United States
Environmental Protection
Agency
EPA/690/R-05/021F
Final
6-17-2005
Provisional Peer Reviewed Toxicity Values for
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
2,3-Toluenediamine
(CASRN 2687-25-4)

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Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and Liability Act
of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
i.v.	intravenous
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
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MTD
maximum tolerated dose
MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
PPb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
Hg
microgram
|j,mol
micromoles
voc
volatile organic compound
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6-17-2005
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
2,3-TOLUENEDIAMINE (CASRN 2687-25-4)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because science and available information evolve, PPRTVs are initially derived with a
three-year life-cycle. However, EPA Regions (or the EPA HQ Superfund Program) sometimes
request that a frequently used PPRTV be reassessed. Once an IRIS value for a specific chemical
becomes available for Agency review, the analogous PPRTV for that same chemical is retired. It
should also be noted that some PPRTV manuscripts conclude that a PPRTV cannot be derived
based on inadequate data.
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Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
No RfD, RfC, or cancer assessment for 2,3-toluenediamine is available in the HEAST
(U.S. EPA, 1997), which includes a comment that data for this chemical were inadequate for
quantitative risk assessment. 2,3-Toluenediamine is not listed on IRIS (U.S. EPA, 2003) or the
Drinking Water Standards and Health Advisories list (U.S. EPA, 2002). The CARA list (U.S.
EPA, 1991, 1994) includes a Health and Environmental Effects Profile (HEEP) for Selected
Toluenediamine (U.S. EPA, 1984), which was the source document for the HEAST listing.
ATSDR (2003) has not produced a Toxicological Profile that includes 2,3-toluenediamine. An
Environmental Health Criteria Document for Diaminotoluenes (WHO, 1987) is available, but
does not include derivation of quantitative risk values. Neither NTP (2003) nor IARC (2003) has
assessed the carcinogenicity of 2,3-toluenediamine. ACGIH (2003), NIOSH (2003), and OSHA
(2003) have not recommended occupational exposure limits for 2,3-toluenediamine. Literature
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6-17-2005
searches were conducted from 1983 through 2004 for studies relevant to the derivation of
provisional toxicity values for 2,3-toluenediamine. Databases searched included: TOXLINE
(supplemented with BIOSIS and NTIS updates), MEDLINE, CANCERLIT, TSCATS, RTECS,
CCRIS, DART, EMIC/ EMICBACK, HSDB, and GENETOX.
2,3-Toluenediamine is one of six diaminotoluene isomers that are components of crude or
commercial grade mixtures used as intermediates in the production of dyes and pigments for
commercial products (WHO, 1987). The crude mixture contains all six isomeric forms, while
the two commercial mixtures are composed primarily of two isomers each. One commercial
mixture, meta-diaminotoluene, contains the 2,4- and 2,6- isomers (80:20 or 65:35), and the other,
ortho-diaminotoluene, contains the 2,3- and 3,4- isomers (40:60).
REVIEW OF PERTINENT DATA
Human Studies
No data regarding the toxicity of 2,3-toluenediamine to humans following chronic or
subchronic exposure by any route were located. Epidemiological studies of male workers
exposed to diaminotoluene and dinitrotoluene mixtures were inconclusive as to whether there
was an increased risk of reproductive effects (sperm production and viability of wife's
pregnancies were evaluated) in the exposed workers (WHO, 1987).
Animal Studies
No data regarding the toxicity of 2,3-toluenediamine to animals following chronic or
subchronic exposure by any route were located. One relevant study of the o-toluenediamine
mixture (approximately 40% 2,3-toluenediamine) was located that evaluated developmental
effects of the mixture in rats and rabbits (Becci et al., 1983).
In the rat experiment, groups of 22 pregnant Sprague-Dawley females were given o-
toluenediamine at doses of 0, 10, 30, 100, or 300 mg/kg-day by gavage in corn oil on gestation
days 6 through 15 (Becci et al., 1983). Observations were conducted daily for general
appearance, behavior, and mortality. Body weights of the dams were recorded on gestation days
0, 6, 9, 12, 15, and 20. On gestation day 20, all females were sacrificed and uterine contents
were removed and examined. One-half of the fetuses were examined for soft tissue anomalies
and the remaining fetuses were examined for skeletal anomalies. No treatment-related effects on
appearance or behavior were observed in treated dams, and all dams survived the duration of the
study. There was a statistically significant decrease in weight gain (-17%) during gestation for
treated dams receiving 300 mg/kg-day compared to controls. No significant differences in
number of live fetuses, implantation sites, or resorption sites were indicated. Fetal effects
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indicative of developmental delay were significant reductions in fetal body weight (-18%) in the
300 mg/kg-day group, and significant increases in skeletal variations (missing sternebrae at 300
mg/kg-day and incomplete ossification of vertebrae at 100 and 300 mg/kg-day). No maternal or
developmental effects were seen at 30 mg/kg-day or below.
The rabbit experiment included groups of 15 pregnant female Dutch-Belted rabbits given
o-toluenediamine at doses of 0, 3, 10, 30, or 100 mg/kg-day by gavage in corn oil on gestation
days 6 through 18 (Becci et al., 1983). Observations were conducted daily for general
appearance, behavior, and mortality. Body weights of the does were recorded on gestation days
0, 6, 9, 12, 15, 18, and 29. On gestation day 29, all females were sacrificed and uterine contents
were removed and examined. All the fetuses were examined for both soft tissue and skeletal
anomalies. Appearance and behavior of does were unaffected by treatment. All does survived
the duration of the study. Body weight gain during gestation was significantly decreased (-60%)
in treated does receiving 100 mg/kg-day compared to controls. Other observations at this dose
were a significant increase in the incidence of resorptions, a 16% decrease in the mean number of
liver fetuses/doe (reported as statistically significant in the text, but not in the table showing the
data), and a significant 22% decrease in fetal body weight. No maternal or developmental effects
were seen at 30 mg/kg-day or below.
Other Studies
Limited data are available on the genotoxicity of 2,3-toluenediamine. The chemical was
weakly mutagenic in Salmonella typhimurium strain TA98 with or without metabolic activation
(Cheung et al., 1996). Administration of 0.2 or 0.5 mg/kg of 2,3-toluenediamine by
intraperitoneal injection had no effect on chromosomal aberrations or mitotic frequency in bone
marrow or ascites tumor cells in male CFW mice (Mikstacki, 1985).
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR 2,3-TOLUENEDIAMINE
No subchronic or chronic studies were located regarding toxicity of 2,3-toluenediamine to
humans or animals by oral exposure. Data on the o-toluenediamine mixture (approximately 40%
2,3-toluenediamine) showed that the mixture produced evidence of embryo/fetotoxicity in both
rats and rabbits, primarily at doses that also reduced gestational body weight gain in maternal
animals. Due to the absence of data for 2,3-toluenediamine itself, derivation of RfD values is
precluded.
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DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR 2,3-TOLUENEDIAMINE
No subchronic or chronic inhalation studies of 2,3-toluenediamine in humans or animals
were located, precluding derivation of RfC values for 2,3-toluenediamine.
DERIVATION OF A PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR 2,3-TOLUENEDIAMINE
No long-term data in humans or animals are available to assess the carcinogenic potential
of 2,3-toluenediamine. Limited data indicate that the chemical is weakly genotoxic in bacteria
(Cheung et al., 1996), but not clastogenic in mice in vivo (Mikstacki, 1985). Under the U.S. EPA
(2005) Guidelines for Carcinogen Risk Assessment, there is inadequate information to assess the
carcinogenic potential of 2,3-toluenediamine.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2003. TLVsŪ and
BEIsŪ: Threshold Limit Values for Chemical Substances and Physical Agents, Biological
Exposure Indices. Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 2003. Toxicological Profile
Information Sheet. U.S. Department of Health and Human Services, Public Health Service.
Online, http://www.atsdr.cdc.gov/toxpro2.html
Becci, P.J., E.L. Reagan, M.J. Knickerbocker et al. 1983. Teratogenesis study of o-
toluenediamine in rats and rabbits. Toxicol. Appl. Pharmacol. 71: 323-329.
Cheung Y.L., J. Snelling, N.N. Mohammed et al. 1996. Interaction with the aromatic
hydrocarbon receptor, CYP1A induction, and mutagenicity of a series of diaminotoluenes:
implications for their carcinogenicity. Toxicol. Appl. Pharmacol. 139(1): 203-11.
IARC (International Agency for Research on Cancer). 2003. Search IARC Monographs.
Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html
Mikstacki, A. 1985. Evaluation of mutagenicity of some aromatic amines used as hair dyes by
chromosomal aberration tests in-vivo. Genet. Pol. 26(1): 109-116.
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NIOSH (National Institute for Occupational Safety and Health). 2003. Online NIOSH Pocket
Guide to Chemical Hazards. Online, http://www.cdc.gov/niosh/npg/npgdcas.html
NTP (National Toxicology Program). 2003. Management Status Report. Online.
http://ntp-server.niehs.nih.gov/cgi/iH Indexes/ATI, SRCH/iH ATI, SRCH Frames.html
OSHA (Occupational Safety and Health Administration). 2003. OSHA Standard 1910.1000
Table Z-l. Part Z, Toxic and Hazardous Substances. Online.
http://www.osha-slc.gov/OshStd data/1910 1000 TABLE Z-l.html
U.S. EPA. 1984. Health and Environmental Effects Profile for Selected Toluenediamine.
Prepared by the Office of Health and Environmental Assessment, Cincinnati, OH for the Office
of Solid Waste and Emergency Response, Washington, DC. EPA600/X-84/148. NTIS PB88-
131073/AS.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment
Cincinnati OH for the Office of Emergency and Remedial Response, Washington, DC. July.
EPA/540/R-97/036. NTIS PB97-921199.
U.S. EPA. 2002. 2002 Edition of the Drinking Water Standards and Health Advisories. Office
of Water, Washington, DC. Summer 2002. EPA 822-R-02-038. Online.
http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf
U.S. EPA. 2003. Integrated Risk Information System (IRIS). Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Online.
http://www.epa.gov/iris/
U.S. EPA. 2005. Guidelines for Carcinogen Risk Assessment. Office of Research and
Development, National Center for Environmental Assessment, Washington, DC.
EPA/63 0/P-03/001F.
WHO (World Health Organization). 1987. Environmental Health Criteria 74. Diaminotoluenes.
Online: http://www.inchem.org/documents/ehc/ehc/ehc74.htm#PartNumber:4
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