atmosphere,
1,3,5-trlnltrobenzene should exist partially 1n the vapor phase, and
partially In the partlculate form. Destruction by the gas-phase reaction
with photjchemlcally produced OH radical or by the reaction with ozone 1s
not expec ed to be significant. Both wet and dry deposition may occur. In
water, neither volatilization to the atmosphere nor hydrolysis are expected
to be Important processes. Information sufficient to predict the Importance
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of mlcroMal degradation of 1,3,5-tr1n1trobenzene were not located In the
available literature; however, rapid anaerobic degradation may occur under
the proper conditions. 1,3,5-TrlnHrobenzene adsorbs light In the environ-
mentally significant range >290 nm (Burllnson et a!., 1973; Spanggord et
al., 19*0; Capellos and Suryanarayanan, 1973) but the light-Induced
transformations of this compound are not well understood. Therefore, the
photolytl: destruction of 1,3,5-tr1n1trobenzene In the environment cannot be
accurately predicted.
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3. EXPOSURE
1,3,5-TMnHrobenzene Is a man-made compound that is usually associated
with the production of munitions and armaments. Limited data are available
on the qjantlty of 1,3,5-tMnltrobenzene In environmental media. Based on
the available data, 1t appears that 1,3,5-trlnltrobenzene can enter the
environment In wastewater effluent from facilities that synthesize, produce
or demilitarize munitions, or from the disposal of solid TNT wastes (Ryon et
al., 1984; Spaldlng and Fulton, 1988; Spanggord et al., 1982a).
3.1. WAFER
1,3,5-TMnltrobenzene was Identified In the condensate wastewater
effluent from the production of TNT. It was found In 3.8% of the samples
taken wee
-------
3.3. INHALATION
Pertinent data regarding the exposure to 1,3,5-trlnltrobenzene through
Inhalatloi were not located 1n the available literature cited 1n Appendix A.
3.4. DUMAL
Pertlient data regarding the dermal exposure to 1,3,5-trlnltrobenzene
were not located In the available literature cited 1n Appendix A.
3.5. SUMMARY
1,3,5-Trlnltrobenzene Is a man-made organic compound that can enter the
environment as a component of wastewater effluent of plants that synthesize,
produce or demilitarize explosives or munitions. 1,3,5-Trlnltrobenzene may
also ente- the environment through the disposal of solid TNT wastes (Ryon et
al., 1984, Spaldlng and Fulton, 1988; Spanggord et al., 1982a). Limited
monitor 1nj data are available on the concentration of this compound In the
environment. Sufficient monitoring data are not available to estimate the
exposure >f l,3,5-tr1n1t1robenzene to the general population.
-------
4. ENVIRONMENTAL TOXICOLOGY
4.1. ACUATIC TOXICOLOGY
4.1.1. Acute Toxtc Effects on Fauna. The static acute toxldty of
l,3,5-tr'n1trobenzene to the fathead minnow, Plmephales promelas. was
evaluatec by Bailey and Spanggord (1983). Juvenile fish averaging 0.28 g
were depMved of food for 24 hours before and during testing. Tests were
conductec In 19 l pickle Jars containing 10 fish/Jar and 15 l of test
solution. Dissolved oxygen, temperature, pH and mortality were checked
dally. tardness, alkalinity and conductivity of the diluent dechlorlnated
tap water were also monitored regularly (Interval not reported). The
96-hour _C for fathead minnows was 1.1 mg/i. Dissolved oxygen concen-
trations ranged from 2.8-9.4 mg/l; pHs ranged from 6-9.2 mg/i (mean
7.6); an! mean temperatures ranged from 19.5-22°C (mean 20.3°C). Hardness
ranged from 12-43 mg/l as CaCCL and mean alkalinity ranged from 15-60
mg/l as (aCOg.
The acute static toxldty of trlnltrobenzene to laboratory-reared
fathead nlnnows, P. promelas. and water fleas, Paphnla magna. was determined
by Pears in et al. (1979). Dechlorlnated water was used 1n tests of both
species. Tests were conducted at 20"C, pH of 7.2-8.6 and an average hard-
ness an( alkalinity of 26 mg/i (as CaC03) and 45 mg/i (as CaCO ),
respectUely. The 96-hour LC-- for fathead minnows was 1.03 mg/i. The
48-hour EC for D. maqna was 2.7 mg/l.
Liu i-t al. (1983) assessed the static acute toxldty of trlnltrobenzene
to fathead minnows, P. promelas. aged 90 (i2) days, and to water fleas, D.
maqna. f'rst Instars, obtained from laboratory-reared stocks and deprived of
food during testing. Tests were conducted In dechlorlnated tap water at
20"C having an average hardness of 33.8 mg/i (SD=19.0) as calcium
0188d
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carbonate (CaC03), pH of 7.7 (SD=0.35), alkalinity of 38.0 mg/t
(SD=20.0) as CaC03, and residual chlorine of 2.2 pg/l (SD=0.95). Mater
temperatires were 20°C for minnows and 12°C for trout. The 96-hour LC,.-
estimate of static acute toxlclty (and 95% confidence levels) for fathead
minnows has 1.1 (1-1.2) mg/fc, and for water fleas, 2.7 (2.4-3.1) mg/i.
Static acute toxlclty of trlnltrobenzene to the water flea, 0. maqna.
blueglll, Lepomls macrochlrus. rainbow trout, Salmo galrdnerl. fathead
minnow, >_. promelas. and channel catfish, Ictalurus punctatus. was deter-
mined by van der Schalle (1983). Filtered, aerated and sterilized well
water wa; used In the tests and monitored weekly for pH, hardness, alka-
linity, :otal organic carbon, suspended solids and ammonia. Animals were
acclimated to the well water for <30 weeks, transferred to holding tanks and
held without food for 48 hours before starting the tests. The fish tests
were conducted In 19 I jars containing 14 I of test solution. Three
jars containing 10 fish, or two jars of 15 smaller fish, were used for each
treatment level.
The Jars were held In a tank at 22 (±2)°C for the warmwater fish
species, and 12(+2)°C for the trout. The 96-hour LC_0 values In mg/i,
(and 95X confidence limits) were reported as follows: bluegllls, 0.85
(0.52-1.28); rainbow trout, 0.52 (0.32-0.8); fathead minnows, 0.49
(0.44-0.56); and channel catfish, 0.38 (0.34-0.43).
van ter Schalle (1983) conducted a static acute test of trlnltrobenzene
In the witer flea, D. magna. Identically to that described above for fish,
except that daphnlds to be tested were obtained from females Isolated from
stock cultures <24 hours before starting the test. Trout chow and yeast
food were provided up to the time that the young were pooled for testing.
0188d
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Five neonates were transferred by eyedropper Into six 200 ml beakers/
treatment level. The 48-hour EC5Q level (and 95X confidence limit) was
2.98 (2.63-3.38) mg/i. A higher 48-hour ECg value of 4.1 (2.6-7.7)
mg/l was determined for this species when fed vitamin-enriched algae,
Anklstrpcesmus falcatus. twice dally (Section 4.1.2.1.).
van der Schalle et al. (1988) determined the acute flowthrough toxlclty
of trlnltrobenzene to bluegllls, L,. macrochlrus. Filtered and sterilized
well wat'»r was used 1n the tests and was maintained at 22(+2}"C; dissolved
oxygen ooncentratlon ranged from 88-98% saturation, pH was 8.2-8.3,
alkallnlly (as CaCO_) averaged 241 (range 227-250) mg/l, and hardness
(as CaCC ) averaged 173 (range 170-174) mg/l. Ten fish were randomly
0
assigned to two test aquaria containing 7.6 i of test solution. Six
treatment levels (0.10, 0.14, 0.34, 0.69, 1.29 and 3.07 mg/l, mean
measured concentration) were tested. Fish were not fed for 48 hours before
starting the tests. Approximately five tank volumes were delivered by a
proportlcnal dlluter to each tank per day. The 96-hour LC was 0.57 (95%
fiducial limits of 0.50-0.65 mg/l).
4.1.2. Chronic Effects on Fauna.
4.1J.1. TOXICITY -- Early life stage tests of trlnltrobenzene's
toxlclty were conducted on fathead minnows, P. promelas. and rainbow trout,
S. galrdierl. by van der Schalle (1983). The water source and treatment
were hanlled similarly to the method described In Section 4.1.1. Fathead
minnow e
-------
mg/l) and controls (0,05 mg/l). These cups were randomly placed In the
water baih, and a rocker-arm apparatus kept the eggs In motion. Temperature
was maintained at 25°C (range 23.8-26.3°C), dissolved oxygen levels were
between f.9 and 8.9 mg/l and pH ranged from 7.9-8.2. When >90% hatch had
occurred, fry were released Into the test tank and fed twice/day. The test
duration was 32 days. No effects were noted on hatching rate, hatching
success ar morphology of offspring at any treatment level. Significantly
reduced survival was noted for all but the lowest dose. Fry at all
treatment levels were less active than the controls. The LOAEL, based on
mortality, is 0.12 ppm for 1,3,5-trlnltrobenzene. Effects noted on fry
length ard weight do not appear to be treatment-related.
van Jer Schalle (1983) obtained eyed eggs of rainbow trout, S. jialrd-
nerl. from a national hatchery for early life stage tests. Eggs were placed
In group; of 60 Into egg baskets suspended In two 191 aquaria containing
15 i of test solution/treatment level. Treatment levels ranged from
0.09-0.71 mg/l, but because significant effects were noted at the lowest
concentration, a second test was conducted. Treatment levels for the second
test wer? 0.17, 0.082, 0.045, 0.022, 0.015 and 0.01 mg/i trlnltrobenzene.
Data discussed here are taken from the second test. Temperatures were
maintained within 1° of 12'C, dissolved oxygen concentrations averaged
8.5-9.0 ng/i and pH averaged between 8.0 and 8.2 (range 7.9-8.5). Feeding
(twice dilly) was Initiated when fry swam out of the egg basket. Total
duration of the rainbow trout test was 71 days (61 days following the 50%
hatch daf for controls). At concentrations of 0.17 and 0.082 mg/i, fish
showed erratic swimming patterns and were lighter In color than the
controls. Significant differences In survival, fry length and fry weight
were not'jd at 0.17 ppm, a LOAEL. No significant effects were reported on
0188d
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hatching success, time to hatch, time to swim-up or fry morphology at
treatment levels <0.71 mg/i. A NOEL of 0.045 ppm and a NOAEL of 0.082 are
thus Identified for these study conditions.
Long-term effects on these same fish species were noted In flowthrough
acute to::1dty tests conducted by van der Schalle (1983). The same test
conditions were used here as described In the static acute test {see Section
4.1.1.), except that fish were tested In 19 l aquaria containing 15 I of
test solitlon. These aquaria measured 40 x 20 x 25 cm and had a drain hole
at a he1jht of 19 cm. For five treatment levels and a control, two repli-
cate tanks housing 15 fish/tank were used. (In the rainbow trout tests, two
replicates of 10 fish each were used.) For fathead minnows, a 10-day LC~Q
of 0.46 mg/i was obtained (95X confidence limits = 0.42-0.53 ppm}. The
rainbow trout dynamic acute test results were an 18-day LC5Q (and 95%
confidence limits) of 0.4 mg/i (0.24-0.73) and a 10-day LC5Q (and 95X
confidence limits) of 0.52 (0.37-0.73) mg/l.
van Jer Schalle et a "I. (1988) determined the effects on ventllatory
patterns and whole-body movement rates caused by chronic exposure of
bluegllls, L,. macrochlrus. to trinltrobenzene. Five fish/group, except for
the highest treatment level 1n which three/group were tested, were exposed
to six treatment levels (at mean measured trinltrobenzene concentrations of
0.613, 0 279, 0.128, 0.061, 0.034 and 0.02 mg/l or below detection limit)
for 6 da/s. Parameters monitored were ventllatory rate, ventllatory depth,
cough rcte and percent movement. The monitoring apparatus was that
described by van der Schalle (1980) but was modified from an anterior/
posterior electrode arrangement for monitoring fish ventllatory signals to a
dorsal/ventral pattern. A proportional toxicant dlluter delivered test
solutions to the ventllatory chambers. Ventllatory parameters were
0188d
-15-
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monitored continuously by microcomputer and compiled every 15 minutes. No
significant differences In ventllatory signal minima were noted among
control i nd treated fish at any exposure level. Effects were noted on
ventllato-y maxima for all parameters except ventllatory rate. Ventllatory
depth was the most sensitive parameter tested, showing significant responses
at concentrations >0.128 mg/i. Significant effects on cough rate and
percent novement were noted at 0.613 mg/l. A concentration of 0.128 ppm
thus represents a LOAEL and 0.061 ppm a NOEL.
Hlatt et al (1957) exposed marine fish, KuhUa sandvlcensls. to
l.3.5-tr1;i1trobenzene concentrations of 10, 50, 100, 1000 and 10,000
iig/8. (Q.U, 0.05, 0.1, 1 and 10 ppm, respectively) for short durations
(time period not specified) and noted slight Irritant effects (excitability,
violent swimming and opercular movement Increases), suggesting respiratory
distress .it the 0.1 ppm exposure level. These reactions were violent at the
higher ex)osure levels and were not noted with exposures of <0.05 ppm. Lack
of Information on duration of this study precludes Identification of effect
levels for risk assessment purposes.
Chron c data were generated by van der Schalle (1983) for D. maqna
exposed tD trlnltrobenzene. Animals used 1n these tests were raised 1n an
In-house culture unit In 2 I tanks with 10 daphnlds/tank. Aerated well
water was maintained at 20°C (range 19-21 days), and light Intensity was
150-350 lux. Daphnlds were fed twice dally with =2 mg/t (dry weight)
vitamin-enriched alga, Anklstrodesmus fajcatus. Daphnlds were exposed to
trlnltrobenzene for 21 days. Ten daphnlds were placed In four replicate
tanks for each treatment level of 2.68, 1.32, 0.75, 0.47, 0.24 and 0.025
(control). Endpolnts monitored were Immobilization, young/replicate tank,
young/femele/reproductlve day (total young divided by total days alive after
0188d
-16-
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onset of reproduction 1n the test tank) and growth. Significant effects
were noted at the three highest concentrations (mean total young/tank and
total lergth). At concentrations >1.32 ppm, number of young/female/repro-
ductlve day differed significantly from that of controls. Daphnlds subjected
to 2.68 |ipm exhibited a marked spinning motion when swimming. No signifi-
cant differences were noted for any treatment level on survival. A concen-
tration of 0.47 ppm represents a chronic NOEL and 0.75 a chronic LOEL.
4.1.2.2. BIOACCUHULATION/BI CONCENTRATION — L1u et al. (1983} calcu-
lated a steady-state BCF for trlnltrobenzene of 6.36 from the estimated log
K valu? of 1.36. This value suggests that trlnltrobenzene will not
significantly bloaccumulate In aquatic organisms.
4.1.3. Effects on Flora.
4.1.3.1. TOXICITY ~ van der Schalle et al. (1983) tested the
toxlclty of trlnltrobenzene In the alga, Selenastrum caprlcornutum. Algae
were exp>sed to solutions of trlnltrobenzene In 100 ml of algal assay
medium ccntalned In 500 ml Erlenmeyer flasks. Triplicate flasks for each
treatment level were Inoculated with 20,000 cells of S. caprl cor nut urn/ma,/
flask an1.18 ppm were
alglddal, and concentrations <1.18 ppm were alglstatlc.
4.1.3.2. BIOCONCENTRATION — Pertinent data regarding the bloaccumu-
Iat1on/b1oconcentrat1on potential of trlnltrobenzene 1n aquatic flora were
not located In the available literature dted 1n Appendix A.
0188d
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4.1.4. Effects on Bacteria. Pertinent data regarding the effects of
exposure of aquatic bacteria to trlnltrobenzene were not located In the
available literature cited In Appendix A.
4.2. TERRESTRIAL TOXICOLOGY
4.2.1. Effects on Fauna. Pertinent data regarding the effects of
exposure of terrestrial fauna to trlnltrobenzene were not located 1n the
available literature cited In Appendix A.
4.2.2. Effects on Flora. Pertinent data regarding the effects of
exposure of terrestrial flora to trlnltrobenzene were not located 1n the
available literature cited In Appendix A.
4.3. FIELD STUDIES
Pertlient data regarding the effects of trlnltrobenzene on flora and
fauna 1n the field were not located 1n the available literature cited In
Appendix \.
4.4. AQJATIC RISK ASSESSMENT
The lack of pertinent data regarding the effects of exposure of aquatic
fauna and flora to trlnltrobenzene precluded the development of a freshwater
criterion by the method of U.S. EPA/OWRS (1986) (Figure 4-1). Additional
data required for the development of a freshwater criterion Include the
results of acute assays with benthlc crustaceans, an Insect, a nonarthropod
and nonciordate species and an Insect or species from a phylum not
previously represented. The development of a freshwater criterion also
requires data from acceptable chronic toxlclty tests with two species of
fauna and at least one bloconcentratlon study.
The lack of pertinent data regarding the effects of exposure of aquatic
fauna and flora to trlnltrobenzene also precluded the development of a
saltwater criterion by the method of U.S. EPA/OWRS (1986). Additional data
0188d
-18-
06/13/89
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TEST TYPE
Family GMAV*
( pprn )
BMCV BCF-
(pprn)
Chordate (Salrnonid-f ish>
O. 52*
NA
NA
Chordate (warrnwater fish)
0. 0. 884-
NA
NA
#3
Chordate (fish or amphibian)
O. 57-
NA
NA
#4
Crustacean (planktonic)
3. 072'
0. 47'
NA
Crustacean (benthic)
NA
NA
In :ectan
NA
NA
NA
non-Art hropc-d/-Chordate
NA
NA
NA
*e
New insect an or phylum
representative
NA
NA
a! gae
XXXXXXXXXXXX
xxxxxxxxxxxx
0. IC.i
NA
#10
Vascular plant
XXXXXXXXXXXX
xxxxxxxxxxxx
NA
NA
* NA=Not fivai lablej* 96-hr LC« e for rainbow trout. Salrnc aairdneri ;
•Mean 96-hr I_C» e for fathead minnows, (Pimephales prornelas) ; '96-
hr LC» a -for bluegill sunfish, Leoornifc macrochirus; "Mean 48-hr
ECm« for the water flea, Daphnia maana; ftl-d*y NOEC for the water
flea. D. maana; •14-day LOEC for the alga, Selenastrum capricornu-
t urn.
FIGURE 4-1
Organisation Chart for Listing GMAVs, GHCVs and BCFs Required to Derive
Numerical Hater Quality Criteria by the Method of U.S. EPA/OURS (1986) for
the Prot?ct1on of Freshwater Aquatic Life from Exposure to Trlnltrobenzene
0188d
-19-
06/13/89
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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
crlterlor also requires data from chronic toxldty tests with two species of
fauna an( one species of algae or vascular plant and at least one bloconcen-
tratlon study.
4.5. SIHMARY
Existing data Indicate that trlnltrobenzene Is highly toxic to aquatic
fauna but that the compound Is not likely to concentrate In them. Acute
toxlclty data have been reported for four species of fish (fathead minnows,
channel catfish, bluegllls and rainbow trout) and one Invertebrate, the
water flua. LC5Q values for fathead minnows range from 0.49-1.1 ppm, and
the othe- three species displayed sensitivity to trlnltrobenzene at LCcn
DU
levels <".0 ppm and ranging from 0.38 to 0.8-5 (Bailey and Spanggord, 1983;
Liu et 0.12 ppm for 32 days. Rainbow trout were similarly
sensitive to trlnltrobenzene, showing a LOEL of 0.17 ppm for survival, fry
length and fry weight (van der Schalle, 1983). VentHatory effects were
noted In bluegllls exposed to treatment levels >0.128 ppm for 6 days (van
der Schalle et al., 1988). Signs of respiratory distress (opercular
0188d
-20-
06/13/89
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movement Increases, excitability and violent swimming) were noted 1n K.
sandvlcensus exposed to >0.1 ppm trlnltrobenzene for short durations (H1att
et al., H57).
A BCf of 6.36 has been calculated for trlnltrobenzene by L1u et al.
(1983) fiom the estimated log K value of 1.36. Bloconcentratlon data
reported by van der Schalle (1983) for fathead minnows, rainbow trout and
the water flea support the conclusion that trlnltrobenzene does not signifi-
cantly bl^accumulate In aquatic animals.
Toxic effects of trlnltrobenzene 1n the alga, S. caprlcornutum. was
Investigated by van der Schalle (1983). Significant reduction 1n growth was
noted at all levels tested (0.01-17.32 ppm) after 5 and H days exposure;
concentrations of 1.18 ppm were alglddal, and lower concentrations were
alglstatl:.
0188d
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5. PHARMACOKINETICS
5.1. ABSORPTION
Pertinent data regarding the absorption of 1,3,5-trlnltrobenzene were
not located In the available literature cited 1n Appendix A.
5.2. DISTRIBUTION
Pertinent data regarding the distribution of !,3,5-tr1n1trobenzene were
not located In the available literature cited In Appendix A.
5.3. METABOLISM
Pertinent data regarding the metabolism of 1,3,5-trlnltrobenzene were
not located In the available literature cited 1n Appendix A.
5.4. EXCRETION
Pertinent data regarding the excretion of 1,3,5-trlnltrobenzene were not
located In the available literature cited 1n Appendix A.
0188d
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposure. Data regarding the subchronlc and chronic
toxlclty of 1,3,5-trlnltrobenzene following Inhalation exposure were not
located In the available literature dted 1n Appendix A.
6.1.2. 3ral Exposure. Data regarding the subchronlc and chronic toxlclty
of 1,3,5 trlnltrobenzene following oral exposure were not located 1n the
available literature cited In Appendix A.
6.1.3. 3ther Relevant Information. Korolev et al. (1977) reported oral
L05Q valies of 600 mg/kg In white mice, 450 mg/kg 1n white rats and 730
mg/kg 1n guinea pigs. Toxlclty was characterized by central nervous system
and resp;ratory disorders and cyanosis. Ten rats were given dally oral
doses of 90 mg/kg (In an unspecified vehicle) for 30 days, and two died. In
a longer-term study (1n the English abstract, the experimental period was
referred to only as "prolonged"), orally administered 1 ,3,5-tr1n1trobenzene
(0.02-2 mg/kg) altered peroxldase, alkaline phosphatase and ceroplasmln
activities In the blood. A 5 mg/kg dose reportedly had weakly allergenlc
properties. Further details were unavailable.
T1mof levskaya and Rodlonova (1973) cited oral
™
values of 572 mg/kg
for 1,3,5-trlnltrobenzene 1n mice. Exposure to air saturated with trlnltro-
benzene for 24 hours was not toxic to mice, but details regarding measured
endpolnts were unavailable. T1mo1evskaya and Rodlonova (1973) also reported
that app Icatlon of trlnltrobenzene to the shaved skin of mice caused
hyperemla, edema and hemorrhages and that Instillation of 50 mg of trlnltro-
benzene into the eyes of rabbits caused Irritation. Further details,
however, were unavailable.
0188d
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Watarabe et al. (1976) compared the ability of various nitrobenzene* to
cause me;hemoglobin formation In the blood of rats. Groups of five male
Wlstar r«.ts were given single IntraperHoneal doses of 100 yirols/kg of the
compounds dissolved In polypropylene glycol. Five hours after Injection,
blood wis examined for methemoglobln level. l,3-D1n1trobenzene and
1,4-d1n1trobenzene caused greater formation of methemoglobln than l,3,5-tr1-
n1troben2ene, but the difference was statistically significant only for
l,4-n1trcbenzene. Data for control animals were not reported. In an _Ut
vJJLro assay, 1,3,5-tr1n1trobenzene, In addition to the three Isomers of
dlnltrobenzene, caused greater formation of methemoglobln than controls.
Senczuk et al. (1976) reported that single oral doses of tMnltrobenzene
(0.4 ymols/kg) also caused methemoglobln formation In Wlstar rats.
Further details were unavailable.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carclnogenlclty of
inhaled ",3,5-tr1n1trobenzene were not located 1n the available literature
cited 1n Appendix A.
6.2.2. Oral. Pertinent data regarding the carclnogenlclty of Ingested
1,3,5-trlnltrobenzene were not located In the available literature cited 1n
Appendix A.
6.2.3. Other Relevant Information. Single applications of 10 or 50 mg
l,3,5-tr1n1trobenzene (dissolved In acetone) to the skin of mice Increased
the Indcence of Inflammation, epidermal hyperplasla and dark cells (Slaga
et al., 1985). The response elicited by these dose levels was similar to
the maximum response obtained with TPA, a potent promoter of two-stage
carcinogenic tumors In the skin of SENCAR mice. 1,3,5-TMnltrobenzene
0188d
-24-
06/13/89
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tested negatively In assays for Initiation of TPA-promoted skin carclno-
genlclty. Post1n1t1at1on assays for the promotion of skin cancers were not
conducted with 1,3,5-trlnltrobenzene.
Intraperltoneal administration of 1,3,5-trlnltrobenzene dissolved In
corn oil (0, 600, 1500 and 3000 mg/kg 3 times weekly for 8 consecutive
weeks) d'd not cause lung tumors In male A/Jax mice (Slaga et al. 1985).
The lungs of five mice/dose were examined 16 weeks after the last Injection.
These results provided equivocal data regarding the carcinogenic potential
of 1,3,5-trlnltrobenzene because demonstrated carcinogens [benzo(a)pyrene
and 4-n1troqu1nol1ne-N-ox1de] did not produce lung tumors In the assay.
6.3. MUTAGENICITY
1,3,5-TMnltrobenzene produced reverse mutations 1n Salmonella typhl-
murlutn strains 1n three separate studies (McGregor et al., 1980; Spanggord
et al., 1982b; Kawal et al., 1987) (Table 6-1). In each study, the presence
of the S-9 activating system reduced, but did not abolish, the mutagenlc
activity of 1,3,5-trlnltrobenzene. Evidence for 1,3,5-tMnltrobenzene-
Induced genetic toxldty was not found In DNA repair assays with Escherlchla
coll strains or In mltotlc recombination assays with Saccharomvces
cerevlsla? D5 (McGregor et al., 1980).
6.4. TEWOGENICITY
Pertinent data regarding the teratogenUHy of 1,3,5-trlnltrobenzene
were not located In the available literature cited 1n Appendix A.
6.5. OT^R REPRODUCTIVE EFFECTS
Pertinent data regarding other reproductive effects were not located 1n
the availible literature dted In Appendix A.
6.6. SUMMARY
Infornation regarding the chronic or subchronlc toxldty of l,3,5-tr1-
n1trobenz?ne following Inhalation exposure Is unavailable. Information
0188d
-25-
06/13/89
-------
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0188d
-26-
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regarding oral exposure of chronic or subchronlc duration 1s limited to an
abstract of a Russian report (Korolev et al.f 1977). "Prolonged" oral
administration of 1,3,5-tMnltrobenzene to mice, rats and guinea pigs
altered the activities of peroxldase, alkaline phosphatase and ceroplasmln
In the blDod, but further details were unavailable.
Published oral L05Q values for 1,3,5-tMnHrobenzene Include: 600
mg/kg 1n white mice, 450 mg/kg In white rats, 730 mg/kg In guinea pigs
(Korolev et al., 1977) and 600 mg/kg In mice (T1mos1evskaya and Roklonova,
1973).
Administration of single oral (0.4 >imol/kg) or Intraperltoneal (0.1
vimol/kg) doses to rats Increased blood levels of methemoglobln (Senczuk et
al., 1975; Watanabe et al., 1976). Intraperltoneal administration of
Isomers oF dlnltrobenzene had a similar effect.
Data regarding the carclnogenlcHy of 1,3,5-trlnltrobenzene were limited
to a single study employing dermal and Intraperltoneal administrations.
Single topical applications of 1,3,5-trlnltrobenzene to the skin of mice
elicited a response (Inflammation, epidermal hyperplasla and cell darkening)
similar to that caused by TPA, a demonstrated promoter of mouse skin tumors.
Direct evidence for the carcinogenic potential of 1,3,5-trlnltrobenzene to
cause moise skin tumors was unavailable. Multiple Intraperltoneal Injec-
tions of 1,3,5-trlnltrobenzene (3 times/week for 8 weeks) did not cause lung
tumors 1n mice, but neither did benzo(a)pyrene, a known carcinogen (Slaga et
al., 1985).
1,3,5-Trlnltrobenzene was mutagenlc 1n assays for reverse mutations 1n
S. typhlnuMum strains, and the mutagenlc activity was reduced, but not
abolished, by the presence of a metabolic activating system (McGregor et
al., 1980; Spanggord et al., 1982b; Kawal et al., 1987).
0188d
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Data regarding teratogenk and other reproductive effects of l,3,5-tr1-
nHrobenzene were not available.
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HIMAN
A chronic oral RfD for 1,3,5-trlnltrobenzene of 0.05 yg/kg/day was
adopted Dy the U.S. EPA (1988). This value was based on the RfO for
1,3-d1n1trobenzene because of the structural similarity between the two
molecules and the Insufficient data on the toxlclty of 1,3,5-tr1n1trobenzene.
7.2. ACUATIC
Pertinent data regarding additional guidelines and standards for
1,3,5-trlnltrobenzene were not located 1n the available literature cited In
Appendix A.
0188d
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8. RISK ASSESSMENT
8.1. CJRCIN06ENICITY
8.1.1. Inhalation. Pertinent data regarding the carclnogenlclty of
1,3,5-trlnltrobenzene to animals or humans by Inhalation exposure were not
located 1n the available literature cited In Appendix A.
8.1.2. Oral. Pertinent data regarding the carclnogenlclty of 1.3,5-tM-
nHrobenzene to animals or humans by oral exposure were not located In the
available literature dted In Appendix A.
8.1.3. Other Routes. Single topical applications of 1,3,5-trlnltro-
benzene > 10 and 50 mg) to the skin of mice caused Inflammation, epidermal
hyperplasla and cell darkening. This response was similar to the maximum
response caused by TPA, a demonstrated promoter of mouse skin tumors.
1,3,5-TrlnHrobenzene did not Initiate TPA-promoted mouse skin tumors, but
tests of the ability of 1,3,5-trlnltrobenzene to promote skin tumors In the
presence of a known Initiator were not conducted. Multiple IntraperUoneal
Injections of 1,3,5-trlnltrobenzene (600, 1500 or 3000 mg/kg, 3 times/week
for 8 weeks) did not cause lung tumors In mice (Slaga et al., 1985).
8.1.4. rielght of Evidence. The available data regarding the carclnogen-
lclty of 1,3,5-trlnltrobenzene are Insufficient to adequately assess the
carcinogenic potential of 1,3,5-trlnltrobenzene 1n humans. The negative
results for 1,3,5-tr1n1trobenzene In the only available study (Slaga et al.,
1985) are Inconclusive because 1) direct tests of the ability of 1,3,5-trl-
nltrobenzene to promote mouse skin tumors In the presence of a known
Initiator were not conducted, and 2) IntraperUoneal administration of
benzo(a)pyrene, a known carcinogen Included as a positive control, did not
produce nouse lung tumors. Applying guidelines for carcinogenic risk
assessment adopted by the U.S. EPA (1986b), 1,3,5-trlnltrobenzene 1s
assigned to EPA Group D - not classifiable as to human carclnogenlclty.
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8.1.5. Quantitative Risk Assessment.
8.1.5.1. INHALATION — Data regarding the cardnogenldty of
1,3,5-trl iHrobenzene by Inhalation exposure are not available; therefore,
estimates of carcinogenic potency cannot be derived.
8.1.5.2. ORAL — Data regarding the cardnogenldty of 1,3,5-tM-
nltrobenzane by oral exposure are not available; therefore, estimates of
cardnogeilc potency cannot be derived.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURE (SUBCHRONIC) — Data regarding
subchronl: Inhalation toxldty of 1,3,5-trlnltrobenzene are not available;
therefore, an RfD for subchronlc Inhalation exposure cannot be derived.
8.2.1.2. CHRONIC EXPOSURE — Data regarding chronic Inhalation
toxldty of 1,3,5-trlnltrobenzene are not available; therefore, an RfD for
chronic lihalatlon exposure cannot be derived.
8.2.2. )ral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURE (SUBCHRONIC) — Data regarding
subchronl: or chronic oral toxldty of 1,3,5-trlnltrobenzene are Insuffi-
cient for derivation of an oral RfD. The U.S. EPA (1988), however, has
adopted a chronic oral RfD for 1,3,5-trlnltrobenzene derived from the RfD
for the structurally similar 1,3-dlnltrobenzene. Justification for this
derivation Included the fact that the LD5Q value for l,3-d1n1trobenzene
(83 mg/kg) In rats (Cody et al., 1981) Is much lower than the LD5_ value
for I,3,!i-tr1n1trobenzene (450 mg/kg) In rats (Korolev et al., 1977).
Additional justification Is provided by the observation that administration
of either 1,3-dlnltrobenzene or 1,3,5-trlnltrobenzene to rats caused similar
Increases In blood levels of methemoglobln (Watanabe et al., 1976).
0188d
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The terlvatlon of the oral RfD for 1,3-dlnltrobenzene Is based on the
results
-------
Confidence 1n the key study for the RfD derivation Is medium because
both a *QAEL and LOAEL were Identified; adequate numbers of animals were
tested;
-------
9. REPORTABLE QUANTITIES
9.1. B/.SED ON SYSTEMIC TOXICITY
As discussed In Chapter 6, data regarding the subchronlc and chronic
toxldty of 1,3,5-trlnHrobenzene are not available. Oral RfDs were derived
by analogy from the RfD for the structurally similar 1,3-d1n1trobenzene.
Following the same logic, a provisional RQ for 1,3,5-trlnHrobenzene can be
derived from subchronlc toxlclty data for 1,3-dlnHrobenzene from the rat
study by Cody et al. (1981). Increased spleen weight and Increased running
wheel activities were noted 1n rats provided with drinking water containing
1,3-dlnl .robenzene at concentrations >8 ppm. Based on water consumption and
body weight data, this concentration corresponded to an average Intake of
1.13 mg/eg/day. An equivalent dally Intake of 1,3,5-trlnltrobenzene 1s 1.44
mg/kg/da;', from which a human equivalent dose of 0.25 mg/kg/day 1s derived
by multlDlylng by the cube root of the ratio of the reference body weight
(0.35 kg) for rats (U.S. EPA, 1980a) to the reference human body weight
(70 kg).
A ch-onlc human MED of 1.7 mg/day 1s derived by multiplying the human
equivalent dose of 0.25 mg/kg/day by 70 kg to express the dose In mg/day for
a 70 kg human and dividing by 10 to approximate chronic from subchronlc
exposure The MED of 1.7 mg/day corresponds to an RV. of 5.15. An RV
of 4 Is assigned to the noted effects (Increased running wheel activity and
spleen weight); when It Is multiplied by the RV of 5.15, a CS of 20.58 1s
derived. The CS of 20.58 corresponds to an RQ for 1,3,5-trlnHrobenzene of
100 (Table 9-1). This RQ, however, Is based on analogy to 1,3-dlnHro-
benzene
-------
TABLE 9-1
1,3,5-Tr1n1trobenzene
Minimum Effective Dose (MED) and Reportable Quantity
Route: oral
Species: rats
Dose*: 1.7 rag/day
Duration: 16 weeks
Effect: increased spleen weight
RVd: 5.15
RVe: 4
CS: 20.58
RQ: 100
Reference: Cody et al., 1981
*Equ1valent human dose, based on analogy to 1,3-dlnHrobenzene
0188d
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0188d
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APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
CHEHLINE
TSCATS
CASK online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTJS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
These searches were conducted In May, 1989, and the following secondary
sources here reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1987. TLVs: Threshold Limit Values for Chemical Substances In the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.D. 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. 2B. John WHey and
Sons, NY. p. 2879-3816.
0186d
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ClaytDn, G.O. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygleie and Toxicology, 3rd rev. ed., Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
Grayssn, M. and 0. Eckroth, Ed. 1978-1984. K1rk-0thmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volum?s.
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.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screeilng for compounds of Interest to the Office of Solid Waste.
EPA JOO/6-84-010. NTIS PB84-243906. SRI International, Menlo
Park, CA.
NTP (National Toxicology Program). 1987. Toxicology Research and
Testlig Program. Chemicals on Standard Protocol. Management
Status.
Ouellitte, 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. /an Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Produ:ers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report 1n the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call In 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.
Verselueren, K. 1983. Handbook of Environmental Data on Organic
Chem1:als, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndhilz, 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.
0188(1
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In addition, approximately 30 compendia of aquatic toxldty 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 Toxldty
of Ciemlcals to Fish and Aquatic Invertebrates. Summaries of
Toxldty 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
Prepared for the Resources Agency of
Quality Control Board. Publ. No. 3-A.
Quality Criteria, 2nd ed.
California, State Water
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
SpecUs. 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.
0188d
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APPENDIX C
DOSE/DURATION RESPONSE GRAPHS FOR EXPOSURE TO 1,3.5-TRINITROBENZENE
C.I. DISCUSSION
Dose/duration-response graph(s) for Inhalation and oral exposure to
1,3,5-tr nitrobenzene generated by the method of Crockett et al. (1985),
using tho computer software by Durkln and Meylan (1988), and developed under
contract to ECAO-Clnclnnatl Is presented 1n Figure C-l. Data used to
generate these graphs are presented In Section C.2. In the generation of
this figure, all responses are classified as adverse (FEL, AEL or LOAEL) or
nonadvene (NOEL or NOAEL) for plotting. For oral exposure, the ordlnate
expresses dosage as human equivalent dose. The animal dosage 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 (Mantel and
Schneider man, 1975). The result 1s then multiplied by 70 kg, the reference
human body weight, to express the human equivalent dose as mg/day for a 70
kg human.
The Boundary for adverse effects (solid line) 1s drawn by Identifying
the lowe:t adverse effect dose or concentration at the shortest duration of
exposure at which an adverse effect occurred. From this point, an Infinite
line Is extended upward, parallel to the dose axis. The starting point Is
then connected to the lowest adverse effect dose or concentration at the
next lomer duration of exposure that has an adverse effect dose or concen-
tration equal to or lower than the previous one. This process Is continued
to the Icwest adverse effect dose or concentration. From this point, a line
Is extended to the right, parallel to the duration axis. The region of
adverse effects lies above the adverse effects boundary.
0188d -49- 07/31/89
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ill
\
I M,_
z
X
1999
•.9091
• .Ml
HUNAN IQUIU BUMTION (friction lir»S»*n)
IMJCLOP KtTHCD
.91
Key:
F - PEL
N - NOAEL
FIGURE C-l
Dose/Duration - Response Graph for Inhalation Exposure to 1,3.5-Trl-
nltrobenzene Envelope Method (expanded experimental concentration)
0188d
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Uslnj the envelope method, the boundary for no adverse effects (dashed
line) 1s drawn by Identifying the highest no adverse effects dose or concen-
tration. From this point, a line parallel to the duration axis Is extended
to the dose or concentration axis. The starting point Is then connected to
the next lower or equal no adverse effect dose or concentration at a longer
duration of exposure. When this process can no longer be continued, a line
Is dropped parallel to the dose or concentration axis to the duration axis.
The no adverse effects region lies below the no adverse effects boundary.
At both tnds of the graph between the adverse effects and no adverse effects
boundaries are regions of ambiguity. The area (1f any) resulting from the
Intersection 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 In the
region oi contradiction are dropped from consideration and the no adverse
effect boundary Is redrawn so that It does not Intersect the adverse effects
boundary and no region of contradiction Is generated. This method results 1n
the most conservative definition of the no adverse effects region.
The lack of data for oral exposure to 1,3,5-trlnltrobenzene Is reflected
In the large area of ambiguity defined In Figure C-l. The boundary for
adverse (ffects for oral exposure to 1,3,5-trlnltrobenzene 1s defined In
Figure C-l by two data points. Starting from the upper left, these points
represent the LD^ value (730 mg/kg/day, Rec. #3) In guinea pigs (Korolev
et al., 977) and the lowest ID., value (572 mg/kg/day, Rec. £4) from the
jU
study by T1mof1evskaya and Rodlonova (1973). The boundary for no adverse
effects for oral exposure to 1,3,5-trlnltrobenzene 1s defined In Figure C-l
by the NCAEL for methemoglobin effects (86 mg/kg/day, Rec. 15} from the rat
study by Jenczuk et al. (1973).
0188d
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C.2. DATA USED TO GENERATE DOSE/DURATION-RESPONSE GRAPHS
C.2.1. Inhalation Exposure
Chemical Name: 1,3,5-TMnltrobenzene
CAS Number: 99-35-4
Document Title: Health and Environmental Effects Document for
1,3,5-Trlnltrobenzene
Document Number:
Document Date:
Document Type: HEED
RECORD #1:
Species:
Sex:
Effect:
Route:
Mice
NR
PEL
Oral (NOS)
Dose:
Duration
Duration
Exposure:
Observation:
600.000
1.0 days
1.0 days
Comment:
Citation:
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 10
value for white mice.
Korolev et al., 1977
RECORD #2
Species:
Sex:
Effect:
Route:
Rats
NR
PEL
Oral (NOS)
Dose:
Duration
Duration
Exposure:
Observation:
450.000
1.0 days
1.0 days
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 10
Comment: 1050 value for white rats.
Citation: Korolev et al., 1977
0188d
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RECORD |3:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Guinea pigs
NR
PEL
Oral (NOS)
Dose: 730.000
Duration Exposure: 1.0 days
Duration Observation: 1.0 days
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 10
1050 value for guinea pigs,
Korolev et a!., 1977
RECORD #4:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Nice
NR
PEL
Oral (NOS)
Dose: 572.000
Duration Exposure: 1.0 days
Duration Observation: 1.0 days
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 10
LD5Q value for mice.
T1moflevskaya and Rodlonova, 1973
RECORD #5:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
NR
NOAEL
Oral (NOS)
Dose: 86.000
Duration Exposure: 1.0 days
Duration Observation: l.Q days
Number Exposed: NR
Number Responses: NR
Type of Effect: ENZYM
Site of Effect: BLOOD
Severity Effect: 2
Single oral dose (0.4 ymol/kg). Increased methemoglobln
formation 1n blood. Degree of Increase not specified In
English abstract.
Senczuk et al. 1976
NR = Not eported
0188d
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