TECHNICAL REPORT DATA
ffleae remd Instructions on the reverie before completing)
1. REPORT NO.
E.PA/500/8-88/032
3. RECIPIENT'S ACCESSION NO
PB88-178793/AS
4. TITLE AND SUBTITLE
Health Effects Assessment for 2,4- and 2,6-Dinitro-
toluene
6. REPORT DATE
«. PERFORMING ORGANIZATION CODE
AUTMOR(S)
a. PERFORMING ORGANIZATION REPORT NO
9. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO
12. SPONSORING AGENCY NAME AND ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
13. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
15 SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 12991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfD5 or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
7.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTlFIERS/OPEN ENDED TERMS C. COSATI Field/Group
8. DISTRIBUTION STATEMENT
Public
19. SECURITY CLASS (This Report!
Unclas5 i fi ed
21. NO. OF PAGES
20. SECURITY CLASS (This page/
Unclassified
22. PRICE
EPA F«n* 2220.1 (R«». 4.77) PMKVIOUS EDITION is OMOLETK
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EPA/600/8-88/032
May, 1987
HEALTH EFFECTS ASSESSMENT
FOR 2,4- AND 2,6-OINITROTOLUENE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
U.S. Environmental Protection Awncy
Region 5, Library (PL-12'J)
77 West Jackson Boulevarjd, 12th Floor
Chicago, IL 60604-3590
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DISCLAIMER
This document has been reviewed 1n accordance with the U.S.
Environmental Protection Agency's peer and administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with 2,4- and
2,6-d1n1trotoluene. All estimates of acceptable Intakes and carcinogenic
potency presented 1n this document should be considered as preliminary and
reflect limited resources allocated to this project. Pertinent toxlcologlc
and environmental data were located through on-line literature searches of
the TOXLINE, CANCERLIME and the CHEMFATE/OATALOG data bases. The basic
literature searched supporting this document 1s current up to June, 1986.
Secondary sources of Information have also been relied upon 1n the prepara-
tion of this report and represent large-scale health assessment efforts that
entail extensive peer and Agency review. The following Office of Health and
Environmental Assessment (OHEA) sources have been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for
D1n1trotoluene. .Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Water Regulations and Standards, Wash-
ington, DC. EPA 440/5-80-045. NTIS PB81-117566.
U.S. EPA. 1983a. Reportable Quantity Document for Benzene,
l-Methyl-2,4-D1n1tro (2,4-D1n1trotoluene). 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. 1983b. Reportable Quantity Document for Benzene,
l-Methyl-2,6-D1n1tro (2,6-01n1trotoluene). 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. 1986a. Health and -Environmental Effects Profile for
D1n1trotoluene. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
The Intent 1n these assessments 1s to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncetDainty factors were employed when the variable data was limited 1n
scope, which tended to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer 1s not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, 1s
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 Hfespan).
111
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This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants 1n ambient air or water where lifetime
exposure 1s assumed. Animal data used for RFO$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD$j) and oral (RfD$rj)
exposures.
The RfO (formerly AIC) 1s similar In concept and addresses chronic
exposure. It 1s an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the llfespan [see U.S. EPA (1980b) for a discussion of this concept]. The
RfD Is route-specific and estimates acceptable exposure for either oral
(RfDg) or Inhalation (RfDj) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores (CSs) for noncarclnogens have also been calculated
where data permitted. These values are used for ranking reportable quan-
tities and the methodology for their development 1s explained In U.S. EPA
(1983).
For compounds for which there 1s sufficient evidence of cardnogenldty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, 1f appro-
priate, based on oral and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation In proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
2,4-01n1trotoluene has been demonstrated to be carcinogenic In rats and
mice when fed 1n the diet (Ellis et al., 1979; Lee et al., 1978) as has
technical grade dlnltrotoluene (CUT, 1982), composed of -76% 2,4-, -19%
2,6- and smaller amounts of other Isomers of dlnltrotoluene., U.S. EPA
(1980a, 1986a) derived several q-|*s based on the occurrence of liver or
liver and mammary tumors In rats and mice from these studies. A human q-|*
of 0.683 (mg/kg/day)-1 based on the Incidence of liver and mammary tumors
in female rats (Ellis et al., 1979; U.S. EPA, 1986a) was selected as the
most stringent estimate of the cardnogenlcHy of 2,4-d1n1trotoluene to
humans.
Data were presented suggesting that the 2,6-lsomer may be more a potent
oral carcinogen than the 2,4-lsomer. The data were sufficient for weight of
evidence classification but Inadequate for quantitative risk analysis.
Data were not located regarding the Inhalation toxlclty of the dlnltro-
toluenes.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Or. Christopher OeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents In this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and Kim Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
vl
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
7.
ENVIRONHENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral
3.3.2. Inhalation
3.4. TOXICANT INTERACTIONS
CARCINOGENICITY
4.1. HUMAN DATA
4.2. BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
4.3. OTHER RELEVANT DATA
4.4. WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfDs)
6.2. REFERENCE DOSE (RfD)
6.3. CARCINOGENIC POTENCY (q-|*)
6.3.1. Oral
6.3.2. Inhalation
REFERENCES
APPENDIX
Paqe
... 1
... 4
... 4
... 4
. . . 5
... 5
. . . 5
6
6
. . . 6
... 8
8
. . . 8
. . . 9
9
10
. . . 10
10
. . . 10
. . . 12
. . . 12
. . . 13
15
16
. . . 16
. . . 16
, , , 16
. . . 16
23
... 24
. . . 32
vll
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LIST OF TABLES
No. Title Page
1-1 Selected Physical and Chemical Properties and Half-lives
for 2,4- and 2,6-01n1trotoluene 2
6-1 Cancer Data Sheet for Derivation of q-|* 1n Female
Sprague-Oawley Rats 17
6-2 Cancer Data Sheet for Derivation of q-|* 1n Female
CD Rats 18
6-3 Cancer Data Sheet for Derivation of q-|* In Male
Swiss Mice 20
6-4 Cancer Data Sheet for Derivation of q-|* 1n Male
F344 Rats 21
6-5 Cancer Data Sheet for Derivation of qi* 1n Female
F344 Rats 22
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LIST OF ABBREVIATIONS
bw Body weight
CAS Chemical Abstract Service
CS Composite score
DMA Oeoxyr1bonucle1c acid
FSH Follicle stimulating hormone
GGT+ y-Glutamyl transpeptldase positive
Koc Soil sorptlon coefficient standardized with
respect to soil organic matter
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
PEL Permissible exposure level
ppm Parts per million
q-j* Cancer potency slope
RfO Reference dose
RfD$ Subchronlc reference dose
STEL Short-term exposed level
TLV Threshold limit value
TWA Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected physical and chemical properties of 2,4-d1n1trotoluene (CAS No.
121-14-2) and 2,6-dlnltrotoluene (CAS No. 606-20-2) are presented In Table
1-1. Synonyms for dlnltrotoluene are methyldlnltrobenzene, dlnltrophenyl-
methane and ONT. Synonyms for 2,4-d1n1trotoluene are l-methyl-2,4-d1n1tro-
benzene, o,p-d1n1trotoluene and 2,4-ONT. Synonyms for 2,6-dlnltrotoluene
are 2-methyl-l,3-d1n1trobenzene and 2,6-DNT.
The atmospheric half-lives listed for 2,4- and 2,6-d1n1trotoluene are
based on the estimated rate constant of SxlO"11 cm3 molecule'1 sec"1
for the reaction of the dlnltrotoluene Isomers with photochemlcally
generated OH radical (OH radical concentration of 8xl05 molecules/cm3)
(U.S. EPA, 1986b). The half-life of 2,4-d1n1trotoluene 1n water was based
on an Investigation of the contaminants In the Rhine River (Zoeteman et a!.,
1980) and laboratory studies using Waconda Bay Water (Spanggord et al.,
1980). 2,6-Dlnltrotoluene is expected to have a half-life similar to that
of 2,4-d1n1trotoluene. Photochemical degradation should be an Important
removal mechanism, considering estimated photolysis half-lives range from 12
minutes for 2,6-d1n1trotoluene In river water to 2.7, 3.7 and 9.6 hours for
2,4-d1n1trotoluene 1n river, pond and bay water, respectively (Spanggord et
al., 1980; Zepp et al., 1984). Blodegradatlon has also been observed to be
a relatively rapid transformation process during some screening studies
(Davis et al., 1981; Spanggord et al., 1980). 2,4-D1n1trotoluene and
2,6-d1n1trotoluene could potentially adsorb to humus and clay partlculate
matter and sediments since polynltroaromatlc compounds have the ability to
form very stable charge-transfer complexes with more highly electronegative
aromatic compounds (Callahan et al., 1979).
0069h -1- 11/13/86
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TABLE 1-1
Selected Physical and Chemical Properties and Half-lives
for 2,4- and 2,6-01n1trotoluene
Property
Value
Reference
Chemical class:
Chemical formula:
nltroaromatlc
Molecular weight:
Melting point:
Boiling point:
Vapor pressure:
Water solubility:
Log octanol/water
partition coefficient:
B1oconcentrat1on factor
Soil adsorption
coefficient:
Half-lives 1n
air:
water:
2,4-dlnltro-toluene
182.14
300°C (slight decomposition)
for 2,4-ONT; NA for 2,6-DNT
67-70°C for 2.4-DNT
64-66°C for 2,6-ONT
2,4-: l.lxlO~* mm Hg at 20°C
(extrapolated)
2,6-
2,4-
2,6-
2,4-
2,6-
2,4-
2.6-
2.4-
2.6-
2.87x10"* mm Hg at 20°C
300 mg/i at 22°C
NA
1.98
1.76 (estimated)
19-25 (estimated)
13 (estimated)
190-285 (estimated)
216 (estimated)
2,4- and 2,6-: 8.0 hours
(estimated)
2,4-: 1.7 days
2,6-dlnltrotoluene
Verschueren,
1983
Aldrlch, 1984
Verschueren,
1983
Spanggord
et al., 1980
Pella. 1977
Dunlap, 1981
Hansch and Leo,
1985
U.S. EPA, 1986c
Lyman et al.,
1982
Lyman et al.,
1982
U.S. EPA, 1986b
Zoeteman
et al., 1980
NA = Not available
0069h
-2-
11/13/86
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Information regarding the persistence of 2,4- and 2,6-d1n1tr1toluene 1n
soil could not be located In the available literature. B1odegradat1on of
2,4- and 2,6-d1n1trotoluene under aerobic and anaerobic conditions In water
suggests that these compounds may undergo mlcroblal decomposition In soil.
The estimated K values of the dlnltrotoluenes Indicate that some
leaching may occur, but that chemical binding with humus and clay components
of soil may reduce the probability of leaching (Callahan et al., 1979).
0069h -3- 11/13/86
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Hodgson et al. (1977) reported that 60-90% of a dose of l*C-r1ng
labelled dlnltrotoluenes was absorbed within 24 hours of oral administration
In rats. The 2,4-1somer was absorbed more readily than the 2,6-lsomer.
U.S. EPA (1981) stated that, based upon urinary and fecal excretion find-
Ings, only 8-12% of an administered oral dose of [l4C]-2,4-d1n1trotoluene
was absorbed 1n mice, but that 75-85% of the dose was absorbed In rats,
rabbits, dogs and monkeys.
Mori et al. (1978) observed peak levels of radioactivity In the blood of
male rats at 6 hours after a single oral 22.2 mg/kg dose of 3H-2,4-d1-
nltrotoluene.
2.2. INHALATION
Turner (1986) analyzed urine samples from workers exposed to mixed
Isomers of dlnltrotoluene, and found that urinary excretion of metabolites
i
of dlnltrotoluenes Increased during the workday and declined to nearly
undetectable levels by the start of the next workday. These data suggest
that rapid absorption of dlnltrotoluenes occurs following Inhalation, but no
conclusions can be drawn regarding the proportion of Inhaled material
absorbed.
0069h -4- 07/31/86
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Ellis et al. (1985) treated male and female beagle dogs
with 1, 5 or 25 mg/kg/day 2,4-d1n1trotoluene 1n gelatin capsules for 4 or 13
weeks before sacrifice. At 5 and 25 mg/kg/day, the Intensity of neuro-
toxlclty, ranging from 1ncoord1nat1on and stiffness to total limb paralysis,
was directly related to both dose and duration of exposure. Hematologlcal
changes (methemoglob1nem1a, compensatory anemia) and testlcular degeneration
were observed 1n the 25 mg/kg/day dogs. As part of a chronic study, Ell 1s
et al. (1985) found neuropathy and anemia 1n dogs treated for 13 weeks with
10 mg/kg/day 2,4-d1n1trotoluene. During this 13-week period, no dog given
0.2 or 1.5 mg/kg/day was apparently affected; the dose of 1.5 mg/kg/day can
therefore be considered a NOEL for subchronlc oral exposure to 2,4-d1n1tro-
toluene.
Twenty-six week dietary studies using rats that were fed with mlxed-
Isomer dlnltrotoluene, revealed methemogloblnemla, anemia, myocarditis,
extramedullary hematopolesls, bile duct necrosis and testlcular degeneration
at 35 mg/kg/day (CUT, 1982). Effects at 14 mg/kg/day were restricted to
Increases 1n hepatic weights, leukocytosls, corneal aberrations and yellow
hepatic foci; 3.5 mg/kg caused a statistically significant decrease 1n body
weight gain.
Hong et al. (1985) found that dietary administration of 2,4-d1n1tro-
toluene (0.2%) for 13 weeks caused Inhibitions In weight gain and hepato-
cellular dysplasla In male mice, whereas 0.7X was associated with mortality.
Several other subchronlc studies In rats (Lee et al., 1985; NCI, 1978;
Kozuka et al., 1979) and mice (NCI, 1978) either reported effect levels at
doses considerably higher than those used by Ellis et al. (1985) and CUT
0069h -5- 11/13/86
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(1982), or do not describe their results In adequate detail for reliable
evaluation and Interpretation.
In the only available study of the subchronlc oral toxldty of pure
2,6-d1n1trotoluene (Ellis et al., 1976), dogs were treated for 13 weeks at
4, 20 or 100 mg/kg/day In gelatin capsules, and rats and mice were fed
dietary levels of 0.01, 0.05 or 0.25%. This Isomer produced effects similar
to those of 2,4-d1n1trotoluene. These effects Included decreased muscular
coordination, weight loss, methemoglob1nem1a, anemia, and splenic, CNS and
testlcular damage. A subchronlc NOAEL for 2,6-d1n1trotoluene was not
defined In this experiment.
3.1.2. Inhalation. Pertinent data regarding the subchronlc Inhalation
toxldty of 2,4- or 2,6-d1n1trotoluene could not be located In the available
literature.
3.2. CHRONIC
3.2.1. Oral. The CUT (1982) administered technical grade dlnltrotoluene
(consisting of a mixture of Isomers) to rats of both sexes In feed at
dietary concentrations that provided doses of 3.5, 14.0 and 35.0 mg/kg
bw/day for 78 weeks. Rats at the high concentration were sacrificed at week
55 Ui extremis. A statistically significant and dose-related depression In
rate of body weight gain was noted 1n all treated groups during the first 52
weeks of the experiment. Hematologlcal data suggested that a low grade
regenerative anemia occurred In high-dose males and females. Treatment-
related elevated relative liver and brain weight In all treated rats and
elevated relative kidney weights In all but the low-dose males were consis-
tently observed. Gross necropsy revealed white or yellow foci In the livers
of all treated rats. At termination, hlstopathologlcal evidence of hepato-
toxlclty, chronic Interstitial nephritis and parathyroid hyperplasla were
observed In all treated groups.
0069h -6- 11/13/86
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In another chronic rat study, diets containing 0, 0.0015, 0.01 and 0.07%
2,4-d1n1trotoluene were administered to groups of 38 males and 38 females
(Elll-s et al.t 1979; Lee et al., 1985). After 12 months, eight males and
eight females from each group were killed and examined, while the remaining
surviving rats were sacrificed after 24 months. Weight gain 1n high-dose
animals was markedly reduced, reaching a plateau after 2 months 1n females
and 4 months In males. Growth In middle-dose males and females began to
decrease during month 9, while low-dose rats had growth rates comparable
with controls. Anemia, partially compensated as evidenced by Increased
retlculocyte counts, was prominent 1n middle- and high-dose males and high-
dose females after 12 months. Cumulative deaths for high-dose males and
females were significantly higher than In controls; 50% mortality occurred
1n high-dose rats by about month 20 and 1n controls by about month 23. The
most striking lesion was the progressive development of hyperplastlc fod 1n
the liver, the severity of which was dose-dependent. These alterations were
observed 1n all male treatment groups and In high-dose females. Neoplastlc
nodules were also present In the majority of high-dose males and females.
Hemos1deros1s of the spleen occurred 1n a majority of high-dose rats.
Similar hepatic changes were found 1n dogs treated with capsules
containing 1.5 or 10 mg/kg/day 2,4-d1n1trotoluene for 104-108 weeks (Ellis
et al., 1985). Dogs were more susceptible to neurotoxlc effects than were
rats. An Intake of 0.2 mg/kg/day had no effect. The Investigators found
compensatory anemia at the high concentration.
Toxlclty data from Hong et al. (1985) for 2,4-d1n1trotoluene failed to
define chronic thresholds 1n mice because mice appear to be less susceptible
than rats and experiments 1n mice used higher dietary concentrations. In a
chronic experiment using rats and mice, the NCI (1978) observed treatment-
related Inhibition of body weight gain 1n both species, but no evidence of
0069h -7- 11/13/86
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hlstopathologlcal changes. These studies are of IHtle value 1n assessment
of chronic toxldty risk because adverse effects were observed at 80 ppm In
the diet, the lowest dietary concentration tested.
Pertinent data regarding the chronic oral toxldty of 2,6-d1n1trotoluene
could not be located 1n the available literature.
3.2.2. Inhalation. McGee et al. (1942) observed that workers exposed to
unspecified levels of 2,4-d1n1trotoluene experienced an unpleasant metallic
taste, headache, muscular weakness, dizziness, pallor, cyanosis and anemia.
There were no additional data 1n the available literature on the toxic
effects of d1n1trotoluene Isomers after chronic Inhalation exposure, except
for occupational studies which measured the effects of exposure upon repro-
ductive performance (Section 3.3.2.).
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. F344 rat dams administered 14-150 mg/kg/day technical grade
dlnltrotoluene on gestation days 7-20 had no significant differences from
controls 1n the numbers of resorptlons, or dead or live fetuses (Price et
al., 1985). At 150 mg/kg/day, there was a 3-fold Increase, over control
values. In prenatal mortality. At 100 mg/kg/day, fetuses had significantly
decreased retlculocyte and red cell counts. Mortality 1n the dams was
Increased at the high dose. Related studies (Ellis et al., 1979: Smith,
1983) Indicated the absence of fetal effects below level; that produced
maternal toxldty.
In chronic dietary studies with 2,4-dlnltrotoluene, decreases 1n sperma-
togenesls, testlcular atrophy, degeneration of the seminiferous tubules and
deficiencies In oogenesls were found 1n rats at 0.57 mg/kg bw/day (Lee et
al., 1985), 1n mice at 14 mg/kg bw/day (Hong et al., 1985) and 1n dogs at 25
mg/kg bw/day (Ellis et al., 1985). In a 3-generatlon rat study, however,
0069h -8- 07/31/86
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Ellis et al. (1979) found that dietary Intakes of 0.57-45 mg/kg bw/day, 1n
both males and females, had no treatment-related effects on any Indices of
reproduction, 1n spite of the hlstologlcal evidence of adverse effects on
germ cell production In males.
Pertinent data regarding the reproductive effects of oral exposure to
2,6-dlnltrotoluene could not be located In the available literature.
3.3.2. Inhalation. Ahrenholz (1980) studied the reproductive effects of
exposure to mixed Isomers of dlnKrotoluene 1n male workers \n a toluene-
dlamlne plant. Measured exposure levels were 0-0.10 mg/m3. There was a
slight, not statistically significant Increase In the number of spontaneous
abortions 1n the wives of dlnltrotoluene-exposed workers and a significant
reduction 1n the sperm count of exposed workers, relative to controls. The
sperm count of the control (nonexposed) group, however, was abnormally high,
obscuring the significance of the results.
Hamlll et al. (1982) studied the effects of exposure to concentrations
of dlnltrotoluene and toluene dlamlne that were within the limits of
unspecified OSHA standards. In 119 controls and 84 exposed workers, there
were no effects on measures of reproductive performance. Including sperm
counts and morphology, serum FSH, testlcular volume, and complete urogenltal
examination.
3.4. TOXICANT INTERACTIONS
Alcohol Ingestlon has a synerglstlc effect on the toxlclty of 2,4-d1-
nltrotoluene (U.S. EPA, 1980a). Exposed workers who drank alcohol shortly
after a workshlft experienced substernal pressure, precardlal palpitation,
fullness of the head, and severe acute nines:. U.S. EPA (1980a) noted that
alcohol Ingestlon usually Increases susceptibility to cyanosis associated
with 2,4-d1n1trotoluene.
0069h -9- 11/12/86
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4. CARCINOGEN!CITY
4.1. HUHAN DATA
Pertinent data regarding the carcinogenic effects 1n humans of oral or
Inhalation exposure to 2,4- or 2,6-d1n1trotoluene could not be located In
the available literature.
4.2. BIOASSAY
4.2.1. Oral. Several long-term dietary cancer bloassays with relatively
pure 2,4-d1n1trotoluene and a technical grade mixture of dlnltrotoluenes
have been performed and were recently reviewed by U.S. EPA (1986a). Because
of the time and budgetary constraints of this task, only salient data
pertaining to the Issue of the cardnogenldty of the dlnltrotoluene Isomers
will be presented.
NCI (1978) performed a cancer bloassay using rats and mice of both sexes
with practical grade 2,4-d1n1trotoluene of -95% purity. The nature of the
Impurities was not reported. Rats received diets containing 0, 80 or 200
ppm and mice received diets containing 0, 80 or 400 ppm. Test diets were
fed for 78 weeks and untreated diets were fed for an additional 26 weeks to
rats and 13 weeks to mice before termination. Survival did not appear to be
affected by treatment. Although neither species had a significantly
Increased Incidence of malignant tumors, male rats In both treated groups
had an Increased Incidence of benign subcutaneous flbromas and high-dose
female rats had an Increased Incidence of benign mammary fIbroadenomas.
In another study with technical grade 2,4-d1n1trotoluene, diets contain-
ing 0, 0.0015, 0.01 or 0.07X were fed to rats for 24 months (Lee et al.,
1978; Ellis et al.. 1979). The on'ij statistically significant Increase of
tumor Incidence was In the occurrence of hepatocellular carcinomas alone or
combined with neoplastlc nodules and the occurrence of benign tumors 1n the
0069h -10- 11/13/86
-------
mammary gland alone or combined with malignant tumors, both tumor types 1n
female rats. Although shortened llfespans were observed In middle- and
high-dose rats of both sexes, mortality did not appear to affect the expres-
sion of the carc1nogen1c1ty of the test chemical, which was judged to be
weak (U.S EPA. 1986a).
Ellis et al. (1979) fed diets containing technical grade 2,4-d1n1tro-
toluene at 0, 100, 700 or 5000 ppm to mice for 24 months. Mortality In the
high-dose mice precluded their Inclusion In the data analysis. The most
noteworthy observation was an Increased Incidence of kidney tumors In 700
ppm male mice.
An extensive study using rats by CUT (1982) contrasts the oncogenldty
of the purified 2,4-lsomer with that of technical grade dlnltrotoluene.
Technical grade dlnltrotoluene was fed 1n the diets to rats to provide dally
dosages of 0, 3.5, 14.0 or 35.0 mg/kg/day for up to 104 weeks. The tech-
nical grade material used consisted of 76.4% 2,4-, 18.8% 2,6- and smaller
amounts of the other Isomers of dlnltrotoluene. The carcinogenic potential
of the technical material appeared to be much greater than that of 2,4-d1-
nltrotoluene alone. Malignant tumors that Included a high Incidence of
hepatocellular carcinomas and a few cholanglocardnomas (considered to be
rare In rats) were noted In 100% of high-dose male and female rats that
survived >12 months.
The greater oncogenlc potential of the technical material compared with
relatively pure 2,4-d1n1trotoluene was attributed by Popp and Leonard (1982)
to the greater oncogenldty of the 2,6-1somer. These Investigators observed
that 100% of all rats fed 14 mg/kg/day, and 95% fed 7 mg/kg/day of >99.9%
pure 2,6-d1n1trotoluene developed hepatocellular carcinomas within 1 year.
0069h -11- 11/12/86
-------
In contrast, 27 mg/kg/day >99.9% pure 2,4-d1n1trotoluene Induced no hepatic
neoplasla after a comparable 1-year period. Actual Incidence data were not
provided. In conjunction with results from Initiation-promotion studies
(Section 4.3.), these data suggest that the 2,6-1somer Is the more potent
hepatocardnogen.
4.2.2. Inhalation. Pertinent data regarding the Induction of cancer 1n
experimental animals after Inhalation exposure to dlnUrotoluene could not
be located 1n the available literature.
4.3. OTHER RELEVANT DATA
Popp and Leonard (1982) tested 2,4-, 2,6- and technical grade dlnltro-
toluene as Initiators In a short-term assay In which rats were treated with
the test chemical orally and subjected to partial hepatectomy 12 hours
later. The presence of GGT+ foci in the liver, suggestive of Initiating
activity, was observed only for 2,6-d1n1trotoluene and the technical
product. In a promotion experiment (Popp and Leonard, 1982), positive
results (Increased GGTt foci) were observed for both the 2,4- and
2,6-1somers, with the 2,6-lsomer yielding the stronger response. The
experiment was conducted In rats Initiated with a single IntraperHoneal
Injection of diethylnltrosamlne; the test chemicals were fed 1n the diet for
12 weeks. These studies suggest that only the 2,6-1somer has detectable
Initiating activity, out that both 2,4- and 2,6-d1n1trotoluene may act as
promoters, with the 2,6-lsomer having the greater potency.
In a two-stage skin-painting study using mice, 2,6- but not 2,4-d1nltro-
toluene given as Initiators followed by promotion with tetradecanoyl
phorbate acetate Increased the Incidence of squamous cell carcinomas,
although the result was not statistically significant.
0069h -12- 11/12/86
-------
Neither 2,4- nor 2,6-d1n1trotoluene Induced Increases In lung tumors In
Strain A ratce (Slaga et al., 1985; Stoner et al., 1984; Schut et al., 1982).
The genotoxlclty of the various dlnltrotoluene Isomers has been studied
extensively, and was recently reviewed by U.S. EPA (1986a). Both 2,4- and
2,6-d1n1trotoluene were slightly mutagenlc In Salmonella typhlmurlum strain
TA98 (Couch et al., 1981). Other studies Indicated that these Isomers
Induced frameshlft mutations In S. typhlmurlum strains TA1536, TA1537 and
TA1538 (Toklwa et al., 1981).
Neither Isomer caused unscheduled DNA synthesis In vitro In primary rat
hepatocytes (Bermudez et al., 1979), although a single dose of technical
grade dlnltrotoluene In male rats Induced significant repair activity _^n
vivo (Mlrsalls and Butterworth, 1982). Pure 2,4-dlnltrotoluene was
Ineffective In the whole animal assay and the Induced repair activity was
attributed by the authors (Mlrsalls and Butterworth, 1982) to the
2,6-lsomer. At high doses, both 2,4- and 2,6-d1n1trotoluene have been found
to cause chromatld breaks In kidney cells and lymphocytes from rats (Lee et
al., 1978). Dominant lethal assays 1n male rats and mice have revealed
equivocal, but generally negative results (Ellis et al., 1979; Borzelleca
and Carchman, 1982).
4.4. WEIGHT OF EVIDENCE
Based upon positive data for oncogenldty from bloassays 1n both rats
and mice (Ellis et al., 1979), and 1n the absence of appropriate human data,
2,4-d1n1trotoluene can be classified an IARC Group 28 carcinogen; that 1s,
this chemical Is probably carcinogenic In humans, based upon experimental
animal studies. According to U.S. EPA (1986d) guidelines, 2,4-dlnHro-
toluene would also be classified as an EPA Group 82 carcinogen because of
the existence of sufficient evidence of carclnogenlclty In two species of
0069h -13- 01/12/87
-------
animals (Ellis et al., 1979). It should be noted, however, that the effects
of the oncogen1c potential of 2,6-d1n1trotoluene (as a minor contaminant) on
the carclnogenldty of the practical grade 2,4-dlnltrotoluene used 1n these
experiments Is unclear.
The results of Popp and Leonard (1982) and CUT (1982) clearly establish
the carclnogenldty of 2,6-d1n1trotoluene In animals, resulting In an IARC
classification 1n Group 2B, or EPA Group 82.
0069h -14- 01/12/87
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5. REGULATORY STANDARDS AND CRITERIA
Based upon a human consumption of 2 l of water and 6.5 g of fish and
shellfish dally, the U.S. EPA (1980a) determined ambient water quality
criteria for 2,4-d1n1trotoluene of 1.1, 0.11 and 0.011 vg/l, based on
excess cancer risks of 10~5, 10"' and 10~7, respectively. These
criteria were based on Increased Incidences of liver and mammary tumors In
rats fed 2,4-d1n1trotoluene In the diet for 24 months (Lee et al., 1978).
ACGIH (1985) adopted a TLV-TWA for commercial dlnltrotoluene of 1.5
mg/m3, accompanied by a "skin" designation for hazards from dermal absorp-
tion, and deleted the TLV-STEL of 5 mg/m3. ACGIH (1986) reported that the
TLV-TWA was derived by analogy to nltro and dlnltrobenzenes. ACGIH (1986)
based the values for each compound upon earlier work Indicating that
methemogloblnemla was the first toxic symptom observed. The OSHA (1985) PEL
for dlnltrotoluene (not otherwise specified) Is also 1.5 mg/m3.
0069h -15- 11/12/86
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfO$)
Both 2,4- and 2,6-d1n1trotoluene have been shown to be carcinogenic In
experimental animals by the oral route, and data are sufficient for deriva-
tion of a q * for the 2,4-lsomer only. Calculation of an RfDc^ or
' *
SO
RfDSI 1s therefore Inappropriate for these compounds.
6.2. REFERENCE DOSE (RfD)
Both 2,4- and 2,6-d1n1trotoluene have been shown to be carcinogenic In
experimental animals by the oral route, and data are sufficient for deriva-
tion of a q,* for the 2,4-1somer only. Calculation of an RfDQ or RfD,
1s therefore Inappropriate for these compounds.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. The chronic bloassays most relevant for assessment of the
oral carcinogenic potency of 2,4-d1n1trotoluene were performed In rats and
mice by Ellis et al. (1979). When animal results were analyzed Individually
(U.S. EPA, 1986a), the Incidences of combined mammary/hepatic tumors In
female rats was strongly concentration-related (Table 6-1). The U.S. EPA
(1986a) observed differences In average body weight among the various groups
of female rats, and converted rat doses (mg/kg/day) to comparable human
doses by multiplying each rat dose by the cube root of the ratio of human
body weight (70 kg) to rat body weight, within each dietary group. The
human q * based upon the computerized model of Howe and Crump (1982), 1s
0.683 (mg/kg/day)"1
The U.S. EPA (1980a, 1982) used the Incidence of combined liver and
mammary tumors 1n female rats 1n the 2-year study by Lee et al. (1978) as
the basis for their q * of 0.31 (mg/kg/day)"1 (Table 6-2). Although the
Lee et al. (1973) study was apparently the same as the Ellis et al. (1979)
0069h -16- 05/13/87
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TABU 6-1
Cancer Data Sheet for Derivation of q-|*
1n Female Sprague-Dawley Rats
Compound: 2,4-d1n1trotoluene
Reference: Ellis et al., 1979; U.S. EPA, 1986a
Species, strain, sex: rat, Sprague-Dawley, female
Body weight: 0.425 kg control; 0.425 kg low dose; 0.410 kg middle dose;
0.325 kg high dose (measured)
Length of exposure (le) = 24 months
Length of experiment (Le) = 24 months
Llfespan of animal (L) = 24 months
Tumor site and type: liver - hepatocellular carcinoma, neoplastlc nodule;
mammary gland - adenoma, fIbroadenoma, fibroma,
adenocardnoma/carclnoma
Route/vehicle: oral, diet
Experimental Doses
or Exposures Transformed Dose Incidence
(ppm)
0
15
100
700
(mg/kg/day)
0
0.706
0.514
45.3
(mg/kg/day)
0
0.129
0.927
7.557
No. Responding/No.
11/23
12/35
17/27
34/35
Examined
Unadjusted q-|* from study = not calculated (see text)
Human q-|* = 0.68 (mg/kg/day)-1
0069h -17- 01/22/87
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TABLE 6-2
Cancer Data Sheet for Derivation of q-]* 1n Female CD Rats
Compound: practical-grade 2,4-d1n1trotoluene
Reference: Lee et al., 1978; U.S. EPA, 1980a
Species, strain, sex: rat, CD, female
Body weight: 0.464 kg
Length of exposure (le) = 720 days
Length of experiment (Le) = 750 days
Llfespan of animal (L) = 750 days
Transformed Dose
(mg/kg/day)
Incidence
No. Responding/No. Tested
0.0
0.75
5.0
35.0
11/31
13/43
18/35
35/43
Human q-|* = 0.31 (mg/kg/day)-1
0069h
-18-
01/20/87
-------
study, the tumor Incidence data used by the U.S. EPA (1980a) were not the
same as those of Ellis et al. (1979), probably because the Lee et al. (1978)
version was a preliminary report. In a later published version of this
study (Lee et al., 1985), still another set of hepatic/mammary tumor data
was presented. Because the Incidence data of the Ellis et al. (1979) study
were the most clearly presented, H Is appropriate to adopt the current
q * of 0.683 (mg/kg/day)'1 derived by U.S. EPA (1986a) as appropriately
representing the carcinogenic potency of 2,4-d1n1trotoluene based on
experiments In rats.
The chronic mouse bloassay (Ellis et al., 1979) can also be used for
carcinogenic risk assessment. Since most high concentration males died
within 1 year, data are restricted to the controls and two lower dose
dietary groups. A human q * of 0.391 (mg/kg/day)'1 was derived by the
U.S. EPA (1986a) based on the occurrence of total kidney tumors 1n male rats
(Table 6-3)!
Because the q^ of 0.683 (mg/kg/day)'* (U.S. EPA, 1986a) based upon
the rat data of Ellis et al. (1979) 1s higher and represents the more
conservative evaluation of the carcinogenic risk of 2,4-d1n1trotoluene to
humans, It 1s adopted as the most appropriate estimate of carcinogenic risk
for the purposes of this document (see Appendix).
The U.S. EPA (1986a) also derived human q *s of 0.23 and 0.21
(mg/kg/day)'1 for technical grade dlnltrotoluene based on the Incidence of
liver tumors In male (Table 6-4) and female (Table 6-5) rats 1n the CUT
(1982) study. Data sufficient for derivation of an oral q * for 2,6-d1-
nltrotoluene were not available, although this Isomer appears to be the more
potent carcinogen.
0069h -19- 11/13/86
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TABLE 6-3
Cancer Data Sheet for Derivation of q-|* 1n Male Swiss Mice
Compound: 2,4-d1n1trotoluene
Reference: Ellis et al., 1979; U.S. EPA, 1986a
Species, strain, sex: mouse, Swiss, male
Body weight: 0.04 kg (measured)
Length of exposure (le) = 24 months
Length of experiment (Le) = 24 months
Llfespan of animal (I) = 24 months
Tumor site and type: kidney; cystic papillary adenoma, cystic papillary
carcinoma, solid renal cell carcinoma
Route/vehicle: oral, diet
Experimental Doses Transformed Dose Incidence
or Exposures (mg/kg/day) No. Responding/No. Examined
(ppm)
0 0 0/20
100 13.3 4/21
700 96.9 16/17
Unadjusted q-|* from study = 3.2xlO-2 (mg/kg/day)-1
Human q-|* = 0.39 (mg/kg/day)-1
0069h -20- 01/22/87
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TABLE 6-4
Cancer Data Sheet for Derivation of q-|* 1n Male F344 Rats
Compound: technical-grade dlnltrotoluene
Reference: CUT, 1982
Species, strain, sex: rat, F344, male
Body weight: 0.37 kg control; 0.35 kg low dose; 0.29 kg high dose;
(measured)
Length of exposure (le) = 104 weeks
Length of experiment (Le) = 104 weeks
Llfespan of animal (L) = 104 weeks
Tumor site and type: liver; hepatocellular carcinoma, neoplastlc nodule
Route/vehicle: oral, diet
Experimental Doses
or Exposures
(mg/kg/day)
0
3.388
13.451
Transformed Dose
(mg/kg/day)
0
0.579
2.160
Incidence
No. Responding/No.
10/61
19/70
23/23
Examined
Unadjusted q-|* from study = not calculated (see text)
Human q-|* = 0.23 (mg/kg/day)-1
0069h -21- 01/22/87
-------
TABLE 6-5
Cancer Data Sheet for Derivation of q-j* 1n Female F344 Rats
Compound: technical-grade dlnltrotoluene
Reference: CUT, 1982
Species, strain, sex: rat, F344, female
Body weight: 0.26 kg control; 0.24 kg low dose; 0.19 kg high dose;
(measured)
Length of exposure (le) = 104 weeks
Length of experiment (Le) = 104 weeks
Llfespan of animal (L) = 104 weeks
Tumor site and type: liver; hepatocellular carcinoma, neoplastlc nodule
Route/vehicle: oral, diet
Experimental Doses
or Exposures
(mg/kg/day)
0
3.379
13.633
Transformed Dose
(mg/kg/day)
0
0.510
1.902
Incidence
No. Responding/No.
5/57
12/61
66/68
Examined
Unadjusted q-|* from study =' not calculated (see text)
Human q-|* = 0.21 (mg/kg/day)-1
0069h -22- 01/22/87
-------
6.3.2. Inhalation. Data regarding the carclnogenlclty of Inhaled
dlnltrotoluene could not be located 1n the available literature and EPA has
not undertaken route to route extrapolation of carcinogenic response. Thus,
an Inhalation risk assessment Is not presently available.
0069h -23- 01/12/87
-------
7. REFERENCES
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TLVs: Threshold Limit Values for Chemical Substances In the Work Environment
Adopted by ACGIH for 1985-1986. Cincinnati, OH. p. 17.
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986.
Documentation of the Threshold Limit Values and Biological Exposure Indices
for Substances 1n Workroom A1r, 5th ed. Cincinnati, OH. p. 216.
Ahrenholz, S.H. 1980. Health hazard evaluation determination report no.
HE79-113-728. Olln Chemical Company, Brandenburg, KY. NIOSH Report
HE-79-113. NTIS PB81-167819. (CA 95:155707w) (Cited 1n U.S. EPA, 1986a)
Aldrlch. 1984. 1984-1985 AldMch Catalog/Handbook of Fine Chemicals.
Aldrlch Chemical Co., Milwaukee, UI. p. 468.
Bermudez, E., D. Tlllery and B.E. Butterworth. 1979. The effect of 2,4-d1-
amlnotoluene and Isomers of dlnltrotoluene on unscheduled DNA synthesis 1n
primary rat hepatocrytes. Environ. Mutagen. 1(4): 391-398.
Borzelleca, J.F. and R.A. Carchman. 1982. Effects of selected organic
drinking water contaminants on male reproduction. EPA 600/1-82-009. NTIS
PB82-259847. 149 p. (Cited 1n U.S. EPA, 1986a)
Callahan, M.A., M.W. Sllmak, N.W. Gabel, et al. 1979. Water-related
environmental fate of 129 priority pollutants. Vol. II. EPA 440/4-79-029B.
U.S. EPA, Washington, DC.
0069h -24- 11/13/86
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CUT (Chemical Industry Institute of Toxicology). 1982. 104-Week chronic
toxldty study In rats: D1n1trotoluene. Final Report. CUT Docket #12362.
Couch, D.B., P.P. Allen and D.J. Abernathy. 1981. The mutagenldty of
dlnltrotoluene 1n Salmonella typhlmurlum. Mutat. Res. 90: 373-384. (CHed
1n U.S. EPA, 1986a)
Davis, E.M., H.E. Murray, J.G. Llehr and E.L. Powers. 1981. Basic
mlcroblal degradation rates and chemical by-products of selected organic
compounds. Water Res. 15(9): 1125-1127.
Dunlap, K.I. 1981-. Nitrobenzene and nltrotoluenes. Iji: K1rk-0thmer
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Eckroth, Ed. John Wiley and Sons, Inc., New York. p. 925-926, 930-931.
Ellis, H.V., III, J.V. Dllley and C.C. Lee. 1976. Subacute toxldty of
2,4-d1n1trotoluene and 2,6-d1n1trotoluene. Toxlcol. Appl. Pharmacol.
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ElHs, H.V., S.H. Hageusen, J.R. Jodgson, et al. 1979. Mammalian Toxldty
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Ellis, H.V., C.B. Hong, C.C. Lee, J.C. Dacle and J.P. Glennon. 1985.
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Beagle dogs. J. Am. Coll. Toxlcol. 4: 233-242.
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HamHI, P.V., E. Ste1nbe1ger, R.J. Levlne, L.J. Rodr1guez-R1gan, S. Lemeshow
and J.S. Avrumln. 1982. The ep1dem1olog1cal assessment of male reproduc-
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Hansch, C. and A.J. Leo. 1985. MedChem Project Issue No. 26. Pomona
College, Claremont, CA.
Hodgson, J.R., S.W. Hwang, 3.C. Dacre and C.C. Lee. 1977. Comparative
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Hong, C.B., H.V. Ellis, III, C.C. Lee, H. SpMnz, J.C. Dacre and J.P.
Glennon. 1985. Subchronlc and chronic toxldty studies of 2,4-d1n1tro-
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Kozuka, H., M.A. Mori and Y. Naruse. 1979. Metabolism and toxldty of
dlnltrotoluenes: Tox1colog1cal study of 2,4-d1n1trotoluene In rats In long-
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of munition compounds. Phase II. Effects of multiple doses. Part II.
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0069h -26- 07/31/86
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Lee, C.C., C.B. Hong, H.V. Ellis, III, J.C. Oacre and J.P. Glennon. 1985.
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Property Estimation Methods. McGraw-Hill Book Co., New York. p. 4-9, 5-5.
McGee, L.C., A. McCausland, C.A. Plume, et al. 1942. Metabolic disturb-
ances In workers exposed to dlnltrotoluene. Am. J. Digest. D1s. 9:
329-331. (Cited In U.S. EPA, 1981, 1986a)
Mlrsalls, J.C. and B.E. Butterworth. 1982. Induction of unscheduled DNA
synthesis In rat hepatocytes following _1ri vivo treatment with dlnltro-
toluene. Carclnogenesls (London). 3(3): 241-246.
Mori, M., Y. Naruse and H. Kozuka. 1978. Studies on the metabolism and
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27(12): 715-719.
NCI (National Cancer Institute). 1978. Bloassay of 2,4-d1n1trotoluene for
possible carc1nogen1c1ty. Carclnogenesls Tech. Rep. Ser. No. 54. Publ. No.
78-1360.
OSHA (Occupational Safety and Health Administration). 1985. OSHA Safety
and Health Standards. 29 CFR 1910.1000.
0069h -27- 11/12/86
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Pella, P.A. 1977. Measurement of the vapor pressures of TNT, 2,4-d1n1tro-
toluene and EGON. J. Chem. Thermodyn. 9: 301-305.
Popp, 3.A. and T.B. Leonard. 1982. The use of ±n vivo hepatic Initiation-
promotion systems 1n understanding the hepatocardnogenesls of technical
grade dinltrotoluene. Toxlcol. Pathol. 10: 190-196. (Cited 1n U.S. EPA,
1986a)
Price, C.J., R.W. Tyl, T.A. Marks, L.L. Paschke, T.A. Ledoux and J.R. Reel.
1985. Terataloglc evaluation of dinltrotoluene 1n the Fischer 344 rat.
Fund. Appl. Toxlcol. 5: 948-961. (Cited In U.S. EPA, 1986a)
Schut, H.A.J., T.R. Loeb and G.D. Stoner. 1982. Distribution, elimination
and test for carclnogenlcHy of 2,4-d1n1troto1uene In Strain A mice.
Toxlcol. Appl. Pharmacol. 64(2): 213-220. (Cited 1n U.S. EPA, 1986a)
Slaga, T.L., L.L. TMplett, L.H. Smith and H.P. WHschl. 1985. Carclnogen-
esls of Nitrated Toluenes and Benzenes, Skin and Lung Tumor Assays 1n Mice.
Final Report. NTIS DE85012081/WEP. p. 33. (CHed 1n U.S. EPA, 1986a)
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APPENDIX
Summary Table for 2,4-D1n1trotoluene*
Route Species Experimental Effect q-|* Cancer Potency Slope
Exposure/Dose (mg/kg/day)-1
Oral rat 15, 100 and hepatocellular 0.68
700 ppm 1n tumors; mammary
diet for benign and
104 weeks malignant tumors
(14 and 95
mg/kg/day)
'Source: Ellis et al., 1979
f
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