United States
kS^laMIjk Environmental Protection
^J^iniiil m11 Agency
EPA/690/R-12/006F
Final
3-12-2012
Provisional Peer-Reviewed Toxicity Values for
3 -Nitro-4-chlorobenzotrifluoride
(CASRN 121-17-5)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Carrie R. Fleming, PhD
National Center for Environmental Assessment, Cincinnati, OH
CONTRIBUTOR
Jason C. Lambert, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
ICF International
9300 Lee Highway
Fairfax, VA 22031
PRIMARY INTERNAL REVIEWERS
Audrey Galizia, DrPH
National Center for Environmental Assessment, Washington, DC
Suryanarayana V. Vulimiri, BVSc, PhD, DABT
National Center for Environmental Assessment, Washington, DC
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300).
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS	iii
BACKGROUND	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVS	1
INTRODUCTION	2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER)	3
HUMAN STUDIES	6
Oral Exposures	6
Inhalation Exposures	6
ANIMAL STUDIES	6
Oral Exposures	6
Inhalation Exposures	7
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)	8
Tests Evaluating Carcinogenicity, Genotoxicity, and/or Mutagenicity	13
Carcinogenicity (Exposures Other Than Oral or Inhalation)	13
Other Toxicity Studies (Exposures Other Than Oral or Inhalation)	13
Short-Term Studies	13
Metabolism/Toxicokinetic Studies	13
Mode of Action/Mechanistic Studies	14
Immunotoxicity	14
Neurotoxicity	14
DERIVATION 01 PROVISIONAL VALUES	15
DERIVATION OF ORAL REFERENCE DOSES	16
Derivation of Subchronic Provisional RfD (Subchronic p-RfD)	16
Derivation of Chronic Provisional RfD (Chronic p-RfD)	16
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS	16
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR	16
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES	16
APPENDIX A. PROVISIONAL SCREENING VALUES	17
APPENDIX B. DATA TABLES	19
APPENDIX C. BMD OUTPUTS	20
APPENDIX D. REFERENCES	21
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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMD
benchmark dose
BMCL
benchmark concentration lower bound 95% confidence interval
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
POD
point of departure
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
UF
uncertainty factor
UFa
animal-to-human uncertainty factor
UFC
composite uncertainty factor
UFd
database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
3-NITRO-4-CHLOROBENZOTRIFLUORIDE (CASRN 121-17-5)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database flittp://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (www.epa.gov/iris). the respective PPRTVs are removed
from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
QUESTIONS REGARDING PPRTVS
Questions regarding the contents and appropriate use of this PPRTV assessment should
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).
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INTRODUCTION
3-Nitro-4-chlorobenzotrifluoride, CAS No. 121-17-5, is a substituted nitrobenzene with
the chemical structure, C7H3CIF3NO2, shown in Figure 1, and Table 1 presents the
physicochemical properties. 3-Nitro-4-chlorobenzotrifluoride is a chemical intermediate of the
herbicide Fluorodifen (HSDB, 2003).
Figure 1. 3-Nitro-4-chlorobenzotrifluoride Structure
Table 1. Physicochemical Properties Table for 3-Nitro-4-chlorobenzotrifluoride
(CASRN 121-17-5)3
Property (unit)
Value
Boiling point (°C)
222
Melting point (°C)
-2
Density (g/inL at 25°C)
1.511
Vapor pressure (Pa at 25°C)
ND
pH (unitless)
ND
Solubility in water
Insoluble
Relative vapor density (air = 1)
ND
Molecular weight (g/mol)
225.55
aSource: Chemical Book (2010).
ND = No data.
No Reference Dose (RfD), Reference Concentration (RfC), or cancer assessment values
for 3-nitro-4-chlorobenzotrifluoride are included in the IRIS database (U.S. EPA, 201 la) or on
the Drinking Water Standards and Health Advisories List (U.S. EPA, 2009). No RfD or RfC
values are reported in the HEAST (U.S. EPA, 201 lb). The Chemical Assessments and Related
Activities (CARA) list does not include a Health and Environmental Effects Profile (HEEP) for
3-nitro-4-chlorobenzotrifluoride	(U.S. EPA, 1994). The toxicity of 3-nitro-
4-chlorobenzotrifluoride	has not been reviewed by the ATSDR (2011) or the World Health
Organization (WHO, 2011). CalEPA (2008, 2009) has not derived toxicity values for exposure
to 3-nitro-4-chlorobenzotrifluoride. No occupational exposure limits for 3-nitro-
4-chlorobenzotrifluoride have been derived by the American Conference of Governmental
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Industrial Hygienists (ACGIH, 2011), recommended by the National Institute of Occupational
Safety and Health (NIOSH, 2010), or adopted by the Occupational Safety and Health
Administration (OSHA, 2006).
The HEAST (U.S. EPA, 2011) does not report a U.S. EPA (1986) cancer
weight-of-evidence classification or an oral slope factor for 3-nitro-4-chlorobenzotrifluoride.
The International Agency for Research on Cancer (IARC, 2011) has not reviewed the
carcinogenic potential of 3-nitro-4-chlorobenzotrifluoride. 3-Nitro-4-chlorobenzotrifluoride is
not included in the 12th Report on Carcinogens (NTP, 2011). CalEPA (2008) has not prepared a
quantitative estimate of the carcinogenic potential of 3-nitro-4-chlorobenzotrifluoride.
Literature searches were conducted on sources published from 1900 through
July 26, 2011 for studies relevant to the derivation of provisional toxicity values for 3-nitro-
4-chlorobenzotrifluoride, CAS No. 121-17-5. Searches were conducted using the EPA's Health
and Environmental Research Online (HERO) database of scientific literature. HERO searches
the following databases: AGRICOLA; American Chemical Society; BioOne; Cochrane Library;
DOE: Energy Information Administration, Information Bridge, and Energy Citations Database;
EBSCO: Academic Search Complete; GeoRef Preview; GPO: Government Printing Office;
Informaworld; IngentaConnect; J-STAGE: Japan Science & Technology; JSTOR: Mathematics
& Statistics and Life Sciences; NSCEP/NEPIS (EPA publications available through the National
Service Center for Environmental Publications [NSCEP] and National Environmental
Publications Internet Site [NEPIS] database); PubMed: MEDLINE and CANCERLIT databases;
SAGE; Science Direct; Scirus; Scitopia; SpringerLink; TOXNET (Toxicology Data Network):
ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP,
GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER, LactMed, Multi-Database Search,
NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI; and TSCATS; Virtual Health Library; Web
of Science (searches Current Content database among others); World Health Organization; and
Worldwide Science. The following databases outside of HERO were searched for toxicity
values: ACGIH, AT SDR, CalEPA, EPA IRIS, EPA HEAST, EPA OW, EPA
TSCATS/TSCATS2, NIOSH, NTP, OSHA, ACToR, and RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
Table 2 provides an overview of the relevant database for 3-nitro-
4-chlorobenzotrifluoride and includes all potentially relevant repeated short-term-, subchronic-,
and chronic duration studies. The phrase, "statistical significance," used throughout the
document, indicates ap-walue of <0.05.
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Table 2. Summary of Potentially Relevant Data for 3-Nitro-4-chlorobenzotrifluoride (CASRN 121-17-5)
Category
Number of Male/female,
Strain, Species, Study Type,
Study Duration
Dosimetry"
Critical Effects
NOAEL'
BMDL/
BMCLa
LOAEL'
Reference
(Comments)
Notesb
Human
1. Oral (mg/kg-day)a
Subchronic
ND
Chronic
ND
Developmental
ND
Reproductive
ND
Carcinogenicity
ND
2. Inhalation (mg/m3)a
Subchronic
ND
Chronic
ND
Developmental
ND
Reproductive
ND
Carcinogenicity
ND
Animal
1. Oral (mg/kg-day)a
Subchronic
10/0, Sprague-Dawley rat,
gavage, 28 or 38 d
0,1,10, or 100 for 28 d; or
100 for 28 d + 300 for 10 d
(Adjusted)
Decreased relative brain
weight; increased triglycerides
ND
NDr
1
Bucchi et al.
(1983)
PS, PR
Chronic
ND
Developmental
ND
Reproductive
ND
Carcinogenicity
ND
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Table 2. Summary of Potentially Relevant Data for 3-Nitro-4-chlorobenzotrifluoride (CASRN 121-17-5)
Category
Number of Male/female,
Strain, Species, Study Type,
Study Duration
Dosimetry3
Critical Effects
NOAEL3
BMDL/
BMCL3
LOAEL3
Reference
(Comments)
Notesb
2. Inhalation (mg/m3)3
Subchronic
ND
Chronic
ND
Developmental
ND
Reproductive
ND
Carcinogenicity
ND
""Dosimetry: NOAEL, BMDL/BMCL, and LOAEL values are converted to human equivalent dose (HED; in mg/kg-day) or human equivalent concentration (HEC; in
mg/m3) units. All long-term exposure values (4 weeks and longer) are converted from a discontinuous to a continuous (daily) exposure. Values for inhalation (cancer and
noncancer) and oral (cancer only) exposure are further converted to an HEC/D. Values from animal developmental studies are not adjusted to continuous exposure.
bNotes: PS = Principal study, PR = Peer reviewed.
ND = No data, NDr = Not determinable.
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HUMAN STUDIES
Oral Exposures
No studies were identified.
Inhalation Exposures
No studies were identified.
ANIMAL STUDIES
Oral Exposures
The effects of oral exposure to 3-nitro-4-chlorobenzotrifluoride have been evaluated in
animals in one sub chronic-duration study (Bucchi et al., 1983).
Subchronic-duration Studies
Bucchi et al. (1983)
The peer-reviewed study by Bucchi et al. (1983) is selected as the principal study for
derivation of the screening subchronic p-RfD. Although the original source was written in
Italian and published in a foreign journal, EPA had the article translated on February 1, 2011.
Articles published in this foreign journal are peer reviewed, but there is no statement regarding
GLP compliance. Male Sprague-Dawley rats (10/treatment group) were administered 0, 1, 10, or
100 mg/kg-day of 3-nitro-4-chlorobenzotrifluoride (purity not reported) daily in dietary milk via
gavage for 28 days. A separate group of 10 rats were administered 100 mg/kg-day 3-nitro-
4-chlorobenzotrifluoride for 28 days followed by 300 mg/kg-day for 10 days (average daily dose
of 153 mg/kg-day). There is no indication that there was a control for this group—so results
from this group are of limited use. The rats were weighed daily and food and water consumption
were measured every 2 days. Urine was collected from two rats per group on Days 14, 21, and
28 and analyzed for sedimentation, albumin, glucose, and acetone levels. At study termination,
blood was collected for hematology (specifics not provided) and clinical chemistry
(proteinaceous nitrogen, glucose, cholesterol, triglycerides, aspartate aminotransferase [AST,
referred to by study authors as SGOT], alanine aminotransferase [ALT, referred to by study
authors as SGPT], gamma glutamyl transferase [yGT], and bilirubin). After necropsy, the brain,
heart, lungs, thymus, liver, spleen, pancreas, kidneys, adrenal glands, testes, bladder, and seminal
vesicles were weighed. Although it was stated that cytochrome P-450, analine hydroxylase, and
/;-nitroani sol e-(9-dernethyl ase were measured in the microsomal fraction of the liver, no results
were presented for these endpoints. Statistical methods used were not reported. The data are
presented only visually without error bars and are reported in text as percent changes from
control. The lack of standard deviations or individual data preclude verifying the statistical
results.
All animals survived until the end of treatment. The study report only provides figures
for endpoints that were considered significant. No treatment-related changes in body weight,
food consumption, or urinalysis were observed, but these data were not provided in the study
report. Animals treated with 100 mg/kg-day or 100 mg/kg-day followed by 300 mg/kg-day
showed yellowing of their fur on the ventral zone. It was stated that all treated groups consumed
12-23% more water than the controls, but no specifics were provided for each dose nor was it
indicated whether this increase was dose related. Changes in clinical chemistry, hematology, and
organ weights are presented in Table B. 1. There was a statistically significant increase in blood
glucose levels in animals that received 100 mg/kg-day 3-nitro-4-chlorobenzotrifluoride
(24.5% higher than control values) and in the 100 + 300 mg/kg-day group (41.1% increase
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compared to controls). There was a statistically significant increase in triglyceride levels in
animals that received 1, 10, or 100 mg/kg-day (27.8, 39.8, and 34.1% increases compared to
controls, respectively). In the 100 + 300 mg/kg-day group there were also significant increases
in cholesterol (22.9% increase compared to controls) and ALT and yGT (51.4% increase
compared to controls). Changes in hematology were sporadic but included a statistically
significant decrease in erythrocytes at 10 mg/kg-day (18.5% decrease), an increase in leukocytes
at 100 mg/kg-day (80.6% increase compared to controls), and a increase in hemoglobin in the
100 + 300 mg/kg-day group (6.6% increase compared to controls).
At necropsy, there were overt signs of cardiac damage and marked yellow coloration of
the adrenal glands in rats administered 100 mg/kg-day or 100 + 300 mg/kg-day. Although body
weight was stated to have been unaffected (data not shown), several changes in the relative organ
weights were reported. There was a statistically significant increase in relative liver weights at
doses >10 mg/kg-day (an 11.6% increase in the 10-mg/kg-day group, 12.1% increase in the
100-mg/kg-day group, and a 22.4% increase in the 100 + 300 mg/kg-day group compared to
controls). There was a statistically significant decrease in relative brain weights in the rats
administered 1, 10, or 100 + 300 mg/kg-day (11.9%, 11.7%, and 24.7%, respectively compared
to controls). The 100-mg/kg-day group also had a decrease in brain weight, but this change was
not statistically significant and was not reported quantitatively. However, based on graphical
representation of the data, the change was of a similar magnitude to that observed in the 1- and
10-mg/kg-day dose groups. Thymus weight was increased 33% in the 10 mg/kg-day group and
decreased 26.6% in the 100 + 300 mg/kg-day group compared to controls. The weight of the
testes decreased by 13.2% at 10 mg/kg-day and the weight of the spleen decreased by 15.1% at
100 + 300 mg/kg-day compared to controls. Although the study authors noted a tendency for
increased relative pancreas weights proportional to dose, this change was not statistically
significant at any dose. Histopathological results were only preliminary and were stated to show
generalized vascular damage across all organs in all treatment groups, but the incidence data
were not provided.
No NOAEL could be determined from the data. A LOAEL of 1 mg/kg-day is available
from the data based on decreased brain weight and increased triglycerides.
Chronic-duration Studies
No studies were identified.
Developmental Studies
No studies were identified.
Reproductive Studies
No studies were identified.
Carcinogenicity Studies
No studies were identified.
Inhalation Exposures
There is no suitable information to provide in this regard.
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OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Several in vitro studies were identified that examined 3-nitro-4-chlorobenzotrifluoride for
its potential genotoxicity (Benigni et al., 1982; Haworth et al., 1983; Mazza et al., 1986).
Table 3A summarizes these in vitro genotoxicity studies, and they are further discussed below.
No studies were identified that investigated the genotoxic potential of
3-nitro-4-chlorobenzotrifluoride in vivo. Other studies that were identified were limited to acute
toxicity tests. Table 3B summarizes these studies, and they are further discussed below.
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Table 3A. Summary of 3-Nitro-4-chlorobenzotrifluoride Genotoxicity Studies
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without
Activation
With
Activation
Genotoxicity studies in prokaryotic organisms
Reverse mutation
Salmonella typhimurium TA98, TA100,
TA1535, TA1537
0.25 (iL


The study authors stated that
the cytotoxic effects of 3-nitro-
4-chlorobenzotri-fluoride only
permitted testing at low doses.
Benigni et al.
(1982)
Reverse mutation
Salmonella typhimurium TA98, TA100,
TA1535, TA1537
NR


At least 5 dose concentrations
were tested. A range-finding
test was conducted in
S. typhimurium TA100 at up to
10 mg/plate or to the limit of
solubility; however, the
specific dose concentrations
tested were not reported.
Haworth et al.
(1983)
Reverse mutation
Salmonella typhimurium TA98, TA100,
TA1535, TA1537, TA1538
2500 (ig/plate


In an accompanying test for
antimicrobial activity in
S. typhimurium TA100,
315 (ig/mL was observed to be
minimally inhibitory.
Mazza et al.
(1986)
SOS repair induction
ND
Genotoxicity studies in nonmammalian eukaryotic organisms
Mutation
ND
Recombination induction
Aspergillus nidulans strain P,
heterozygous for /? - fl uo ro -p lie n v 1 a 1 a nine
resistance
1.0 |iL


Results were also reviewed in
Crebelli (1987).
Benigni et al.
(1982)
Chromosomal aberration
ND
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Table 3A. Summary of 3-Nitro-4-chlorobenzotrifluoride Genotoxicity Studies
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without
Activation
With
Activation
Chromosomal
malsegregation
Saccaromyces cerevisiae strain 6117
2000 (ig/mL


In an accompanying test for
antimicrobial activity in
S. cerevisiae strain 6117,
1250 (ig/mL was observed to
be minimally inhibitory.
Mazza et al.
(1986)
Mitotic arrest
ND
DNA Damage
Rec-assay in Bacillus subtilis strains
PB 1652 (trpC2 metBlO lys3) and
PB 1791 (trpC2 metBlO recE4)
1000 (ig/disk

NDr
5000 and 10,000 (ig/disk dose
concentrations were also tested;
however, complete inhibition
of the growth of the tester
strains was observed at these
dose concentrations. In an
accompanying test for
antimicrobial activity in
B. subtilis PB 1652, 315 (ig/mL
was observed to be minimally
inhibitory.
Mazza et al.
(1986)
Genotoxicity studies in mammalian cells—in vitro
Mutation
ND
Chromosomal aberrations
ND
Sister chromatid exchange
(SCE)
ND
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Table 3A. Summary of 3-Nitro-4-chlorobenzotrifluoride Genotoxicity Studies
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without
Activation
With
Activation
DNA damage
Epithelial-like human cells collected
from skin and muscle explants from
human embryos
1.0 (iL/mL
+
NDr
Unscheduled DNA synthesis
was observed. The study
authors state that the positive
results did not fit a
dose-response curve; 10 |iL/mL
was also tested but the results
were negative.
Benigni et al.
(1982)
DNA adducts
ND
Genotoxicity studies in mammals—in vivo
Chromosomal aberrations
ND
Sister chromatid exchange
(SCE)
ND
DNA damage
ND
DNA adducts
ND
Mouse biochemical or
visible specific locus test
ND
Dominant lethal
ND
Genotoxicity studies in subcellular systems
DNA binding
ND
aLowest effective dose for positive results; highest dose tested for negative results.
b+ = Positive, ± = Equivocal or weakly positive, - = Negative, T = Cytotoxicity, NA = Not applicable, ND = No data, NDr = Not determined, NR = Not reported,
NR/Dr = Not reported by the study author but determined from data.
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Table 3B. Other 3-Nitro-4-chlorobenzotrifluoride Studies
Test
Materials and Methods
Results
Conclusions
References
Carcinogenicity studies
(exposures other than oral
or inhalation)
ND
Other toxicity studies
(exposures other than oral
or inhalation)
4 (sex not reported), New
Zealand White rabbit, acute
dermal toxicity
(clipped/intact or abraded
skin), 24-hr exposure; 316,
1000, 3160, or 10,000 mg/kg
Absence of feces followed by death observed in 1/4 animals on
Day 8; body weight loss in 2/4 animals; depression, labored
respiration in an unspecified number of animals
Numerous cyst-like structures throughout the lobes of the liver
observed in 1/4 animals administered either 3160 or 10,000 mg/kg
LD50 >> 10,000 mg/kg
Hazleton Labs
(1992)
Short-term studies
5/5 (M/F), Sprague-Dawley
rat, single gavage, observed
for 14 d; 460, 613, 791,
1025, 1319, or 1706 mg/kg
Dark red lungs, mottled liver, pale spleen, dark zone between the
cortex and medulla of the kidney, body weight loss and moderate
to severe autolysis observed at death in animals administered
>460 mg/kg
Depression, labored respiration after 1 hr in males and females
administered >613 mg/kg
Convulsions in 1/5 males observed 4 hr after administration of
791 mg/kg
Blanched stomach observed in animals administered 1025 mg/kg
Distended stomach with thin walls observed in animals
administered >1319 mg/kg
LD50 (females) =
1250 mg/kg
(confidence limits,
984-1588 mg/kg)
LD50 (males) =
1275 mg/kg
(confidence limits,
931-1747 mg/kg)
Hazleton Labs
(1992)
Metabolism/toxicokinetic
ND
Mode of action/
mechanistic
ND
Immunotoxicity
ND
Neurotoxicity
ND
ND = No data.
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Tests Evaluating Carcinogenicity, Genotoxicity, and/or Mutagenicity
The genotoxicity of 3-nitro-4-chlorobenzotrifluoride has been studied using several
prokaryotic, nonmammalian eukaryotic, and mammalian in vitro test systems (Benigni et al.,
1982; Haworth et al., 1983; Mazza et al., 1986). Table 3A summarizes these genotoxicity
studies. With the exception of the finding that 3-nitro-4-chlorobenzotrifluoride caused
unscheduled DNA synthesis in cultured epithelial-like human cells (Benigni et al., 1982), these
studies indicate that 3-nitro-4-chlorobenzotrifluoride is not mutagenic, genotoxic, or clastogenic
in vitro. Benigni et al. (1982) observed unscheduled DNA synthesis at concentrations of 1.0 and
2.0 [iL/mL 3-nitro-4-chlorobenzotrifluoride, but not 10.0 [jL/mL. Studies investigating the in
vivo genotoxic potential of 3-nitro-4-chlorobenzotrifluoride were not identified.
Carcinogenicity (Exposures Other Than Oral or Inhalation)
No studies were identified.
Other Toxicity Studies (Exposures Other Than Oral or Inhalation)
One unpublished, acute study was identified that examined the effects of
3-nitro-4-chlorobenzotrifluoride	through routes of exposure other than oral or inhalation
(Hazleton Labs, 1992). Table 3B summarizes this and other studies on 3-nitro-
4-chlorobenzotrifluoride.	In an acute dermal toxicity study, Hazleton Labs (1992) exposed
four New Zealand White rabbits (sex not reported, initial body weights of 2.4-3.1 kg) to 316,
1000, 3160, or 10,000 mg/kg of 3-nitro-4-chlorobenzotrifluoride for 24 hours. In two of the
animals per exposure group, the skin was clipped and left intact while in the other two animals
the skin was abraded prior to the application of 3-nitro-4-chlorobenzotrifluoride. Binders were
applied to the exposed area and the animals were fitted with collars to avoid ingestion of the test
material. Following exposure, the researchers observed the animals for up to 14 days. One
animal in the 10,000-mg/kg exposure group did not produce feces and died 8 days after
exposure. An LD50 of >10,000 mg/kg was assigned by the study authors based on this death.
Short-term Studies
In addition to the study on acute dermal toxicity, Hazleton Labs (1992) also conducted an
unpublished, acute oral toxicity study in rats. Five male and five female Sprague-Dawley rats
(initial body weights of 150-212 g for males and 142-182 g for females) were administered a
single dose of 460, 613, 791, 1025, 1319, or 1706 mg/kg 3-nitro-4-chlorobenzotrifluoride (purity
assumed to be 100% by study authors) via gavage in corn oil. There was no indication of a
concurrent control group. The animals were examined for mortality and signs of any clinical
effects immediately after dosing, after 1, 4, and 24 hours, and once daily thereafter for up to
14 days. Depression and labored respiration were observed at >613 mg/kg at 1 hour after dosing.
At 791 mg/kg, convulsions were observed in 1/5 males. At all dose levels necropsy revealed
dark red lungs, mottled liver, pale spleen, a dark zone between the cortex and medulla of the
kidney, and moderate-to-severe autolysis. The raw incidence data of these findings were not
provided. It was stated that some body-weight loss was observed. At a dose of 1706 mg/kg the
cardiac portion of the stomach had thickened, was white in color, and had adhered to the liver in
an unspecified number of animals. Other effects to the stomach included blanching at
1025 mg/kg and distention with thin walls at 1319 and 1706 mg/kg. LD50S of 1250 mg/kg for
females and 1275 mg/kg for males were estimated from this study.
Metabolism/Toxicokinetic Studies
No studies were identified.
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Mode of Action/Mechanistic Studies
No studies were identified.
Immunotoxicity
No studies were identified.
Neurotoxicity
No studies were identified.
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DERIVATION OF PROVISIONAL VALUES
Tables 4 and 5 present a summary of noncancer and cancer reference values, respectively. IRIS data are indicated in the table, if
available.
Table 4. Summary of Noncancer Reference Values for 3-Nitro-4-chlorobenzotrifluoride (CASRN 121-17-5)
Toxicity Type (units)
Species/Sex
Critical Effect
p-Reference
Value
POD
Method
POD
UFC
Principal Study
Screening subchronic p-RfD
(mg/kg-day)
Rat/M
Decreased relative brain
weight and increased
triglycerides
1 x 10~4
LOAEL
1
10,000a
Bucchi et al. (1983)
Chronic p-RfD
(mg/kg-day)
None
None
None
None
None
None
None
Subchronic p-RfC (mg/m3)
None
None
None
None
None
None
None
Chronic p-RfC (mg/m3)
None
None
None
None
None
None
None
aThe maximum allowed total composite uncertainty factor is 10,000.
Table 5. Summary of Cancer Reference Values for 3-Nitro-4-chlorobenzotrifluoride (CASRN 121-17-5)
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF
None
None
None
None
p-IUR
None
None
None
None
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DERIVATION OF ORAL REFERENCE DOSES
Derivation of Subchronic Provisional RfD (Subchronic p-RfD)
No subchronic p-RfD can be derived because doing so would require the application of a
composite uncertainty factor of 10,000, which is greater than the maximum allowable
uncertainty factor of 3000. However, a screening subchronic p-RfD is provided in Appendix A.
The Bucchi et al. (1983) subchronic study in male rats is the only study available to consider for
derivation of the subchronic p-RfD.
Derivation of Chronic Provisional RfD (Chronic p-RfD)
No chronic p-RfD can be derived because doing so would require the application of a
composite uncertainty factor in excess of 10,000.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
No subchronic or chronic p-RfC values can be derived because there are no human or
animal inhalation studies currently available.
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
Table 6 identifies the cancer weight-of-evidence descriptor for 3-nitro-
4-chl orob enzotrifluori de.
Table 6. Cancer Weight of Evidence (WOE) Descriptor for
3-Nitro-4-chlorobenzotrifluoride
Possible WOE
Descriptor
Designation
Route of Entry (Oral,
Inhalation, or Both)
Comments
"Carcinogenic to
Humans "
ND
ND
No comments
"Likely to Be
Carcinogenic to
Humans "
ND
ND
No comments
"Suggestive Evidence
of Carcinogenic
Potential"
ND
ND
No comments
"Inadequate
Information to Assess
Carcinogenic
Potential"
Selected
Both
No carcinogenic studies are available
that analyze either route of exposure.
"Not Likely to Be
Carcinogenic to
Humans "
ND
ND
No comments
ND = No data
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
The lack of data on the carcinogenicity of 3-nitro-4-chlorobenzotrifluoride precludes the
derivation of quantitative estimates for either oral (p-OSF) or inhalation (p-IUR) exposure.
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APPENDIX A. PROVISIONAL SCREENING VALUES
For the reasons noted in the main document, it is inappropriate to derive a provisional
subchronic p-RfD for 3-nitro-4-chlorobenzotrifluoride. However, information is available
which, although insufficient to support derivation of a provisional toxicity value under current
guidelines, may be of limited use to risk assessors. In such cases, the Superfund Health Risk
Technical Support Center summarizes available information in a supplemental appendix and
develops a screening value. Appendices receive the same level of internal and external scientific
peer review as the main document to ensure their appropriateness within the limitations detailed
in the document. Users of screening toxicity values in a supplement to a PPRTV assessment
should understand that there is considerably more uncertainty associated with the derivation of a
supplemental screening toxicity value than for a value presented in the body of the assessment.
Questions or concerns about the appropriate use of screening values should be directed to the
Superfund Heath Risk Technical Support Center.
DERIVATION OF SCREENING PROVISIONAL ORAL REFERENCES DOSES
Derivation of Screening Subchronic Provisional RfD (Subchronic p-RfD)
There is a single repeated dose study (Bucchi et al., 1983) available on
3-nitro-4-chlorobenzotrifluoride. The study by Bucchi et al. (1983) is selected as the principal
study for derivation of the screening subchronic p-RfD. The critical endpoints are decreased
relative brain weight (no changes in body weight were noted) and increased triglycerides in male
rats. This study was published in a foreign language; however, the journal is peer reviewed and
EPA had the study translated on February 1, 2011. The study does not provide a GLP
compliance statement. Although numerous endpoints were examined, histopathology was only
preliminary at the time of publication. The preliminary histopathology results indicate that
generalized vascular damage occurred at the dose selected for POD; however, neither incidence
nor severity data were provided. The study is limited in that only male rats were examined and
limited data are available for review. Details are provided in the "Review of Potentially
Relevant Data" section. BMD analysis is not possible with these data because the data are
presented only graphically and as percent change from controls. As the only available and
acceptable study, this study represents the lowest POD for developing a subchronic p-RfD.
The POD in this study is a LOAEL of 1 mg/kg-day for decreased relative brain weight
and increased serum triglycerides.
No dosimetric adjustments were required because the doses in the principal study were
administered via gavage in mg/kg-day, presumably for 7 days per week for the entire study
duration.
The screening subchronic p-RfD for 3-nitro-4-chlorobenzotrifluoride, based on
1 mg/kg-day in male rats, is derived as follows:
Screening Subchronic p-RfD = LOAELadj ^ UF
= 1 mg/kg-day10,000
= 1 x 10~4 mg/kg-day
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Table A. 1 summarizes the uncertainty factors for the screening subchronic p-RfD for
3 -nitro-4-chl orob enzotrifluori de.
Table A.l. Uncertainty Factors for the Screening Subchronic p-RfD of
3-Nitro-4-chlorobenzotrifluoride
UF
Value
Justification
Notes
ufa
10
A UFa of 10 is applied for interspecies extrapolation to account for
potential toxicokinetic and toxicodynamic differences between rats
and humans.
No notes
ufd
10
A UFd of 10 is selected because there are no acceptable
two-generation reproduction studies or developmental studies by this
route.
No notes
UFh
10
A UFh of 10 is applied for intraspecies differences to account for
potentially susceptible individuals in the absence of information on
the variability of response in humans.
No notes
ufl
10
A UFl of 10 is applied for using a POD based on a LOAEL because a
NOAEL cannot be determined from the available database.
No notes
UFS
1
A UFS of 1 is applied because a subchronic study was utilized.
No notes
UFC
<3000
10,000
Composite of the five uncertainty factors.
This value is a screening
value. The composite UF
maximum is 10,000.
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APPENDIX B. DATA TABLES
Table B.l. Changes in organ Weights, Clinical Chemistry, and Hematology in
Rats Exposed to 3-Nitro-4-chlorobenzotrifluoride by Gavage for 28 Days
Parameter
Exposure Group (mg/kg-day)
1
10
100
100 + 300a
Relative Organ Weights
Liver
NS
+11.6%b
+12.1%
+22.4%
Brain
-11.9%
-11.7%
NS
-24.7%
Thymus
NS
+33%
NS
+26.6%
Testes
NS
-13.2%
NS
NS
Spleen
NS
NS
NS
-15.1%
Clinical Chemistry
Blood glucose
NS
NS
+24.5%
+41.1%
Triglycerides
+27.8%
+39.8%
+34.1%
NS
Cholesterol
NS
NS
NS
+22.9%
ALT & yGT°
NS
NS
NS
+51.4%
Hematology
Erythrocyte count
NS
-18.5%
NS
NS
Leukocyte count
NS
NS
+80.6%
NS
Hemoglobin
NS
NS
NS
+6.6%
aThis group received 100 mg/kg-day for 28 days and then 300 mg/kg-day for an additional 10 days.
bData presented are percent difference from controls as reported in study (actual values and
variance were not reported).
These parameters were reported together by the study authors.
NS = Not significantly different from controls (0 mg/kg-day in dietary milk gavage for 28 days).
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APPENDIX C. BMD OUTPUTS
There are no BMD outputs to report.
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