United States
Environmental Protection
1=1 m m Agency
EPA/690/R-16/002F
Final
9-29-2016
Provisional Peer-Reviewed Toxicity Values for
1,2-Dichloropropane
(CASRN 78-87-5)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

-------
AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
J. Phillip Kaiser, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
CONTRIBUTORS
Harlal Choudhury, DVM, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
Chris Cubbison, PhD (Mentor)
Custodio V. Muianga, PhD, MPH (Student Services Contractor)
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Anuradha Mudipalli, MSc, PhD
National Center for Environmental Assessment, Research Triangle Park, NC
Ghazi Danna, PhD
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 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).
li
1,2-Dichloropropane

-------
TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS	iv
BACKGROUND	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVs	1
INTRODUCTION	2
REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER)	6
HUMAN STUDIES	18
ANIMAL STUDIES	20
Oral Exposures	20
Inhalation Exposures	34
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)	43
Genotoxicity Studies	43
Supporting Human Studies	44
Supporting Animal Toxicity Studies	44
Absorption, Distribution, Metabolism, and Elimination (ADME) Studies	46
Mode-of-Action/Mechanism Studies	46
DERIVATION 01 PROVISIONAL VALUES	69
DERIVATION OF ORAL REFERENCE DOSES	69
Derivation of a Subchronic Provisional Referece Dose	69
Derivation of a Chronic Provisional Reference Dose	75
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS	79
Derivation of a Subchronic Provisional Reference Concentration	79
Derivation of a Chronic Provisional Reference Concentratoin	84
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR	84
MODE-OF-ACTION DISCI SSION	86
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES	86
Derivation of a Provisonal Oral Slope Factor	86
Derivation of a Provisional Inhalation Unit Risk	87
APPENDIX A. SCREENING PROVISIONAL VALUES	90
APPENDIX B. DATA TABLES	91
APPENDIX C. BENCHMARK DOSE MODELING RESULTS	128
APPENDIX D. BENCHMARK DOSE CALCULATIONS FOR PROVISIONAL
CANCER POTENCY VALUES	164
APPENDIX E. REFERENCES	190
in
1,2-Dichloropropane

-------
COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
MN
micronuclei
ACGIH
American Conference of Governmental
MNPCE
micronucleated polychromatic

Industrial Hygienists

erythrocyte
AIC
Akaike's information criterion
MOA
mode of action
ALD
approximate lethal dosage
MTD
maximum tolerated dose
ALT
alanine aminotransferase
NAG
N-acetyl-P-D-glucosaminidase
AST
aspartate aminotransferase
NCEA
National Center for Environmental
atm
atmosphere

Assessment
ATSDR
Agency for Toxic Substances and
NCI
National Cancer Institute

Disease Registry
NOAEL
no-observed-adverse-effect level
BMD
benchmark dose
NTP
National Toxicology Program
BMDL
benchmark dose lower confidence limit
NZW
New Zealand White (rabbit breed)
BMDS
Benchmark Dose Software
OCT
ornithine carbamoyl transferase
BMR
benchmark response
ORD
Office of Research and Development
BUN
blood urea nitrogen
PBPK
physiologically based pharmacokinetic
BW
body weight
PCNA
proliferating cell nuclear antigen
CA
chromosomal aberration
PND
postnatal day
CAS
Chemical Abstracts Service
POD
point of departure
CASRN
Chemical Abstracts Service Registry
PODadj
duration-adjusted POD

Number
QSAR
quantitative structure-activity
CBI
covalent binding index

relationship
CHO
Chinese hamster ovary (cell line cells)
RBC
red blood cell
CL
confidence limit
RDS
replicative DNA synthesis
CNS
central nervous system
RfC
inhalation reference concentration
CPN
chronic progressive nephropathy
RfD
oral reference dose
CYP450
cytochrome P450
RGDR
regional gas dose ratio
DAF
dosimetric adjustment factor
RNA
ribonucleic acid
DEN
diethylnitrosamine
SAR
structure activity relationship
DMSO
dimethylsulfoxide
SCE
sister chromatid exchange
DNA
deoxyribonucleic acid
SD
standard deviation
EPA
Environmental Protection Agency
SDH
sorbitol dehydrogenase
FDA
Food and Drug Administration
SE
standard error
FEV1
forced expiratory volume of 1 second
SGOT
glutamic oxaloacetic transaminase, also
GD
gestation day

known as AST
GDH
glutamate dehydrogenase
SGPT
glutamic pyruvic transaminase, also
GGT
y-glutamyl transferase

known as ALT
GSH
glutathione
SSD
systemic scleroderma
GST
glutathione-S-transferase
TCA
trichloroacetic acid
Hb/g-A
animal blood-gas partition coefficient
TCE
trichloroethylene
Hb/g-H
human blood-gas partition coefficient
TWA
time-weighted average
HEC
human equivalent concentration
UF
uncertainty factor
HED
human equivalent dose
UFa
interspecies uncertainty factor
i.p.
intraperitoneal
UFh
intraspecies uncertainty factor
IRIS
Integrated Risk Information System
UFS
subchronic-to-chronic uncertainty factor
IVF
in vitro fertilization
UFd
database uncertainty factor
LC50
median lethal concentration
U.S.
United States of America
LD50
median lethal dose
WBC
white blood cell
LOAEL
lowest-observed-adverse-effect level


iv
1,2-Dichloropropane

-------
FINAL
09-29-2016
PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
1,2-DICHLOROPROPANE (CASRN 78-87-5)
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 (http://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 (http://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.
This document has been reviewed in accordance with U.S. EPA policy and approved for
publication. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
QUESTIONS REGARDING PPRTVs
Questions regarding the contents 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).
1
1,2-Dichloropropane

-------
FINAL
09-29-2016
INTRODUCTION
1,2-Dichloropropane, CASRN 78-87-5, also known as propylene dichloride, 1,2-DCP
and 1,2-D, is a chemical intermediate for a variety of organic compounds, especially small
chlorinated hydrocarbons, such as tetrachloroethylene and carbon tetrachloride (OECD, 2003).
1,2-DCP is a known impurity in 1,3-dichloropropene (1,3-D), which is an EPA registered
fumigant (U.S. EPA. 1998). 1,2-DCP was discontinued from direct use as a grain and soil
fumigant in the 1980's (OECD. 2003). Additional uses attributed to 1,2-DCP include as a
solvent for fats and greases, in dry cleaning fluids, in rubber making and vulcanization, and as a
solvent for film production. However, it is likely that many of these additional uses are either
outdated or account for only minor use (OECD, 2003). For example, it is known that use of
1,2-DCP as a solvent for film production was phased out in the early 1980's (ATSDR. 1989). In
addition, in EPA's 2012 Chemical Data Reporting database, the only reported use for 1,2-DCP
was as an intermediate (U.S. EPA. 2012d).
1,2-DCP is a liquid with a high vapor pressure and a high measured Henry's law
constant. These indicate that volatilization from both dry and moist surfaces is expected to be an
important fate process for 1,2-DCP. Although not susceptible to direct photolysis, 1,2-DCP does
react with photochemically generated hydroxy radicals and has an estimated half-life in the
troposphere of 25-27 days (OECD, 2003). 1,2-DCP is listed as a hazardous air pollutant under
the Clean Air Act, as amended in 1990 (U.S. Congress. 1990). It is not expected to contribute to
either global warming or depletion of stratospheric ozone (OECD. 2003). The high water
solubility and relatively low soil adsorption coefficient of 1,2-DCP indicate that it is likely to
leach to groundwater or undergo runoff after a rain event. As a result, removal from soil by
leaching with water is expected to compete with volatilization, depending on the local conditions
(wet, dry, etc.). The federal drinking water standard for 1,2-DCP is 5 |ig/L (HSDB, 2014). The
molecular formula for 1,2-DCP is C3H5CI2 (see Figure 1). Physicochemical properties are
provided in Table 1.
CI
CI
Figure 1. 1,2-Dichloropropane Structure
2
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 1. Physicochemical Properties of 1,2-Dichloropropane (CASRN 78-87-5)a
Property (unit)
Value
Physical state
Liquid
Boiling point (°C)
96.4
Melting point (°C)
-100.4
Density (g/cm3 at 25°C)
1.159
Vapor pressure (mm Hg at 25 °C)
53.3
pH (unitless)
ND
pKa (unitless)
ND
Solubility in water (mg/L at 25 °C)
2,800
Octanol-water partition constant (log Kow)
1.98
Henry's law constant (atm-m3/mol at 25°C)
2.82 x 10-3
Soil adsorption coefficient Koc (mL/g)
60.7 (estimated)13
Atmospheric OH rate constant (cm3/molecule-sec at 25°C)
4.6 x KT13c
Atmospheric half-life
25-27 d (estimated for the troposphere)0
Relative vapor density (air = 1)
3.9
Molecular weight (g/mol)
112.99
"Data were gathered from the HSDB (2014) database unless otherwise specified.
bU.S. EPA (2012a).
°OECD (2003).
ND = no data.
A summary of available toxicity values for 1,2-DCP from the EPA and other
agencies/organizations is provided in Table 2.
3
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 2. Summary of Available Toxicity Values for 1,2-Dichloropropane (CASRN 78-87-5)
Source
(parameter)ab
Value
(applicability)
Notes
Reference
Noncancer
IRIS (RfC)
4 x 10 3 mg/m3
Based on hyperplasia of the nasal mucosa in a
rat 13-wk inhalation study
U.S. EPA (2002a)
HEAST (sRfC)
1.3 x 10 2 mg/m3
Based on hyperplasia of the nasal mucosa in a
rat 13-wk inhalation study
U.S. EPA (201 la)
DWSHA
NV
NA
U.S. EPA (2012b)
ATSDR (oral MRL)
0.1 mg/kg-d
(acute);
0.07 mg/kg-d
(intermediate);
0.09 mg/kg-d
(chronic)
Acute: based on neurological effects in a 10-d
rat study;
Intermediate: based on hematological effects
(anemia) in a 13-wk rat study;
Chronic: based on liver damage in a 2-yr
mouse study
ATSDR (1989);
ATSDR (2016)
ATSDR
(inhalation MRL)
0.05 ppm
(0.23 mg/m3)
(acute);
0.007 ppm
(0.032 mg/m3)
(intermediate)
Based on degeneration of the nasal mucosa in
a 14-d rat study and a 13-wk rat study
ATSDR (1989):
ATSDR (2016)
IPCS
NV
NA
IPCS (2016): WHO
(2016)
Cal/EPA
NV
NA
Cal/EPA (2014):
Cal/EPA (2016a):
Cal/EPA (2016b)
OSHA (PEL)
75 ppm
(350 mg/m3)
8-hr TWA for general industry, construction
and shipyard employment
OSHA (2006a): OSHA
(2006b): OSHA (2011)
NIOSH (REL)
NV
An REL was not established because 1,2-DCP
is a potential occupational carcinogen
NIOSH (1994):
NIOSH (2011)
ACGIH (TLV-TWA)
10 ppm
(46 mg/m3)
Based on body weight and nasal pathology
observed in rats following a 13 wk inhalation
exposure; potential to produce dermal
sensitization
ACGIH (2014a):
ACGIH (2014b)
Cancer
IRIS
NV
NA
U.S. EPA (2002a)
HEAST (WOE)
Group B2
B2 indicates sufficient evidence in animals and
inadequate or no evidence in humans
U.S. EPA (1987): U.S.
EPA (2011a)
HEAST (OSF)
6.8 x 10-2
(mg/kg-d)"1
Quantitative estimate of carcinogenic risk from
oral exposure based on liver tumors in a mouse
gavage study
U.S. EPA (2011a)
DWSHA (WOE)
Group B2
B2 indicates sufficient evidence in animals and
inadequate or no evidence in humans
U.S. EPA (2012b)
DWSHA
(1(T4 cancer risk)
0.06 mg/L
Quantitative estimate of carcinogenic risk
U.S. EPA (2012b)
NTP
NV
NA
NTP (2014)
4
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 2. Summary of Available Toxicity Values for 1,2-Dichloropropane (CASRN 78-87-5)
Source
(parameter)ab
Value
(applicability)
Notes
Reference
IARC (WOE)
Group 1,
carcinogenic to
humans
Based on sufficient evidence in humans that
exposure to 1,2-DCP causes biliary-tract
cancer (cholangiocarcinoma) and sufficient
evidence in experimental animals, with
malignant lung and hepatocellular tumors
observed in exposed mice
Benbrahim-Tallaa et al.
(2014); IARC (2015)
Cal/EPA (OSF)
0.036 (mg/kg-d) 1
Hepatocellular adenomas and carcinomas in
male mice from a 2-yr gavage study.
Calculated under the Public Health Goals for
Drinking Water program using interspecies
conversion factor given by the ratio of animal
to human body weights raised to the
one-fourth power
Cal/EPA (2016a):
Cal/EPA (1999)
Cal/EPA (OSF)
0.072 (mg/kg-d)"1
Hepatocellular adenomas and carcinomas in
male mice from a 2-yr gavage study.
Calculated under the Proposition 65 "No
Significant Risk Level" (NSRL) program using
interspecies conversion factor given by the
ratio of animal to human body-weights raised
to the one-third power
Cal/EPA (2004)
ACGIH (WOE)
Category A4, not
classifiable as a
human carcinogen
Based on negative and equivocal evidence of
tumorigenicity in rat and mouse bioassays
ACGIH (2014a):
ACGIH (2014b)
NIOSH (WOE)
Ca
Any substance that NIOSH considers to be a
potential occupational carcinogen is
designated by the notation "Ca"
NIOSH (2011):
NIOSH (2015)
aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Research; Cal/EPA = California Environmental Protection Agency; DWSHA = Drinking
Water Standards and Health Advisories; HEAST = Health Effects Assessment Summary Tables;
IARC = International Agency for Research on Cancer; IPCS = International Programme on Chemical Safety;
IRIS = Integrated Risk Information System; NIOSH = National Institute for Occupational Safety and Health;
NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration.
Parameters: MRL = minimal risk level; OSF = oral slope factor; PEL = permissible exposure level;
REL = recommended exposure level; sRfC = subchronic reference concentration; TLV = threshold limit value;
TWA = time-weighted average; WOE = weight of evidence.
NA = not applicable; NV = not available.
Non-date-limited literature searches were conducted in September 2016 for studies
relevant to the derivation of provisional toxicity values for 1,2-DCP (CASRN 78-87-5).
Searches were conducted using U.S. EPA's Health and Environmental Research Online (HERO)
database of scientific literature. HERO searches the following databases: PubMed, ToxLine
(including TSCATS1), and Web of Science. The following databases were searched outside of
HERO for health-related values: ACGIH, ATSDR, Cal/EPA, U.S. EPA IRIS, U.S. EPA HEAST,
U.S. EPA Office of Water (OW), U.S. EPA TSCATS2/TSCATS8e, NIOSH, NTP, and OSHA.
5
1,2-Dichloropropane

-------
FINAL
09-29-2016
REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Tables 3A and 3B provide an overview of the relevant noncancer and cancer databases
for 1,2-DCP, respectively, and include all potentially relevant repeated-dose short-term-,
subchronic-, and chronic-duration studies. Principal studies are identified. The phrases
"statistical significance" and "significant," used throughout the document, indicate a p-value
of < 0.05, unless otherwise noted.
6
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 3A. Summary of Potentially Relevant Noncancer Data for 1,2-Dichloropropane (CASRN 78-87-5)
Category
Number of
Male/Female,
Strain, Species,
Study Type, Study
Duration
Dosimetry3
Critical Effects
NOAELa
BMDL/
BMCLa
LOAELa
Reference
(comments)
Notesb
Human
ND
Animal
1. Oral (mg/kg-d)a
Short-term
5 M/0 F, B6C3Fi
mice, gavage in
corn oil, up to 4 wk
0, 125, 250
ADD: 0, 89.3, 179
Fatty change in the liver,
increased absolute and
relative liver-weight,
increased serum
cholesterol, glycerin, and
albumin
ND
NDr
89.3
Gi et al. (2015a)
PR
Short-term
5 M/0 F, Syrian
hamsters, gavage in
corn oil, up to 4 wk
0, 125, 250
ADD: 0, 89.3, 179
Mortality, fatty change in
the liver, increased
relative liver weight
ND
NDr
89.3 (FEL)
Gi et al. (2015a)
PR
Subchronic0
15-16 M/0 F, S-D
rat, gavage in corn
oil, 5 d/wk, 13 wk
0, 100, 250, 500,
750
ADD: 0,71.4,
179, 357, 536
Increased serum
bilirubin, hemosiderosis
and hyperplasia of the
spleen, decreased Hct,
decreased Hb, increased
relative liver, kidney, and
spleen weights, mortality
ND
DUB
71.4
Bruckner et al.
(1989)
PR
Subchronic
15 M/15 F, F344
rat, gavage in corn
oil, 5 d/wk, 13 wk
0, 20, 65, 200
ADD: 0, 14, 46,
143
Decreased body weight
in males
46
NDr
143
Dow Chemical Co
(1988b)
NPR

7
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 3A. Summary of Potentially Relevant Noncancer Data for 1,2-Dichloropropane (CASRN 78-87-5)
Category
Number of
Male/Female,
Strain, Species,
Study Type, Study
Duration
Dosimetry3
Critical Effects
NOAELa
BMDL/
BMCLa
LOAELa
Reference
(comments)
Notesb
Subchronic
10 M/10 F, F344/N
rat, gavage in corn
oil, 5 d/wk, 13 wk
0, 60, 125, 250,
500, 1,000
ADD: 0, 43, 89.3,
179,357,714
Increased mortality (50%
mortality in males at
357 mg/kg-d;
100% mortality in males
and females at
714 mg/kg-d), decreased
body weight (M)
179
NA
357 (FEL)
NTP (1986)
PR
Subchronic
10 M/10 F, B6C3Fi
mouse, gavage in
corn oil, 5 d/wk,
13 wk
0, 30, 60, 125,
250, 500
ADD:0, 21,43,
89.3, 179, 357
No effects observed
357
NA
ND
NTP (1986)
PR
Chronicd
50 M/50 F, F344/N
rat, gavage in corn
oil, 5 d/wk, 103 wk
0, 62, 125 in males
0, 125, 250 in
females
ADD:
M: 0, 45, 89.3
F: 0, 89.3, 179
Decreased body weight
in males and females
45
DUB
89.3
NTP (1986)
PR
Chronic
50 M/50 F, B6C3Fi
mouse, gavage in
corn oil, 5 d/wk,
103 wk
0, 125, 250
ADD: 0, 89.3, 179
Hepatocytomegaly and
hepatic necrosis in males.
Increased mortality in
females in the high-dose
group compared with
controls; however,
findings are confounded
by evidence of infection
in 60% of all females that
died
89.3
M: 58.5
179
NTP (1986)
PR
8
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 3A. Summary of Potentially Relevant Noncancer Data for 1,2-Dichloropropane (CASRN 78-87-5)

Number of








Male/Female,








Strain, Species,








Study Type, Study



BMDL/

Reference

Category
Duration
Dosimetry3
Critical Effects
NOAELa
BMCLa
LOAELa
(comments)
Notesb
Chronic
6-15 M/0 F,
0, 62.5, 125
Decreased body weight at
44.6
NDr
89.3
Gietal. (2015b)
PR

hamsters, gavage in

Wk 17



(Effects were only


corn oil, 5 d/wk, 17
ADD: 0, 44.6,




observed in


or 19 wk
89.3 +N-




hamsters receiving



nitrosobis(2-




both 1,2-DCP and



oxopropyl)amine




N-nitrosobis[2-



0, 89.3 without N-




oxopropyl] amine)



nitrosobis(2-








oxopropyl)amine






Reproductive/
30 M/30 F, S-D rat,
0,0.024,0.1,
F0 M: Decreased body
F0 M: 82.7
NDr
F0 M: 152
Dow Chemical Co
NPR
developmental
drinking water,
0.24%
weight at Wk 1 and



(1990): Dow


10-12 wk

Wk 10 and decreased



Chemical Co


premating plus
ADD:
platelets



(1989b)


mating, gestation,
F0:







and lactation;
M: 0, 24.8, 82.7,
F0 maternal: Decreased
F0 maternal:
NDr
F0 maternal:



-18-21 wk,
152
body weight and anemia
127

254



2 generations
F: 0, 38.8, 127,








254
Fl offspring: Decreased
Fl offspring:
NDr
Fl offspring:





neonatal weight and
127

254




Fl:
survival associated with







M: 0, 28.3, 109,
reduced body weight in







213
dams







F: 0, 42.7, 148,








293
Fl M: Decreased body
FlM: 109
NDr
FlM:213





weight








Fl maternal: Decreased
Fl maternal:
NDr
Fl maternal:





body weight
148

293





F2 offspring: No effects
F2 offspring:
NA
F2 offspring:





observed
293

ND


9
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 3A. Summary of Potentially Relevant Noncancer Data for 1,2-Dichloropropane (CASRN 78-87-5)
Category
Number of
Male/Female,
Strain, Species,
Study Type, Study
Duration
Dosimetry3
Critical Effects
NOAELa
BMDL/
BMCLa
LOAELa
Reference
(comments)
Notesb
Reproductive/
developmental
(range-finding)
0 M/10 F, S-D rat,
gavage in corn oil,
GDs 6-15
0, 50, 125, 250,
500
ADD: 0, 50, 125,
250, 500
Maternal: Increased
salivation and perineal
staining; decreased
maternal body weight
Fetal: ND
Maternal:
250
Fetal: ND
NDr
Maternal:
500
Fetal: ND
Dow Chemical Co
(1989c)
NPR
Reproductive/
developmental
0 M/30 F, S-D rat,
savage in corn oil,
GDs 6-15
0,10, 30,125
ADD: 0,10,30,
125
Maternal: Transient
clinical signs (CNS
depression, salivation,
lacrimation), decreased
maternal body-weight
gain
Fetal: Delayed skeletal
ossification of fetal skull
Maternal:
30
Fetal: 30
Maternal:
NDr
Fetal: 5.6
Maternal:
125
Fetal: 125
Kirk et al. (1995)
PR, PS
Reproductive/
developmental
(range-finding)
0 M/7 F, NZW
rabbit, gavage in
corn oil, GDs 7-19
0, 25, 100, or 250
ADD: 0, 25, 100,
or 250
Maternal: Anemia
Fetal: ND
Maternal: 25
Fetal: ND
NDr
Maternal:
100
Fetal: ND
Dow Chemical Co
(1988d)
NPR
Reproductive/
developmental
0 M/18 F, NZW
rabbit, gavage in
corn oil, GDs 7-19
0, 15, 50, 150
ADD: 0, 15, 50,
150
Maternal: Anemia,
anorexia
Fetal: Delays in skeletal
ossification of fetal skull
Maternal: 50
Fetal: 50
Maternal:
NDr
Fetal: 10
Maternal:
150
Fetal: 150
Kirk et al. (1995)
PR
10
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 3A. Summary of Potentially Relevant Noncancer Data for 1,2-Dichloropropane (CASRN 78-87-5)
Category
Number of
Male/Female,
Strain, Species,
Study Type, Study
Duration
Dosimetry3
Critical Effects
NOAELa
BMDL/
BMCLa
LOAELa
Reference
(comments)
Notesb
2. Inhalation (mg/m3)a
Subchronic
10 M/10 F,
F344/DuCij (SPF)
rat, 6 hr/d, 5 d/wk,
13 wk
0, 125.3,250.8,
500.5, 1,000.4,
2,001.3 ppm
HEC:
M: 0, 13.63,
27.28, 54.42,
108.79, 217.62e
F: 0, 10.03, 20.09,
40.08, 80.112,
160.26e
Nasal lesions (atrophy of
the olfactory epithelium
and hyperplasia of
respiratory epithelium)
ND
DUB
10.03
Uineda et al. (2010)
(Other effects
include: anemia,
increased bilirubin,
splenic
hemosiderosis and
hematopoiesis,
bone marrow
hematopoiesis,
centriloubular
swelling in liver
[males only], and
decreased body
weight)
PR
Subchronic
10 M/10 F, F344
rat, 6 hr/d, 5 d/wk,
13 wk
0,15, 50,
151 ppm
HEC:
M: 0,1.6,5.4,
16.5e
F: 0,1.2,4.0,
12.1e
Nasal lesions
(hyperplasia of
respiratory epithelium,
degeneration of the
olfactory epithelium)
1.2
F: 0.12
4.0
Dow Chemical Co
NPR, IRIS,
PS
f1988a)
(Other effects
include: decreased
body weight in
males)
11
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 3A. Summary of Potentially Relevant Noncancer Data for 1,2-Dichloropropane (CASRN 78-87-5)
Category
Number of
Male/Female,
Strain, Species,
Study Type, Study
Duration
Dosimetry3
Critical Effects
NOAELa
BMDL/
BMCLa
LOAELa
Reference
(comments)
Notesb
Subchronic
10 M/10 F,
B6D2Fi/Crlj (SPF)
mouse, 6 hr/d,
5 d/wk, 13 wk
0, 50.0, 100.1,
200.0, 300.2,
399.9 ppm
HEC:
M: 0,6.21, 12.43,
24.83, 37.27,
49.66e
F: 0, 5.14, 10.29,
20.55, 30.86,
41.11s
Lesions of the nasal
cavity (olfactory
epithelium metaplasia,
atrophy, and necrosis)
20.55
M: 11.6
30.86
Matsumoto et al.
(2013)
(Other effects
include: decreased
body weight in
males, increased
liver weight,
increased relative
spleen weight,
anemia, increased
bilirubin and ALTs
[males only],
forestomach
hyperplasia,
pathological
changes in liver,
bone marrow,
spleen, and heart)
PR
Subchronic
10 M/10 F, B6C3Fi
mouse, 6 hr/d,
5 d/wk, 13 wk
0, 15, 50, 151 ppm
HEC:
M: 0,2.1,7.3,
22.2e
F: 0, 1.6, 5.6, 17.1e
No effects observed
22.2
NA
ND
Dow Chemical Co
f 1988a)
NPR
12
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 3A. Summary of Potentially Relevant Noncancer Data for 1,2-Dichloropropane (CASRN 78-87-5)
Category
Number of
Male/Female,
Strain, Species,
Study Type, Study
Duration
Dosimetry3
Critical Effects
NOAELa
BMDL/
BMCLa
LOAELa
Reference
(comments)
Notesb
Subchronic
7 M/7 F, NZW
rabbit, 6 hr/d,
5 d/wk, 13 wk
0, 151, 502,
1,003 ppm
HEC:
M: 0, 71.0, 236,
471.8e
F: 0, 66.4, 221,
441.2e
No respiratory system
effects observed
471.8
ND
ND
Dow Chemical Co
(1988a)
(Other effects
include: bone
marrow
hyperplasia,
anemia, and
increased liver
weight in males)
NPR
Chronic
50 M/50 F,
F344/DuCij (SPF)
rat, 6 hr/d, 5 d/wk
for 104 wk
0, 80.2, 200.5,
500.2 ppm
HEC:
M: 0, 16.2, 40.54,
101.1s
F: 0, 10.7, 26.75,
66.71e
Nasal lesions
(transitional epithelium
hyperplasia, squamous
cell hyperplasia and
metaplasia, atrophy of
the olfactory epithelium,
inflammation of the
respiratory epithelium)
ND
NDr
10.7
Uineda et al. (2010)
(Other effects
include: decreased
body weight in
males)
PR
Chronic
50 M/50 F,
B6D2Fi/Crlj (SPF)
mouse, 6 hr/d,
5 d/wk, 104 wk
0, 32.1, 80.2,
200.5 ppm
HEC:
M: 0,4.73, 11.8,
29.55e
F: 0, 4.27, 10.7,
26.6T
Lesions of the nasal
cavity (olfactory
epithelium atrophy)
4.27
NDr
10.7
Matsumoto et al.
(2013)
(Other effects
include: decreased
absolute spleen
weight in males,
increased kidney
weight in males,
and pathological
changes in the
kidneys of males)
PR
13
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 3A. Summary of Potentially Relevant Noncancer Data for 1,2-Dichloropropane (CASRN 78-87-5)
Category
Number of
Male/Female,
Strain, Species,
Study Type, Study
Duration
Dosimetry3
Critical Effects
NOAELa
BMDL/
BMCLa
LOAELa
Reference
(comments)
Notesb
Reproductive/
developmental
0 M/6-9 F, F344
rat, 8 hr/d, 7 d/wk,
3 wk
0, 50.7, 99.9,
200.7 ppm
0, 7.58, 14.9,
30.00e
Respiratory system
effects were not
evaluated
ND
ND
ND
Sekiguchi et al.
PR;
a significant
limitation
of this study
is that the
study
authors did
not evaluate
airway/
respiratory
system
effects
(2002)
(Other effects
include: increased
number of estrous
cycles lasting >6 d;
at highest dose
ovulation was also
decreased)
aDosimetry: The units for oral values are expressed as an ADD (mg/kg-day). All long-term exposure values (>4 weeks) are converted from a discontinuous to a
continuous exposure. Values from animal developmental studies are not adjusted to a continuous exposure. The units for inhalation exposures are expressed as
HECs (mg/m3) for ET using the equation recommended by the U.S. EPA (1994b) (see Footnote E).
bNotes: NPR = not peer reviewed; PR = peer reviewed; PS = principal study; IRIS = utilized by Integrated Risk Information System.
°Subchronic = repeated exposure for >30 days <10% lifespan for humans (>30 days up to approximately 90 days in typically used laboratory animal species)
(U.S. EPA. 2002b).
'Chronic = repeated exposure for >10% lifespan for humans (more than approximately 90 days to 2 years in typically used laboratory animal species) (U.S.
EPA. 2002b).
TTECet = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week exposed ^ 7) x RGDRet (animal:human) (U.S. EPA. 1994b).
ADD = adjusted daily dose; DUB = data unamenable to benchmark dose modeling software; ET = extrathoracic respiratory effects; F = female(s); FEL = frank
effect level; Hb = hemoglobin; Hct = hematocrit; HEC = human equivalent concentration; M = male(s); MW = molecular weight; NA = not applicable;
ND = no data; NDr = not determined; NZW = New Zealand white; S-D = Sprague-Dawley.
14
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 3B. Summary of Potentially Relevant Cancer Data for 1,2-Dichloropropane (CASRN 78-87-5)
Category
Number of Male/Female,
Strain, Species, Study
Type, and Duration
Dosimetry3
Critical Effects
BMDL/
BMCLa
Reference
(comments)
Notesb
Human
Carcinogenicity
(occupational)
62 M/0 F, workers from
1 print shop in Osaka, Japan
(51 printers, 11 front-room
workers), 1 factory (Osaka,
Japan), inhalation exposure
to DCM and/or 1,2-DCP,
8 hr/shift (unspecified
shifts/wk), 1-17 yr
Printers: 880-1,400;
Front-room: 320-510
(range of mean ambient
exposures estimated based on
amount of chemical
reportedly used)
Cholangiocarcinoma in
11/51 printers (22%);
0/11 front-room workers
ND
Kumaeai et al.
PR
(2013)
Carcinogenicity
(occupational)
88 M/23 F, workers from
1 print shop in Osaka, Japan,
inhalation exposure to TCE,
DCM, and/or 1,2-DCP,
6-19 yr
NR
Cholangiocarcinoma in
17/111 printers (15%)
ND
Kubo et al.
(2014c)
PR
Carcinogenicity
(occupational)
6 M/0 F, printers from 3 print
shops in 3 Japanese cities,
inhalation exposure to
1,2-DCP at all 3 shops
(additional solvents used
included TCE in Shop 1,
DCM and DCFE at Shop 2,
and DCM and TCE at
Shop 3), 9-11.5 hr/shift
(unspecified shifts/wk),
10-16 yr
Shop 1: 370-550;
Shop 2: 290-920;
Shop 3: 510-1,100
(TWA shift exposures;
modeled estimates based on
amount of chemical
reportedly used)
Cholangiocarcinoma (case-series
report)
ND
Yatnada et al.
(2014)
PR
Carcinogenicity
(occupational)
9 M/0 F, workers from
7 print shops in 7 Japanese
cities, inhalation exposure to
TCE, DCM, and/or 1,2-DCP,
6-19 yr
NR
Cholangiocarcinoma (case-series
report)
ND
Kubo et al.
(2014a)
PR
15
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 3B. Summary of Potentially Relevant Cancer Data for 1,2-Dichloropropane (CASRN 78-87-5)
Category
Number of Male/Female,
Strain, Species, Study
Type, and Duration
Dosimetry3
Critical Effects
BMDL/
BMCLa
Reference
(comments)
Notesb
Animal
1. Oral (mg/kg-d)a
Carcinogenicity
50 M/50 F, F344/N rat,
gavage in corn oil, 5 d/wk,
103 wk
M: 0, 62, 125;
F: 0, 125, 250
HED:
M: 0, 11,21.4
F: 0,21.4, 43.0
Significant increases in mammary
gland adenocarcinoma at high dose
once adjusted for intercurrent
mortality; preneoplastic lesions
(hyperplasia) were observed at low
dose; all in females
F: 30.4
NTP (1986)
PR
Carcinogenicity
50 M/50 F, B6C3Fi mouse,
gavage in corn oil, 5 d/wk,
103 wk
0,125, 250
HED: 0,12.5,25.1
Dose-related increase in combined
incidence of hepatocellular
adenoma or carcinoma in both
males and females, increased
combined incidence of thyroid
follicular cell adenoma or
carcinoma in female mice
M: 2.71
NTP (1986)
PR, PS

Carcinogenicity
(tumor promotion)
6-15 M/0 F, hamsters,
gavage in corn oil, 5 d/wk,
17 or 19 wk
0, 62.5, 125 via gavage
HED: 0, 9.37, 18.8
No effects observed
NA
Gi et al. (2015b)
PR
2. Inhalation (mg/m3)a
Carcinogenicity
50 M/50 F, F344/DuCrj
(SPF) rat, 6 hr/d, 5 d/wk
for 104 wk
0, 80.2, 200.5, 500.2 ppm
HECet:
M: 0,16.2,40.54,101.1c
F: 0,10.7,26.75, 66.71c
Increased incidence of tumors in
the nasal cavity of both male and
female rats
M: 26.7
limed a et al.
PR, PS
(2010)

16
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 3B. Summary of Potentially Relevant Cancer Data for 1,2-Dichloropropane (CASRN 78-87-5)
Category
Number of Male/Female,
Strain, Species, Study
Type, and Duration
Dosimetry3
Critical Effects
BMDL/
BMCLa
Reference
(comments)
Notesb
Carcinogenicity
50 M/50 F, B6D2Fi/Crlj
(SPF) mouse, 6 hr/d, 5 d/wk,
104 wk
0, 32.1,80.2, 200.5 ppm
HECpu:
M: 0, 77.2, 192, 482.5d
F: 0, 69.2, 173, 432.0d
Significant increase in combined
incidence of bronchiolo-alveolar
adenoma or carcinoma in females
that exceeded maximal control
historical incidence in the high
exposure group
F: 177
Matsumoto et al.
(2013)
(Other effects
include significant
trend for increased
Harderian gland
adenoma in males,
exceeding
maximal control
historical
incidence in the
high exposure
group)
PR
aDosimetry: The units for oral exposures are expressed as HEDs (mg/kg-day); HEDs were calculated using species-specific DAFs based on the animal:human
BW"4 ratio recommended by U.S. EPA (2011b): mouse:human ratio = 0.14; rat:human ratio = 0.24. All intermittent exposures were converted to from a
discontinuous to a continuous exposure. The units for inhalation exposures from animal studies are expressed as HECs (mg/m3) for PU or ET using the
equations recommended by the U.S. EPA (1994b) (see Footnotes C and D).
bNotes: NPR = not peer reviewed; PR = peer reviewed; PS = principal study.
°HECet = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week exposed ^ 7) x RGDRet (animal:human) (U.S. EPA. 1994b).
dHECpu = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week exposed ^ 7) x RGDRPU (animal:human); see Equations 4-28 in U.S. EPA (1994b)
for calculation of RGDRPU and default values for variables.
BMCL = benchmark concentration lower confidence limit; BMDL = benchmark dose lower confidence limit; F = female(s); DAF = dosimetric adjustment
factors; DUB = data unamenable to benchmark dose modeling software; ET = extrathoracic respiratory effects; HEC = human equivalent concentration;
HED = human equivalent dose; M = male(s); NA = not applicable; ND = no data; NR = not reported; PU = pulmonary effects; TCE = trichloroethylene;
TWA = time-weighted average.
17
1,2-Dichloropropane

-------
FINAL
09-29-2016
HUMAN STUDIES
Human studies include three retrospective cohort studies and two case-series reports in
print-shop workers in Japan evaluating the potential correlation between exposure to 1,2-DCP
(and other solvents) and chol angi ocarci noma, a rare form of bile duct cancer (Kumagai et al..
2016; Kubo et al.. 2014c; Kubo et aL 2014a; Kumagai et al.. 2014; Yamada et al.. 2014;
Kumagai et ai, 2013). These key studies are summarized in Table 3B and are described in detail
below. Individual case reports of cholangiocarcinoma in offset Japanese print shop workers
exposed to 1,2-DCP and/or dichloromethane (DCM) support findings from the key studies
(Kumagai et al.. 2014; Tomimaru et al.. 2014). A single case report of severe acute hepatitis has
also been reported in a Japanese print shop worker exposed to chlorinated organic solvents,
including 1,2-DCP, DCM, and 1,1,1-trichloroethane (TCE) (Kubo et al.. 2014b).
Kumayai et al. (2014); Kumayai et al. (2013)
An occupational study evaluated the potential relationship between cholangiocarcinoma
and exposure to 1,2-DCP and/or DCM in a small printing company in Osaka, Japan (Kumagai et
al.. 2013). Study subjects included 51 men employed as offset color proof-printers and 11 men
employed in the adjacent front room of the same printing company employed for at least 1 year
between 1991-2006. Between 1991-1997/1998, color proof-printers used both 1,2-DCP and
DCM as solvents for ink removal 150-400 times per shift. After 1997/1998, use of DCM was
discontinued and only 1,2-DCP was used for this process. Workers in the adjacent front room
were exposed to lower vapor levels of the solvents used by printers (due to poor ventilation).
Based on work histories, all of the printers and front-room workers were exposed to 1,2-DCP for
an average of 6 and 7 years, respectively, and 27 of the printers and 8 of the front-room workers
were also exposed to DCM for an average of 4 and 6 years, respectively. Workers wore gloves
while using 1,2-DCP and DCM, but neither proof-printers nor front-room workers wore
respiratory protection. Employees worked 8-hour shifts; the number of shifts per week was not
reported. A follow-up report by Kumagai et al. (2014) reviewed blood test records of workers
diagnosed with cholangiocarcinoma from annual health exams conducted during employment
and after retirement, including levels of liver enzymes (aspartate aminotransferase [AST],
alanine aminotransferase [ALT], and y-glutamyl transferase [GGT]) and parameters of
hematology (red blood cell [RBC], hemoglobin [Hb], hematocrit [Hct]), lipid metabolism (total
cholesterol, triglycerides), and glucose metabolism (fasting plasma glucose).
Chemical exposures were estimated based on reported quantities of 1,2-DCP and DCM
used and experimental data generated by the Japanese National Institute of Occupational Safety
and Health [NIOSH (2012) as cited in Kumagai et al. (2013)1. For printers, estimated mean
exposures to 1,2-DCP were 220 ppm from 1991-1992/1993, 190 ppm from
1992/1993-1997/1998, and 310 ppm from 1997/1998-2006 and estimated mean exposures to
DCM were 140 ppm from 1991-1992/1993 and 360 ppm from 1992/1993-1997/1998. For
front-room workers, estimated mean exposures to 1,2-DCP were 80 ppm from 1991-1992/1993,
70 ppm from 1992/1993-1997/1998, and 110 ppm from 1997/1998-2006 and mean exposures to
DCM were 50 ppm from 1991-1992/1993 and 130 ppm from 1992/1993-1997/1998. Thus, the
ranges of mean ambient exposure to 1,2-DCP from 1991-2006 were 190-310 ppm
(880-1,400 mg/m3) for printers and 70-110 ppm (320-510 mg/m3) for front-room workers.
Eleven cases of cholangiocarcinoma were identified in printers (mean age: 36 years);
six cases were fatal. No cases were identified in front-room workers. All clinically diagnosed
patients were exposed to 1,2-DCP for 7-17 years (mean 10 years), and 10 patients were also
18
1,2-Dichloropropane

-------
FINAL
09-29-2016
exposed to DCM for 1-13 years. Diagnosis of cholangiocarcinoma was 7-20 years (mean
14 years) after initial exposure. The standardized mortality ratio (SMR) from 1991-2011 for all
workers was calculated to be 2,900 based on 0.00204 expected deaths (95% confidence interval
[CI]: 1,100-6,400). The vital status of 11 proof-printers and 3 front-room workers could not be
determined at the time of the study; however, for the purpose of the SMR calculation, it was
assumed that these individuals were alive. Therefore, the mortality risk may have been
underestimated. In cholangiocarcinoma cases, the majority of blood parameters were within
standard ranges; however, GGT levels exceeded the standard range during 1,2-DCP exposure for
6/11 cases. Of these six cases, two were diagnosed while still employed and the other four were
diagnosed 1-9 years after ceasing 1,2-DCP exposure. In the remaining five cases, which were
all diagnosed 4-10 years after ceasing 1,2-DCP exposure, GGT levels were within the normal
range during 1,2-DCP exposure, but were elevated thereafter. In most cases, serum AST and
ALT levels increased subsequent to increased GGT levels. These findings suggest that 1,2-DCP
and/or DCM may cause cholangiocarcinoma in occupationally exposed workers, and that the
elevated GGT levels may be an early marker for cholangiocarcinoma development.
Kubo et al. (2014c)
Seventeen cholangiocarcinoma cases were identified between 1996-2012 in young men
currently or formerly employed in the offset color proof-printing department of a printing
company in Osaka, Japan between 1981-2012. Nine cases were fatal. Based on details in the
report, it appears that this is the same printing company described by Kumagai et al. (2014) and
Kumagai et al. (2013) above; however, slightly different solvent usage patterns were reported for
cleaning ink residues. The study authors indicated that TCE was used up until 1992, DCM was
used up until 1996, and 1,2-DCP was used up until 2006. No exposure estimates were reported;
however, based on job history, it was determined that all 17 individuals were exposed to
1,2-DCP, 11 were exposed to DCM, and 8 were exposed to TCE. The average length of
chemical exposure was 11 years, 4 months (range 6 years, 1 month-19 years, 9 months). The
mean age of diagnosis was 36 years of age, compared to the mean age of onset of 65.4 years in
the general Japanese population. The study authors identified a total of 111 former or current
workers (88 men and 23 women) who were exposed during the same time period, indicating that
17/111, or 15%, of exposed workers developed cholangiocarcinoma. None of the patients had
known risk factors for developing cholangiocarcinoma (e.g., primary sclerosing cholangitis,
hepatolithiasis, pancreaticobiliary maljunction, or infection with liver flukes). These cases
support that occupational exposure to high levels of chlorinated organic solvents, including
1,2-DCP, may cause cholangiocarcinoma in humans.
In addition. Sob tie et al. (2015) performed a retrospective cohort study to determine the
risk of bile duct cancer in the same printing workers described by Kumagai et al. (2014).
Kumagai et al. (2013). and Kubo et al. (2014c) that were exposed to 1,2-DCP and DCM. The
study authors calculated standardized incidence ratios (SIRs) for the cumulative years of
exposure to 1,2-DCP and DCM with reference to the nationwide incidence. For workers
exposed to both chemicals, the SIR was 1,319.9 (95% CI: 658.9-2,361.7). For workers only
exposed to 1,2-DCP, the SIR was 1,002.8 (95% CI: 368.0-2,182.8). There was also a tendency
for SIRs to increase with longer exposure to 1,2-DCP. The study authors concluded that there
was an exceptionally high risk of bile duct cancer in printing workers, which may be due to
exposure to 1,2-DCP. Kumagai et al. (2016) later identified a relationship between the risk of
cholangiocarcinoma in printing workers and increased cumulative exposure to 1,2-DCP.
19
1,2-Dichloropropane

-------
FINAL
09-29-2016
Yamada et al. (2014)
Six cholangiocarcinoma cases were diagnosed in 1998-2013 in males currently or
formerly employed in one of three small printing companies (<50 employees) in Miyagi,
Fukuoka, or Hokkaido, Japan. There is no overlap between the cases presented in this study and
the studies conducted by Kumagai et al (2014). Kumagai et al (2013). and Kubo et al (2014c).
Detailed exposure assessments were done for each employee based on work history. All workers
were exposed to 1,2-DCP for 10-16 years. Employees worked 10-hour shifts in Shop 1, 9-hour
shifts in Shop 2, and 11.5-hour shifts in Shop 3; the number of shifts per week was not reported.
Shift time-weighted average (TWA) exposure estimates based on modeling of the amount of
chemical reportedly used were 80-170 ppm (370-550 mg/m3) for printers in Shop 1,
62-200 ppm (290-920 mg/m3) for printers in Shop 2, and 110-240 ppm (510-1,100 mg/m3) for
printers in Shop 3. Additional solvents used in the different shops included DCM (<1 ppm in
Shop 1, 0-180 ppm in Shops 2 and 3), TCE (Shops 1 and 3; estimate not reported), and
1,1-dichloro-l-fluoroethane (DCFE) (Shop 2; estimate not reported). These cases support that
occupational exposure to high levels of chlorinated organic solvents, including 1,2-DCP, may
cause cholangiocarcinoma in humans.
Kubo et al. (2014a)
Nine cholangiocarcinoma cases were identified between 1988-2011 in males currently or
formerly employed in one of seven printing companies in Hokkaido, Aomori, Miyagi, Saitama,
Aichi, Osaka, and Fukuoka, Japan. Five cases were fatal. It is unclear if the six cases included
in the report by Yamada et al. (2014) (described above) are included in this report. All patients
had been exposed to "high" levels of chlorinated organic solvents at work for 3-19 years
(average 13 years). Five were exposed to DCM and 1,2-DCP, two were exposed to TCE, DCM,
and 1,2-DCP, and two were exposed to TCE and DCM. No exposure estimates were reported.
The average age at diagnosis was 44 years. None of the patients had known risk factors for
developing cholangiocarcinoma (e.g., primary sclerosing cholangitis, hepatolithiasis,
pancreaticobiliary maljunction, or infection with liver flukes). These cases support that
occupational exposure to high levels of chlorinated organic solvents, including 1,2-DCP, may
cause cholangiocarcinoma in humans.
ANIMAL STUDIES
Oral Exposures
The effects of oral exposure of animals to 1,2-DCP have been evaluated in one
short-term-duration study in mice and hamsters (Gi et al.. 2015a). three subchronic-duration
studies in rats or mice (Bruckner et al, 1989; Dow Chemical Co. 1988b; NTP, 1986), a
chronic-duration/carcinogenic study in rats and mice (NTP. 1986). a chronic study in hamsters
(Gi et al. 2015b). a two-generation reproductive/developmental study in rats (Dow Chemical Co.
1990). and a teratology study in rats and rabbits with accompanying maternal dose-range finding
studies (Kirk et al. 1995; Dow Chemical Co. 1989a. 1988d). These key studies are summarized
in Tables 3 A and 3B and are described in detail below. Additional information regarding oral
exposure is available from several acute and short-term studies and a sub chroni c-durati on study
available only as an abstract (see Table 4B).
Short-term-Duration Studies
Gi et al. (2015a) (Mouse study)
Gi et al. (2015a) performed 4-hour, 3-day, and 4-week gavage experiments in male
B6C3Fi mice. For the 4-hour component of the study, male mice (five/group) received a single
20
1,2-Dichloropropane

-------
FINAL
09-29-2016
administration of 1,2-DCP (purity >98%) at doses of 0 or 500 mg/kg-day via gavage in corn oil.
Male mice were euthanized 4 hours after gavage. At sacrifice, livers were removed and weighed
and preserved for histological examination. For the 3-day experiment, mice (five/group) were
gavaged once a day for 3 days with 1,2-DCP at doses of 0 or 500 mg/kg-day. Mice were
monitored twice daily for mortality and morbidity. Body weight and food/water consumption
were recorded daily. At sacrifice, livers were removed, weighed and preserved for histological
examination and analyzed for glutathione (GSH) concentration. Lung, kidney, spleen, and bile
duct were also removed from these animals and preserved for histological examination. For the
4-week experiment, groups of male mice (five/group) were administered 1,2-DCP via gavage in
corn oil at doses of 0, 125, or 250 mg/kg-day for 4 weeks (5 days/week). Before each gavage
treatment, body weight was recorded. Food and water consumption were recorded daily. At
termination, blood was collected from the vena cava for hematology and serum chemistry, and
livers were removed, weighed and preserved for histological examination. Lung, kidney, spleen,
and bile duct were also removed from these animals and preserved for histological examination.
Livers from the 4-week component were analyzed for the following parameters:
immunohistochemical staining of CYP2E1, GST-T1, and Ki-67, messenger ribonucleic acid
(mRNA) and protein expression of CYP450 enzymes and GST-T1, GSH concentration, and
oxidative damage.
In the 4-hour experiment, the incidence of fatty change in the liver was significantly
increased at 500 mg/kg-day. Also, the concentration of GSH in the liver significantly decreased
at 500 mg/kg-day. In the 3-day component of the study, the incidence of fatty change as well
centrilobular necrosis in the liver was significantly increased at 500 mg/kg-day. In the 4-week
experiment, absolute liver weight was statistically and biologically significantly increased at
>125 mg/kg-day. Relative liver weight was statistically significantly increased at
>125 mg/kg-day and biologically significantly increased at 250 mg/kg-day. The following
serum biochemistry parameters were significantly increased at 250 mg/kg-day: total cholesterol,
total glycerin, and albumin. The incidence of fatty change in the liver was significantly
increased at >125 mg/kg-day. The following significant mRNA changes were observed:
increased CYP1A1 at 250 mg/kg-day, increased CYP2A4 at >125 mg/kg-day, decreased
CYP2C9 at >125 mg/kg-day, decreased CYP3CA11 at >125 mg/kg-day, increased CYP4A14 at
>125 mg/kg-day, and decreased GST-T1 at >125 mg/kg-day. A lowest-observed-adverse-effect
level (LOAEL) of 125 mg/kg-day is identified for significantly increased incidence of fatty
change in the liver and for statistically and biologically significantly increased absolute liver
weight; both observed in the 4-week experiment. Because 125 mg/kg-day is the lowest dose
tested, identification of a no-observed-adverse-effect level (NOAEL) is precluded. For the
4-week component of the study, gavage doses of 125 and 250 mg/kg day were converted to
adjusted daily doses (ADDs) of 89.3 or 179 mg/kg-day by multiplying the administered gavage
dose by (5/7) days/week.
Gi etal. (2015a) (Hamster study)
Gi et al. (2015a) performed 4-hour, 3-day, and 4-week gavage experiments in male
Syrian hamsters as described above for male B6C3Fi mice. The only exception is that in the
3-day experiment, the dose of 500 mg/kg-day was lowered to 250 mg/kg-day due to mortality
(one hamster) and morbidity observed after the first gavage treatment. In the 4-hour experiment,
absolute and relative liver weight was statistically and biologically significantly decreased at
500 mg/kg-day. The incidence of fatty change in the liver was significantly increased at
500 mg/kg-day. The concentration of GSH in the liver significantly decreased at 500 mg/kg-day.
21
1,2-Dichloropropane

-------
FINAL
09-29-2016
In the 3-day component of the study, final body weight was significantly decreased at
250 mg/kg-day. The incidence of fatty change as well as centrilobular necrosis in the liver was
significantly increased at 250 mg/kg-day. For the 4-week experiment, final body weight was
biologically (but not statistically) significantly reduced at 250 mg/kg-day. Mortality was
observed at >125 mg/kg-day with one hamster dead in Week 1 and three hamsters dead (one
each at Weeks 1, 2 and 3) at 250 mg/kg-day. Relative liver weight was statistically and
biologically significantly increased at 250 mg/kg-day. The incidence of fatty change in the liver
was significantly increased at >125 mg/kg-day. A frank effect level (FEL) of 125 mg/kg-day is
identified for mortality observed in the 4-week experiment. Because 125 mg/kg-day is the
lowest dose tested, identification of a LOAEL or NOAEL is precluded. For the 4-week
component of the study, gavage doses of 125 and 250 mg/kg day were converted to ADDs of
89.3 or 179 mg/kg-day by multiplying the administered gavage dose by (5/7) days/week.
Subchronic-Duration Studies
Bruckner et al. (1989)
Adult male Sprague-Dawley (S-D) rats (15-16/group) were administered 1,2-DCP
(purity 99%) at doses of 0, 100, 250, 500, or 750 mg/kg-day via gavage in corn oil, 5 days/week
for 13 weeks. The frequency of evaluations for animal health and clinical signs of toxicity was
not reported; however, the study authors indicate that all moribund animals were removed during
the study and sacrificed. Body weight (BW) was measured weekly. Blood samples were
collected for serum chemistry (sorbitol dehydrogenase [SDH], ALT, ornithine carbamoyl
transferase [OCT], blood urea nitrogen [BUN], total bilirubin) from six to eight rats/group prior
to initial dosing as well as at 2, 4, 6, 8, 10, and 12 weeks and again after a 1-week post-treatment
recovery period; all animals served as blood donors 3 times during the course of the study at
approximately 4-week intervals. Twenty-four-hour urine samples were collected once per month
for urinalysis (total volume, protein, glucose, alkaline phosphatase [ALP], acid phosphatase,
A'-acetyl-[3- D-glucosaminidase [NAG]) from animals not participating as blood donors. At the
conclusion of the study, six to eight rats were sacrificed. All remaining animals were allowed a
recovery period of 1 week after the last exposure prior to sacrifice. At scheduled sacrifices,
blood was collected for hematology (Hct, Hb), the liver, kidney, and spleen were removed and
weighed, and the liver, kidneys, lungs, brain, adrenals, spleen, stomach, testis, and epididymis
were removed and preserved for histological examination. Tissues from animals sacrificed
moribund were also preserved for histological examination. Portions of the liver were processed
for evaluation of cytochrome P450 (CYP450) content and glucose-6-phosphatase (G-6-Pase)
activity, and portions of the liver and kidney were utilized for measurement of nonprotein
sulfhydryl levels.
High mortality occurred in the 750-mg/kg-day group, with approximately 55% mortality
within the first 10 days; the surviving animals in this exposure group were sacrificed moribund at
10 days. In the 500-mg/kg-day group, approximately 60% mortality was observed over the
13-week exposure period; all surviving animals were sacrificed at 13 weeks (no 1-week recovery
group at this dose level). Survival was >90% in all other groups. Clinical signs of toxicity
observed in the two highest dose groups included pronounced central nervous system (CNS)
depression coupled with a reduction in food and water intake. Significant, dose-dependent
reductions in body weight were reported throughout the study in all dose groups; however, based
on graphically presented data, it appears that body weights in the 100- and 250-mg/kg-day
groups remained within 10% of control weights. Using Grab It! Software, terminal body weights
were reduced by ~4, 9, and 22% in the 100-, 250-, and 500-mg/kg-day groups, respectively. At
22
1,2-Dichloropropane

-------
FINAL
09-29-2016
moribund sacrifice on Day 10, body weights in the 750-mg/kg-day group were decreased by
-45%.
Hematological evaluation at 13 weeks showed a significant 15-16% decrease in Hct and
34-38%) decrease in Hb in the 250- and 500-mg/kg-day groups. After the 1-week recovery
period, Hct levels were comparable to control levels in the 250-mg/kg-day group (not assessed in
500-mg/kg-day group), but Hb levels were still reduced by 20% (see Table B-l). Significant,
dose-related increases in serum bilirubin levels were observed in the 250- and 500-mg/kg-day
groups at the majority of evaluated time-points (see Table B-l). At 12 weeks, significant
bilirubin increases of ~6-10-fold were observed in the 100-, 250-, and 500-mg/kg-day groups,
compared with controls (see Table B-l). Serum OCT levels were generally higher in exposed
animals, with significant increases of ~10-fold at 12 weeks in the 250- and 500-mg/kg-day
groups, compared with controls (see Table B-l). No significant, biologically-relevant changes
were observed in other serum markers of liver function (SDH, ALT) or kidney function (BUN).
The study authors indicated that kidney toxicity was not suggested by urinary enzyme levels or
urinary protein or glucose content; however, no data were presented for urinalysis parameters in
the study publication. Liver and kidney nonprotein sulfhydryl levels were statistically elevated
by 37-50%) in the 250- and 500-mg/kg-day rats, compared with controls, at 13 weeks
(see Table B-l). After the 1-week recovery period, nonprotein sulfhydryl levels were
comparable to control levels in the 250-mg/kg-day group (not assessed in 500-mg/kg-day group)
(see Table B-l). These findings may be attributable to a transient "rebound" or "overshoot" in
compensatory GSH synthesis. No changes were observed in liver microsomal CYP450 levels of
G-6-Pase activity in treated rats, compared with controls.
Significant changes in relative organ weights at 13 weeks included a 27-39%> increase in
liver weight at >250 mg/kg-day, a 100-205%) increase in spleen weight at >250 mg/kg-day, and
a 14%o increase in kidney weight at 500 mg/kg-day (see Table B-l). After the 1-week recovery
period, relative liver and spleen weights were partially recovered in the 250-mg/kg-day group
(not assessed in 500-mg/kg-day group); however, they were still significantly elevated by 20 and
40%o, respectively, compared with 13-week control values (see Table B-l). Absolute organ
weights were not reported. No organ-weight effects were observed in the 100-mg/kg-day group.
Microscopic changes in the spleen, including hemosiderosis and hyperplasia of
erythropoietic components, were observed at 13 weeks in most exposed animals in a dose-related
manner (incidence not reported). Other histopathological changes observed at 13 weeks were
limited to the 500-mg/kg-day group, including renal tubular cell hemosiderosis and hepatic
Kupffer cell hemosiderosis (incidence data not reported); morphological changes in the liver
(periportal vacuolization and active fibroplasia; incidence not reported); testicular degeneration,
reduced sperm production, and increased spermatid giant cells (3/9 rats); excessive number of
degenerate spermatogonia and reduction in the number of sperm in epididymides (4/9 rats); and
increased fat storage in the adrenal cortex (5/9 rats). In high-dose rats sacrificed moribund on
Day 10, histopathological changes included splenic hemosiderosis (10/10 rats), mild hepatitis
(9/10 rats), vacuolization of the adrenal medulla and lipidosis of the adrenal cortex (4/10 rats),
reduced spermatozoa in the epididymis (majority; incidence not reported), and testicular
degeneration (2/9 rats). The only histopathological effects reported following the 1-week
recovery were excessive amounts of iron in the spleen of the 250-mg/kg-day group. The study
authors also reported a modest degree of hepatic fibrosis in the 500-mg/kg-day group after
recovery; however, elsewhere in the report, the study authors stated that all surviving rats from
23
1,2-Dichloropropane

-------
FINAL
09-29-2016
the 500-mg/kg-day group were sacrificed at 13 weeks, and none were utilized for the recovery
period.
A LOAEL of 100 mg/kg-day was identified for evidence of hemolytic anemia, including
significantly increased serum bilirubin levels and hemosiderosis and hyperplasia of
erythropoietic elements of the spleen. Decreased Hct and Hb were also observed at higher doses.
A NOAEL was not identified. A FEL of 500 mg/kg-day was identified for increased mortality.
Gavage doses of 100, 250, 500, and 750 mg/kg-day were converted to ADDs of 71.4, 179, 357,
or 536 mg/kg-day by multiplying the administered gavage dose by (5/7) days/week.
Dow Chemical Co (1938b)
In an unpublished neurotoxicity study, groups of F344 rats (15/sex/group) were
administered 1,2-DCP (purity 99.9%) via gavage in corn oil at doses of 0, 20, 65, or
200 mg/kg-day for 13 weeks (5 days/week). Rats were observed twice daily for signs of clinical
toxicity or morbidity. Body weights and detailed clinical exams were recorded weekly.
Neurological function was evaluated monthly by a functional observational battery (FOB),
hindlimb grip strength test, and motor activity assessment. At 13 weeks, body temperature was
recorded. At the end of dosing, four rats/sex/group were sacrificed for gross necropsy. The
brain was removed, and length, width, and weight were recorded. Nervous system tissues (brain,
spinal cord, Gasserian ganglia, dorsal and ventral spinal nerve roots, dorsal root ganglia, sciatic
nerve, tibial nerve, sural nerve) as well as the liver, kidney, and spleen from the control and
high-dose rats were fixed for histopathological examination. The remaining rats were observed
for a 9-week recovery period prior to sacrifice. Daily observations, weekly body-weight
measurements and detailed clinical examinations, and periodic body temperature readings were
collected during the recovery period. At the end of the recovery period, five rats/sex/group were
sacrificed for gross necropsy; the remaining animals were sacrificed and discarded.
No mortalities were observed. Transient clinical signs of toxicity were observed
immediately following gavage administration on Days 1-2 in all dose groups and on Day 3 in
the high-dose group, including tearing and blinking and decreased spontaneous locomotion. No
other clinical findings were reported during daily or weekly exams. Body weights were
decreased in mid- and high-dose males throughout the treatment period, with significant 3 and
10% decreases, respectively, at 13 weeks (see Table B-2). At the end of the 9-week recovery
period, body weights in high-dose males were still significantly reduced by 8%; male body
weight in the mid-dose group was no longer significantly decreased compared with control
(see Table B-2). Minor weight reductions were also observed in females; however, findings
were not significant (see Table B-2). No consistent, significant differences were observed
between the exposed and control rats during the FOB, hindlimb grip strength, or motor activity
assessments. At 13 weeks, body temperature was slightly, but significantly, decreased by 0.3
and 0.6°C in high-dose male and females, respectively. While these changes persisted during the
recovery period, this finding is not considered biologically relevant because body temperatures
were still within the normal circadian variation. Brain weight, length, or width and all findings
during gross or microscopic examination were similar between treated and control rats.
In male rats, a NOAEL of 65 mg/kg-day and a LOAEL of 200 mg/kg-day were identified
for significant body-weight reductions >10%. Neurotoxicity was not observed in either sex.
Gavage doses of 20, 65, or 200 mg/kg-day were converted to ADDs of 14, 46, or 143 mg/kg-day
by multiplying the administered gavage dose by (5/7) days/week.
24
1,2-Dichloropropane

-------
FINAL
09-29-2016
NTP (1986) (Rat study)
F344/N rats (10/sex/group) were administered 1,2-DCP (purity 99.4%) at doses of 0, 60,
125, 250, 500, or 1,000 mg/kg-day via gavage in corn oil 5 days/week for 13 weeks. All animals
were observed twice daily for mortality and clinical signs of toxicity. Detailed clinical
examinations, including palpation for tissue masses or swelling, were conducted weekly. Body
weights were also recorded weekly. Animals determined to be moribund were sacrificed and
necropsied. At the conclusion of the 13-week study, necropsies were performed on all of the
remaining animals. A complete set of 26 tissues were microscopically examined in the control
and two highest dose groups only.
All male and female rats receiving 1,000 mg/kg-day and 5/10 males receiving
500 mg/kg-day died before the conclusion of the study; no deaths were observed in other dose
groups (see Table B-3). Terminal body weights were significantly decreased by 16% in males
and 8%> in females in the 500 mg/kg-day group, compared with controls (see Table B-3); mean
body weights were not reported for the high-dose group due to 100% mortality. Body weights in
lower dose groups were comparable to controls (see Table B-3). Histopathological lesions in the
liver of high-dose rats attributed to exposure included centrilobular congestion in 5/10 males and
2/10 females, and hepatic fatty changes and centrilobular necrosis in 2/10 females. Histological
findings for other groups were not reported.
In males, a NOAEL of 250 mg/kg-day and a LOAEL (FEL) of 500 mg/kg-day were
identified based on increased mortality (50%). Significant decreases in body weight (>10%)
were also observed in male rats at the FEL. Gavage doses of 60, 125, 250, 500, or
1,000 mg/kg-day were converted to ADDs of 43, 89.3, 179, 357, or 714 mg/kg-day by
multiplying the administered gavage dose by (5/7) days/week.
NTP (1986) (Mouse study)
B6C3Fi mice (10/sex/group) were administered 1,2-DCP (purity 99.4%) at doses of 0,
30, 60, 125, 250, or 500 mg/kg-day via gavage in corn oil 5 days/week for 13 weeks. Endpoints
evaluated were identical to those described above for the 13-week National Toxicology Program
(NTP) study in rats. The only mortalities included one male in the 60-mg/kg-day group and one
female in the 500-mg/kg-day group. Body weights were comparable between treated and control
mice; terminal body weights were all within 10% of control values. No histopathologic effects
attributable to exposure were reported.
A free-standing NOAEL of 500 mg/kg-day (the highest dose tested) was identified in
male and female mice for lack of effects on survival, body weight, or histology. Gavage doses of
30, 60, 125, 250, or 500 mg/kg-day were converted to ADDs of 0, 21, 43, 89.3, 179, or
357 mg/kg-day by multiplying the administered gavage dose by (5/7) days/week.
Chronic-Duration/Carcinogenicity Studies
NTP (1986) (Rat study)
Male F344/N rats (50/group) were administered 1,2-DCP (purity 94%) at doses of 0, 62,
or 125 mg/kg-day via gavage in corn oil 5 days/week for 103 weeks. Groups of female F344/N
rats (50/group) were similarly administered 1,2-DCP at doses of 0, 125, or 250 mg/kg-day. All
animals were observed twice daily for mortality and morbidity. Clinical signs of toxicity were
recorded daily. Body weights were recorded every week for the first 13 weeks and then monthly
thereafter. Hematology, clinical chemistry, and urinalysis evaluation were not performed. Gross
25
1,2-Dichloropropane

-------
FINAL
09-29-2016
necropsies were performed on all animals found dead or sacrificed moribund, as well as those
sacrificed at the end of the study (unless precluded by autolysis or cannibalization).
Examinations for grossly visible lesions were performed on major tissues and organs. A
complete set of 27 tissues, as well as all gross lesions, were microscopically examined in all
animals.
High-dose females had significantly reduced survival rates (32%) compared with controls
(74%); survival in the low-dose group (86%) was comparable to controls (see Table B-4). No
significant differences in survival were reported among males. Terminal body weights were
decreased in all exposed animals; however, the changes were only biologically significant
(>10%) in the high-dose males (—10%) and females (-21%) (see Table B-4). The incidences of
hemosiderosis and hematopoiesis of the spleen and clear cell foci and necrosis of the liver were
significantly increased in high-dose females, compared with controls (see Table B-5). In
low-dose females, but not high-dose females, a significant increase in mammary gland
hyperplasia was observed, compared with control (see Table B-5). While mammary gland
hyperplasia was not significantly elevated in high-dose females, mammary gland
adenocarcinoma incidence was marginally increased (5/50) compared with controls (1/50); this
increase was statistically significant once incidences were adjusted for intercurrent mortality
(26.7 vs. 2.7%), respectively) (see Table B-5). The lack of significant increase in mammary
gland hyperplasia in high-dose females may be due to the progression from hyperplasia to
neoplasia and/or high mortality. Other neoplastic findings in females included a significant
dose-response trend in the incidence of endometrial stromal polyps of the uterus (without
significant findings in either group using pair-wise comparison) following adjustment for
intercurrent mortality (see Table B-5). There were no non-neoplastic or neoplastic lesions
attributable to exposure observed in any of the tissues examined in male rats.
In male rats, a NOAEL of 62 mg/kg-day and a LOAEL of 125 mg/kg-day were identified
based on a 10% decrease in body weight. There was equivocal evidence of carcinogenicity in
female rats exposed to doses up to 250 mg/kg-day via gavage for 5 days/week for up to
103 weeks based on a marginal, but significant, increase in mammary gland adenocarcinoma
after adjustment for intercurrent mortality. There was no evidence of carcinogenicity in male
rats exposed to doses up to 125 mg/kg-day via gavage for 5 days/week for up to 103 weeks.
Gavage doses of 62, 125, or 250 were converted to ADDs of 0, 45, 89.3, or 179 mg/kg-day by
multiplying the administered gavage dose by (5/7) days/week and to human equivalent doses
(HEDs) of 0, 11, 21.4, and 43.0 mg/kg-day using the rat-to-human dosimetric adjustment factor
(DAF) of 0.24 based on the animal:human BW1 4 ratio recommended by U.S. EPA (201 lb).
NTP (1986) (Mouse study)
B6C3Fi mice (50/sex/group) were administered 1,2-DCP (purity 94%) at doses of 0, 125,
or 250 mg/kg via gavage in corn oil 5 days/week for 103 weeks. Endpoints evaluated were
identical to those described above for the 103-week NTP study in rats.
The survival of high-dose female mice (52%) was reduced compared with controls
(70%>); however, these findings are confounded by evidence of infection (characterized by
suppurative inflammation of the reproductive tract) in 60% of all females that died. Survival of
treated male mice was similar to controls. No clinical signs of toxicity or body-weight effects
were observed in either sex. Significantly increased non-neoplastic lesions were only observed
in the livers of high-dose males, including a 30% incidence of hepatocytomegaly and a 20%
26
1,2-Dichloropropane

-------
FINAL
09-29-2016
incidence of hepatic necrosis (including focal, not otherwise specified [NOS], and centrilobular
combined), compared with control incidences of 6 and 4%, respectively (see Table B-6).
Neoplastic lesions attributable to exposure were observed in the liver in male and female
mice and in the thyroid of female mice (see Table B-6). A significant positive trend was
observed for hepatic adenoma in both male and female mice, with significantly increased
incidences in the high-dose group in males (both before and after adjustment for intercurrent
mortality) and females (after adjustment for intercurrent mortality only), compared with controls.
Similarly, a significant positive trend was observed for the combined incidence of hepatic
adenoma or carcinoma in both male and female mice, with significantly increased incidences in
the high-dose males and low- and high-dose females, compared with control, both before and
after adjustment for intercurrent mortality. Incidences of hepatic carcinomas alone were not
significantly elevated with exposure. In the thyroid, incidences of follicular cell adenomas
(alone) or carcinomas (alone) were not significantly increased in males or females; however, a
significant positive trend was observed for the combined incidence of thyroid follicular cell
adenoma or carcinoma in female mice, with significantly increased incidence in the high-dose
group, compared with control, after adjustment for intercurrent mortality.
A NOAEL of 125 mg/kg-day and a LOAEL of 250 mg/kg-day were identified for
hepatocytomegaly and hepatic necrosis in male mice. A NOAEL/LOAEL determination was not
made for female mice due to high mortality associated with an infection in the colony. There
was evidence of carcinogenicity in male and female mice exposed to doses up to 250 mg/kg-day
via gavage for 5 days/week for up to 103 weeks based on increased incidence of liver tumors.
Gavage doses of 0, 125, or 250 mg/kg-day were converted to ADDs of 0, 89.3, or 179 mg/kg-day
by multiplying the administered gavage dose by (5/7) days/week and to HEDs of 0, 12.5, or
25.1 mg/kg-day using the mouse-to-human DAF of 0.14 based on the animakhuman BW1/4 ratio
recommended by U.S. EPA (201 lb).
Gi et al. (2015b)
Gi et al. (2015b) investigated the modifying effects of 1,2-DCP on the known hamster
carcinogen A-nitrosobis(2-oxopropyl)amine-induced cholangiocarcinomas in male hamsters.
The study authors also determined the effect of 1,2-DCP on pancreatic, lung, and renal cancer.
Gi et al. (2015b) also investigated the effect of 1,2-DCP on the expression of CYP2E1 and
GST-T1 in hepatic and pancreatic preneoplastic and neoplastic lesions. At 6 weeks of age, male
hamsters were divided into five groups. During Week 1, hamsters in Groups 1-3 (24/group)
received four subcutaneous injections of A-nitrosobis(2-oxopropyl)amine (10 mg/kg) on Days 1,
3, 5, and 7. Hamsters in the remaining groups (4 and 5) received 0.9% saline injections as a
vehicle. One week after hamsters received the last dose of A-nitrosobis(2-oxopropyl)amine, they
were administered 1,2-DCP at doses of 0, 62.5, or 125 mg/kg via gavage in corn oil 5 days/week
for 15 (17 weeks total treatment, 9 hamsters per dose group) or 17 (19 weeks total treatment,
15 hamsters per dose group) weeks. Hamsters receiving saline injections were then treated via
gavage with 125 mg/kg of 1,2-DCP (9 hamsters per dose group) or corn oil vehicle (6 hamsters
per dose group) for 17 weeks. At the end of 17 weeks, 9 hamsters from Groups 1-3 were
euthanized and examined. The liver and pancreas were removed and preserved for histological
examination; liver weight was also determined. All remaining hamsters were euthanized at the
end of 19 weeks. The liver, pancreas, lung, kidney, spleen, and bile duct were removed from
these animals and preserved for histological examination. Liver and pancreas samples from
control and 125 mg/kg 1,2-DCP groups in the 19-week component of the study that were
27
1,2-Dichloropropane

-------
FINAL
09-29-2016
identified to have preneoplastic or neoplastic lesions, were tested via immunohistochemistry for
expression of CYP2E1, GST-T1, and Ki-67. From the 17-week component of the study,
pancreas samples identified to contain neoplastic lesions were also examined for expression of
CYP2E1, GST-T1, and Ki-67.
In the 19-week component of the study, one hamster from Group 2 (62.5 mg/kg
1,2-DCP + A-nitrosobis(2-oxopropyl)amine) died of unknown causes at Week 12; no other
deaths were observed. Body weight was statistically and/or biologically significantly decreased
in hamsters from Group 3 (125 mg/kg 1,2-DCP +/V-nitrosobis[2-oxopropyl]amine) by 13 and
8.8% at the end of 17 and 19 weeks, respectively. No significant effects were observed on
absolute or relative liver weight. The study authors reported no significant histopathological
findings in the liver, pancreas, lung, or kidneys. There were also no significant effects on the
expression of CYP2E1, GST-T1, and Ki-67. A LOAEL of 125 mg/kg-day is identified for
statistically and biologically (>10%) significantly decreased body weight with a corresponding
NOAEL of 62.5 mg/kg-day. Gavage doses of 62.5 or 125 mg/kg-day were converted to ADDs
of 0, 44.6, or 89.3 mg/kg-day by multiplying the administered gavage dose by (5/7) days/week
and to HEDs of 9.37 and 18.8 mg/kg-day using a hamster-to-human DAF of 0.21 based on the
animal:human BW1 4 ratio recommended by U.S. EPA (201 lb).
Reproductive/Developmental Studies
Dow Chemical Co (1990); Dow Chemical Co (1989b)
In an unpublished two-generation study, groups of S-D rats (30/sex/generation) were
administered 1,2-DCP (purity 99.9%) via drinking water at concentrations of 0, 0.024, 0.10, or
0.24%. F0 female rats were exposed via drinking water from 10 weeks prior to mating, through
mating (for up to 3 weeks), gestation, and lactation (-18 weeks). F0 males were similarly
exposed, with the exception of 2 weeks during the post mating period when they received tap
water (-16 weeks). F1 rats were exposed via dams during gestation and lactation and via
drinking water for 12 weeks prior to mating to produce the F2 generation, through mating,
gestation, and lactation (-21 weeks). Based on 1,2-DCP intakes calculated by the study authors
for premating and postmating periods (gestational/lactational) using measured body weight and
water intake, the TWA dose levels were determined to be 0, 24.8, 82.7, or 152 mg/kg-day for
F0 males, 0, 38.8, 127, or 254 mg/kg-day for F0 females, 0, 28.3, 109, or 213 mg/kg-day for
F1 males, and 0, 42.7, 148, or 293 mg/kg-day for F1 females (see footnotes for Tables B-7 to
B-ll).
F0 and F1 parental rats were examined daily for mortality and clinical signs of toxicity.
All spontaneous deaths and moribund animals were submitted for pathologic examination. Body
weights and water and food consumption were recorded weekly throughout the study except
during breeding periods. All animals were given ophthalmological examinations prior to study
initiation and at necropsy. For each litter, the following parameters were recorded: litter size on
the day of parturition (Day 0); number of live and dead pups on Postnatal Days (PNDs) 0, 1,4, 7,
14, and 21 (note: litters were culled to four per sex on PND 4); and the weight and sex of each
pup and lactating female on PNDs 1, 4, 7, 14, and 21. Pups were also evaluated for any visible
external physical abnormalities or changes in behavior during lactation. All F0 and F1 parental
rats were sacrificed after weaning on PND 21 and subjected to a full necropsy. Blood was
collected from 10 rats/sex/group/generation for hematology (Hct, Hb, and erythrocyte, total
leukocyte, and platelet counts). Liver and kidney weights were recorded for all rats. The
28
1,2-Dichloropropane

-------
FINAL
09-29-2016
following tissues were processed for histological examination in the control and 0.24% groups:
bone/bone marrow, cervix, coagulating glands, epididymides, gross lesions, kidneys, ovaries,
oviducts, pituitary, prostate, seminal vesicles, testes, uterus, and vagina. Tissues processed for
histological examination in the 0.024 and 0.10% groups included all gross lesions and the liver.
Ten pups/sex/group were randomly selected from the F1 and F2 litters for complete gross
necropsy on PND 21. Also at this time, blood was collected for hematology and liver and kidney
weights were recorded. Histologic examinations were not conducted in F1 or F2 pups.
Additionally, F0 male rats from all groups were bred with unexposed, virgin female rats
(two successive matings) after mating to F0 females (dominant lethal study). F0 males were
exposed to tap water during this 2-week breeding period. Bred female rats (confirmed by
copulatory plug) were sacrificed about 14 days from the middle of the breeding period, and the
numbers of corpora lutea, implantations, and resorptions were counted to determine
preimplantation loss and resorption rates. Uteri of females that appeared nonpregnant were
removed and stained for identification of early resorptions.
F0 generation: Two males and two females from the low-dose group and one high-dose
F0 female died during the study. The deaths were not considered treatment-related. Since the
high-dose female died on Day 6 of the study, it was replaced with another female. No clinical
signs of toxicity were observed. Body weights were significantly decreased by 9-11% in
high-dose F0 males throughout the study (see Table B-7). In high-dose F0 females, body
weights at the end of the gestation and lactation periods were significantly reduced by 10—14%
(see Table B-7). Body weights were within 10% of controls throughout the experiment in
F0 males and females from the low- and mid-dose groups. In both male and female F0 rats,
water intake was reduced by 38—47% in the high-dose group and 13—30% in the mid-dose group,
suggesting a decrease in palatability (see Table B-7). Feed intake was reduced —10% in
high-dose females during lactation only; food intakes in all other groups were comparable to
controls.
There were no changes in the reproductive indices of treated F0 male or female rats,
compared to control, either in the main study or the dominant lethal study. There were no
significant differences in mean litter size, the number of live or dead pups on PND 0, or the sex
ratio in F1 litters. However, pup survival after birth was significantly reduced by 2—10% at the
high dose, compared with controls; survival in the low- and mid-dose groups was comparable to
controls (see Table B-8). Neonatal body weights for F1 animals from the high-dose group were
significantly depressed by 8—16% throughout lactation (see Table B-8). These neonatal effects
may be related to decreased water consumption and reduced body weights in dams from the
high-dose group. External observations in F1 pups from treated and control groups were
comparable.
At the end of the lactation period, statistically significant hematological changes in
high-dose F0 rats included a 16% decrease in platelet count in males, 7—9% decreases in
erythrocyte count, Hb, and Hct in females, and a 2.3-fold increase in the percent of reticulocytes
in females (see Table B-9). Polychromasia was seen in a few females (1-2) at the two lower
doses and in 5/10 females at the higher-dose group. These findings are suggestive of anemia in
females. In F1 weanlings, Hb levels were marginally, but significantly, elevated by 7% in male
pups from the high-dose group; no other hematological changes were reported in F1 weanlings.
29
1,2-Dichloropropane

-------
FINAL
09-29-2016
The only significant, biologically relevant (>10%) organ-weight change in F0 animals
was increased absolute and relative liver weight in females from all exposure groups, which did
not, however, increase with increasing dose. Absolute liver weights were increased by 19, 14,
and 12% and relative liver weights were increased by 12, 10, and 13% in the low-, mid-, and
high-dose groups, respectively. No significant, biologically relevant organ-weight changes were
observed in F1 weanlings. The livers in both male and female F0 rats showed an increase in
incidence of "very slight-to-slight" granularity of the hepatocellular cytoplasm in the high-dose
group (see Table B-10). No changes attributable to exposure were found in any other F0 organs
examined, including reproductive organs. No histology was performed on F1 weanlings.
For the F0 males, NOAEL and LOAEL values of 82.7 and 152 mg/kg-day, respectively,
were identified based on decreased body weight. Maternal NOAEL and LOAEL values of 127
and 254 mg/kg-day, respectively, were identified for anemia and decreased body weights in
F0 females. The toxicological significance of increased "very slight-to-slight" granularity of the
hepatocellular cytoplasm is unclear, as this may represent an adaptive response to 1,2-DCP
exposure. F1 offspring NOAEL and LOAEL values were 127 and 254 mg/kg-day, respectively,
based on decreased neonatal body weights and survival (secondary to maternal body-weight
effects).
F1 generation: One female from the low-dose group died during the study due to a
thrombus in the heart; this death was not considered treatment-related. At weaning, high-dose
F1 males and females selected to produce the F2 generation weighed significantly less than
controls (decreased 11—14%; see Table B-l 1). Body weights during pre- and postmating
exposure (including gestation/lactation) were also significantly decreased by 9—14% in
F1 parental animals; however, body-weight depression did not increase with continued exposure,
suggesting that observed depressions are reflecting low neonatal body weights (see Table B-l 1).
As with the F0 generation, water intake was significantly reduced throughout the exposure
period by 28-49%> in the high-dose animals, with inconsistent decreases in the low-dose males
and mid-dose males and females ranging from —4—34% (see Table B-l 1), suggesting a decrease
in water palatability. Food consumption was slightly decreased in high-dose F1 males by an
average of ~8%> throughout the exposure period. In F1 females, food consumption was
decreased in a dose-related manner by 11—23% during the last week of gestation only. No other
changes in food consumption were observed.
There were no changes in the reproductive indices of treated F1 male or female rats,
compared with control. There were no significant differences in mean litter size, sex ratio,
number of live or dead pups on PND 0, neonatal survival, or pup weight or growth in F2 litters.
External observations in F2 pups from treated and control groups were comparable.
At the end of the lactational period, reticulocyte count was dose-dependently increased
by 22-67%) in F1 adult males; no other hematological changes or changes in RBC morphology
were observed in F1 parental animals or F2 weanlings. Significant changes in organ weight
included a 6—9% increase in relative (but not absolute) kidney weight in F1 males and females
and F2 female weanlings and a 15% decrease in absolute (but not relative) liver weight in males;
these findings are considered secondary to body-weight effects and therefore not biologically
relevant. Similar to the F0 adults, the only histopathological observation was increased
incidence of "very slight-to-slight" cytoplasmic granularity of the hepatocytes in high-dose
animals (see Table B-10).
30
1,2-Dichloropropane

-------
FINAL
09-29-2016
For the F1 males, NOAEL and LOAEL values of 109 and 213 mg/kg-day, respectively,
were identified for decreased body weight. Maternal NOAEL and LOAEL values based on
reduced body weight were 148 and 293 mg/kg-day, respectively. A NOAEL of 293 mg/kg-day
was identified for lack of effects in F2 offspring. The toxicological significance of increased
"very slight-to-slight" granularity of the hepatocellular cytoplasm is unclear, as this may
represent an adaptive response to 1,2-DCP exposure.
Dow Chemical Co (1989c)
Dow Chemical Co (1989c) is an unpublished dose-range-finding study in rats that was
performed to select the correct dose for a more comprehensive developmental toxicity study
[see "Kirk et al. (1995)"belowl. Groups of mated female S-D rats (10/group) were administered
1,2-DCP (purity 99.9%) at doses of 0, 50, 125, 250, or 500 mg/kg-day via gavage in corn oil
gavage from Gestation Days (GDs) 6-15. All dams were observed daily for mortality and
clinical signs of toxicity. A more detailed observational battery was performed by a blinded
observer for approximately 60 minutes after dosing on GDs 6, 7, and 15, including the following
endpoints: pupil size, respiration, movement (including muscle tone, extensor thrust reflex,
behavior, tremors, convulsions, etc.), skin and haircoat (including grooming condition,
piloerection, etc.), salivation, lacrimation, and urine and fecal staining. Body weights of dams
were recorded on GD 0 and daily from GDs 6-16 (dosing period). Food and water consumption
was measured every 3-4 days beginning on GD 0. Dams were sacrificed on GD 16, and blood
was collected for hematology (Hct, Hb concentration, erythrocyte count, total leukocyte count,
platelet count). All dams, including those that died prior to the conclusion of the study,
underwent a full necropsy. Eyes were examined in situ by a glass slide technique. Kidney, liver,
and spleen weights were recorded. Dams were examined for the number of corpora lutea,
implantations, resorptions, and fetuses.
One animal in the 250-mg/kg-day group died immediately after treatment on GD 7;
however, after necropsy, it was determined to be due to a gavage error. No other mortalities
occurred. Clinical signs of toxicity (lethargy, salivation, and/or perineal staining) were observed
on GDs 6-8 in 5/10 and 10/10 dams from the 250- and 500-mg/kg-day groups, respectively,
compared with 0/10 controls. Findings from the detailed observational battery showed a
significant increase in the signs of CNS depression on GD 6 in all dose groups within an hour of
administration of 1,2-DCP, including decreased respiration, movement, muscle tone, and
extensor thrust reflex and increased salivation and lacrimation. Perineal urine staining was also
observed on GD 6 in some animals receiving doses >125 mg/kg-day. These effects were
observed with less frequency on GD 7, and only at >250 mg/kg-day. The only significant
observations on GD 15 were increased incidence of salivation and perineal urine staining at
500 mg/kg-day.
Numbers of confirmed pregnancies were 4, 9, 8, 6, and 10 in the 0, 50, 125, 250, and
500 mg/kg-day, respectively. In pregnant dams, maternal body-weight gain and food
consumption were significantly decreased compared with controls during the first 3 days of
1,2-DCP administration (GDs 6-9) at >125 mg/kg-day (see Table B-12). However, food
consumption and body weights in the 125- and 250-mg/kg-day groups were comparable to
control from GD 9-16, and terminal body weights were not significantly altered. In contrast,
body-weight gain during the entire dosing period (GDs 6-16) and gestation (GDs 0-6), as well
as terminal body weight, were significantly decreased in dams from the 500-mg/kg-day group,
despite food consumption comparable to control from GDs 9-16 (see Table B-12). Water intake
31
1,2-Dichloropropane

-------
FINAL
09-29-2016
was also decreased from GDs 6-9 at >125 mg/kg-day, but not in a significant, dose-related
manner. Spleen, liver, and kidney weights and hematologic parameters were comparable
between exposed and control animals. At necropsy, no gross pathologic treatment-related effects
were reported in animals at any dose. No changes were observed between treated and control
dams in any of the pregnancy outcomes evaluated.
A maternal NOAEL of 250 mg/kg-day and LOAEL of 500 mg/kg-day were identified
based on clinical signs of toxicity that persisted throughout the exposure period and decreased
maternal body weight. Based on these findings, the doses selected for the teratology study were
0, 10, 30, and 125 mg/kg-day (see below).
Kirketal. (1995) (Rat study)
Groups of mated female S-D rats (30/group) were administered 1,2-DCP (purity 99.9%)
at doses of 0, 10, 30, or 125 mg/kg-day via gavage in corn oil from GDs 6-15. Animals were
observed daily for mortality and clinical signs of toxicity, and an observational battery was
performed on GDs 6 and 7 as described above (Dow Chemical Co. 1989c). Body weights were
recorded on GD 0, daily during dosing (GDs 6-15), and on GDs 16 and 21. Food and water
consumption were measured every 2-4 days beginning on GD 0. On GD 21, dams were
sacrificed and weights of liver, kidney, spleen, and gravid uterus were recorded. For each dam,
the number of corpora lutea and the number and position of implantations, resorptions, and live
or dead fetuses were recorded. Uteri of nonpregnant females were examined for early
resorptions. The sex and body weight of each fetus and any external anomalies were recorded.
At least half of rat litters were randomly selected for dissection and examination for visceral or
skeletal alterations.
No mortalities were observed. In the high-dose group, clinical signs of toxicity were
observed on GD 6, with individual signs (decreased movement, muscle tone, and extensor thrust
reflex and increased salivation and lacrimation) occurring in 6-23/30 high-dose animals,
compared with 0-1/30 controls. These signs were less frequent (1-3/30) on GD 7. No
significant clinical signs were observed in rats exposed to 10 or 30 mg/kg-day. High-dose dams
also experienced significantly decreased body weight on GDs 9, 12, and 16 (4-5% lower than
controls). Body-weight gain was significantly reduced on GDs 6-9 (—122%), GDs 16-21
(-28%>), and GDs 0-21 (— 10%>) (see Table B-13). During the first three exposure days
(GDs 6-9), food consumption was also significantly decreased by 25%> in this group;
consumption from GDs 9-21 was comparable to control. Water consumption was significantly
increased by ~25%> from GDs 9-15. There were no significant differences in organ weight
between treated animals and controls.
The number of confirmed pregnancies was 25, 29, 28, and 30 in 0-, 10-, 30-, and
125-mg/kg-day groups, respectively. One dam dosed with 10 mg/kg-day delivered early
(GD 20); the cause of the premature delivery could not be ascertained upon gross examination.
This dam was excluded from the analysis of pregnancy outcomes and fetal
malformations/variations. Pregnancy outcomes were not significantly different between exposed
and control groups. In fetuses, there was a significant increase in the incidence of delayed
ossification of the skull at 125 mg/kg-day (16/30 litters), compared with controls (8/25 litters)
(see Table B-14). A nonsignificant increase in the incidence of delayed ossification of the
thoracic centra was also observed at 125 mg/kg-day (10/30 litters), compared with controls
32
1,2-Dichloropropane

-------
FINAL
09-29-2016
(4/25 litters) (see Table B-14). Delayed ossification of cervical centra was observed in all dose
groups, including controls, with similar frequency (see Table B-14).
Maternal and fetal NOAEL and LOAEL values of 30 and 125 mg/kg-day, respectively
were identified based on the maternal toxicity (clinical signs [CNS depression, salivation, and
lacrimation], decreased body-weight gain) and delayed skull ossification in fetuses.
Dow Chemical Co (1988d)
Dow Chemical Co (1988d) is an unpublished dose-range-finding study in rabbits that was
performed to select the correct dose for a more comprehensive developmental toxicity study
(Kirk et al.. 1995). Groups of artificially inseminated New Zealand white (NZW) rabbits
(seven/group) were administered 1,2-DCP (purity 99.9%) at doses of 0, 25, 100, or
250 mg/kg-day via gavage in corn oil from GDs 7-19. Animals were observed daily for
mortality and signs of clinical toxicity. Body weights were recorded on GD 0, daily throughout
the exposure-period (GDs 7-19), and on the day of sacrifice (GD 20). Blood samples were
collected on GD 19 for hematology (reticulocyte count, Hct, Hb, erythrocyte count, total
leukocyte count, erythrocyte indices mean corpuscular volume [MCV], mean corpuscular
hemoglobin [MCH], and mean corpuscular hemoglobin concentration [MCHC], and erythrocyte
morphology). Detailed necropsies were performed on all rabbits. Maternal liver, kidney, and
spleen weights were recorded. Numbers of corpora lutea and numbers and position of
implantations and resorptions were also documented. Uteri of females appearing nonpregnant
were examined for early resorptions. Histologic examinations were not performed.
Two rabbits in the high-dose group died during the study (on GDs 15 and 18). The cause
of death was not determined for either animal; however, the study authors noted that there was
no apparent target organ toxicity. Two additional high-dose animals exhibited weight loss and
complete litter loss. However, overall, body weight and body-weight gains were not
significantly different between exposed and control groups. A higher resorption rate was
observed in the high-dose group, compared with controls, but the increase was not statistically
significant and values were within historical control incidence data (see Table B-15).
Significant hematological findings included 22-24% decreases in erythrocyte count, Hb,
and Hct in high-dose does and a 2-3.7-fold increase in the percentage of reticulocytes in
mid- and high-dose does (see Table B-16). Erythrocyte morphology showed a significant
increase in the incidence of slight-to-moderate polychromasia at >100 mg/kg-day and a
significant increase in slight-to-moderate anisocytosis at 250 mg/kg-day. These changes are
indicative of regenerative anemia. At necropsy, absolute or relative organ weights and gross
pathology did not differ between exposed and control groups.
A maternal NOAEL of 25 mg/kg-day and a LOAEL of 100 mg/kg-day were identified
based on maternal anemia. A FEL of 250 mg/kg-day was identified based on complete litter loss
and/or maternal death. Based on these findings, the doses selected for the teratology study were
0, 15, 50, and 150 mg/kg-day (see below).
Kirk et al. (1995) (Rabbit study)
Groups of artificially inseminated NZW rabbits (18/group) were administered 1,2-DCP
(purity 99.9%) at doses of 0, 15, 50, or 150 mg/kg-day via gavage in corn oil from GDs 7-19.
Animals were observed daily for signs of clinical toxicity. Body weights were recorded on
33
1,2-Dichloropropane

-------
FINAL
09-29-2016
GD 0, daily during dosing (GDs 7-19), and on GDs 20 and 28. Food and water consumption
were measured every 2-4 days beginning on GD 0. On GD 19, blood samples were collected for
hematology (Hct, Hb concentration, erythrocyte count, total leukocyte count, platelet count). On
GD 28, does were sacrificed. Endpoints evaluated were identical to those described above for
the developmental study in rats (Kirk et al.. 1995).
Two rabbits in the 150-mg/kg-day group died during the study (on GDs 17 and 22).
One animal died due to an intubation error and the other animal's cause of death was not
identified after pathologic examination. At the high dose, 17/18 does showed intermittent
anorexia, resulting in decreased food consumption (data were not presented by the study
authors). Significantly decreased weight gains were observed in high-dose rabbits during dosing
(GDs 7-20), but no significant differences were observed in absolute body weight compared to
controls (see Table B-17). Significantly altered hematological findings in the high-dose does
included decreased erythrocytes counts, Hb concentration, and Hct and increased platelet,
leukocyte, and reticulocyte counts, compared with controls (see Table B-18). Microscopic
examination of erythrocytes revealed slight-to-moderate anisocytosis, poikilocytosis, and/or
polychromasia in high-dose pregnant rabbits. These findings are suggestive of regenerative
anemia in high-dose does. No hematological changes were observed at 15 or 50 mg/kg-day.
Absolute and relative organ weights (liver, kidney, spleen, and gravid uterus) were not altered by
treatment.
Numbers of litters evaluated were 18, 16, 17, and 15 in the 0-, 15-, 50-, and
150-mg/kg-day groups, respectively. Pregnancy outcomes were not significantly different
between exposed and control groups. In fetuses, a significant increase in the litter incidence of
delayed ossification of the skull was observed at 150 mg/kg-day (6/15 litters, 6/140 fetuses),
compared with controls (0/18 litters, 0/149 fetuses). At 50 mg/kg-day, a nonsignificant increase
in the litter incidence of delayed ossification of the skull was observed (2/17 litters,
2/142 fetuses). No other adverse findings were observed in exposed fetuses.
A maternal and fetal NOAEL of 50 mg/kg-day and a LOAEL of 150 mg/kg-day were
identified based on maternal toxicity (anemia, anorexia) and delayed skull ossification in fetuses.
Inhalation Exposures
The effects of inhalation exposure of animals to 1,2-DCP have been evaluated in five
subchronic-duration studies in three species (Matsumoto et al. 2013; Umeda et al. 2010; Dow
Chemical Co, 1988a; SRI, 1975), two chronic-duration studies in two species (Matsumoto et al,
2013; Umeda et al, 2010), and a reproductive study in female rats (Sekieuchi et al, 2002).
These key studies are summarized in Tables 3 A and 3B and are described in detail below.
Additional information regarding inhalation exposure is available from several acute, short-term,
and limited subchronic- and chronic-duration studies (inadequate reporting and/or study designs)
(see Table 4B).
Subchronic-Duration Studies
Umeda et al. (2010)
Groups of F344/DuCij (SPF) rats (10/sex/group) were exposed to 1,2-DCP vapor
(purity >99.5%) at target concentrations of 0, 125, 250, 500, 1,000, or 2,000 ppm, 6 hours/day,
5 days/week for 13 weeks. Mean analytical concentrations (± standard deviation [SD]) were
measured at 0, 125.3 ± 0.7, 250.8 ± 1.0, 500.5 ± 2.6, 1,000.4 ± 3.4, and 2,001.3 ± 5.9 ppm.
34
1,2-Dichloropropane

-------
FINAL
09-29-2016
Animals were observed daily for clinical signs and mortality. Body weight and food
consumption were measured once a week. All rats, including those found dead or moribund,
received complete necropsy. Blood was collected at terminal necropsy after overnight fasting for
hematology and clinical chemistry (parameters measured were not reported by the study
authors). Organs (unspecified) were removed, weighed, and examined for macroscopic lesions
at necropsy. A complete set of tissues and the entire respiratory tract (including nasal cavity,
pharynx, and larynx) were examined for histopathology in all animals.
A single female from the 2,000-ppm group died during the twelth week of exposure
(cause of death was not reported); no other mortalities or clinical signs of toxicity were observed.
Body weights were significantly reduced by 5-27% in all exposed male groups and by 5-18% in
female groups at >500 ppm; body-weight reductions only exceeded 10% in male and female
groups exposed to 1,000 ppm (see Tables B-19 and B-20). Food consumption was reduced in
both male and female rats exposed to 2,000 ppm (no further information was reported). Minor,
but statistically significant, changes in erythrocyte parameters included 4—19% decreases in
erythrocyte count in males and females at >500 ppm, 3—10% decreases in Hb in males at
>500 ppm and females at >1,000 ppm, and 4—5% decreases in Hct in males and females at
>1,000 ppm (see Tables B-19 and B-20). Additionally, the percentage of reticulocytes was
significantly increased approximately two- to sixfold in males at >1,000 ppm and females at
>500 ppm (see Tables B-19 and B-20). Taken together, reductions in erythrocyte parameters
with concomitant increases in reticulocytes are suggestive of hemolytic anemia. The number of
platelets was also significantly increased by 14—23% in males at >1,000 ppm and females at
2,000 ppm. Significant clinical chemistry alterations included significant 25-56% increases in
total serum bilirubin levels in males at 2,000 ppm and females at >1,000 ppm and significant
-two- to threefold increases in GGT activity in males at 2,000 ppm and females at >1,000 ppm
(see Tables B-19 and B-20).
At necropsy, significant organ-weight changes included increased absolute and relative
liver weights in female rats exposed to >500 ppm and increased relative spleen weight in both
male and female rats exposed to 2,000 ppm, compared with controls (quantitative data not
reported by study authors). Histopathological lesions attributable to exposure were observed in
the nasal cavity, spleen, bone marrow, liver, and adrenal glands (see Tables B-21 and B-22). In
the nasal cavity, hyperplasia of the respiratory epithelium and atrophy of the olfactory epithelium
were observed in all exposed male rats and almost all exposed female rats. Lesion severity
generally increased with increasing concentration in males (nasal hyperplasia and atrophy) and
females (nasal atrophy). Hyperplasia of the respiratory epithelium was characterized by an
increased number of ciliated columnar epithelial cells and accompanied by goblet cell
hyperplasia. The hyperplasia was located diffusely in the dorsal or septum region of Level 1
(anterior nasal cavity). Atrophy of the olfactory epithelium was characterized by decreases in
epithelial thickness and the number of olfactory sensory cells and often accompanied by necrosis
of the olfactory sensory cells and respiratory metaplasia of the olfactory epithelium. Atrophy
was located in the dorsal region of Levels 2 and 3. Inflammation of the respiratory epithelium in
the nasal cavity was also significantly increased in male rats and marginally increased in female
rats at >1,000 ppm. In the spleen, there was a significant increase in hemosiderin deposits and
increased extramedullary hematopoiesis in males and females at >1,000 ppm; hemosiderin
deposits were also significantly increased in females at 500 ppm. Bone marrow hematopoiesis
was also significantly increased in both sexes at >1,000 ppm. In the liver, a significant increase
in the incidence of centrilobular hepatocyte swelling was observed in both male and female rats
35
1,2-Dichloropropane

-------
FINAL
09-29-2016
exposed at 2,000 ppm. Fatty change in the adrenal gland was significantly increased in the
female rats, but not male rats, exposed to 2,000 ppm.
A LOAEL of 125 ppm was identified for nasal lesions in male and female rats; no
NOAEL was identified. Analytical exposure concentrations of 125.3, 250.8, 500.5, 1,000.4, and
2,001.3 ppm were converted to human equivalent concentrations (HECs) of 0, 13.63, 27.28,
54.42, 108.79, or 217.62 mg/m3 and 0, 10.03, 20.09, 40.08, 80.112, or 160.26 mg/m3 for male
and female rats, respectively, for extrathoracic respiratory effects by treating 1,2-DCP as a
Category 1 gas and using the following equation: HECet = (ppm x MW ^ 24.45) x (hours/day
exposed ^ 24) x (days/week exposed ^ 7) x RGDRet.
Dow Chemical Co (1988a) (Rat study)
In an unpublished study, groups of F344 rats (10/sex/group) were exposed to 1,2-DCP
(purity >99.94%) at target concentrations of 0, 15, 50, or 150 ppm 1,2-DCP, 6 hours/day,
5 days/week for 13 weeks. Mean analytical concentrations (±SD) were determined to be 15 ± 1,
50 ± 3, or 151 ± 3 ppm. The fur, eyes, mucous membranes, and respiration of all animals were
evaluated after each exposure. Rats were examined daily for mortality and clinical signs of
toxicity. Body weights were recorded weekly. At ~11 weeks, blood was collected for
hematology (packed cell volume, erythrocyte counts, Hb, total and differential leukocyte counts,
MCV, MCH, MCHC, and platelet counts) and determination of RBC and plasma cholinesterase
activity levels, and urine was collected for urinalysis (specific gravity, pH, glucose, ketones,
bilirubin, urobilinogen, occult blood, and protein). Eyes were examined under fluorescent
illumination, and rats were weighed prior to sacrifice on the day following the last exposure to
1,2-DCP. Rats were fasted for 24 hours after final exposure prior to sacrifice. At sacrifice,
blood was collected for clinical chemistry (total bilirubin, ALT, AST, ALP, BUN, and glucose)
and organ weights (brain, heart, liver, kidneys, thymus, and testes) were recorded. A complete
set of 47 tissues, including the respiratory tract (nasal tissues, larynx, trachea, lungs, and organs
normally present on sections with these organs), was collected for histopathologic examination
in the control and high-exposure groups. The respiratory tract was also examined in low- and
mid-exposure groups.
No mortalities attributed to treatment or clinical signs of toxicity were observed; one
low-exposure male died from hemorrhagic cystitis (considered unassociated to exposure). Body
weights of male rats were significantly reduced by 7-11% throughout the entire exposure period
in the 150-ppm group, with a significant 10% decrease at study termination (see Table B-23).
Females in the 150-ppm group also showed significant body-weight reductions throughout the
study; however, body weights remained within 10% of control and were not significantly
depressed at study termination (see Table B-23). No body-weight effects were observed in the
low- or mid-exposure groups. There were no biologically-relevant, concentration-related
changes in hematology, clinical chemistry, urinalysis, or organ weights. At necropsy, a decrease
in adipose tissue of the abdominal cavity was observed in males at 150 ppm, consistent with
body-weight changes. No other gross observations were considered related to the inhalation of
1,2-DCP.
The only histopathological effects attributable to exposure were observed in the upper
respiratory tract of exposed rats. Lesions of the respiratory epithelium were observed in males
and females from all exposure groups. The incidence and severity of hyperplasia of the
respiratory epithelium increased in a concentration-related fashion, with statistically significant
36
1,2-Dichloropropane

-------
FINAL
09-29-2016
increases in incidences at >50 ppm (see Table B-23). Hyperplasia occurred mainly in the
anterior region of the nasal cavity. Degeneration of the olfactory mucosa was also significantly
increased in males and females at >50 ppm, with increased severity at 150 ppm (see Table B-23).
In the larynx, the incidence of submucosal inflammation was significantly increased in male rats
at 150 ppm only (see Table B-23). All other histopathologic effects were considered
spontaneous in nature and, therefore, not related to exposure.
A LOAEL of 50 ppm was identified for increased incidence of nasal lesions in male and
female rats with a corresponding NOAEL of 15 ppm. Analytical exposure concentrations of 15,
50, and 151 ppm were converted to HECs of 0, 1.6, 5.4, and 16.5 mg/m3 for male rats and 0, 1.2,
4.0, and 12.1 for female rats for extrathoracic respiratory effects by treating 1,2-DCP as a
Category 1 gas and using the following equation: HECet = (ppm x MW ^ 24.45) x (hours/day
exposed ^ 24) x (days/week exposed ^ 7) x RGDRet.
Matsumoto et al. (2013)
Groups of B6D2Fi/Crlj (SPF) mice (10/sex/group) were exposed to 1,2-DCP at
concentrations of 0, 50, 100, 200, 300, or 400 ppm, 6 hours/day, 5 days/week for 13 weeks.
Mean (±SD) analytical concentrations were reported as 0, 50.0 ± 0.3, 100.1 ± 0.8, 200.0 ± 1.2,
300.2 ± 1.4, and 399.9 ± 2.6 ppm, respectively. Animals were observed daily for clinical signs
of toxicity. Body weight and food consumption were measured weekly. At terminal sacrifice,
blood was collected for hematology (RBC and white blood count [WBC], Hb, Hct, MCV, and
platelet count) and blood chemistry (bilirubin, phospholipids, AST, ALT, ALP, and lactate
dehydrogenase [LDH]). All mice that died or were sacrificed were subject to gross necropsy.
Major organs (not specified) were removed, weighed, and examined for gross lesions. A
complete set of tissues, including nasal cavity, pharynx, and larynx, was examined
microscopically for histopathological lesions.
Mortality was significantly increased in males exposed to 400 ppm (see Table B-24),
with 6/10 males dying. Additionally, 2/10 males exposed to 200 ppm and 1/10 females exposed
to 400 ppm died. All male deaths occurred during the first 2 weeks of exposure; no other
mortalities were observed. Body weight was significantly decreased by 9-18% in males exposed
to >200 ppm (see Table B-24). No body-weight effects were observed in females. Food
consumption was decreased during the first week of exposure in males exposed to >200 ppm and
females exposed to >300 ppm (data not provided by the study authors). Mild hemolytic anemia,
characterized by slight but significant decreases (<20%) in erythrocyte parameters (RBC count,
Hb, and Hct) and increased MCV, was observed in males exposed to >50 ppm and females
exposed to >300 ppm (see Table B-25). Significant increases (7-19%) in platelets were
observed in males exposed to >300 ppm and females exposed to 400 ppm (see Table B-25).
Several significant changes were observed in blood chemistry parameters, compared with
control, including increased phospholipid levels in males and females exposed to >300 ppm,
increased ALP in males exposed to >300 ppm, and increased total bilirubin, AST, ALT, and
LDH in males and females exposed to 400 ppm; however, biologically relevant changes
(>twofold) were only observed for AST, ALT, ALP (males only), and LDH in the 400-ppm
group (see Table B-26).
Significant organ-weight changes included a 14-66%> increase in absolute and relative
liver weights in males and females exposed to >300 ppm and a 21—38%> increase in relative
spleen weight in males and females exposed to 400 ppm (see Table B-24). These weight
37
1,2-Dichloropropane

-------
FINAL
09-29-2016
changes were accompanied by increased incidence of histopathological lesions in the liver and
spleen, including swelling of centrolobular hepatocytes in males and females exposed to
>300 ppm; fatty changes, vacuolic changes, mineralization, and necrosis in the liver of males and
females exposed to 400 ppm; and atrophy, increased extramedullary hematopoiesis, hemosiderin
deposits, and megakaryocytes in the spleen of males and females exposed to 400 ppm
(see Table B-27). Lesions attributable to exposure were also observed in the olfactory
epithelium of the nasal cavity in males and females exposed to >300 ppm, including respiratory
metaplasia, atrophy, necrosis, and desquamation (see Table B-28). In mice exposed to 400 ppm,
increased incidence of bone marrow congestion, forestomach hyperplasia, and "ground glass"
appearance in the heart were also observed, compared with control (see Table B-27).
A NOAEL of 200 ppm and a LOAEL of 300 ppm were identified based on increased
incidence of nasal lesions in male and females. The following systemic effects were also
observed at 300 ppm: >10% decreases in body weight in males, >10% decreases in erythrocyte
parameters in males and females, and liver lesions in males and females. For the nasal lesions,
analytical concentrations of 50.0, 100.1, 200.0, 300.2, and 399.9 ppm were converted to HECs of
6.21, 12.43, 24.83, 37.27, and 49.66 mg/m3 for male mice and 5.14, 10.29, 20.55, 30.86, and
41.11 for female mice for extrathoracic (nasal) respiratory effects by treating 1,2-DCP as a
Category 1 gas and using the following equation (U.S. EPA. 1994b): HECet =
(ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week exposed ^ 7) x RGDRet.
Dow Chemical Co (1988a) (Mouse study)
In an unpublished study, groups of B6C3Fi mice (10/sex/group) were exposed to
1,2-DCP (purity >99.94%) at target concentrations of 0, 15, 50, or 150 ppm 1,2-DCP
6 hours/day, 5 days/week for 13 weeks. Mean analytical concentrations (±SD) were determined
to be 15 ± 1, 50 ± 3, or 151 ± 3 ppm. The fur, eyes, mucous membranes, and respiration of all
animals were evaluated after each exposure. Mice were examined daily for mortality and
clinical signs of toxicity. Body weights were recorded weekly. Eyes were examined under
fluorescent illumination and mice were weighed prior to sacrifice on the day following the last
exposure to 1,2-DCP. At sacrifice, blood was collected for hematology (packed cell volume,
erythrocyte counts, Hb, total and differential leukocyte counts, and platelet counts), and organ
weights (brain, heart, liver, kidneys, thymus, and testes) were recorded. A complete set of
48 tissues, including the respiratory tract (nasal tissues, larynx, trachea, lungs, and organs
normally present on sections with these organs) was collected for histopathologic examination in
the control and high-exposure groups. The respiratory tract, liver, gallbladder, kidney, and
thymus were also examined in the low- and mid-exposure groups.
No mortalities due to treatment or clinical signs of toxicity were reported. Body weights
of both male and female mice were comparable to control values throughout the 13-week
exposure period. RBC counts, Hb, and packed cell volume were statistically significantly
decreased for male mice exposed to 15 and 150 ppm; however, changes are not considered
biologically relevant as they were minor (<10%) when compared with control values and were
not observed in female mice. Organ weights and histology did not differ significantly between
the treated and control mice.
Based on a lack of effects, a NOAEL of 150 ppm was identified for male and female
mice. Analytical exposure concentrations of 15, 50, and 151 ppm were converted to HECs of
2.1, 7.3, and 22.2 mg/m3 for male mice and 1.6, 5.6, and 17.1 for female mice for extrathoracic
38
1,2-Dichloropropane

-------
FINAL
09-29-2016
respiratory effects by treating 1,2-DCP as a Category 1 gas and using the following equation
(U.S. EPA. 1994b): HECet = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week
exposed ^ 7) x RGDRet.
Dow Chemical Co (1988a) (Rabbit study)
In an unpublished study, groups of NZW rabbits (7/sex/group) were exposed to 1,2-DCP
(purity >99.94%) at target concentrations of 0, 150, 500, or 1,000 ppm 1,2-DCP 6 hours/day,
5 days/week for 13 weeks. Mean analytical concentrations (±SD) were determined to be
151 ± 3, 502 ± 7, or 1,003 ± 8 ppm. During each exposure period, the fur, eyes, mucous
membranes, and respiration of all animals were evaluated. Rabbits were examined daily for
mortality and clinical signs of toxicity. Body weights were recorded weekly. At ~11 weeks,
blood was collected for hematology (packed cell volume, erythrocyte counts, Hb, total and
differential leukocyte counts, and platelet counts). Eyes were examined under fluorescent
illumination, and rabbits were weighed prior to sacrifice on the day following the last exposure
to 1,2-DCP. At sacrifice, blood was collected again for hematology (see parameters above plus
reticulocyte count) and clinical chemistry (total bilirubin, glutamic pyruvic transaminase
[SGPT], glutamic oxaloacetic transaminase [SGOT], ALP, BUN, and glucose) and testes
weights were recorded (no other organs were weighed). A complete set of 49 tissues, including
the respiratory tract (nasal tissues, larynx, trachea, lungs, and organs normally present on
sections with these organs), was collected for histopathologic examination in the control and
high-exposure groups. The respiratory tract, liver, gallbladder, bone, bone marrow, and spleen
were also examined in low- and mid-exposure groups.
No mortalities due to treatment or clinical signs of toxicity were observed. Body weights
were comparable between exposed and control rabbits. At 11 weeks, statistically significant
hematological findings included 10-25% reductions in erythrocyte count, Hb, and packed cell
volume at >500 ppm in both males and females; erythrocyte count was also significantly
decreased by 10% in males at 150 ppm (see Table B-29). Similar results were reported at
terminal sacrifice, with additional findings of a significant two- to fourfold increase in percent
reticulocytes at >500 ppm in both males and females and a nonsignificant fourfold increase in
nucleated erythrocytes at 1,000 ppm in males only (see Table B-29). None of the clinical
chemistry parameters were affected by exposure. Absolute and relative liver weights were
statistically significantly increased by 21-30%) in male rabbits at >500 ppm, compared with
controls; no other significant organ-weight changes were observed.
Histopathological lesions attributed to exposure were observed only in the bone marrow
and nasal cavity (see Table B-30). Slight-to-moderate bone marrow hyperplasia was
significantly elevated in males at >500 ppm and females at 1,000 ppm. Additionally,
nonsignificant increases were observed in the incidence of increased hemosiderin-laden
macrophages in the bone marrow at 1,000 ppm in both sexes. A marginally significant increase
in the incidence of olfactory epithelium degeneration of the nasal cavity was observed in male
rabbits exposed to 1,000 ppm, compared with controls (p = 0.07), suggesting a potential
treatment-related effect; observed lesions were very slight-to-slight in severity (see Table B-30).
The incidence of nasal lesions in exposed female rabbits was not increased relative to controls
(see Table B-30). All other microscopic changes reported in the rabbits were considered
spontaneous and not related to 1,2-DCP exposure.
39
1,2-Dichloropropane

-------
FINAL
09-29-2016
Based on the lack of respiratory system effects, a NOAEL of 1,003 ppm was identified.
Other effects observed that may not be related to the respiratory system include: bone marrow
hyperplasia and anemia in both sexes and increased liver weight in males. Analytical exposure
concentrations of 151, 502, and 1,003 ppm were converted to HECs of 71, 236, and 471.8 mg/m3
for male rabbits and 66.4, 221, and 441.2 mg/m3 for female rabbits for extrathoracic respiratory
effects by treating 1,2-DCP as a Category 1 gas and using the following equation (U.S. EPA,
1994b): HECi i = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week
exposed ^ 7) x RGDRet.
Chronic-Duration/Carcinogenicity Studies
Umedaetal. (2010)
Groups of F344/DuCij (SPF) rats (50/sex/group) were exposed to 1,2-DCP vapor
(purity >99.5%) at target concentrations of 0, 80, 200, or 500 ppm, 6 hours/day, 5 days/week for
104 weeks. Mean analytical concentrations (±SD) were measured at 0, 80.2 ± 0.5, 200.5 ± 1.3,
and 500.2 ± 2.4 ppm. The animals were observed daily for clinical signs and mortality. Body
weight and food consumption were measured once a week for the first 14 weeks and once every
4 weeks thereafter. All rats, including those found dead or moribund, received complete
necropsy. Blood was collected after overnight fasting for hematology and clinical chemistry
(parameters measured were not reported by the study authors). Organs (unspecified) were
removed, weighed, and examined for macroscopic lesions. A complete set of tissues and the
entire respiratory tract (including nasal cavity, pharynx, and larynx) were examined for
histopathology in all animals.
There were no mortalities due to treatment or clinical signs of toxicity. Food
consumption was similar between groups. Growth was slightly suppressed in male rats in a
concentration-related manner throughout the study, and terminal body weights were statistically
significantly decreased by 11% in males and 8% in females exposed to 500 ppm. The only
hematological change was a 4% decrease in erythrocyte count in female rats at 500 ppm (data
not provided by the study authors). Females in the 500-ppm group also had a statistically
significant increase in GGT (quantitative data not provided by the study authors).
Significant increases in non-neoplastic and neoplastic nasal lesions were observed in
exposed males and females, compared with controls (see Tables B-31 and B-32). Atrophy of the
olfactory epithelium was observed in 96-100% of all exposed rats, compared with 0% of
controls, and severity of the lesion increased with increasing concentration. All exposure groups
also showed a significant increase in squamous cell metaplasia of the respiratory epithelium,
compared with controls. Metaplasia incidences in the 0-, 80-, 200-, and 500-ppm groups were
10, 62, 82, and 98% in males, respectively, and 6, 30, 74, and 92% in females, respectively;
severity increased with concentration in females, but not in males. Incidence of respiratory
epithelium inflammation was also significantly increased in all exposure groups, compared with
controls. Incidences in the 0-, 80-, 200-, and 500-ppm groups were 40, 70, 94, and 94% in
males, respectively, and 20, 60, 78, and 80% in females, respectively; severity of the lesion did
not increase with increasing concentration. Non-neoplastic lesions were located in the dorsal
region of Levels 2 and 3. A significant increase was observed in hyperplasia of the transitional
epithelium in both sexes at >80 ppm and squamous cell hyperplasia in males at >200 ppm and in
females at 500 ppm. The study authors characterized these as preneoplastic lesions. Hyperplasia
of the transitional epithelium was characterized by an increased number of nonciliated cuboidal
epithelial cells in a focal area, and squamous cell hyperplasia was characterized by a thickening
40
1,2-Dichloropropane

-------
FINAL
09-29-2016
of five or more epithelial layers. These lesions were accompanied by hyperplasia of the
submucosal gland. A significant increase in the number of nasal papillomas was observed in
both male and female rats at 500 ppm; tumors were located in the dorsal region at Levels 1 and 2
(anterior region). A rare nasal tumor (esthesioneuroepithelioma) was observed in two males at
80 ppm and one male at 200 ppm; since historical control data show no cases of
esthesioneuroepithelioma, these tumors may be attributable to 1,2-DCP exposure. All other
histopathologic effects were considered spontaneous in nature and, therefore, not related to
1,2-DCP exposure.
A LOAEL of 80 ppm was identified for nasal lesions in male and female rats; no NOAEL
was identified. 1,2-DCP was carcinogenic in both male and female rats under the conditions of
this study, leading to significantly increased nasal tumors in exposed rats relative to controls.
Analytical exposure concentrations of 80.2, 200.5, and 500.2 ppm were converted to HECs of
16.2, 40.54, and 101.1 mg/m3 for male rats and 10.7, 26.75, and 66.71 mg/m3 for female rats for
extrathoracic respiratory effects by treating 1,2-DCP as a Category 1 gas and using the following
equation (U.S. EPA. 1994b): HECet = (ppm x MW ^ 24.45) x (hours/day
exposed ^ 24) x (days/week exposed ^ 7) x RGDRet.
Matsumoto et al. (2013)
Groups of B6D2Fi/Crlj (SPF) mice (50/sex/group) were exposed to 1,2-DCP at
concentrations of 0, 32, 80, or 200 ppm, 6 hours/day, 5 days/week for 104 weeks. Mean (±SD)
analytical concentrations were reported as 0, 32.1 ± 0.2, 80.2 ± 0.4, or 200.5 ±1.2 ppm,
respectively. Animals were observed daily for clinical signs of toxicity. Body weight and food
consumption were measured weekly. At terminal sacrifice, blood was collected for hematology
(RBC and WBC count, Hb, Hct, MCV, and platelet count) and blood chemistry (bilirubin,
phospholipids, AST, ALT, ALP, and LDH). All mice that died or were sacrificed were subject
to gross necropsy. Major organs (not specified) were removed, weighed, and examined for gross
lesions. A complete set of tissues, including nasal cavity, pharynx, and larynx, was examined
microscopically for non-neoplastic and neoplastic lesions.
No changes were observed for survival, clinical signs of toxicity, body weight, or food
consumption in exposed mice, compared with controls. At terminal sacrifice, MCH
concentration was decreased in males exposed to >80 ppm and females exposed to 200 ppm
(data not provided by the study authors); no other hematological or biochemical differences were
observed between exposed and control groups. In males, the absolute kidney weight was
significantly increased by 13-57% in all exposure groups, and the relative kidney weight was
significantly increased by 48% in the 200-ppm group (see Table B-33). The absolute spleen
weight was significantly decreased by 21% in males exposed to 200 ppm, compared with
controls (see Table B-33); however, the study authors attributed this finding to an extremely high
spleen weight in one of the control males. No significant changes were observed in relative
spleen weight in males (see Table B-33). All other organ weights were comparable between
treated and control mice.
Significant increases in non-neoplastic lesions were observed in the kidney and nasal
cavity of exposed mice, compared with controls (see Table B-34). In the kidney, basophilic
changes and cortical mineralization were significantly increased relative to controls in male mice
from all treated groups. Renal lesion incidence did not, however, increase with increasing
exposure concentration. No renal lesions were seen in female mice. In the olfactory epithelium
41
1,2-Dichloropropane

-------
FINAL
09-29-2016
of the nasal cavity, the incidence of atrophy was significantly increased in males exposed to
>80 ppm. In females, atrophy was significantly elevated only at 80 ppm; however, the incidence
of respiratory metaplasia of the olfactory epithelium was significantly increased in females
exposed to 200 ppm. Respiratory metaplasia of the submucosal gland was also significantly
elevated in males and females exposed to 200 ppm.
Significant increases in neoplastic lesions were observed in the lung, Harderian gland,
and spleen of exposed mice, compared with controls (see Table B-35). In the lung, the combined
incidence of bronchiolo-alveolar adenoma or carcinoma was significantly increased in males
exposed to 32 and 200 ppm and females exposed to 200 ppm. A significant,
concentration-related trend was only observed in females. The combined lung tumor incidence
in 200-ppm female mice reportedly exceeded the maximum historical control incidence for this
laboratory, although supporting data were not shown. There was a significant trend for increased
Harderian gland adenomas in male mice, but not females. Incidence was not significantly
greater than controls at any exposure level, but reportedly exceeded historical control values at
200 ppm. In the spleen, the combined incidence of hemangioma or hemangiosarcoma, as well as
the incidence of hemangiosarcoma alone, was significantly increased in males exposed to
200 ppm. However, significant trends were not observed and incidences were reportedly within
the maximum observed in historical control data. Splenic tumors were not increased in females.
Significant increases in neoplastic lesions were not observed in other tissues, including the nasal
cavity.
A NOAEL of 32 ppm and a LOAEL of 80 ppm were identified in male and female mice
for nasal lesions, including increased incidence of atrophy of the olfactory epithelium in both
sexes at 80 ppm and increased respiratory metaplasia of the olfactory epithelium and/or
submucosal gland in both sexes at 200 ppm. Other effects occurring at 32 ppm not necessarily
related to the respiratory system include: increased absolute kidney weight and pathological
changes in males. There was some evidence of carcinogenicity in both male and female mice
under the conditions of this study, the strongest being significant increases in the incidence of
combined bronchiolo-alveolar adenoma or carcinoma in females and Harderian gland adenoma
in males.
For this study, the analytical concentrations of 32.1, 80.2, and 200.5 ppm were converted
to HECs for pulmonary and extrathoracic effects. HECs of 69.2, 173, and 432.0 mg/m3 for
female mice and 0, 77.2, 192, 482.5 mg/m3 for male mice were calculated for pulmonary effects
by treating 1,2-DCP as a Category 1 gas and using the following equation (U.S. EPA. 1994b):
HECpu = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week
exposed ^ 7) x RGDRpu; see Equations 4-28 in U.S. EPA (1994b) for calculation of RGDRpu
and default values for variables. HECs of 4.73, 11.8, and 29.55 mg/m3 for male mice and 4.27,
10.7, 26.67 for female mice were calculated for extrathoracic respiratory effects by treating
1,2-DCP as a Category 1 gas and using the following equation (U.S. EPA. 1994b):
HECet = (ppm x MW 24.45) x (hours/day exposed ^ 24) x (days/week
exposed ^ 7) x RGDRet.
Reproductive/Developmental Studies
Sekisuchi et al. (2002)
Groups of female F344 rats (six to nine/group) were exposed to 1,2-DCP (purity not
reported) at target concentrations of 0, 50, 100, or 200 ppm, 8 hours/day, 7 days/week for
42
1,2-Dichloropropane

-------
FINAL
09-29-2016
approximately 3 weeks. Analytical concentrations were measured at 0, 50.7 ±1.1, 99.9 ± 2.7,
and 200.7 ± 4.4 ppm. Prior to exposure, three consecutive estrous cycles were monitored using a
vaginal smear test. Only rats exhibiting regular cycles were used in the experiment. Daily
body-weight measurements and vaginal smears were collected. Rats were sacrificed after
21-24 days during an estrous stage. At sacrifice, the reproductive organs were removed and the
weights of the ovaries and uterus were measured. The number of ovulated ova and the mass of
the cumulus cells collected from the oviduct were recorded.
No significant changes were observed in body or reproductive organ weights between
exposed and control groups. Estrous cycle parameters show that 1,2-DCP exposure is associated
with increased estrous cycle length and decreased ovulation (see Table B-36). The number of
total cycles lasting >6 days (all rats combined/group) was significantly more at >100 ppm,
compared with controls. Nonsignificant, concentration-related trends toward decreased number
of estrous cycles/rat and increased number of rats with cycles lasting >6 days were observed.
Additionally, the number of ovulated ova was significantly decreased by 35% in rats exposed to
200 ppm compared with controls.
Because the study authors did not evaluate respiratory system effects, a NOAEL and
LOAEL cannot be determined. Reproductive effects were observed at 100 ppm. The analytical
concentrations of 50.7, 99.9, and 200.7 ppm were converted to HECs of 0, 7.58, 14.9, 30.00 for
extrathoracic respiratory effects by treating 1,2-DCP as a Category 1 gas and using the following
equation: HECet = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week
exposed ^ 7) x RGDRet.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Genotoxicity Studies
The genotoxicity of 1,2-DCP has been evaluated in numerous in vitro studies and a
limited number of in vivo studies. Available studies are summarized below (see Table 4A for
more details). In general, the data indicate that 1,2-DCP is not a potent mutagen, but may cause
deoxyribonucleic acid (DNA) damage and clastogenic effects.
Available evidence from in vitro studies indicates that 1,2-DCP is not a strong mutagen.
Some early assays (pre-1985) report that 1,2-DCP was mutagenic to Salmonella typhimurium
strains TA100 and TA1535 at high 1,2-DCP concentrations (>750 |ig/plate) (Haworth et aL.
1983; Carere and Morpurgo. 1981; Principe et aL 1981; De Lorenzo et aL 19771 although
Stolzenberg and Hine (1980) reported that 1,2-DCP was not mutagenic to TA100 at similar
concentrations. Based on more stringent evaluation criteria implemented after 1985, these
findings are not considered evidence of mutagenicity (e.g., responses seen at doses >500 |ig/plate
are disregarded) (Prival andDunkel. 1989). Subsequent assays found only marginal increases
(1,000 |ig/plate), and were therefore considered negative (N I P. 1986; SRI.
1975). 1,2-DCP was not mutagenic in the S. typhimurium strains TA98, TA 1537, TA 1538, or
TA1978 or the Streptomyces coelicolor strain A3 (Prival and Dunkel. 1989; N'l'P. 1986; Carere
and Morpurgo. 1981; Principe et aL. 1981; De Lorenzo et aL. 1977; SRI. 1975). In mammalian
cells (L5178Y mouse lymphoma cells), 1,2-DCP increased the mutation frequency at the TK
locus with metabolic activation; it was not mutagenic without metabolic activation (Mvhr and
Caspary. 1991).
43
1,2-Dichloropropane

-------
FINAL
09-29-2016
1,2-DCP was not mutagenic in in vivo studies. The numbers of pig- a-gene mutations in
RBCs collected from male B6C3Fi mice or gpt mutations in liver samples collected from male
gpt Delta C57BL/6J mice were not significantly increased in mice exposed to 1,2-DCP via
inhalation for 6 hours/day, 5 days/week for 4-6 weeks (Suzuki et aL 2014). 1,2-DCP also did
not cause dominant lethal mutations in S-D rats (Dow Chemical Co, 1989b) or sex-linked
recessive mutations in fruit flies (Drosophila melanogaster) (Kramers et aL, 1991; Woodruff et
aL 1985).
There is some evidence that 1,2-DCP is clastogenic. Although 1,2-DCP did not cause
mitotic recombination in Saccharomyces cerevisiae strain D3 with or without metabolic
activation (SRI, 1975), mitotic recombination was observed in the J). melanogaster wing spot
test (Chroust et at., 2006). Chromosomal aberrations (CAs) and sister chromatid exchanges
(SCEs) were observed in Chinese hamster ovary (CHO) cells both with and without metabolic
activation (Galloway et aL 1987; Von Per Hude et al„ 1987; NTP, 1986). In vivo, micronuclei
(MN) were not induced in reticulocytes or normochromatic erythrocytes from mice exposed to
1,2-DCP via inhalation for 6 hours/day, 5 days/week for 6 weeks (Suzuki et aL 2014).
In vitro, 1,2-DCP did not induce SOS repair in Escherichia coli strain PQ37 or
unscheduled DNA synthesis in human lymphocytes with or without metabolic activation (von
der Hude et al„ 1988; Perocco et al„ 1983). However, DNA damage was observed using the
Comet assay in liver cells obtained from male B6C3Fi mice exposed to 1,2-DCP via inhalation
for 6 hours/day, 5 days/week for 6 weeks (Suzuki et aL 2014). Additionally,
immunohistochemical analysis of surgically resected specimens of human cholangiocarcinoma
cases in print shop workers associated with 1,2-DCP and/or DCM exposure showed increased
DNA double-strand breaks in precursor lesions (biliary intraepithelial neoplasia [BilIN] and/or
intraductal papillary neoplasm of the bile duct [IPNB]), compared with cholangiocarcinoma
cases associated with other causes (e.g., hepatolithiasis) (Sato et aL 2014).
Supporting Human Studies
Several case studies have shown that accidental or intentional exposure to very high
levels of 1,2-DCP via the oral, inhalation, or dermal routes can lead to CNS depression, liver
toxicity, kidney damage, hemolytic anemia, and intravascular coagulation syndrome [Tiaccadori
et al. (2003); l.ucantoni et al. (1992); Imberti et al. (1987); Chiappino and Secchi (1968); Secchi
and Alessio (1968) as cited in Imberti et al. (1990); Di Nucci et al. (1988); Thorel et al. (1986);
Perbellini et al. (1985); Zedda et al. (1900); Po/./.i et al. (1985)1. Contact dermatitis has also
been reported in case studies with occupational exposure to 1,2-DCP (Baruffini et al.. 1989;
Grzywa and Rud/.ki. 1981).
Supporting Animal Toxicity Studies
A number of inadequately reported animal toxicity studies, studies available only from
secondary sources, short-term studies, and studies via other routes (e.g., dermal, injection, etc.)
were identified. Together, these studies identify the liver and kidney as the main targets of
1,2-DCP toxicity; limited evidence also suggests that the spleen may also be a target. Key
findings are summarized below (see Table 4B for additional details).
Supporting Studies for Noncarcinogettic Effects in Animals
Several acute and short-term duration oral and inhalation studies indicate that the liver is
a target of 1,2-DCP toxicity in animals. Histopathological liver damage (e.g., centrilobular
44
1,2-Dichloropropane

-------
FINAL
09-29-2016
swelling and necrosis; fatty degeneration) was observed in rats exposed via gavage to
>500 mg/kg-day for 1-10 days (Bruckner et aL 1989). rats and rabbits exposed to
>300 mg/kg-day via gavage for 13-14 days (Dow Chemical Co. 1989a. 1988c). rats and guinea
pigs exposed to 10,200 mg/m3 for 1-5 daily 7-hour exposures (Highman and Heppel. 1946). and
mice exposed to 1,800 mg/m3 for 7 hours/day for up to 12 exposures (Heppel et al. 1948).
Another short-term inhalation study reported unspecified morphological changes in the
centrilobular region of the liver and increased hepatocyte proliferation were observed in rats
continuously exposed to 500 mg/m3 for 1-2 weeks (Belvaeva et aL. 1977).
Subchronic/chronic-duration inhalation studies considered inadequate due to limited reporting
and/or study design also indicate that the liver is a target organ of 1,2-DCP toxicity; however,
these studies are difficult to interpret due to limitations (Matsumoto et aL. 1982; Sidorenko et aL.
1979; Belvaeva et aL, 1977; Heppel et aL, 1948; Mellon Institute of Industrial Research, 1947a,
b; Heppel and Neal. 1946). Liver damage and altered biochemistry have also been reported in
acute, short-term, and subchronic-duration parental exposure studies (Trevisan et aL, 1991;
Trevisan et aL, 1989; Matsumoto et aL. 1982).
Several acute and short-term duration oral and inhalation studies indicate that the kidney
is a target of 1,2-DCP toxicity in animals. Impaired kidney function (based on biochemical
findings) was reported in rats after a single gavage administration of 930 mg/kg (Imberti et aL.
1990). In short-term gavage studies, gross kidney changes (red renal medullae and pale kidneys)
were reported in rats exposed to 2,000 mg/kg-day, mice exposed to >500 mg/kg-day, and rabbits
exposed to >250 mg/kg-day via gavage for 13—14 days (Dow Chemical Co. 1988c; N'l'P. 1986)
and tubular cell hemosiderosis was observed in rats exposed to >500 mg/kg-day for 10 days
(Bruckner et aL. 1989). However, no histopathological changes were observed in rats exposed
up to 500 mg/kg-day via gavage for 14 days (Dow Chemical Co. 1989a). In inhalation studies,
fatty degeneration of the kidney was reported in rats and guinea pigs exposed to 10,200 mg/m3
for 7 hours/day for up to 5 days (Highman and Heppel, 1946) and in mice exposed to
1,800 mg/m3 for 7 hours/day for up to 12 exposures (Heppel et aL. 1948). Subchronic/chronic
duration inhalation studies considered inadequate due to limited reporting and/or study design
also indicate that the kidney is a target organ of 1,2-DCP toxicity; however, these studies are
difficult to interpret due to limitations (Heppel et aL. 1948; Heppel and Neal. 1946). Kidney
damage and altered biochemistry have also been reported following acute or subchronic-duration
parental exposure (Trevisan et aL. 1988).
One oral and two inhalation studies suggest that the spleen may be a target of 1,2-DCP
exposure. Hemosiderin accumulation and hyperplasia of the hematopoietic elements was
observed in the spleen of rats exposed to >500 mg/kg-day via gavage for 5 or 10 days (Bruckner
et aL. 1989). Hemosiderin accumulation was also observed in rats and guinea pigs following
1-5 daily 7-hour exposures to 2,200 ppm (10,200 mg/m3) (Highman and Heppel. 1946). A
chronic-duration inhalation study in dogs considered inadequate due to limited reporting also
indicates increased hemosiderin accumulation in the spleen following 1,2-DCP exposure;
however, data reporting is inadequate for independent review (Heppel et aL. 1948).
Acute-duration lethality studies with 1,2-DCP report oral median lethal dose (LD50)
values of 487-1,900 mg/kg and 960 mg/kg in rats and mice, respectively (Kennedy and Graepel,
1991; Matsumoto et aL, 1982; Shell Oil Co, 1982; Bio Dynamics. 1981). a 10-hour inhalation
median lethal concentration (LC50) of 480 ppm (1,850 mg/m3) in mice (Dow Chemical Co.
1968). and a 24-hour dermal LC50 > 2,340 mg/kg (Shell Oil Co. 1982). A 4-hour approximate
45
1,2-Dichloropropane

-------
FINAL
09-29-2016
lethal concentration (ALC) (lowest dose causing mortality) was reported as 2,000 ppm
(9,200 mg/m3) in rats (Kennedy and Graepel. 1991). Numerous clinical signs of toxicity were
observed in these acute-duration lethality studies (see Table 4B for details).
Supporting Studies for Carcinogenic Effects in Animals
Carcinogenicity of 1,2-DCP was evaluated in mice in a short-term-duration tumor assay
consisting of 37 exposures to 400 ppm (1,800 mg/m3) followed by a 7-month observation period
(Heppel et aL 1948). While hepatomas were observed in surviving exposed mice, high mortality
(77/88) and a lack of control data preclude drawing any conclusions from this study.
Absorption, Distribution, Metabolism, and Elimination (ADME) Studies
1,2-DCP is readily absorbed following oral, inhalation, or dermal exposure and
distributed throughout the body via the blood, with preferential distribution to body fat (Take et
al.. 2014; Timchalk et aL 1991; Fiserova-Bergerova et al.. 1990). The blood:air partition
coefficients for human and rats are 8.75 ± 0.50 and 18.7 ± 0.5 , respectively (Gargas et al.. 1989).
The EPA calculated a human skin permeability constant of 0.01 cm/hour and a permeability
coefficient of 0.206 cm/hour (U.S. EPA. 1992). Following absorption in rats, 1,2-DCP is rapidly
metabolized and eliminated from the body, generally in <24 hours (Take et al.. 2014; Timchalk
et al.. 1991; Di Nucci et al.. 1990; Trcvisan et al.. 1989; Di Nucci et al.. 1988). The primary
routes of elimination after oral or inhalation exposure include urinary excretion and respiratory
expiration, and the contribution of respiratory expiration increases with increasing
dose/concentration (Timchalk et al. 1991). Following a single oral dose of radiolabeled
1,2-DCP, 90% of the administered radioactivity was shown to be eliminated in urine [Hutson et
al. (1971) as cited in ACGIH (2014a)l. Elimination patterns were similar with single and repeat
oral exposures, indicating that 1,2-DCP is not likely to accumulate in the body with repeated oral
exposures (Timchalk et al. 1991). However, Take et al. (2014) indicated that 1,2-DCP will
concentrate in body fat if the metabolic capacity is exceeded following high acute inhalation
exposure.
The major urinary metabolites of 1,2-DCP in rats include three mercapturic acids:
(A-acetyLY-[2-hyroxypropyl]-/.-cysteine, A'-acetykY-([-ocopropyl]-A-cysteine, and
A/-acetyl-.S'-[ 1 -carboxyethyl]-/,-cysteine) (Timchalk et al. 1991; Battels and Timchalk. 1990;
Jones and Gibson. 1980). Minor metabolites included A'-acetyl-.S'-(2,3-dihydroxypropl )cysteine,
/?-chlorolactaldehyde, and /?-chlorolactate (Jones and Gibson. 1980). It is proposed that
metabolites result from oxidation of the C-l position of the parent compound followed by GSH
conjugation (Battels and Timchalk. 1990). In vitro data support this proposal, indicating that
1,2-DCP is conjugated to GSH following oxidation by human CYP2E1 (Guengerich et al..
1991).
Mode-of-Action/Mechanism Studies
There are very few studies regarding the mechanism(s) of 1,2-DCP toxicity. Proposed
mechanisms of toxicity include GSH depletion and DNA damage subsequent to the generation of
GSH-conjugated reactive metabolites (Sato et al.. 2014; Imberti et al.. 1990).
Imberti et al. (1990) proposed that acute 1,2-DCP toxicity may be mediated by GSH
depletion. Acute oral exposure to high levels of 1,2-DCP (2 mL/kg) resulted in GSH depletion
in the liver and kidney of Wistar rats that was statistically associated with altered clinical
chemistry parameters and hemolysis. Pretreatment with a GSH-depleting agent
46
1,2-Dichloropropane

-------
FINAL
09-29-2016
(buthionine-sulfoximine) increased the mortality of the acute 1,2-DCP dose, while pretreatment
with a GSH precursor (A'-acetylcysteine) prevented GSH depletion and reduced the extent of
injury to target tissues.
Sato et al. (2014) proposed that cholangiocarcinoma observed in printers exposed to
1,2-DCP and/or DCM may be caused by DNA damage in biliary epithelial cells caused by
GSH-conjugated reactive metabolites. In this study, immunohistochemical analysis of surgically
resected specimens of cholangiocarcinoma cases associated with 1,2-DCP and/or DCM exposure
showed increased DNA double-strand breaks in precursor lesions (BilIN and/or IPNB) compared
with cholangiocarcinoma cases associated with other causes (e.g., hepatolithiasis). In printing
company cases, p53 expression was observed in non-neoplastic biliary epithelial cells and BilIN
cellGSHs, and KR.AS and GNAS mutations were detected in foci of BilIN in 1/3 cases. Sato et
al. (2014) also confirmed constitutional expression of GST Tl-1 in the normal hepatobiliary
tract, which is known to catalyze DCM into its reactive intermediates implicated for genotoxic
actions of DCM. Additionally, 1,2-DCP has been shown to damage liver DNA in male B6C3Fi
mice exposed to 1,2-DCP via inhalation for 6 hours/day, 5 days/week for 6 weeks (Suzuki et al..
2014). supporting DNA damage as a possible mode of action (MOA) for liver damage.
Zhang et al. (2015) investigated the effect of 1,2-DCP exposure on the hepatic
distribution of GSTT1, GSTM1, and GSTPi and on the expression of Ki67 (a marker
proliferation). C57BL/6J mice, Balb/cA mice, F344 rats, Syrian hamsters, and guinea pigs for 7
or 14 days (mice and hamsters only). The study authors reported that 1,2-DCP exposure had no
effect on any of the tested parameters.
47
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 4A. Summary of 1,2-Dichloropropane Genotoxicity
Endpoint
Test System
Dose/
Concentration
Results without
Activation3
Results with
Activation3
Comments
References
Genotoxicity studies in prokaryotic organisms
Mutation
Salmonella typhimurium strains TA98,
TA100, TA1535, TA1537, TA1538
0, 10 |iL/platc
(~12 mg/plate)b
+
TA100, TA1535
TA98, TA1537,
TA1538
+
TA100, TA1535
TA98, TA1537,
TA1538
Spot test. A two- to fourfold increase
was observed in the number of
revertants in strains TA100 and
TA1535.
Care re and
Moroureo
(1981);
Principe et al.
(1981)
Mutation
S. typhimurium strains TA100,
TA1535
1-10 nL/plate
(-1-12 mg/plate)b
+
TA100, TA1535
+
TA100, TA1535
Plate incorporation assay.
Care re and
Moroureo
(1981);
Principe et al.
(1981)
Mutation
S. typhimurium strains TA100,
TA1535, TA1978
0, 10, 20,
50 mg/plate
+
TA1535, TA100
TA1978
+
TA1535, TA100
TA1978
Plate incorporation assay. A 21-fold
increase was observed in the number
of revertants in strains TA100 and
TA1535.
De Lorenzo et
al. (1977)
Mutation
S. typhimurium strain TA100
0, 1, 10,
100 |imol/platc
(-113, 1,130,
11,300 (ig/plate)°


Plate incorporation assay.
Cytotoxicity was observed at
100 |imol/platc.
Stolzenberg
and Hine
(1980)
48
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 4A. Summary of 1,2-Dichloropropane Genotoxicity
Endpoint
Test System
Dose/
Concentration
Results without
Activation3
Results with
Activation3
Comments
References
Mutation
S. typhimurium strains TA98, TA100,
TA1535, TA1537
Study 1 (Case
Western Reserve
University): 0, 10,
33, 100,333,750,
1,000, 1,500, 1,667,
3,333, 6,667,
10,000 (ig/plate
Study 2 (EG&G
Mason Research
Institute): 0, 100,
333, 750, 1,000,
1,500 |ig/platc


Preincubation assay. In Study 1,
marginal induction of revertants
(1,667 ng/plate inTAlOO without
metabolic activation. Toxicity was
observed at 10,000 ng/plate. In
Study 2, marginal induction of
revertants (750 ng/plate in TA100
with or without metabolic activation.
Studies reported as positive by
Haworth et al. (1983). but considered
negative by stricter evaluation
criteria used bv Prival and Dunkel
(1989). including disregard for
responses 500 ng/plate.
Prival and
Dunkel
(1989);
Haworth et al.
(1983)
Mutation
S. typhimurium strains TA98, TA100,
TA1535, TA1537
0, 33, 100, 333,
1,000,
2,000 (ig/plate


Plate incorporation assay. Marginal
induction of revertants (1,000 |ig/plate
without metabolic activation in
TA100.
NTP (1986)
Mutation
S. typhimurium strains TA98, TA100,
TA1535, TA1537, TA1538
0, 1, 10, 50, 100,
500, 1,000, 2,000,
3,000, 4,000,
5,000 ng/plate


Plate incorporation assay. Marginal
induction of revertants (
-------
FINAL
09-29-2016
Table 4A. Summary of 1,2-Dichloropropane Genotoxicity
Endpoint
Test System
Dose/
Concentration
Results without
Activation3
Results with
Activation3
Comments
References
Mutation
Streptomyces coelicolor A3
2-100 |iL/platc
(-2-116 mg/plate)b

ND
Spot test and plate incorporation
assay.
Care re and
Morourgo
(1981);
Principe et al.
(1981)
SOS repair
induction
Escherichia Coli PQ37
3-5 concentrations
at half-log intervals
(actual
concentrations not
reported)


Three methods used to determine the
SOS induction: (1) centrifugation
method; (2) subtraction method; and
(3) X-gal method.
von der Hude
et al. (1988)
Genotoxicity studies in nonmammalian eukaryotic organisms
Mitotic
recombination
Saccharomyces cerevisiae D3
0,0.01,0.05,0.1,
0.5%


Cytotoxicity was observed at 0.5%.
1,2-DCP did not cause an increase in
mitotic recombinants at doses that
did not cause toxicity.
SRI (1975)
Mitotic
recombination
(wing spot
assay)
Drosophila melanogaster mwh and
fir3 mutants were exposed to 1,2-DCP
via inhalation for 48 hr.
0, 8.8 ng/L
+
ND
1,2-DCP caused an increase in the
total number of wing spots observed
at 48 hr. Tested dose was the LCso.
Chroust et al.
(2006)
Sex-linked
recessive lethal
mutations
D. melanogaster wild-type males were
exposed to 1,2-DCP for 24 or 96 hr or
2 wk via inhalation; treated males
were mated to new groups of three
unexposed virgin females of the Base
strain at 2-3 d intervals for up to
5 mating cycles.
24 hr: 1,600,
4,800 mg/m3
96 hr: 680,
1,360 mg/m3
2 wk: 680 mg/m3

ND
1,2-DCP exposure did not increase
the number of sex-linked recessive
lethal mutations.
Kramers et al.
(1991)
50
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 4A. Summary of 1,2-Dichloropropane Genotoxicity
Endpoint
Test System
Dose/
Concentration
Results without
Activation3
Results with
Activation3
Comments
References
Sex-linked
recessive lethal
mutations
D. melanogaster males (Base strain)
were exposed to 1,2-DCP for 4 hr via
inhalation or via a single injection;
exposed males were mated to new
groups of unexposed females (Base
strain) at 2-3-d intervals for 3 mating
cycles; mating occurred immediately
after inhalation exposure or 24-48 hr
after injection.
Inhalation 0,
7,200 ppm
Injection 0,
4,200 ppm

ND
1,2-DCP exposure did not increase
the number of sex-linked recessive
lethal mutations.
Woodruff et
al. (1985)
Genotoxicity studies in mammalian cells—in vitro
Unscheduled
DNA synthesis
Human lymphocytes
10~4, 10~3,10~2 M
—
—
No cytotoxicity was observed.
Perocco et al.
(1983)
Mutation
L5178Y mouse lymphoma cells
Without activation
(3 trials):
0-1,000 nL/mL
With activation
(2 trials):
0-100 nL/mL

+
1,2-DCP did not cause an increase in
mutation frequency at the TK locus
at doses up to 750 nL/mL (highest
soluble dose) without activation.
With activation, 1,2-DCP caused
1.6-10-fold increase in mutation
frequency at >10 nL/mL. Doses
>80 nL/mL were lethal.
Mvfar and
Casoarv
(1991)
CAs
CHO cells
Without activation:
0, 1,180, 1,370,
1,580 (ig/mL
With activation:
0, 460, 660,
950 iig/mL
+
+
1,2-DCP induced a >twofold increase
in aberrations/100 cells at
>1,370 |ig/mL without activation and
at >660 |ig/mL with activation.
Gallowav et al.
(1987); NTP
(1986)
SCE
CHO cells
0, 112.7, 376.0,
1,127.0 (ig/mL
+
+
1,2-DCP induced a >twofold increase
in SCE/cell at >376.0 ng/mL with
and without activation.
Gallowav et al.
(1987); NTP
(1986)
51
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 4A. Summary of 1,2-Dichloropropane Genotoxicity
Endpoint
Test System
Dose/
Concentration
Results without
Activation3
Results with
Activation3
Comments
References
SCE
CHO cells
0, 1.0, 3.3,
10.0 mM
+
+
1,2-DCP significantly induced SCEs
at >3.3 mMby 1.6-2.7-fold without
metabolic activation (28 hr) and
1.5-1.8-fold with metabolic
activation (3 hr).
Von Der Hude
etal. (1987)
Cell
transformation
HL-60 cells
0, 200 nM

ND
At 20 hr, cells had 67.7% viability.
Surviving cells were not transformed
into macrophages.
Utsumi et al.
(1992)
Genotoxicity studies in mammals—in vivo
Dominant
lethal
mutagenicity
Male S-D rats (30/group) were
administered 1,2-DCP via drinking
water for 14 wk; exposed males were
then mated to unexposed females;
females were sacrificed 14 d after the
middle of their breeding period and
uteri were examined.
0, 28,91,
162 mg/kg-d


1,2-DCP did not significantly alter
male fertility index, preimplantation
loss, or resorption rate.
Dow Chemical
Co f1989b)
Mutation
Male B6C3Fi mice (8-10/group) were
exposed to 1,2-DCP via inhalation for
6 hr/d, 5 d/wk for 6 wk; blood was
collected at 3 and 6 wk and evaluated
for the Pig-a-gene mutation assay in
RBCs.
0, 150, 300,
600 ppm (TWA: 0,
120, 250,
500 mg/m3)


NA
Suzuki et al.
(2014)
Mutation
Male gpt Delta C57BL/6J mice
(five/group) were exposed to 1,2-DCP
via inhalation for 6 hr/d, 5 d/wk for
4 wk; at 4 wk, animals were sacrificed
and liver samples were assessed for
gpt mutations.
0, 300 ppm
(TWA: 0,
250 mg/m3)


A nonsignificant 32% increase in gpt
mutations was observed.
Suzuki et al.
(2014)
52
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 4A. Summary of 1,2-Dichloropropane Genotoxicity
Endpoint
Test System
Dose/
Concentration
Results without
Activation3
Results with
Activation3
Comments
References
MN
Male B6C3Fi mice (8-10/group) were
exposed to 1,2-DCP via inhalation for
6 hr/d, 5 d/wk for 6 wk; blood was
collected at 6 wk for the MN assays in
reticulocytes and normochromatic
erythrocytes.
0, 150, 300,
600 ppm
(TWA: 0, 120, 250,
500 mg/m3)


NA
Suzuki et al.
(2014)
DNA damage
DNA damage was assessed in cells
obtained from precursor lesions
(BilIN and IPNB) from human
cholangiocarcinoma cases in print
shop workers associated with 1,2-DCP
and/or DCM exposure (n = 8), human
cholangiocarcinoma cases associated
with hepatolithiasis (n = 16), and
conventional IPNB cases (n = 19).
DNA damage was determined using
y-H2AX immunohistochemical
staining.
NR
+
+
DNA double-strand breaks were
observed in IPNB invasive foci in 7/8
cholangiocarcinoma cases associated
with 1,2-DCP and/or DCM exposure,
compared with 7/16 cases associated
with hepatolithiasis and 6/19 cases of
conventional IPNB. DNA
double-strand breaks were observed
in BilIN preneoplastic lesions in 6/8
cholangiocarcinoma cases associated
with 1,2-DCP and/or DCM exposure,
compared with 3/16 cases associated
with hepatolithiasis.
Sato et al.
(2014)
DNA damage
Male B6C3Fi mice (8-10/group) were
exposed to 1,2-DCP via inhalation for
6 hr/d, 5 d/wk for 6 wk; at 6 wk,
animals were sacrificed and DNA
damage in the liver was assessed using
the comet assay.
0, 150, 300,
600 ppm
(TWA: 0, 120, 250,
500 mg/m3)
+
+
1,2-DCP increased the percent tail
intensity in a
concentration-dependent manner,
with significant increases at
>300 ppm.
Suzuki et al.
(2014)
a+ = positive; ± = equivocal or weakly positive; - = negative; ND = no data; NR = not reported.
bDose was converted from [iL/platc to mg/plate based on the density of 1,2-DCP (1.159 g/mL) for comparison purposes.
Dose was converted from |imol/platc to ng/plate based on the density of 1,2-DCP (1.159 g/mL) for comparison purposes.
BilIN = biliary intraepithelial neoplasia; CA = chromosomal aberration; CHO = Chinese hamster ovary; DNA = deoxyribonucleic acid; fir3 = flare; HL-60 = human
leukemia; IPNB = intraductal papillary neoplasm of the bile duct; LC50 = median lethal concentration; MN = micronuclei; mwh = multiple wing hairs; NA = not
applicable; RBC = red blood cell; SCE = sister chromatid exchange; S-D = Sprague-Dawley; TWA = time-weighted average.
53
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Supporting evidence—noncancer effects in animals following oral exposure
Acute3 (oral)
The LD5o was determined in groups of
rats. No further details were provided.
ND
LD50 = 1,900 mg/kg
Kennedy and
Graeoel (1991)
Acute (oral)
Groups of male Wistar rats
(5-12/group/time-point) were given
1,2-DCP dissolved in corn oil (40% v/v)
at a volume of 2 mL/kg via gavage.
Based on the density of 1,2-DCP
(1.159 g/mL), the administered dose was
~2 g/kg. Rats were sacrificed 24, 48, and
96 hr later. Serum ALP, ALT, AST,
GGT, 5'-nucleotidase, urea, creatinine,
and glucose were measured. Blood was
evaluated for hemolysis. GSH and
GSSG levels were measured in the liver,
kidney, and blood.
Serum ALT, AST, 5'-nucleotidase, urea, and creatinine
and hemolysis were significantly increased in exposed rats
at 24 hr postexposure, and serum ALP and GGT were
significantly increased in exposed rats at 48 hr
postexposure. GSH was decreased in the liver, kidney, and
blood 24 hr postexposure; no change was observed in
GSSG levels. Several indices of liver and kidney damage
were correlated with GSH depletion in the liver and
kidney, respectively. All values returned to control levels
by 96 hr.
Treatment with the GSH precursor, Y-acctylcystcinc. 2 and
16 hr after 1,2-DCP exposure reduced GSH depletion and
led to a more rapid restoration of control levels of GSH by
48 hr.
Based on biochemical
indicators, the administered
dose of ~2 g/kg is a
LOAEL for impaired liver
and kidney function. Data
indicate that these effects
are caused by GSH
depletion.
Imberti et al.
(1990)
Acute (oral)
Groups of male S-D rats were given a
single dose of 1,2-DCP at doses of 0,
100, 250, 500, or 1,000 mg/kg via
gavage (6-8/group). Endpoints
evaluated included clinical signs, body
weight, serum chemistry, urinalysis, liver
and kidney weight, histology (liver,
kidney, lungs, brain, adrenals, spleen,
stomach, testis, and epididymis).
Transient CNS depression and dose-related body-weight
depression were observed in exposed animals (data not
reported). Serum SDH was significantly elevated by
sevenfold at 1,000 mg/kg. Hepatic nonprotein sulfhydryl
levels were significantly decreased by 62% at 1,000 mg/kg.
In contrast, a significant 42-65% increase in nonprotein
sulfhydryl levels was observed in the kidney at
>250 mg/kg.
Slight to moderate cytoplasmic condensation was observed
in centrilobular hepatocytes at >500 mg/kg.
NOAEL: 250 mg/kg
LOAEL: 500 mg/kg (liver
and spleen effects)
Bruckner et al.
(1989)
54
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute (oral)
Groups of Wistar rats (5/group), were
given single dose of 1,2-DCP at doses of
0 or 55 mg/kg via gavage in propylene
glycol. Rats were sacrificed 4, 8, 24, 72,
and 144 hr after treatment. Endpoints
evaluated included liver weight and liver
biochemistry (GSH, thiobarbituric acid
reactants, and total protein levels).
No changes were observed in liver weight at any
time-point. Total protein and GSH levels were
significantly reduced by 23-29 and 45-96%, respectively,
at all time-points evaluated. Based on levels of
thiobarbituric acid reactants, lipid peroxidation was
significantly increased by 72% at 72 hr and 51% at 144 hr
after treatment, compared with control. Levels at 4-24 hr
postexposure did not differ relative to controls.
Data are consistent with
mechanistic studies
reporting lipid peroxidation
and/or GSH depletion
following exposure to
1,2-DCP.
Di Nucci et al.
(1988)
Acute (oral)
Groups of ddY male mice (number
unspecified) were administered 1,2-DCP
in olive oil to determine LD5o (dose and
route unspecified). Toxicity was
monitored for 24 hr prior to sacrifice and
gross necropsy. Additional groups of
mice (number unspecified) were
administered 1,2-DCP at 5 and 10% of
the LD50. After 24 hr, blood was
collected for analysis of liver function
(AST, ALT, and cholinesterase).
The LD50 was determined to be 960 mg/kg. At necropsy,
peeling of the mucous membrane and bleeding were noted
in the stomach and intestines. No gross pathological
changes were noted for brain, cerebellum, lung, liver, or
kidney.
AST, ALT, and cholinesterase were increased following a
single administration of 10% of the LD50 (quantitative data
not reported). It is unclear if control animals were
evaluated.
Oral LD50 = 960 mg/kg
Available data are
inadequate to make a
NOAEL/LOAEL
determination based on
liver function.
Matsumoto et
al. (1982)
[abstract only]
Acute (oral)
Groups of Wistar rats (six/sex/group)
were given single doses of 1,2-DCP at
doses of 145, 230, 366, 582, 926, or
1,472 mg/kg via gavage (undiluted).
Rats were observed for mortality and
clinical signs of toxicity for 14 d.
100% mortality at 1,472 mg/kg, >8/12 died at >582 mg/kg;
clinical signs included cyanosis, gait abnormalities,
lethargy, increased salivation and/or lacrimation, and
discolored urine.
Oral LD50 (95% CI) = 487
(387-613) mg/kg
Shell Oil Co
(1982)
55
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute (oral)
Groups of rats (five/sex/group) were
administered 1,2-DCP at doses of 1,000,
1,470, 2,150, 3,160, 4,680, 6,810, or
10,000 mg/kg via gavage (no vehicle).
Rats were observed for 14 d prior to
sacrifice. Endpoints evaluated included
mortality, clinical signs, body weight,
and gross necropsy.
Mortality was 2/10, 3/10, 8/10, 10/10, 10/10, 10/10, 10/10
in the 1,000-, 1,470-, 2,150-, 3,160-, 4,680-, 6,810-, or
10,000-mg/kg groups, respectively. Time-to-death was
dose-related, with the majority of deaths occurring within
24 hr. Clinical signs of toxicity on the day of dosing
included ataxia, hypopnea, hypoactivity, prostration,
hypothermia, wet rales, and oral, nasal, or ocular discharge.
Clinical signs persisted for up to 6 d. Most surviving
animals showed weight losses at 7 d, which recovered by
14 d. No adverse changes were observed at necropsy in
animals sacrificed at 14 d; animals that died showed a
variety of changes in the lungs and gastrointestinal tract
(unspecified).
Male: LD5o
(95% CI) = 1,100
(800-1,700) mg/kg
Female: LD50
(95% CI) = 1,800
(1,200-2,400) mg/kg
Combined: LD5o
(95% CI) = 1,600
(1,300-1,900) mg/kg
Bio Dynamics
(1981)
Short-termb (oral)
Groups of male S-D rats (six to
eight/group/time-point) were given
1,2-DCP at doses of 0, 100, 250, 500, or
1,000 mg/kg-d via gavage in corn oil for
up to 10 d (six to
eight/group/time-point). Endpoints
evaluated included clinical signs, body
weight, serum chemistry, urinalysis,
histology (liver, kidney, lungs, brain,
adrenals, spleen, stomach, testis,
epididymis).
Transient CNS depression and dose-related body-weight
depression were observed in exposed animals (data not
reported). Various biochemical changes were observed in
exposed animals, including elevated bilirubin levels at
>250 mg/kg-d and elevated serum BUN at 1,000 mg/kg-d
at both time-points, elevated SDH at 1,000 mg/kg-d at 5 d,
and increased serum ALT at 1,000 mg/kg-d at 5 d. Hepatic
nonprotein sulfhydryl levels were significantly decreased
at >250 mg/kg-d after 5 d and at 1,000 mg/kg-d after 10 d.
In contrast, significantly increased nonprotein sulfhydryl
levels were observed in the kidney at >250 mg/kg-d at both
time-points. Histopathological findings attributed to
exposure in rats treated at >500 mg/kg-d (incidence data
not reported) included slight-to-moderate toxic hepatitis,
tubular cell hemosiderosis, and splenic hemosiderosis and
hyperplasia of the hematopoietic elements of the red pulp.
NOAEL: 250 mg/kg
LOAEL: 500 mg/kg (liver,
kidney, and spleen effects)
Bruckner et al.
(1989)
56
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Short-term (oral)
Groups of F344/N rats (five/sex/group)
were administered 1,2-DCP at doses of 0,
125, 250, 500, 1,000, or 2,000 mg/kg-d
via gavage in corn oil, 5 d/wk for 14 d.
Endpoints evaluated included clinical
signs, body weight, and gross necropsy.
100% mortality was observed at 2,000 mg/kg-d. Body
weights were significantly reduced by 14% in males at 500
and 1,000 mg/kg-d and nonsignificantly reduced by 15% in
females at 1,000 mg/kg-d (Student /-test performed for this
review). The only finding at gross necropsy attributed to
exposure was red renal medullae reported in 4/5 males and
5/5 females at 2,000 mg/kg-d.
NOAEL: 250 mg/kg-d
LOAEL: 500 mg/kg-d
(J, body weight in males)
NIP (1986)
Short-term (oral)
Groups of B6C3Fi mice (five/sex/group)
were administered 1,2-DCP at doses of 0,
125, 250, 500, 1,000, or 2,000 mg/kg-d
via gavage in corn oil, 5 d/wk for 14 d.
Endpoints evaluated included clinical
signs, body weight, and gross necropsy.
Increased mortality was observed in males at
>500 mg/kg-d (60-100%) and females at >1,000 mg/kg-d
(80-100%). Body-weight effects were not observed in
surviving mice. The only finding at gross necropsy
attributed to exposure was red renal medullae in 60-100%
of mice at >500 mg/kg-d.
NOAEL: 250 mg/kg-d
FEL: 500 mg/kg-d
(t mortality in males)
NIP (1986)
Short-term (oral)
Groups of NZW rabbits (two
females/group) were administered
1,2-DCP at doses of 0, 250, 500, or
1,000 mg/kg-d via gavage in corn oil for
13 d. Endpoints evaluated included
clinical signs, body weight, gross
necropsy, and histology of liver, kidney,
and all gross lesions.
Increased mortality was observed (2/2 high dose; 2/2 mid
dose; 1/2 low dose, 0/2 controls). Clinical signs of toxicity
(lethargy, ataxia, anorexia) and hepatic necrosis were
increased at >500 mg/kg-d, compared with control.
"Some" exposed rabbits had pale kidneys associated with
dilation of the collecting ducts/renal tubules.
An apparent FEL of
250 mg/kg-d is identified
for increased mortality;
however, interpretation of
data is limited based on
small animal groups.
Dow Chemical
Co (1988c)
Short-term (oral)
Groups of F344 rats (10/sex/group) were
administered 1,2-DCP at doses of 0, 300,
or 500 mg/kg-d via gavage for 14 d.
Endpoints evaluated included clinical
signs, body weight, FOB, motor activity,
hematology, organ weights (liver,
kidney, and spleen), gross necropsy, and
histology of liver and kidney.
Significant findings attributed to treatment included
transient clinical signs at >300 mg/kg-d (increased
lacrimation and blinking, decreased respiration, lethargy);
decreased terminal body weight (11-18% in males at
>300 mg/kg-d; 6% in females at 500 mg/kg-d group);
increased liver and kidney weights at >300 mg/kg-d; and
mild histopathological changes in the liver of exposed
males and females, including prominent nucleoli of
hepatocytes in the centrilobular region of the hepatic lobule
(80-100% incidence at >300 mg/kg-d) and degeneration
and necrosis of individual hepatocytes (-50% incidence at
>300 mg/kg-d).
NOAEL: not identified
LOAEL: 300 mg/kg-d
(clinical signs of toxicity,
increased liver weight,
hepatic lesions, | body
weight in males).
Dow Chemical
Co (1989a)
57
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Short-term (oral)
Groups of ddY mice (number and sex not
specified) were administered 1,2-DCP at
doses of 400-600 mg/kg-d via gavage in
olive oil for 30 d. It is unclear if a
control group was used. Endpoints
evaluated included body weight, clinical
chemistry (liver function), and histology
(brain, cerebellum, lung, stomach,
intestine, liver, kidney).
No body-weight effects were noted. Fatty degeneration of
the liver was observed in treated mice (dose not reported).
No changes in liver function were detected with clinical
chemistry.
Available data are
inadequate to make a
NOAEL/LOAEL
determination.
Matsumoto et
al. (1983)
[abstract only]
Supporting evidence—noncancer effects in animals following inhalation exposure
Acute (inhalation)
The ALC, or the concentration at which
mortality was first observed following a
4-hr exposure, was determined in rats.
No further details were provided.
Effects due to exposure of 1,2-DCP were not reported.
ALC (4-hr) = 2,000 ppm
(9,200 mg/m3)
Kennedy and
Graeoel (1991)
Acute (inhalation)
Groups of Wistarrats (10 males/group)
were given a single 4-hr inhalation
exposure to 1,2-DCP at concentrations of
0, 15, 50, 100, 250, 450, 1,000, 1,300, or
4,900 mg/m3; rats were sacrificed
immediately or 20 hr after exposure
ceased. Endpoints evaluated included
blood serum chemistry (ALP, ALT,
AST) and liver biochemistry (GSH,
thiobarbituric acid, and total protein).
No adverse changes were observed in serum biochemistry,
total liver protein content, or lipid peroxidation (as
determined by thiobarbituric acid levels). Liver GSH
concentration was significantly reduced at concentrations
>100 mg/m3 immediately after exposure, although findings
were not concentration-dependent (decreased 24, 62, 43,
33, and 28% at 100, 250, 450, 1,000, 1,300, and
4,900 mg/m3, respectively). After 20 hr, GSH
concentration was significantly increased by 23-26% at
concentrations >1,300 mg/m3.
Data are consistent with
mechanistic studies
reporting GSH depletion
following exposure to
1,2-DCP.
Di Nucci et al.
(1990)
Acute (inhalation)
Groups of mice (10-30/group, sex and
species not specified) were exposed to
300, 380, 390, 700, 715, and 1,625 ppm
for 10 hr. Mortality was assessed during
exposure and postexposure (undefined
period).
Mortality during exposure was 0/30, 1/10, 2/20, 5/10,
11/30, and 9/10 in the 300-, 380-, 390-, 700-, 715-, and
1,625-ppm groups, respectively. Total mortality (during
exposure + postexposure observation period) was 2/10,
11/20, 7/10, 30/30, and 10/10.
LC50 (10-hr) = 480 ppm
(1,850 mg/m3)
Dow Chemical
Co (1968)

58
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute (inhalation)
S-D rats and "stock" guinea pigs
(33/species, sex unspecified) were given
a single 7-hr exposure to 2,200 ppm.
The control group contained three
unexposed animals/species. Animals
were sacrificed at intervals (two to
five/time-point) up to 14 d for rats and
21 d for guinea pigs and subjected to
gross necropsy. Tissues (unspecified)
were fixed for histologic examination.
Rats: Transient hepatic effects were observed 1-4 d after
exposure (fine droplet fatty degeneration, centrilobular
necrosis, marked glycogen depletion, and hemosiderin in
Kupffer cells). Depletion of the lipoid material of the
adrenal cortex was also observed immediately and 1 d after
exposure.
Guinea pigs: Transient hepatic effects were observed 1-4 d
after exposure (centrilobular swelling, altered glycogen
content). Necrosis of the adrenal glands was observed in
all exposed guinea pigs at all time-points.
2,200 ppm (10,200 mg/m3)
is a free-standing LOAEL
in both species (liver and
adrenal lesions)
Highman and
Hennel (1946)
Acute/short-term
(inhalation)
Groups of rats, guinea pigs, and rabbits
(2-13/group) were exposed to 0 or
1,600 ppm (7,400 mg/m3) for 7 hr for 1
or 5 d.
Single exposure:
Mortality: 3/12 rats, 0/6 guinea pigs, 0/2 rabbits;
Rats showed incoordination towards the end of the 7 hr
exposure. No clinical signs of toxicity were observed in
guinea pigs or rabbits.
5-d exposure:
Mortality: 0/13 rats, 0/10 guinea pigs, 1/2 rabbits;
Rats and guinea pigs showed weight loss during exposure
period, which recovered after exposure ceased.
A NOAEL/LOAEL
determination could not be
made due to lack of control.
Hennel and
Neal (1946)
59
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute/short-term
(inhalation)
Groups of S-D rats and "stock" guinea
pigs (three to six/group/species; sex
unspecified) were exposed to 2,200 ppm
for 7 hr/d for 1-5 d; and additional
3 animals/species were given a single
4-hr exposure to 2,200 ppm. The control
group contained 6 unexposed rats. Rats
were sacrificed immediately after
exposure and subjected to gross
necropsy. Tissues (unspecified) were
fixed for histologic examination.
Rats: Fatty degeneration and hepatic centrilobular necrosis
were observed, with increased lesion severity with repeated
exposure. Fatty degeneration in the kidney was increased
with 1-3 d of exposure, but was minimal after 4-5 d of
exposure. Depletion of the lipoid material of the adrenal
cortex was observed within 1-3 d of exposure.
Hemosiderin was observed in the spleen after 4-5 d of
exposure.
Guinea pigs: Fatty degeneration of the liver was observed
with 1-3 d of exposure, but was minimal after 4-5 d of
exposure. Fatty degeneration was also observed in the
kidney. In the adrenal gland, cortical necrosis and
congested medulla were observed in all exposed animals,
increasing with severity with repeated exposure. Cortical
hyperplasia was also observed following 3-4 d of
exposure.
Rat: 2,200 ppm
(10,200 mg/m3) is a
free-standing LOAEL
(liver, kidney, spleen, and
adrenal lesions)
Guinea pig: 2,200 ppm
(10,200 mg/m3) is a
free-standing LOAEL
(liver, kidney, and adrenal
lesions)
Highman and
Hennel (1946)
Short-term
(inhalation)
Groups of rats, mice, guinea pigs and
rabbits (4-20/species/group) were
exposed to 2,200 ppm (10,000 mg/m3)
for 7 hr/d for up to 8 d.
Mortality: 8/20 rats, 10/11 mice, 11/15 guinea pigs,
2/4 rabbits;
Clinical signs of toxicity observed in rats, mice, and guinea
pigs included gross incoordination, prostration, shallow
and labored respiration, crusting around nose, and rough
coat. Guinea pigs also had severe conjunctival swelling.
Rabbits did not show clinical signs of toxicity.
The single exposure
concentration of 2,200 ppm
(10,000 mg/m3) was an
FEL for all species tested.
Hennel and
Neal (1946)
Short-term
(inhalation)
18 C57 mice (sex unspecified) were
exposed to 400 ppm for up to
12 exposures (7 hr/exposure, exposure
schedule not reported); five unexposed
controls were used for comparison in
"histologic" examinations.
Two mice died during the first exposure, and an additional
eight mice died within 48 hr of the first exposure. Slight
fatty degeneration of the liver was observed in five of eight
mice that died within the first 2 d. Slight fatty
degeneration of the kidney was observed in one of two
mice sacrificed after the second exposure. No further
information was provided.
The only exposure level
(400 ppm; 1,800 mg/m3) is
an apparent FEL for
mortality.
Hennel et al.
(1948)
60
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute/short-term/
subchronic0
(inhalation)
Groups of rats (noninbred albino, sex
unspecified) were continuously exposed
to 1,2-DCP at concentrations of 0 or
2.2 mg/L for 20 hr or 3 d (four to
seven/group); 0 or 1.1 mg/L for 1 wk
(2 exposed, 13 control); 0, 0.1, or
0.5 mg/L for 2 wk (three to four/group);
or 0, 0.00045, 0.0017, or 0.009 mg/L for
3 mo (four to six/group). At the end of
exposure, rats were sacrificed and the
liver was examined for morphological
changes and percentages of hepatocytes
of different ploidy were determined.
Morphological changes (unspecified) were observed in the
livers of rats exposed for 1 or 2 wk, with most severe
damage in the centrolobular region. Lesions were also
observed in rats exposed to lower concentrations for 3 mo
(incidence data not provided). Histopathological findings
from the 1- and 3-d studies were not reported. No liver
lesions were observed in any control rats.
Increased intermediate ploidy of hepatocytes (indicative of
proliferation) was observed following exposure to
2.2 mg/L for 1 or 3 d, 1.1 mg/L for 1 wk, or >0.1 mg/L for
2 wk. In the 3-mo study, the percentages of hepatocytes of
different ploidy were comparable to control.
An acute/short-term
LOAEL of 0.5 mg/L
(500 mg/m3) was identified
for liver damage.
A subchronic
NOAEL/LOAEL
determination could not be
made due to inadequate
data reporting.
Bclvacva et al.
(1977)
Short-term/
subchronic
(inhalation)
Male white rat (strain and number not
specified), were exposed to 9, 100, 500,
1,000, or 2,000 mg/m3 via inhalation for
up to 7 d with high concentrations (1,000
and 2,000 mg/m3) or up to 86 d with
lower concentrations. It is unclear if
exposure was continuous or for limited
periods during the day. Endpoints
evaluated included body weight, serum
catalase activity, blood cholinesterase
activity, and hematology at various
points during exposure. At the end of the
experiment, liver and lungs were
removed for histology and electron
microscopy (lungs only), and the content
of RNA and activity of oxidizing
enzymes in the organs were evaluated.
Increased catalase and cholinesterase activity were reliable
markers of exposure to 1,2-DCP, with the latency to
statistically significant changes decreasing with increasing
concentrations. Enzyme activity changes were phasic
response with high concentrations: enzyme activity
increased and dropped within first 2-3 d of exposure.
Histopathological effects in the lungs were observed at all
exposure levels, including increased macrophages, edema,
and accumulation of osmiophilic corpuscles in alveolar
cells. Histopathological effects in the liver included
degranulation of cloudy cells with occasional degeneration.
Oxidizing enzymes in the lungs (SDH, NAD,
NADPH-diaphorase, DDG, T-6-phDG [the last two
enzymes were not defined in the paper and these acronyms
are not currently in common usage]) were increased at low
concentrations and suppressed at 2,000 mg/m3; SDH and
T-6-phDG were suppressed in the liver at 9 mg/m3 (effects,
or lack thereof, unclear at higher concentrations).
Inadequate methods
reporting and lack of a
control group preclude a
NOAEL/LOAEL
determination.
Sidorenko et al.
(1979)
61
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Subchronic
(inhalation)
Rats, mice, guinea pigs, and rabbits were
exposed to 1,2-DCP at concentrations of
0 or 1,500 ppm 7 hr/d, 5 d/wk for up to
2 mo. Animal numbers ranged from
4-22/group per species. Endpoints
examined included clinical signs, body
weight, hematology, clinical chemistry,
and gross necropsy. Sections of the liver
and spleen were examined for
hemosiderin and sections of the heart,
liver, and kidney were stained for fat.
Rats: Mortality was 40% (8/18) in the exposed group,
compared with 7% (1/14) in the control group. Transient
clinical signs of toxicity (unsteadiness) were observed
during the exposure periods. Growth was "adversely
affected." Slight centrolobular fatty degeneration of the
liver and increased hemosiderin in the spleen were
observed in exposed animals.
Mice: All exposed mice (22/22) died during the first
exposure period. Liver and kidney damage, including fatty
degeneration and centrolobular congestion, were observed
in several of the mice that died.
Guinea pigs: Mortality was 28% (5/18) in the exposed
group, compared with 4% (1/25) in the control group.
Transient clinical signs of toxicity (drowsiness) were
observed during the exposure periods. Growth was
"adversely affected." Necrosis in the adrenal gland and
liver and fatty degeneration of the liver and kidney were
observed in exposed animals.
Rabbits: Mortality was 25% (1/4) in the exposed group,
compared with 0% (0/4) in the control group. No
histopathological changes attributable to exposure were
reported.
The only exposure level
(1,500 ppm) is an apparent
FEL for all species;
however, reporting of study
design and results are
inadequate for independent
review.
Hiehtnan and
Hennel (1946)
62
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Chronicd
(inhalation)
Rats, mice, guinea pigs, rabbits, and dogs
(adults and puppies) were exposed to
1,2-DCP at concentrations of 0 or
1,000 ppm 7 hr/d, 5 d/wk for up to
4-6 mo. Animal numbers ranged from
2-45/group per species. Endpoints
examined included clinical signs, body
weight, hematology, and clinical
chemistry. Gross necropsy was
performed, but was only reported for
rabbits and dogs.
Rats: Mortality was 55% (25/45) in exposed rats, compared
with 3% (1/37). Transient clinical signs of toxicity
(unsteadiness) were observed in all animals during initial
exposure periods. Body-weight gain in the exposed rats
was decreased by 73-80% during the first 2 mo of
exposure, compared with unexposed controls; body-weight
data were not reported for Mo 3 and 4. Average daily food
intake was also decreased by 41% in exposed rats.
Mice: All exposed mice (26/26) died during the first
exposure period.
Guinea pigs: Mortality was 25% (3/12) in exposed rats,
compared with 7% (1/14). Transient clinical signs of
toxicity (drowsiness) were observed in all animals during
initial exposure periods. No body-weight effects were
noted.
Rabbits: There were no mortalities in exposed (0/4) or
control (0/4) animals. No adverse effects were observed.
Dogs: Mortality was 60% (3/5) for exposed adult dogs and
50% (1/2) for exposed puppies, compared with 0% (0/3)
for adult controls. Clinical signs of toxicity included
lethargy, vomiting, and severe anorexia. All dogs that died
showed moderate to marked fatty degeneration of the liver
and convoluted tubules of the kidney. Two also showed
marked fatty degeneration and lipoid depletion of the
adrenal cortex. These lesions were not observed in
surviving dogs or controls.
The only exposure level
(1,000 ppm) is an apparent
FEL for rats, mice, guinea
pigs, and dogs. The same
exposure level (1,000 ppm)
was an apparent NOAEL
for rabbits. However,
reporting of study design
and results are inadequate
for independent review.
Henoel and
Neal (1946)
63
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Chronic
(inhalation)
Rats, "young" guinea pigs, "mature"
guinea pigs, and dogs were exposed to 0
or 400 ppm 7 hr/d, 5 d/wk for a total of
128-140 exposures (~6 mo). Animal
numbers ranged from 5-26/sex/group
per species. Animals were observed for
mortality and clinical signs, and body
weight was monitored throughout the
study (details not provided). The
majority of surviving animals were
sacrificed immediately after the exposure
period for pathological examination (no
further details were provided). Recovery
groups (10-21 rats/group, 5-7 guinea
pigs/group) were maintained for 6-8 mo
postexposure prior to sacrifice.
Rats: Mortality was 6% (3/49) in exposed rats, compared
with 0% (0/30) in the controls. Terminal body weights
were decreased by 11-15% in exposed rats. The only
pathological finding attributed to exposure was
hemosiderin deposition in the liver, predominantly in the
Kupffer cells, in 24/49 exposed rats.
Guinea pigs: Survival and body weights were similar
between exposed and control groups. Histopathological
lesions attributed to exposure included minimal fatty
changes in the heart, liver, and kidney, and
slight-to-moderate hemosiderosis of the spleen and adrenal
gland (incidence data were not reported; it is unclear if
these changes were observed in young or mature animals).
After 134 exposures, 2/12 guinea pigs had extensive renal
fibrosis, amyloidosis, and only a small amount of normal
renal parenchyma. Tubular atrophy and fatty degeneration
were apparent in areas; dilated tubules contained
eosinophilic hyaline and Hb casts. "Several" additional
exposed and control animals experienced similar, but less
marked, kidney effects.
Dogs: No changes in mortality, clinical signs, or body
weight were observed between exposed and control dogs.
Hemosiderosis was observed in the spleen of 5/5 exposed
dogs and liver of 1/5 exposed dogs. Scattered
granulomatous lesions in the kidney were also observed in
2/5 dogs, and 1/5 dogs showed a large calcified area in the
adventitia of the aorta. Lesion incidences were not
reported for control dogs.
The single concentration
tested (400 ppm) is an
apparent LOAEL for rats
and dogs, based on
decreased body weight and
liver lesions in rats and
spleen lesions in dogs. The
same concentration is an
apparent NOAEL for
guinea pigs, based on a lack
of adverse pathological
changes. However, data
reporting is inadequate for
independent review.
Henoel et al.
(1948)
64
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Chronic
(inhalation)
Groups of S-D rats (12/sex/group) and
mongrel dogs (one male/group) were
exposed to 1,2-DCP at concentration of 0
or 200 ppm 7 hr/d every other day for
6 mo (75 total exposure d). Due to an
infection of the rat colony, replacement
rats (1-4/sex/group) were added
(receiving a maximum of 45 exposures).
Endpoints examined included body
weight and length, hematology, clinical
chemistry (dogs only), liver and kidney
weight and length, and histological
examination of the adrenal gland, kidney,
liver, lung, spleen, testis, and nervous
tissue (dogs only).
Rats: A lung infection in the colony led to a high number
of deaths prior to the thirtieth exposure. The total mortality
rate was 55 and 57% in the exposed and control group,
respectively. Body weights in the exposed group were
generally within 10% of controls. No adverse
hematological changes were observed. No adverse
changes were observed for liver or kidney weight. Major
pathology of the kidney, liver, or lung was observed in
-50% of the animals, with similar incidence in exposed
and control groups.
Dogs: Both dogs survived until terminal sacrifice. The
male dog exposed to 1,2-DCP had no functional testes and
showed a trend toward obesity, confounding assessment of
any potential body-weight effects of 1,2-DCP exposure.
Liver and kidney function tests and hematology values
were generally within normal limits. Cloudy swelling of
the liver and lung congestion were observed in the dog
exposed to 1,2-DCP; other examined tissues were
pathologically normal. No major pathology was observed
in any of the examined tissues in the control dog.
A NOAEL/LOAEL
determination for the rat
study is precluded based on
high mortality (>50%) in
both exposed and control
groups due to an endemic
infection in the colony.
A NOAEL/LOAEL
determination cannot be
made for dogs based on
inadequate animal numbers.
Mellon
Institute of
Industrial
Research
(1947a. 1947b)
Supporting evidence—noncancer effects in animals following other exposure routes (dermal, injection, etc.)
Acute (dermal)
Wistar rats (six/sex/group) were given a
single dermal application of 1,2-DCP at
2,340 mg/kg (undiluted) under occluded
conditions for 24 hr. Rats were observed
for mortality and clinical signs of toxicity
for 14 d.
No deaths were observed. Clinical signs of toxicity
included reddened and inflamed skin, increased salivation,
and discolored urine.
Dermal 24-hr LC50
>2,340 mg/kg.
Shell Oil Co
(1982)
65
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Short-term (i.p.)
Groups of Wistar rats (five males/group)
were given i.p. injections of 1,2-DCP in
corn oil at doses of 0, 50, 100, 250, or
500 mg/kg-d for 5 d. 24 hr after
exposure, rats were sacrificed and
kidneys were removed and weighed.
Renal proximal tubule of kidney
measured for ACE.
Kidney weights did not differ between exposed and control
rats. ACE activity was significantly increased by 23% at
250 mg/kg-d and significantly decreased by 16% at
500 mg/kg-d. Enlargement and fraying of microvilli of
brush border of the proximal tubule was observed at
>250 mg/kg-d. Epithelial coagulative necrosis of the brush
border was observed at higher doses. In the glomerulus,
mesangial proliferative glomerulonephritis was observed at
all doses with increased severity with increasing dose.
NOAEL: Not identified
LOAEL: 50 mg/kg-d
(kidney lesions)
Trevisan et al.
(1988)
Short-term (i.p.)
Groups of Wistar rats (five males/group)
were given i.p. injections of 1,2-DCP in
corn oil at doses of 0, 10, 25, 50, 100,
250, or 500 mg/kg-d for 5 d. 24 hr after
exposure, rats were sacrificed and
evaluated for liver biochemistry and
histology.
Liver GST activity was significantly increased at
500 mg/kg-d. No significant changes were observed in
GSH content or CYP450 activity. Liver hyperplasia was
observed in 5/5 rats at >10 mg/kg-d and slight steatosis
was observed in 3/5 rats at 100 mg/kg-d and 5/5 rats at
>250 mg/kg-d. Incidence of liver necrosis was not dose
related.
NOAEL: Not determined
LOAEL: 10 mg/kg-d (liver
lesions)
Trevisan et al.
(1989)
Short-term
(injection)
ddY male mice (number unspecified)
were given daily injections of 1,2-DCP
for lid; type of injection and
administered dose(s) were not reported.
After exposure, liver histology was
examined.
The study authors reported slight swelling of cells and
increase in lipid droplets in the liver of exposed mice. It is
unclear if control animals were examined.
Inadequate data reporting
and lack of control data
preclude a
NOAEL/LOAEL
determination.
Matsumoto et
al. (1982)
[abstract only]
66
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Subchronic (i.p.)
Groups of Wistarrats (10 males/group)
were given i.p. injections of 1,2-DCP in
corn oil at doses of 0, 50, 100, 250, or
500 mg/kg-d, 5 d/wk for 4 wk. Half the
rats were sacrificed 24 hr after the last
exposure; the remaining rats were
sacrificed 4 wk later. Endpoints
evaluated included serum biochemistry
(AST, ALT), Phase I (AOH, ADEM, and
CYP450) and Phase II (GSH, GST)
enzymes in liver and kidney, and ACE in
the proximal renal tubule brush border.
Main group: No adverse changes were observed in serum
chemistry values. Significant changes in liver included an
18-78% increase in GSH and GST at >50 mg/kg-d, a
41-62% decrease in ADEM at >100 mg/kg-d, and a 26%
decrease in CYP450 at 500 mg/kg-d. Significant changes
in kidney biochemistry included a 16-35% decrease in
ACE at >100 mg/kg-d, a 14-30% increase in GSH at
>250 mg/kg-d, a 53% increase in GST at 500 mg/kg-d, and
a 30% decrease in CYP450 at 500 mg/kg-d.
Recovery group: The only significant finding after the
recovery period was a marginal 21% increase in GSH in
the liver at 500 mg/kg-d. All other endpoints were
comparable to controls.
The toxicological
significance of altered
enzymes in the absence of
altered serum biochemistry
(and lack of histological
examination) is unclear.
Trevisan et al.
(1991)
Subchronic (i.p.)
Groups of Wistar rats (five males/group)
were given i.p. injections of 1,2-DCP in
corn oil at doses of 0, 10, 25, 50, 100,
250, or 500 mg/kg-d, 5 d/wk for 4 wk.
24 hr after exposure, rats were sacrificed
and evaluated for liver biochemistry and
histology.
Significant, dose-dependent increases were observed in
GSH content and GST activity at >50 mg/kg-d; CYP450
activity was significantly decreased at 250 and
500 mg/kg-d. Liver hyperplasia was observed in all
exposed rats, slight steatosis was also observed at
>250 mg/kg-d.
NOAEL: Not identified
LOAEL: 10 mg/kg-d (liver
lesions)
Trevisan et al.
(1989)
Subchronic (i.p.)
Groups of Wistar rats (five males/group)
were given i.p. injections of 1,2-DCP in
corn oil at doses of 0, 50, 100, 250, or
500 mg/kg-d 5 d/wk for 4 wk. 24 hr
after exposure, rats were sacrificed and
kidneys were removed and weighed.
One kidney was examined
microscopically while the other one was
evaluated for ACE levels in the renal
proximal tubule brush border.
Kidney weights did not differ between exposed and control
rats. ACE levels were significantly decreased by 17-41%
at >100 mg/kg-d, compared to controls. Dose-dependent
enlargement and fraying of microvilli of brush border of
the proximal tubule was observed. Epithelial coagulative
necrosis of the brush border was observed at higher doses.
In the glomerulus, mesangial proliferative
glomerulonephritis was observed at all doses with
increased severity with increasing dose.
NOAEL: Not identified
LOAEL: 50 mg/kg-d
(kidney lesions)
Trevisan et al.
(1988)
67
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Supporting evidence—cancer in animals following inhalation exposure
Short-term tumor
assay
C3H mice (80, sex unspecified) were
exposed to 400 ppm (1,800 mg/m3) for a
total of 37 exposures (4-7 hr/exposure;
exposure schedule not specified); mice
were observed for 7 mo after exposure
prior to sacrifice for hepatic histology.
The majority of mice died during the exposure period; only
three mice survived the exposure and observation periods.
All three mice showed multiple hepatomas. Nine rats that
died between 14 and 28 exposures showed non-neoplastic
liver lesions. It is unclear if a control group was used.
High mortality (and lack of
control data) precludes
conclusions regarding the
hepatic carcinogenicity of
1,2-DCP.
Heooel et al.
(1948)
"Acute = exposure for <24 hours (U.S. EPA. 2002b').
' Short-term = repeated exposure for >24 hours <30 days (U.S. EPA. 2002b).
°Subchronic = repeated exposure for >30 days <10% lifespan (>30 days up to approximately 90 days in typically used laboratory animal species) (U.S. EPA. 2002b).
'Chronic = repeated exposure for >10% lifespan for humans (more than approximately 90 days to 2 years in typically used laboratory animal species) (U.S. EPA. 2002b).
ACE = angiotensin converting enzyme; ADEM = aminopyrinc- Y-dcmcthylasc: AOH = aniline hydroxylase; ALC = approximate lethal concentration; ALP = alkaline
phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CI = confidence interval; CNS = central nervous system;
FEL = frank effect level; FOB = functional observational battery; GGT = '/-glutamyl transferase; GSH = reduced glutathione; GSSG = oxidized glutathione;
GST = g 1 utathionc-,S'-transfcrase: Hb = hemoglobin; i.p. = intraperitoneal; LCso = median lethal concentration; LD5o = median lethal dose;
LOAEL = lowest-observed-adverse-effect level; NAD = nicotinamide adenine dinucleotide; NADPH = nicotinamide adenine dinucleotide phosphate; ND = no data;
NOAEL = no-observed-adverse-effect level; NZW = New Zealand white; RNA = ribonucleic acid; S-D = Sprague-Dawley; SDH = sorbitol dehydrogenase.
68
1,2-Dichloropropane

-------
FINAL
09-29-2016
DERIVATION OF PROVISIONAL VALUES
Tables 5 and 6 present summaries of noncancer and cancer reference values, respectively.
IRIS data are indicated in the tables, if available.
Table 5. Summary of Noncancer Reference Values for 1,2-Dichloropropane
(CASRN 78-87-5)
Toxicity Type
(units)
Species/Sex
Critical Effect
p-Reference
Value
POD
Method
POD
UFc
Principal
Study
Subchronic p-RfD
(mg/kg-d)
Rat/M and
F pups
Delayed skeletal
ossification of skull
bones
4 x i(r2
BMDLos
(HED)
1.3
30
Kirk et al.
(1995)
Chronic p-RfD
(mg/kg-d)
Rat/M and
F pups
Delayed skeletal
ossification of skull
bones
4 X 1(T2
BMDLos
(HED)
1.3
30
Kirk et al.
(1995)
Subchronic p-RfC
(mg/m3)
Rat/F
Hyperplasia of
respiratory mucosa
of the nasal cavity
4 x 1(T3
BMCLio
(HEC)
0.12
30
Dow Chemical
Co f 1988a)
Chronic RfC
(mg/m3)
Inhalation RfC value of 4 x 10 3 is available on IRIS.
BMCL = benchmark concentration lower confidence limit; BMDL = benchmark dose lower confidence limit;
F = female(s); HEC = human equivalent concentration; HED = human equivalent dose; M = male(s); POD = point
of departure; p-RfC = provisional reference concentration; p-RfD = provisional reference dose; UFc = composite
uncertainty factor.
Table 6. Summary of Cancer Values for 1,2-Dichloropropane (CASRN 78-87-5)
Toxicity Type
(units)
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF (mg/kg-d) 1
Mouse/M
Hepatocellular adenoma or carcinoma
3.7 x 10-2
NTP (1986)
p-IUR (mg/m3)-1
Rat/M
Total nasal cavity tumors (papillomas
or esthesioneuroepithelioma)
3.7 x 10-3
Uincda et al. (2010)
M = male(s); p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor.
DERIVATION OF ORAL REFERENCE DOSES
Derivation of a Subchronic Provisional Referece Dose
The database of potentially relevant studies for derivation of a subchronic oral reference
value for 1,2-DCP includes a short-term-duration study in both mice and hamsters (Gi et al..
2015a). three subchronic-duration studies in rats (Bruckner et al.. 1989; Dow Chemical Co.
1988b; NTP, 1986). a subchroni c-durati on study in mice (NIP. 1986). a two-generation
reproductive study in rats (Dow Chemical Co. 1990. 1989b). and developmental studies in rats
and rabbits along with associated dose-range-finding studies (Kirk et al.. 1995;
69
1,2-Dichloropropane

-------
FINAL
09-29-2016
Dow Chemical Co. 1989c. 1988d). The developmental study in rats (Kirk et aL 1995) was
selected as the principal study, and delayed fetal ossification was identified as the critical effect.
Justification of the Critical Effect
All potential 1,2-DCP-induced effects observed in the studies listed above were evaluated
to determine the most sensitive response. The most sensitive effects, with LOAELs ranging
from 71.4-150 mg/kg-day (and corresponding NOAELs of 25-50 mg/kg-day), included reduced
body weight, clinical signs of toxicity (CNS depression), hematological changes and
histopathological changes in the spleen consistent with anemia, and delayed fetal ossification in
the studies by Bruckner et al. (1989). Dow Chemical Co (1988b). and Kirk et al. (1995)
(see Table 7). All endpoints in Table 7 with adequate data were modeled with Benchmark Dose
Software (BMDS, Version 2.5), and the estimated benchmark dose lower confidence limits
(BMDLs) are also summarized in Table 7 (see Appendix C for benchmark dose [BMD]
modeling methodology and detailed results). Among all of the candidate endpoints for potential
critical effect, the increased litter incidence of delayed fetal ossification in rats following
gestational exposure to 1,2-DCP, reported by Kirk et al. (1995). resulted in the lowest candidate
point of departure (POD) (BMDLos = 5.6 mg/kg-day). The next lowest candidate POD was
increased litter incidence of delayed fetal ossification in rabbits (BMDLos = 10. mg/kg-day), also
reported by Kirk et al. (1995).
The delays in skeletal ossification were considered by the study authors to be related to
decreased maternal body weight. However, in the rat component of the Kirk et al. (1995) study,
only body-weight gain, not actual body weight, was significantly decreased. Furthermore, the
EPA Guidelines for Developmental Toxicity Risk Assessment note that even when developmental
effects are associated with maternal toxicity, they are still toxic manifestations and are "generally
considered a reasonable basis for Agency regulation and/or toxicity assessment" (U.S. EPA.
1991). Delays in skeletal ossification of skull bones were also seen in rabbits (Kirk et al.. 1995).
with rats being the more sensitive species. The developmental period is recognized as a
susceptible life-stage where exposure during certain time windows is more relevant to the
induction of developmental effects than a subchronic-duration or lifetime exposure (U.S. EPA,
1991). Therefore, the developmental effects in rats are considered appropriate for deriving the
subchronic p-RfD.
Justification of the Principal Study
The oral developmental toxicity study by Kirk et al. (1995) with a NOAEL of
30 mg/kg-day and a LOAEL of 125 mg/kg-day for delayed skeletal ossification of skull in fetus
is selected as the principal study for derivation of a subchronic p-RfD. The critical effect is
increased incidence of delayed ossification of the bones of the skull in fetuses. This study is a
peer-reviewed published study with an adequate number of dose groups and dose spacing,
sufficient group sizes, comprehensive endpoint assessment, and quantitation of results to
describe dose-response relationships for the critical effects in rats associated with gestational oral
exposure to 1,2-DCP. Among the available candidate endpoints (see Table 7), delayed
ossifications in rats reported by Kirk et al. (1995) represents the lowest candidate POD for
deriving a subchronic p-RfD (BMDLos of 5.6 mg/kg-day).
70
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 7. Candidate Points of Departure for the Derivation of the Subchronic p-RfDa
Endpoint
Male
Female
Reference
Comments
NOAEL
(mg/kg-d)
LOAEL
(mg/kg-d)
BMDLb
(mg/kg-d)
POD
NOAEL
(mg/kg-d)
LOAEL
(mg/kg-d)
BMDLb
(mg/kg-d)
POD
Hemosiderosis
and hyperplasia of
the spleen;
increased bilirubin
in S-D rats
NDr
71.4
DU
LOAEL
NDr
NDr
NDr
NDr
Bruckner et
al. (1989)
Data reporting inadequate for BMD
analysis; spleen incidence data not
reported, exact animal number not
provided for bilirubin data.
Reduced body
weight in F344
rats
46
143
DU
NOAEL
143
NDr
NDr
NDr
Dow
Chemical Co
f1988b)
NA
Transient CNS
depression
(maternal) in
S-D rat
NDr
NDr
NDr
NDr
30
125
DU
NOAEL
Kirk et al.
(1995)
Data reporting inadequate for BMD
analysis (no summary incidence
data).
Increased litter
incidence of
delayed
ossification
(fetal) in S-D rat
NDr
NDr
NDr
NDr
30
125
5.6
BMDLos
Kirk et al.
(1995)
Most-sensitive endpoint.
Increased
reticulocytes
(maternal) in
NZW rabbit
NDr
NDr
NDr
NDr
50
150
30
BMDLi sd
Kirk et al.
(1995)
Elevated reticulocytes showed the
clearest dose-response effect of
observed hematological effects at
150 mg/kg-d, so it was the only
hematological effect modeled from
this study.
71
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 7. Candidate Points of Departure for the Derivation of the Subchronic p-RfDa
Endpoint
Male
Female
Reference
Comments
NOAEL
(mg/kg-d)
LOAEL
(mg/kg-d)
BMDLb
(mg/kg-d)
POD
NOAEL
(mg/kg-d)
LOAEL
(mg/kg-d)
BMDLb
(mg/kg-d)
POD
Increased litter
incidence of
delayed
ossification (fetal)
in NZW rabbit
NDr
NDr
NDr
NDr
50
150
10
BMDLo5
Kirk et al.
(1995)
Second-most sensitive endpoint.
aThe units for oral values are expressed as ADDs (mg/kg-day). All long-term exposure values (>4 weeks) are converted from a discontinuous to a continuous exposure.
Values from animal developmental studies are not adjusted to a continuous exposure.
bAll modeling was conducted using U.S. EPA BMDS (Version 2.5). BMD analysis details are available in Appendix C.
ADD = adjusted daily dose; BMD = benchmark dose; BMDL = benchmark dose lower confidence limit; BMDS = Benchamark Dose Software; CNS = central nervous
system; DU = data unsuitable; LOAEL = lowest-observed-adverse-effect level; NA = not applicable; NDr = not determined; NOAEL = no-observed-adverse-effect
level; NZW = New Zealand white; POD = point of departure; p-RfD = provisional reference dose; S-D = Sprague-Dawley; SD = standard deviation.
72
1,2-Dichloropropane

-------
FINAL
09-29-2016
Approach for Deriving the Subchronic p-RfD
The BMDL05 of 5.6 mg/kg-day is the selected POD for derivation of the subchronic
p-RfD. In Recommended Use of Body Weight 3/4 as the Default Method in Derivation of the
Oral Reference Dose (U.S. EPA. 201 lb), the Agency endorses a hierarchy of approaches to
derive human equivalent oral exposures from data from laboratory animal species, with the
preferred approach being physiologically based toxicokinetic modeling. Other approaches may
include using some chemical-specific information, without a complete physiologically based
toxicokinetic model. In lieu of chemical-specific models or data to inform the derivation of
human equivalent oral exposures, EPA endorses body-weight scaling to the 3/4 power
(i.e., BW3/4) as a default to extrapolate toxicologically equivalent doses of orally administered
agents from all laboratory animals to humans for the purpose of deriving an RfD under certain
exposure conditions. More specifically, the use of BW3 4 scaling for deriving an RfD is
recommended when the observed effects are associated with the parent compound or a stable
metabolite but not for portal-of-entry effects or developmental endpoints.
A validated human PBPK model for 1,2-DCP is not available for use in extrapolating
doses from animals to humans. In addition, the selected POD of 5.6 mg/kg-day is based on
increased incidence of delayed ossification, which is associated with the parent compound or a
stable metabolite. Furthermore, this fetal skeletal variation is not a portal-of-entry effect. Therefore,
scaling by BW3/4 is relevant for deriving HEDs for this effect.
Following U.S. EPA (2011b) guidance, the POD for the developmental study in rats is
converted to a HED through the application of a DAF derived as follows:
DAF = (BWa1/4 - BWh1/4)
where:
DAF = dosimetric adjustment factor
BWa = animal body weight
BWh = human body weight
Using a reference BWa of 0.25 kg for rats and a reference BWh of 70 kg for humans (U.S.
EPA. 1988). the resulting DAF is 0.24. Applying this DAF to the BMDL05 identified in the
developmental rat study yields a BMDL05 (HED) as follows:
POD (HED) = BMDL05 (mg/kg-day) x DAF
= BMDL05 (mg/kg-day) x 0.24 = 5.6 mg/kg-day x 0.24
= 1.3 mg/kg-day
Subchronic p-RfD = POD (HED) UFc
= 1.3 mg/kg-day -^30
= 4 x 10"2 mg/kg-day
Table 8 summarizes the uncertainty factors for the subchronic p-RfD for 1,2-DCP.
73
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 8. Uncertainty Factors for the Subchronic p-RfD for 1,2-Dichloropropane
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty associated with extrapolating from animals
to humans when cross-species dosimetric adjustment (HED calculation) is performed.
UFh
10
A UFh of 10 is applied for inter-individual variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of 1,2-DCP in humans.
UFd
1
A UFd of 1 is applied because the database is relatively complete, with a short-term-duration study
in mice and hamsters, three subchronic-duration studies in rats and mice (Bruckner et al.. 1989;
Dow Chemical Co. 1988b: NTP. 19861 chronic-duration/carcinoeenic studies in rats and mice
(NTP. 19861 a two-generation reproductive toxicity studv in rats (Dow Chemical Co. 1990). and
developmental toxicity studies in rats and rabbits (Kirk et al.. 1995). all via the oral route.
UFl
1
A UFl of 1 is applied because POD is a BMDL.
UFS
1
A UFS of 1 is applied because developmental toxicity resulting from a narrow period of exposure
was used as the critical effect. The developmental period is recognized as a susceptible life stage
when exposure during a time window of development is more relevant to the induction of
developmental effects than lifetime exposure (U.S. EPA. 1991).
UFC
30
Composite UF = UFA x UFH x UFD x UFL x UFS.
BMDL = benchmark dose lower confidence limit; HED = human equivalent dose; POD = point of departure;
p-RfD = provisional reference dose; UF = uncertainty factor.
The confidence of the subchronic p-RfD for 1,2-DCP is high as explained in Table 9.
74
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 9. Confidence Descriptors for the Subchronic p-RfD for 1,2-Dichloropropane
Confidence
Categories
Designation
Discussion
Confidence in
principal study
H
Confidence in the principal study is high. This study is a peer-reviewed published
study with an adequate number of dose groups and dose spacing, sufficient group
sizes, comprehensive endpoint assessment, and quantitation of results to describe
dose-response relationships for the critical effects in rats associated with
gestational oral exposure to 1,2-DCP. Although other effects were observed in
studies at varying administered doses, the delayed skeletal ossification in rats
represents the most sensitive effect, and this effect was also seen in a 2nd species
(rabbit). The selection of delayed skeletal ossification as the critical effect is
confirmed through BMD analysis, increasing confidence in the study.
Confidence in
database
H
Confidence in the database is high as it includes a short-term-duration study in
mice and hamsters, three subchronic-duration studies in rats and mice,
chronic-duration/carcinogenic studies in rats, mice, and hamsters, a
two-generation reproductive toxicity study in rats, and developmental toxicity
studies in rats and rabbits (Kirk et al.. 1995; Dow Chemical Co. 1990; Bruckner et
al.. 1989; Dow Chemical Co. 1988b; NTP. 1986). The majority of these studv
results were reported in peer-reviewed journals, increasing confidence in the
database.
Confidence in
subchronic p-RfDa
H
The overall confidence in the subchronic p-RfD is high.
aThe overall confidence cannot be greater than the lowest entry in the table (high).
BMD = benchmark dose; H = high; p-RfD = provisional reference dose.
Derivation of a Chronic Provisional Reference Dose
The database of potentially relevant studies for derivation of a chronic oral reference
value for 1,2-DCP includes NTP-sponsored chronic studies in rats and mice (N I P. 1986) and
hamsters (Gi et al.. 2015b) in addition to the subchronic-duration (Bruckner et aL 1989; Dow
Chemical Co. 1988b; N I P. 1986). two-generation reproductive (Dow Chemical Co. 1990.
1989b) and developmental studies (Kirk et al.. 1995; Dow Chemical Co. 1989c. 1988d). The
developmental study in rats (Kirk et al. 1995) was selected as the principal study, and delayed
fetal ossification was identified as the critical effect.
Table 10 shows candidate endpoints for derivation of the chronic p-RfD from the chronic
(NTP. 1986) and developmental (Kirk et al. 1995) studies. All endpoints listed in Table 10 with
adequate data were modeled with BMDS (Version 2.5); the BMDLs are summarized in Table 10
(see Appendix C for BMD modeling methodology and detailed results).
While chronic toxicity testing of 1,2-DCP has been conducted, the effects in fetal rats
appears to be more sensitive when comparing potential POD values. It should be noted however
that the only chronic effect that could be modeled (e.g., liver effects in mice) were modeled at a
benchmark response (BMR) level of 10% whereas developmental effects (e.g., delayed
ossification) were modeled at a BMR 5%. The selected critical endpoint is delayed ossification
of skull bones in rat fetuses in the study by Kirk et al. (1995). which is the same study and
critical effect used to derive the subchronic p-RfD. A full description concerning the selection of
this endpoint as the critical effect and calculation of the POD (HED) is provided in the section on
75
1,2-Dichloropropane

-------
FINAL
09-29-2016
the derivation of the subchronic p-RfD. Consistent with current EPA practice, the
developmental period is recognized as a susceptible life-stage where exposure during certain
time windows are more relevant to the induction of developmental effects than lifetime exposure
(U.S. EPA. 1991). Therefore, an uncertainty factor (UF) for extrapolation from
less-than-chronic exposure durations is not applied. As a result, the chronic p-RfD is
4 x 10 2 mg/kg-day, the same value as the subchronic p-RfD.
76
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 10. Candidate Points of Departure for the Derivation of the Chronic p-RfDa
Endpoints
Male
Female
Reference
Comments
NOAEL
LOAEL
BMDLb
POD
NOAEL
LOAEL
BMDLb
POD
Reduced mean body weight
inF344 rats,
chronic-duration gavage
study
45
89.3
DU
NOAEL
89.3
179
DU
NOAEL
NIP (1986)
BMD modeling not possible
because SDs not reported
Hyperplasia of mammary
gland in female F344 rats,
chronic-duration gavage
study
NDr
NDr
NDr
NDr
NDr
89.3
DU
LOAEL
NIP (1986)
Data unsuitable for BMD
analysis (nonmonotonic
dose-response). Lack of
increase at high-dose consistent
with progression to neoplasms
and high mortality observed in
high-dose group
Hepatocytomegaly and
necrosis in male B6C3Fi
mice, chronic-duration
gavage study
89.3
179
58.5
(hepato-cytomegaly)
BMDLio
NDr
NDr
NDr
NDr
NIP (1986)
BMD modeling provided
appropriate fit for
hepatocytomegaly; BMD not
attempted for necrosis (lower
incidence)
Increased litter incidence
of delayed ossification
(fetal) in S-D rat
NDr
NDr
NDr
NDr
30
125
5.6
BMDLos
Kirk et al.
Most sensitive endpoint for
derivation of the chronic
p-RfD
(1995)

Increased litter incidence of
delayed ossification (fetal) in
NZW rabbit
NDr
NDr
NDr
NDr
50
150
10.
BMDL05
Kirk et al.
(1995)
Second-most sensitive endpoint
aThe units for oral values are expressed as an ADD (mg/kg-day). All long-term exposure values (>4 weeks) are converted from a discontinuous to a continuous
exposure. Values from animal developmental studies are not adjusted to a continuous exposure.
bAll modeling was conducted using U.S. EPA BMDS (Version 2.5). BMD analysis details are available in Appendix C.
BMD = benchmark dose; BMDL = benchmark dose lower confidence limit; BMDS = Benchmark Dose Software; DU = data unsuitable; LOAEL = lowest-adverse-effect
level; NDr = not determined; NOAEL = no-observed-adverse-effect level; NZW = New Zealand white; p-RfD = provisional reference dose; S-D = Sprague-Dawley;
SD = standard deviation.
77
1,2-Dichloropropane

-------
FINAL
09-29-2016
The chronic p-RfD for 1,2-DCP, based on the BMDL05 of 5.6 mg/kg-day (BMDL05
[HED] of 1.3 mg/kg-day) for delayed ossification in rat offspring (Kirk et aL 1995). is derived
as follows:
Chronic p-RfD = POD (HED) - UFC
= 1.3 mg/kg-day -^30
= 4 x 10"2 mg/kg-day
Table 11 summarizes the uncertainty factors for the chronic p-RfD for 1,2-DCP.
Table 11. Uncertainty Factors for the Chronic p-RfD for 1,2-Dichloropropane
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty associated with extrapolating from
animals to humans when cross-species dosimetric adjustment (HED calculation) is performed.
UFh
10
A UFh of 10 is applied for inter-individual variability to account for human-to-human variability
in susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of 1,2-DCP in humans.
UFd
1
A UFd of 1 is applied because the database is relatively complete, with
chronic-duration/carcinosenic studies in rats and mice CNTP. 19861 three subchronic-duration
studies in rats and mice (Bruckner et al.. 1989; Dow Chemical Co. 1988b: NTP. 1986). a
short-term study in mice and hamsters, a two-generation reproductive toxicity study in rats (Dow
Chemical Co. 1990). and developmental toxicity studies in rats and rabbits (Kirk et al.. 19951 all
via the oral route.
UFl
1
A UFl of 1 is applied because POD is a BMDL.
UFS
1
A UFS of 1 is applied to account for subchronic-to-chronic extrapolation because developmental
toxicity resulting from a narrow period of exposure was used as the critical effect. The
developmental period is recognized as a susceptible life stage when exposure during a time
window of development is more relevant to the induction of developmental effects than lifetime
exposure (U.S. EPA. 19911
UFC
30
Composite UF = UFA x UFH x UFD x UFL x UFS.
BMDL = benchmark dose lower confidence limit; HED = human equivalent dose; POD = point of departure;
p-RfD = provisional reference dose; UF = uncertainty factor.
The confidence of the chronic p-RfD for 1,2-DCP is high as explained in Table 12.
78
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 12. Confidence Descriptors for Chronic p-RfD for 1,2-Dichloropropane
Confidence Categories
Designation
Discussion
Confidence in principal
study
H
Confidence in the principal study is high. This study is a peer-reviewed
published study with an adequate number of dose groups and dose spacing,
sufficient group sizes, comprehensive endpoint assessment, and
quantitation of results to describe dose-response relationships for the
critical effects in rats associated with gestational oral exposure to 1,2-DCP.
Although other effects were observed in studies at varying administered
doses, the delayed skeletal ossification in rats represents the most sensitive
effect, and this effect was also seen in a second species (rabbit). The
selection of delayed skeletal ossification as the critical effect is confirmed
through BMD analysis, increasing confidence in the study.
Confidence in database
H
Confidence in the database is high as it includes
chronic-duration/carcinogenic studies in rats and mice, three
subchronic-duration studies in rats, mice, and hamsters, a short-term study
in mice and hamsters, a two-generation reproductive toxicity study in rats,
and developmental toxicity studies in rats and rabbits (Kirk et al.. 1995;
Dow Chemical Co. 1990; Bruckner et al.. 1989; Dow Chemical Co. 1988b;
NTP. 1986). The majority of these study results were reported in
peer-reviewed journals, increasing confidence in the database.
Confidence in chronic
p-RfDa
H
The overall confidence in the chronic p-RfD is high.
"The overall confidence cannot be greater than lowest entry in table (high).
BMD = benchmark dose; H = high; p-RfD = provisional reference dose.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
Derivation of a Subchronic Provisional Reference Concentration
The database of potentially relevant studies for derivation of a subchronic inhalation
reference value for 1,2-DCP includes two studies in F344 rats (TJmeda et aL 2010; Dow
Chemical Co. 1988a). a study in B6C3Fi mice (Dow Chemical Co. 1988a). a study in
B6D2Fi/Crlj (SPF) mice (Matsumoto et ai. 2013). and a study in NZW rabbits (Dow Chemical
Co. 1988a). The sub chronic-duration study in F344 rats (Dow Chemical Co. 1988a) was
selected as the principal study, and nasal lesions were identified as the critical effect.
Justification of the Critical Effect
All potential 1,2-DCP-induced effects following subchronic exposure were evaluated to
determine the most sensitive response. The most sensitive effect in rats and mice was nasal
lesions, with increases in lesion incidence in rats at HECs >4.0 mg/m3 (Umeda et aL 2010; Dow
Chemical Co. 1988a) and in mice at HECs >30.86 mg/m3 (Matsumoto et aL. 2013). In rabbits,
nasal lesions were observed (not statistically significant) at an HEC of 471.8 mg/m3, which was
slightly higher than the HEC of 414 mg/m3 associated with systemic effects in rabbits for bone
marrow hyperplasia and anemia (Dow Chemical Co. 1988a).
Nasal effects in rats and mice were considered candidate critical effects and selected for
BMD modeling (see Table 13; additional BMD details in Appendix C). Among the candidate
endpoints for potential critical effect, the increased incidence of nasal lesions in female rats
following inhalation exposure to 1,2-DCP for 13 weeks (Dow Chemical Co. 1988a) resulted in
79
1,2-Dichloropropane

-------
FINAL
09-29-2016
the lowest candidate POD (benchmark concentration lower confidence limit [BMCLJio
[HEC] = 0.12 mg/m3). The next lowest candidate POD was nasal lesions in male rats from the
same study (BMCLio [HEC] = 0.26 mg/m3).
80
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 13. Candidate Point of Departures for the Derivation of the Subchronic p-RfC
Endpoints
Male
Female
Reference
Comments
NOAEL
(HEC)
LOAEL
(HEC)
BMCL
(HEC)a
POD
NOAEL
(HEC)
LOAEL
(HEC)
BMCL
(HEC)a
POD
Nasal cavity
lesions in
F344ratsb
1.6
5.4
0.26
BMCLio
(HEC)
1.2
4.0
0.12
BMCLio
(HEC)
Dow Chemical
BMCL for females is
most sensitive POD
Co (1988a)

Nasal cavity
lesions in
F344/DuCrj (SPF)
ratsb
NDr
13.63
DU
LOAEL
(HEC)
NDr
10.03
DU
LOAEL
(HEC)
Umeda et al.
(2010)
Data not amenable to
BMD modeling
(incidence goes from
0/10 in controls to
10/10 in all exposure
groups)
Nasal cavity
lesions in
B6D2Fi/Crlj
(SPF) miceb
24.83
37.27
11.6
BMCLio
(HEC)
20.55
30.86
17.1
BMCLio
(HEC)
Matsumoto et al.
(2013)

aAll modeling was conducted using U.S. EPA BMDS (Version 2.5). BMD analysis details are available in Appendix C.
bHEC values (mg/m3) are based on extrathoracic respiratory effects.
BMCL = benchmark concentration lower confidence limit; BMD = benchmark dose; BMDS = Benchmark Dose Software; DU = data unsuitable; HEC = human
equivalent concentration; LOAEL = lowest-observed-adverse-effect level; NDr = not determined; NOAEL = no-observed-adverse-effect level; POD = point of
departure; p-RfC = provisional reference concentration.
81
1,2-Dichloropropane

-------
FINAL
09-29-2016
Justification of the Principal Study
The subchronic-duration inhalation study by Dow Chemical Co (1988a) with a LOAEL
(HEC) of 4.0 mg/m3, and a BMCLio (HEC) of 0.12 mg/m3 for nasal lesions in female F344 rats
is selected as the principal study for derivation of a subchronic p-RfC. The critical effect is
increased incidence of hyperplasia of the nasal mucosa in female rats. While this study is
unpublished, it has an adequate number of exposure groups and exposure spacing, sufficient
group sizes, comprehensive endpoint assessment, and quantitation of results to describe
concentration-response relationships for the critical effects in rats associated with subchronic
inhalation exposure to 1,2-DCP. This study and critical effect were used in the derivation of the
IRIS chronic RfC (U.S. EPA. 2002a); therefore, the study is considered suitable for derivation of
a subchronic p-RfC. The following dosimetric adjustments are made for inhalation with a
LOAEL for respiratory effects in the ET region.
Exposure concentration adjustment for continuous exposure:
CONCadj
Exposure CONC x (MW - 24.45) x
(hours exposed ^ 24) x (days exposed ^ 7 days per week)1
15 ppm x (112.99 24.45) x (6 hours 24 hours) x
(5 days ^ 7 days)
12 mg/m3
HEC conversion for respiratory effects:
CONC (HEC) = CONCadj x RGDRet
where:
where:
RGDRet
VE[rat]
Ve [human]
SA[rat]
SA[human]
- (Ye SAet)
'rat
(Ve SAet)ii uman
Rat minute volume (rat = 0.101 L/min and 0.137 L/min,
based on a default body weight of 0.124 kg for F344
female rat and 0.180 kg for F344 male rat, respectively)
(U.S. EPA. 1994b)
13.8 L/min
Rat default surface area of the ET region (15 cm2)
Human default surface area of the ET region (200 cm2)
Female rat RGDRet =	(0.101 L/min 15 cm2) (13.8 L/min 200 cm2)
=	0.097
Male rat RGDRet =	(0.137 L/min 15 cm2) (13.8 L/min 200 cm2)
=	0.132
CONCresp (HEC)
CONCadj x RGDRet
0.097 for females, 0.132 for males
1.2 mg/m3 for female rats or 1.6 mg/m3 for male rats
'CONC = concentration from the Dow Chemical Co (1988a) study.
82
1,2-Dichloropropane

-------
FINAL
09-29-2016
Approach for Deriving the Subchronic p-RfC
The BMCLio (HEC) for increased incidence of nasal lesions in female rats exposed to
1,2-DCP by inhalation for 13 weeks is selected as the POD for derivation of the subchronic
p-RfC.
Subchronic p-RfC = BMCLio (HEC) - UF
= 0.12 mg/m3 ^ 30
= 4 x 10"3 mg/m3
Table 14 summarizes the uncertainty factors for the subchronic p-RfC for 1,2-DCP.
Table 14. Uncertainty Factors for Subchronic p-RfC for 1,2-Dichloropropane
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty associated with extrapolating from animals
to humans when cross-species dosimetric adjustment (HEC calculation) is performed.
UFh
10
A UFh of 10 has been applied for inter-individual variability to account for human-to-human
variability in susceptibility in the absence of quantitative information to assess the toxicokinetics
and toxicodynamics of 1,2-DCP in humans.
UFd
1
A UFd of 1 has been applied because there are subchronic inhalation studies available in three
species, and the critical effect (nasal lesions) has been observed in all three species, with increased
sensitivity in rats and mice compared with rabbits CMatsumoto et al.. 2013; Utneda et al.. 2010; Dow
Chemical Co. 1988a). Svstemic effects were also observed in several of the inhalation studies,
however the effects occurred at concentrations equal to or greater than those that induced nasal
lesions. Further, while there are no acceptable two-generation reproductive toxicity or
developmental toxicity studies following inhalation exposure, oral reproductive and developmental
studies indicate that reproductive or developmental effects will not occur at doses that do not cause
svstemic effects (Kirk et al.. 1995; Dow Chemical Co. 1990. 1989c. 1988d). The oral o-RfDs are
based on a developmental effect (delayed ossification) that co-occurred with maternal toxicity
(clinical signs, decreased body weight).
UFl
1
A UFl of 1 is applied because POD is a BMCL.
UFS
1
A UFS of 1 has been applied because a subchronic-duration study was selected as the principal
study.
UFC
30
Composite UF = UFA x UFH x UFD x UFL x UFS.
BMCL = benchmark concentration lower confidence limit; HEC = human equivalent concentration; POD = point
of departure; p-RfC = provisional reference concentration; p-RfD = provisional reference dose; UF = uncertainty
factor.
The confidence of the subchronic p-RfC for 1,2-DCP is high as explained in Table 15.
83
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 15. Confidence Descriptors for the Subchronic p-RfC for 1,2-Dichloropropane
Confidence Categories
Designation
Discussion
Confidence in principal study
H
The confidence in the orinciral studv is hieh. Dow Chemical Co
(1988a) conducted a series of subchronic experiments in rats,
mice, and rabbits. The studies utilized an adequate number of
exposure groups and exposure spacing, sufficient group sizes,
comprehensive endpoint assessment, and quantitation of results to
describe concentration-response relationships for the critical
effects of subchronic inhalation exposure to 1,2-DCP.
Additionally, the studv conducted in rats (Dow Chemical Co.
1988a) was used to derive the IRIS chronic RfC (U.S. EPA.
2002a).
Confidence in database
H
The confidence in the database is high. Multiple
subchronic-duration inhalation studies are available in three
soecies (Matsumoto et al.. 2013; Utile da et al.. 2010; Dow
Chemical Co. 1988a) and a reproductive studv is available in
female rats (Sekiguchi et al.. 2002); however, while there are no
male reproductive or developmental studies following inhalation
exposure, there are oral reproductive and developmental studies to
indicate that reproductive or developmental effects will not occur
at doses that do not cause svstemic effects (Kirk et al.. 1995; Dow
Chemical Co. 1990. 1989c. 1988d).
Confidence in subchronic p-RfCa
H
The overall confidence in the subchronic p-RfC is high.
aThe overall confidence cannot be greater than lowest entry in table (high).
H = high; IRIS = Integrated Risk Information System; p-RfC = provisional reference concentration.
Derivation of a Chronic Provisional Reference Concentratoin
A chronic p-RfC value was not derived because an inhalation RfC value is available on
EPA's IRIS database.
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
The cancer weight-of-evidence (WOE) descriptor for 1,2-DCP is "Likely to be
Carcinogenic to Humans" (see details below and in Table 16).
84
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 16. Cancer WOE Descriptor for 1,2-Dichloropropane
Possible WOE Descriptor
Designation
Route of Entry
(oral, inhalation,
or both)
Comments
"Carcinogenic to Humans "
NS
NA
There are insufficient data to support this
descriptor.
"Likely to Be
Carcinogenic to Humans"
Selected
Both oral and
inhalation route
of exposure
Recent human epidemiological studies and
case-series reports in Japanese workers indicate
a potential correlation between occupational
exposure to 1,2-DCP (and other solvents) and
cholangiocarcinoma. There is equivocal
evidence of mammary gland tumors in female
rats and evidence of liver tumors in male and
female mice in two-vear oral bioassavs (NTP.
1986). There is evidence of nasal tumors in male
and female rats, Harderian gland tumors in
male mice, and lung tumors in female mice in
two-vear inhalation bioassavs (Matsumoto et al..
2013: timed a et aL. 2010).
"Suggestive Evidence of
Carcinogenic Potential"
NS
NS
Evidence of the carcinogenic potential of 1,2-DCP
supports a stronger descriptor.
"Inadequate Information to
Assess Carcinogenic
Potential"
NS
NS
Adequate information is available to assess the
carcinogenic potential of 1,2-DCP.
"Not Likely to Be
Carcinogenic to Humans "
NS
NA
Evidence of the carcinogenic potential of 1,2-DCP
is available in humans and animals.
NA = not applicable; NS = not selected; WOE = weight of evidence.
Following U.S. EPA (2005) Guidelines for Carcinogen Risk Assessment, the database for
exposure to 1,2-DCP provides evidence that it is "Likely to be Carcinogenic to Humans. "
Recent epidemiological studies and case-series reports indicate that occupational exposure to
1,2-DCP (and other solvents) in the Japanese printing industry may be associated with the
development of cholangiocarcinoma, a rare form of bile duct cancer (Kubo et aL 2014c; Kubo et
al.. 2014a; Yamada et aL 2014; Kumagai et al.. 2013). In animals, various tumors types have
been observed in both rats and mice following long-term exposure to 1,2-DCP, including:
1)	A marginal increase in mammary gland tumors in female F344 rats administered
1,2-DCP by gavage for 103 weeks ( N I P. 1986);
2)	Significant increases in liver tumors in B6C3Fi mice of both sexes administered 1,2-DCP
by gavage for 103 weeks (N I P. 1986);
3)	Significant increases in nasal tumors in F344 rats of both sexes exposed to 1,2-DCP via
inhalation for 104 weeks (TJmeda et al. 2010); and
4)	A significant increase in combined incidence of bronchiolo-alveolar adenoma or
carcinoma in female SPF mice and a significant trend for increased Harderian gland
adenoma in male SPF mice exposed to 1,2-DCP via inhalation for 104 weeks
(Nlatsumoto et aL. 2013).
85
1,2-Dichloropropane

-------
FINAL
09-29-2016
While evidence for cancer following exposure to 1,2-DCP is available from both human
and animal studies, a stronger cancer hazard descriptor {"Carcinogenic to Humans") is not
appropriate due to limitations of the available human evidence including: (1) evidence is from a
small number of studies limited to case-series reports with small numbers of subjects from a few
Japanese factories; (2) affected workers were often exposed to several solvents, limiting the
ability to identify a causal relationship for 1,2-DCP alone; (3) exposure assessments were not
available in all studies; and (4) statistical analyses adjusted for confounding variables were not
conducted.
MODE-OF-ACTION DISCUSSION
The Guidelines for Carcinogenic Risk Assessment (U.S. EPA. 2005) define
mode-of-action (MO A) ".. .as a sequence of key events and processes, starting with interaction
of an agent with a cell, proceeding through operational and anatomical changes, and resulting in
cancer formation." Examples of possible modes of carcinogenic action for any given chemical
include "mutagenicity, mitogenesis, programmed cell death, cytotoxicity with reparative cell
proliferation, and immune suppression."
The available evidence suggests that 1,2-DCP is not a potent mutagen, but may cause
DNA damage and clastogenic effects (see "Genotoxicity Studies" section for more details).
While Sato et al. (2014) propose that cholangiocarcinoma observed in printers exposed to
1,2-DCP may be caused by DNA damage in biliary epithelial cells caused by reactive
intermediates formed via GST Tl-1 catalyzation, data regarding the metabolism of 1,2-DCP are
insufficient to determine if this mechanism is relevant (see "Mode-of-Action/Mechanism
Studies" section above for more details). Thus, a detailed MOA discussion for 1,2-DCP is
precluded, and a linear approach is applied as recommended by U.S. EPA (2005).
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of a Provisonal Oral Slope Factor
An NTP 2-year bioassay in rats and mice is available for the development of a
provisional oral slope factor (p-OSF) (NTP. 1986). This study was conducted in accordance
with Good Laboratory Practice (GLP) principles, the results are peer-reviewed, and the study
meets the standards of study design and performance with respect to the number of animals used,
the examination of potential toxicity endpoints, and the presentation of information.
In the rat study, equivocal evidence of carcinogenicity was observed in female rats based
on a marginal increase in mammary gland adenocarcinomas; no evidence of carcinogenicity was
observed in male rats. In the mouse study, there was some evidence of carcinogenicity in male
and female mice based on increases in combined adenoma or carcinoma of the liver at all
treatment doses. BMD modeling was performed for each of these tumor types (see Table 17;
additional BMD details in Appendix D). Prior to modeling, all doses were converted to HEDs
using BW3/4 scaling, as described in the "Derivation of a Subchronic p-RfD" section. Among all
of the candidate endpoints, the increased incidence of combined hepatocellular adenomas or
carcinomas in male mice resulted in the lowest POD (BMDLio (HED) = 2.71 mg/kg-day).
86
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 17. Benchmark Dose Modeling Results for Possible Tumor Endpoints for
Derivation of the p-OSFa
Study
Citation
Tumor Endpoint
Model Type
Goodness-of-Fit
p-Value
BMD io
(HED)
(mg/kg-d)
BMDLio
(HED)
(mg/kg-d)
Potential
p-OSF
(mg/kg-d)1
NTP
(1986)
Hepatocellular
adenoma or
carcinoma in male
mice
Multistage-Cancer
-1st order
0.878
4.25
2.71
3.7 x 10"2
NTP
(1986)
Hepatocellular
adenoma or carcinoma
in female mice
Multistage-Cancer-
1st order
0.417
14.5
8.51
1.2 x IO"2
NTP
(1986)
Mammary gland
tumor in female rats
Multistage-Cancer-
2nd order
0.985
47.7
30.4
3.3 x IO"3
"All modeling was conducted using U.S. EPA BMDS (Version 2.5). BMD analysis details are available in
Appendix D.
BMD = benchmark dose; BMDL = benchmark dose lower confidence limit; BMDS = Benchmark Dose Software;
HED = human equivalent dose; p-OSF = provisional oral slope factor.
The p-OSF is derived as follows:
p-OSF = BMR -h BMDLio (HED)
= 0.1 ^ 2.71 mg/kg-day
= 3.7x 10"2 (mg/kg-day)"1
Derivation of a Provisional Inhalation Unit Risk
One chronic inhalation study in rats and one chronic inhalation study in mice were
available for the development of a provisional inhalation unit risk (p-lUR) (Matsumoto et aL
2013; limed a et al.. 2010). Both studies were well conducted, and data are able to support a
quantitative cancer dose-response assessment. The studies are peer-reviewed, published, and
were performed according to GLP principles.
The rat study reported significant increases in the incidences of total nasal cavity tumors
including papillomas in both male and female rats and esthesioneuroepitheliomas in male rats
exposed to 1,2-DCP via inhalation for 104 weeks (Umeda et al., 2010). The mouse study
reported a significant increase in the combined incidence of bronchiolo-alveolar adenoma or
carcinoma in females and a significant trend for increased incidence of Harderian gland adenoma
in males exposed to 1,2-DCP via inhalation for 104 weeks (Matsumoto et al„ 2013). All tumor
types described above were selected for BMD modeling (see Table 18; additional BMD details
in Appendix D). Among the candidate endpoints, the increased incidence of nasal tumors in
male rats resulted in the lowest POD (BMCLio (HEC) = 26.7 mg/m3).
87
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table 18. Benchmark Dose Modeling Results for Possible Tumor Endpoints for
Derivation of the p-IUR
Study
Citation
Tumor Endpoint
Model Type
Goodness-of-Fit
p-Value
BMCio
(HEC)
(mg/m3)
BMCLio
(HEC)
(mg/m3)
Potential
p-IUR
(mg/m3)"1
Umeda et al.
(2010)
Nasal tumors in
male rats
Multistage-Cancer
-3rd order
0.944
45.1
26.7
3.7 x 10"3
Umeda et al.
(2010)
Nasal tumors in
female rats
Multistage-Cancer-
3 rd order
0.877
55.4
46.2
2.2 x 10-3
Matsumoto et
al. (2013)
Harderian gland
adenoma in male
mice
Multistage-Cancer-
1st order
0.994
476
251
4.0 x 10-4
Matsumoto et
al. (2013)
Bronchiolo-alveolar
adenoma or
carcinoma in
female mice
Multistage-Cancer-
1st order
0.904
342
177
5.6 x 10-4
"All modeling was conducted using U.S. EPA BMDS (Version 2.5). BMD analysis details are available in
Appendix D.
BMC = benchmark concentration; BMCL = benchmark concentration lower confidence limit; BMD = benchmark
dose; BMDS = Benchmark Dose Software; HEC = human equivalent concentration; p-IUR = provisional inhalation
unit risk.
The following is the HEC conversion from bioassay inhalation concentrations by Umeda
et al. (2010) based on respiratory effects in the ET region (e.g., nasal tumors).
Exposure concentration unit conversation (ppm to mg/m3) and adjustment for continuous
exposure:
CONCadj = Exposure CONC x (MW - 24.45) x
(hours exposed ^ 24) x (days exposed ^ 7 days per week)2
= 80.2 ppm x (112.99 24.45) x (6 hours 24 hours) x
(5 days ^ 7 days)
= 66.2 mg/m3
HEC conversion for respiratory effects:
CONC (HEC) = CONCadj x RGDRet
where:
RGDRet = (Ye ^ SAET)rat
(Ve SAET)h uman
2CONC = concentration from the Umeda et al. (2010) study.
88
1,2-Dichloropropane

-------
FINAL
09-29-2016
where:
Ve [human]
SA[rat]
SA[human]

VE[rat]
Rat minute volume (rat = 0.167 L/min and 0.254 L/min, based
on a default body weight of 0.229 kg for F344 female rat and
0.380 kg for F344 male rat, respectively) [see U.S. EPA
(1994a)l
13.8 L/min
Rat default surface area of the ET region (15 cm2)
Human default surface area of the ET region (200 cm2)
Female rat RGDRet = (0.101 L/min 15 cm2) (13.8 L/min 200 cm2)
= 0.161
Male rat RGDRet = (0.137 L/min 15 cm2) (13.8 L/min 200 cm2)
= 0.245
CONCresp (HEC) = CONCadj x RGDRet
= 66.2 mg/m3 x 0.161 for females,
66.2 mg/m3 x 0.245 for males
= 10.7 mg/m3 for female or 16.2 mg/m3 for male rats
The p-IUR is derived as follows:
p-IUR
BMR -h BMCLio (HEC)
0.1 26.7 mg/m3
3.7 x 10"3 (mg/m3)"1
89
1,2-Dichloropropane

-------
FINAL
09-29-2016
APPENDIX A. SCREENING PROVISIONAL VALUES
No provisional screening values are derived.
90
1,2-Dichloropropane

-------
FINAL
09-29-2016
APPENDIX B. DATA TABLES
Table B-l. Selected Hematology, Clinical Chemistry, and Organ Weight Findings in Male
S-D Rats Administered 1,2-Dichloropropane via Gavage for 13 Weeks"
Endpoint'
Dose Group, mg/kg-d (ADD, mg/kg-d)b
0
100 (71.4)
250 (179)
500 (357)
Hematology
Hct (%):
13	wk
14	wk (1-wk recovery)
46.9 ±0.5
46.9 ±0.5
46.4 ± 0.6 (-1%)
47.4 ± 0.8 (+1%)
39.8 ± 1.1* (-15%)
46.6 ± 1.1 (-1%)
39.3 ± 2.2* (-16%)
NDr"1
Hb (g/dL):
13	wk
14	wk (1-wk recovery)
15.8 ±0.1
15.8 ±0.1
15.2 ± 0.4 (-4%)
15.0 ± 0.2 (-5%)
10.4 ± 0.4* (-34%)
12.6 ± 1.0* (-20%)
9.8 ± 0.5* (-38%)
NDr*1
Clinical chemistry
OCT (nmol C02
released/mL serum/24 hr):
2 wk
4 wk
6 wk
8 wk
10 wk
12 wk
49 ± 17
22 ±6
45 ±2
38 ±4
69 ± 11
15 ±8
76 ± 8 (+55%)
54 ± 5 (+145%)
52 ± 9 (+16%)
46 ± 8 (+21%)
68 ± 7 (-1%)
33 ± 9 (+120%)
92 ± 6 (+88%)
69 ± 12* (+214%)
28 ± 6* (-38%)
52 ± 4 (+37%)
85 ± 7 (+23%)
141 ± 16* (+840%)
66 ± 9 (+35%)
64 ±7* (+191%)
64 ± 6 (+42%)
81 ±9* (+113%)
114 ±21 (+65%)
148 ± 30* (+887%)
Bilirubin (mg/dL):
2 wk
4 wk
6 wk
8 wk
10 wk
12 wk
0.06 ± 0.02
0.09 ±0.02
0.08 ±0.00
0.09 ±0.01
0.39 ±0.02
0.03 ±0.00
0.06 ±0.01 (0%)
0.22 ±0.10 (+144%)
0.14 ±0.03 (+75%)
0.15 ±0.03 (+67%)
0.56 ± 0.04* (+44%)
0.27 ± 0.04* (+800%)
0.25 ±0.03* (+317%)
0.21 ±0.01* (+133%)
0.26 ± 0.06* (+225%)
0.24 ±0.03* (+167%)
0.62 ±0.12 (+59%)
0.20 ± 0.02* (+567%)
0.32 ± 0.08* (+433%)
0.30 ± 0.05* (+233%)
1.36 ±0.06* (+1,600%)
0.75 ±0.18* (+733%)
1.15 ±0.19* (+195%)
0.32 ± 0.04* (+967%)
Nonprotein sulfhydryls (jimol/g tissue)
Liver:
13	wk
14	wk (1-wk recovery)
7.2 ±0.3
7.2 ±0.3
6.9 ± 0.3 (-4%)
8.0 ±0.3 (+11%)
9.9 ± 0.4* (+38%)
8.2 ± 0.4 (+14%)
10.3 ± 0.5* (+43%)
NDr"1
Kidney:
13	wk
14	wk (1-wk recovery)
2.2 ±0.2
2.2 ±0.2
2.6 ±0.1 (+18%)
2.9 ±0.1 (+32%)
3.3 ±0.2* (+50%)
2.6 ±0.1 (+18%)
3.1 ±0.4* (+41%)
NDr"1
91
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-l. Selected Hematology, Clinical Chemistry, and Organ Weight Findings in Male
S-D Rats Administered 1,2-Dichloropropane via Gavage for 13 Weeks"
Endpoint'
Dose Group, mg/kg-d (ADD, mg/kg-d)b
0
100 (71.4)
250 (179)
500 (357)
Relative organ weights® (g/100 g body weight)
Liver:
13	wk
14	wk (1-wk recovery)
3.04 ± 0.08b
NDr
3.29 ±0.15 (+8%)
3.25 ± 0.06 (+7%)
3.86 ±0.08* (+27%)
3.64 ±0.09* (+20%)
4.23 ± 0.24* (+39%)
NDr"1
Kidney:
13	wk
14	wk (1-wk recovery)
0.63 ±0.03
NDr
0.62 ± 0.02 (-2%)
0.62 ± 0.02 (-2%)
0.65 ± 0.03 (+3%)
0.65 ±0.01 (+3%)
0.72 ±0.03* (+14%)
NDr"1
Spleen:
13	wk
14	wk (1-wk recovery)
0.20 ±0.01
NDr
0.21 ±0.01 (+5%)
0.19 ±0.00 (-5%)
0.40 ± 0.04* (+100%)
0.28 ±0.01* (+40%)
0.61 ± 0.06* (+205%)
NDr"1
"Bruckner et al. (1989).
bADD = dose x (5 days/7 days).
°Values are expressed as mean ± SEM (percent change compared with control) for 6-8 rats/group; % change
control = ([treatment mean - control mean] + control mean) x 100.
dNDr = not determined; all surviving rats in the high-dose group were sacrificed at 13 weeks.
"Absolute organ weights were not reported by the study authors. Body weights were reported graphically.
* Significantly different from controls at p< 0.05, as reported by the study authors (ANOVA or Kruskal-Wallis
method).
ADD = adjusted daily dose; Hb = hemoglobin; Hct = hematocrit; NDr = not determined; S-D = Sprague-Dawley;
SEM = standard error of the mean.
92
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-2. Body Weight in Rats Administered 1,2-Dichloropropane via Gavage
5 Days/Week for 13 Weeks"
Parameters0
Dose Group, mg/kg-d (ADD, mg/kg-d)b
0
20 (14)
65 (46)
200 (143)
Males
Initial weight (g) (D 1)
188.7 ±6.6
188.2 ± 6.2 (0)
187.9 ±7.0 (0)
189.1 ±5.3 (0%)
Weight at end of exposure (g)
(D 91)
341.7 ± 11.2
334.9 ± 13.7 (-2%)
331.0 ±25.7* (-3%)
308.0 ± 14.8* (-10%)
Weight at end of recovery
period (g) (D 152)
377.0 ± 11.0
367.4 ± 16.5 (-3%)
363.2 ± 16.1 (-4%)
345.4 ± 22.7* (-8%)
Females
Initial weight (g) (D 1)
138.0 ±5.5
139.7 ± 4.3 (+1%)
139.9 ± 4.6 (+1%)
142.6 ± 8.4 (+3%)
Weight at end of exposure (g)
(D 91)
195.8 ± 10.2
201.0 ± 11.4 (+3%)
199.2 ± 10.3 (+2%)
189.3 ± 10.1 (-3%)
Weight at end of recovery
period (g) (D 152)
213.5 ±7.9
218.9 ± 13.4 (+3%)
213.5 ± 12.4(0)
205.7 ± 12.2 (-4%)
"Dow Chemical Co (1988b).
bADD = dose x (5 days/7 days).
°Values expressed as mean ± SD (percent change compared with control) for 11-15 rats; % change
control = ([treatment mean - control mean] control mean) x 100.
* Statistically significantly different from the controls at p< 0.05, as reported by the study authors (by Dunnett's or
Wilcoxon's test).
ADD = adjusted daily dose; SD = standard deviation.
93
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-3. Survival and Terminal Body Weights of F334/N Rats Administered
1,2-Dichloropropane via Gavage for 13 Weeks3
Parameter
Dose Group, mg/kg-d (ADD, mg/kg-d)b
Males
0(0)
60 (43)
125 (89.3)
250 (179)
500 (357)
1,000 (714)
Survival
10/10
10/10
10/10
10/10
5/10d
0/10d
Terminal body weight
(g)c
300.1 ±7.8
334.3 ±7.7d
(+11%)
308.2 ±8.3
(+3%)
297.7 ±4.0
(-1%)
252.4 ± 14.7d
(-16%)
NAe
Females
0(0)
60 (43)
125 (89.3)
250 (179)
500 (357)
1,000 (714)
Survival
10/10
10/10
10/10
10/10
10/10
0/10d
Terminal body weight
(g)c
188.2 ±2.9
191.5 ±3.7
(+2)
191.2 ±3.7
(+2)
183.7 ±4.5
("2)
173.3 ±3.0d
("8)
NAe
"NTP (1986).
bADD = dose x (5 days/7 days).
°Values are expressed as mean ± SEM (percent change compared with control) for rats surviving to 13 weeks;
% change control = ([treatment mean - control mean] + control mean) x 100.
Statistically significantly different from controls at p< 0.05, as calculated for this review (Fisher's exact test,
Student /-test; 2-tailed).
eNA = not applicable; no body-weight data were presented by the study authors due to 100% mortality in the
high-dose animals.
ADD = adjusted daily dose; NA = not applicable; SEM = standard error of the mean.
Table B-4. Survival and Terminal Body Weights for F334/N Rats Administered
1,2-Dichloropropane via Gavage for 103 Weeks"
Parameter
Dose Group, mg/kg-d (ADD, mg/kg-d)b
Males
0(0)
62 (45)
125 (89.3)
Survival0
39/50 (78%)
42/50 (84%)
41/50 (82%)
Terminal body weight (g)d
459
444 (-3%)
413 (-10%)
Females
0(0)
125 (89.3)
250 (179)
Survival0
37/50 (74%)
43/50 (86%)
16/50* (32%)
Terminal body weight (g)d
321
308 (-4%)
252 (-21%)
"NTP (1986).
bADD = dose x (5 days/7 days).
°Values expressed as number of animals alive at 103 weeks/number of animals at start of study (% survival).
dValues are expressed as mean (percent change compared with control) for rats surviving to 103 weeks; % change
control = ([treatment mean - control mean] + control mean) x 100.
* Statistically significantly different from controls at p< 0.001, as reported by the study authors (Cox's method).
ADD = adjusted daily dose.
94
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-5. Non-neoplastic and Neoplastic Lesions in Female F334/N Rats Administered
1,2-Dichloropropane via Gavage for 103 Weeks3

Dose Group, mg/kg-d (ADD, mg/kg-d) [HED, mg/kg-d]b
0(0)
125 (89.3) [21.4]
250 (179) [42.9]
Non-neoplastic lesions0
Mammary gland hyperplasia
10/50 (20%)
20/50d (40%)
1/50 (2%)
Spleen:
Hemosiderosis
Hematopoiesis
0/50 (0%)
1/50 (2%)
0/50 (0%)
1/50 (2%)
20/47d (43%)
7/47d (15%)
Liver:
Clear cell foci
Necrosis (combined):
Focal necrosis
Centrilobular necrosis
3/50 (6%)
2/50 (4%)
1/50 (2%)
1/50 (2%)
5/50 (10%)
1/50 (2%)
0/50 (0%)
1/50 (2%)
1 l/50d (22%)
12/50d (24%)
3/50 (6%)
9/50d (18%)
Neoplastic lesions
Mammary gland adenocarcinoma:
Overall rates0
Adjusted rates6
1/50 (2%)
2.7%
2/50 (4%)
4.7%
5/50 (10%)
26.7%*
Uterine endometrial stromal polyp:
Overall rates0
Adjusted rates0
10/50 (20%)
25.1%+
17/49 (35%)
37.5%
11/50 (22%)
45.6%
aNTP (1986).
bADD = dose x (5 days/7 days); HEDs were calculated using species-specific DAFs based on the animal:human
BW1/4 ratio recommended by U.S. EPA (2011b): rat:human ratio = 0.24.
0Values reported as number of animals with lesion/number of animals evaluated (% incidence).
Statistically significantly different from controls atp< 0.05, as calculated for this review (Fisher's exact test).
"Adjusted for intercurrent mortality.
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Fisher's exact test,
life table test, or incidental tumor test).
f Statistically significant dose-related trend (p < 0.05), as reported by the study authors (Cochran-Armitage trend
test, life table test, or incidental tumor test).
ADD = adjusted daily dose; B W = body weight; DAF = dosimetric adjustment factor; HED = human equivalent
dose.
95
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-6. Non-neoplastic and Neoplastic Lesions in Male and Female B6C3Fi Mice
Administered 1,2-Dichloropropane via Gavage for 103 Weeks3

Dose Group, mg/kg-d (ADD, mg/kg-d) [HED, mg/kg-d]b
0(0)
125 (89.3) [12.5]
250 (179) [25.1]
Non-neoplastic lesions in males0
Liver:
Hepatocytomegaly
Necrosis (focal, NOS and centrilobular, combined)
3/50 (6%)
2/50 (4%)
5/49 (10%)
5/49 (10%)
15/50d (30%)
10/50d (20%)
Neoplastic lesions in males
Liver tumors:
Adenoma
Overall rates0
Adjusted rates6
Carcinoma
Overall rates0
Adjusted rates0
Carcinoma or adenoma (combined)
Overall rates0
Adjusted rates0
7/50t (14%)
20%t
11/50 (22%)
28.1%
18/50"!" (36%)
46.7%t
10/50 (20%)
28.8%
17/50 (34%)
41.9%
26/50 (52%)
62.9%
17/50* (34%)
45.5%*
16/50 (32%)
37.3%
33/50* (66%)
74.7%*
Neoplastic lesions in females
Liver tumors:
Adenoma
Overall rates0
Adjusted rates0
Carcinoma
Overall rates0
Adjusted rates0
Ademona or carcinoma (combined)
Overall rates0
Adjusted rates0
1/50 (2%)
2.9%t
1/50 (2%)
2.9%
2/50"! (4o/o)
5.7%t
5/50 (10%)
17.2%
3/50 (6%)
9.7%
8/50* (16%)
26.4%*
5/50 (10%)
19.25%*
4/50 (8%)
12.6%
9/50* (18%)
30.8%*
Thyroid follicular cell tumors:
Ademona or carcinoma (combined)
Overall rates0
Adjusted rates0
l/48t (2%)
2.9%t
0/45 (0%)
0%
5/46(11%)
20.8%*
aNTP (1986).
bADD = dose x (5 days/7 days); HEDs were calculated using species-specific DAFs based on the animal:human
BW1'4 ratio recommended by U.S. EPA (2011b): mouse:human ratio = 0.14.
0Values reported as number of animals with lesion/number of animals evaluated (% incidence).
Statistically significantly different from controls atp< 0.05, as calculated for this review (Fisher's exact test).
"Adjusted for intercurrent mortality.
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Fisher's exact test,
life table test, or incidental tumor test).
f Statistically significant dose-related trend (p < 0.05), as reported by the study authors (Cochran-Armitage trend
test, life table test, or incidental tumor test).
ADD = adjusted daily dose; B W = body weight; DAF = dosimetric adjustment factor; HED = human equivalent
dose.
96
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-7. Body Weights and Water Intake for F0 Male and Female S-D Rats
Administered 1,2-Dichloropropane in Drinking Water for 16-18 Weeks"
F0 Males0
Exposure Group, % in Drinking Water (TWA doses, mg/kg-d)b
0
0.024 (24.8)
0.10 (82.7)
0.24 (152)
Body weights (g)
Wk 1
263.1 ±27.7
261.4 ± 21.9 (-1%)
253.2 ±25.7 (-4%)
237.8 ±31.9* (-10%)
End of premating (Wk 10)
524.8 ±39.9
522.2 ± 40.3 (0)
501.5 ±46.3 (-4%)
465.7 ±38.3* (-11%)
End of postmating (Wk 18)
575.8 ±47.9
577.8 ±45.5 (0)
559.6 ± 55.0 (-3%)
525.0 ± 45.0* (-9%)
Water intake (g/dayj
Wk 1
36.4 ±5.6
35.5 ±5.1 (-2%)
28.7 ± 3.7e (-21%)
20.4 ± 3.2e (-44%)
End of premating (Wk 10)
41.5 ±4.8
40.4 ± 7.9 (-3%)
36.1 ± 6.7e (-13%)
23.6 ± 4.3e (-43%)
End of postulating (Wk 18)
40.7 ± 10.2
40.9 ± 7.5 (0)
30.9 ± 5.0e (-24%)
23.5 ± 4.1e (-42%)
F0 Females0
Exposure Group, % in Drinking Water (TWA doses, mg/kg-d)d
0
0.024 (38.8)
0.10 (127)
0.24 (254)
Body weights (g)
Wk 1
149.8 ±8.0
151.7 ± 11.9 (+1%)
150.3 ±9.3 (0)
146.8 ± 8.7 (-2%)
End of premating (Wk 10)
279.1 ±25.9
293.1 ±24.0 (+5%)
285.1 ±31.1 (+2%)
268.3 ±21.0 (-4%)
End of gestation (Wk 15)
428.9 ±38.4
441.5 ±36.4 (+3%)
416.9 ±31.9 (-3%)
383.9 ±30.6* (-10%)
End of lactation (Wk 18)
337.7 ±25.1
334.7 ± 19.0 (-1%)
317.8 ±22.6* (-6%)
290.6 ± 18.9* (-14%)
Water intake (g/day)
Wk 1
28.4 ±6.4
27.4 ± 6.3 (-4%)
21.5 ± 2.1e (-24%)
15.4 ± 2.2e (-46%)
End of premating (Wk 10)
34.7 ± 11.6
33.9 ±7.0 (-2%)
27.9 ± 6.T (-20%)
19.1 ± 3.4e (-45%)
End of gestation (Wk 15)
57.2 ±8.2
62.9 ± 14.7 (+10%)
45.1 ± 12.9e (-21%)
30.4 ± 5.4e (-47%)
End of lactation (Wk 18)
129.0 ±29.5
112.8 ± 16.5e ("13%)
90.9 ± 15.8® (-30%)
79.7 ± 19.2e (-38%)
aDow Chemical Co (1990).
bl,2-DCP intakes for F0 males in the 0.024, 0.1, and 0.24% exposure groups were calculated by the study authors
using body weight and water consumption data for the premating time period (28.0, 91.1, and 162 mg/kg-day,
respectively) and postulating time period (18.1, 65.2, and 131 mg/kg-day, respectively). A TWA dose was
calculated for the entire study duration for this review using the following formula: ([premating dose x premating
duration] + [postulating dose x postulating duration]) + total duration. Pre- and postmating durations for the
F0 generation were 71 and 34 days, respectively.
°Values expressed as mean ± SD (percent change compared with control) for 14-29 rats/group; % change
control = ([treatment mean - control mean] + control mean) / 100.
dl,2-DCP intakes for F0 females in the 0.024, 0.1, and 0.24% exposure groups were calculated by the study authors
using body weight and water consumption data for the premating time period (33.2, 108, and 189 mg/kg-day,
respectively), gestation time period (38.4, 121, and 217 mg/kg-day, respectively), and lactation time period (58.3,
197, and 507 mg/kg-day, respectively). A TWA dose was calculated for the entire study duration for this review
using the following formula: ([premating dose x premating duration] + [gestation dose x gestation
duration] + [lactation dose x lactation duration]) + total duration. Premating, gestation, and lactation durations for
the F0 generation were 71,21, and 21 days, respectively.
"Statistically significantly different from the controls atp < 0.05, as calculated for this review (Student's t-test).
* Statistically significantly different from control at p< 0.05, as reported by the study authors (Dunnett's test).
S-D = Sprague-Dawley; TWA = time-weighted average; SD = standard deviation.
97
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-8. Neonatal Survival and Body Weights of F1 Pups of S-D Rats Administered
1,2-Dichloropropane in Drinking Water for 18 Weeks11

Exposure Group, % in Drinking Water (TWA doses, mg/kg-d)b
0
0.024 (38.8)
0.10 (127)
0.24 (254)
Survival index
PND 0C
98.7 (441/447)
98.3 (410/417)
99.5 (374/376)
99.0 (378/382)
PND ld
99.1 (437/441)
98.8 (405/410)
97.9 (366/374)
96.8 (366/378)*
PND 4d
98.2 (433/441)
94.5 (388/410)
94.7 (354/374)
88.4 (334/378)*
PND T
100 (231/231)
99.5 (219/220)
99.0 (196/198)
95.6 (196/205)*
PND 14e
100 (231/231)
99.5 (219/220)
99.0 (196/198)
92.2 (189/205)*
PND 21e
99.6 (230/231)
99.5 (219/220)
99.0 (196/198)
91.7 (188/205)*
Body weights (g)f
PND 1
6.4 ±0.6
6.8 ± 0.6* (+6%)
6.4 ± 0.9 (0)
5.9 ± 0.6* (-8%)
PND 4:
Before culling
After culling
8.7 ± 1.1
8.7 ± 1.1
9.4 ± 1.4 (+8%)
9.4 ± 1.4 (+8%)
8.8 ± 1.9 (+1%)
8.8 ± 1.8 (+1%)
7.7 ± 1.3* (-11%)
7.7 ± 1.3* (-11%)
PND 7:
Male
Female
15.1 ± 1.9
14.5 ± 1.6
15.7 ± 2.2 (+4%)
15.2 ± 2.0 (+5%)
14.9 ± 2.6 (-1%)
14.1 ±2.1 (-3%)
13.2 ±2.5* (-13%)
12.4 ± 2.2* (-14%)
PND 14:
Male
Female
32.0 ±2.8
31.4 ±2.6
32.9 ±3.4 (+3%)
32.1 ±3.3 (+2%)
31.2 ±3.5 (-2%)
29.5 ± 2.4 (-6%)
27.9 ±3.5* (-13%)
26.3 ± 3.3 (-16%)
PND 21:
Male
Female
51.7 ±5.1
49.9 ±4.1
53.9 ±5.6 (+4%)
51.9 ±5.1 (+4%)
50.7 ± 5.6 (-2%)
48.2 ±3.9 (-3%)
44.3 ± 5.2* (-14%)
42.6 ±4.1* (-15%)
aDow Chemical Co (1990).
bl,2-DCP intake for nursing offspring is based on TWA maternal doses. See Footnote D in Table B-6 for TWA
dose calculations for F0 females.
cValue expressed as % (number of live pups at birth/total number of pups at birth).
dValue expressed as % (number of live pups/number of live pups at birth).
"Values expressed % (number of live pups/number of pups after culling).
fValues expressed as mean ± SD (percent change compared with control) for 334-443 pups/group (prior to culling)
and 94-116 per sex per group after culling; % change control = ([treatment mean - control mean] control
mean) x 100.
* Statistically significantly different from control at p< 0.05, as reported by the study authors (Dunnett's test).
S-D = Sprague-Dawley; TWA = time-weighted average; SD = standard deviation.
98
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-9. Hematological Parameters for F0 Male and Female S-D Rats Administered
1,2-Dichloropropane in Drinking Water for 18 Weeks11
F0 Males
Exposure Group, % in Drinking Water (TWA doses, mg/kg-d)b
0
0.024 (24.8)
0.10 (82.7)
0.24 (152)
Hematology0
RBC (x 106/mm3)
7.41 ±0.32
7.07 ± 0.22* (-5%)
7.25 ± 0.20 (-2%)
7.11 ±0.37 (-4%)
Hb (g/dL)
16.4 ± 1.2
15.9 ± 9.5 (-3%)
16.0 ± 0.4 (-2%)
16.3 ± 0.9 (-1%)
Hct (%)
43.9 ±2.3
42.7 ± 1.3 (-3%)
43.4 ± 1.1 (-1%)
44.1 ± 2.3 (0%)
Platelet (x 103/mm3)
1,170 ± 156
1,064 ± 114 (-9%)
1,132 ± 104 (-3%)
984 ± 144* (-16%)
Reticulocytes (%)
1.5 ±0.8
1.0 ±0.3 (-33%)
1.2 ± 0.3 (-20%)
0.9 ± 0.3 (-40%)
F0 Females
Exposure Group, % in Drinking Water (TWA doses, mg/kg-d)d
0
0.024 (38.8)
0.10 (127)
0.24 (254)
Hematology0
RBC (x 106/mm3)
7.21 ±0.45
6.77 ± 0.36 (-6%)
6.98 ±0.48 (-3%)
6.56 ±0.33* (-9%)
Hb (g/dL)
17.8 ± 1.1
16.6 ± 0.6* (-7%)
17.1 ± 1.4 (-4%)
16.2 ± 0.5* (-9%)
Hct (%)
46.4 ±2.5
44.3 ± 2.1 (-5%)
45.3 ± 3.3 (-2%)
43.0 ± 1.5* (-7%)
Platelet (x 103/mm3)
1,080 ± 120
960 ± 172 (-11%)
1,124 ± 93 (+4%)
1,033 ± 124 (-4%)
Reticulocytes (%)
0.3 ±0.1
0.5 ± 0.2 (+67%)
0.4 ± 0.2 (+33%)
0.7 ±0.3* (+133%)
aDow Chemical Co (1990).
bSee Footnote B in Table B-7 for TWA dose calculations for F0 males.
°Values expressed as mean ± SD (percent change compared with control) for 10/sex/group; % change
control = ([treatment mean - control mean] + control mean) x 100.
dSee Footnote D in Table B-7 for TWA dose calculations for F0 females.
* Statistically significantly different from control at p< 0.05, as reported by the study authors (Dunnett's test).
Hb = hemoglobin; Hct = hematocrit; RBC = red blood cell; S-D = Sprague-Dawley; TWA = time-weighted
average; SD = standard deviation.
99
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-10. Select Histopathological Observations of the Liver of F0 and F1 S-D Rats
Administered 1,2-Dichloropropane in Drinking Water for 18-21 Weeks"
F0 Males
Exposure Group, % in Drinking Water (TWA doses, mg/kg-d)b
0
0.024 (24.8)
0.10 (82.7)
0.24 (152)
Increased cytoplasmic granularity0:
Panlobular, slight
Central lobular and midzonal, very slight
Central lobular and midzonal, slight
0/30 (0%)
2/30 (7%)
0/30 (0%)
0/30 (0%)
3/30 (10%)
2/30 (7%)
0/30 (0%)
2/30 (7%)
4/30 (13%)
3/30 (10%)
2/30 (7%)
7/30d (23%)
F0 Females
Exposure Group, % in Drinking Water (TWA doses, mg/kg-d)e
0
0.024 (38.8)
0.10 (127)
0.24 (254)
Increased cytoplasmic granularity0:
Panlobular, slight
Central lobular and midzonal, very slight
Central lobular and midzonal, slight
0/30 (0%)
0/30 (0%)
0/30 (0%)
0/30 (0%)
4/30 (13%)
4/30 (13%)
1/30 (3%)
2/30 (7%)
1/30 (3%)
2/30 (7%)
6/3 0d (20%)
9/30d (30%)
F1 Males
Exposure Group, % in Drinking Water (TWA doses, mg/kg-d)f
0
0.024 (28.3)
0.10 (109)
0.24 (213)
Increased cytoplasmic granularity0:
Central lobular and midzonal, very slight
Central lobular and midzonal, slight
1/30 (3%)
0/30 (0%)
3/30 (10%)
1/30 (3%)
2/30 (7%)
2/30 (7%)
2/30 (7%)
3/30 (10%)
F1 Females
Exposure Group, % in Drinking Water (TWA doses, mg/kg-d)g
0
0.024 (42.7)
0.10 (148)
0.24 (293)
Increased cytoplasmic granularity0:
Central lobular and midzonal, very slight
Central lobular and midzonal, slight
2/30 (7%)
0/30 (0%)
2/30 (7%)
1/30 (3%)
2/30 (7%)
0/30 (0%)
5/30 (17%)
5/3 0h (17%)
aDow Chemical Co (1990).
bSee Footnote B in Table B-7 for TWA dose calculations for F0 males.
°Values expressed as number of animals with lesion/number of animals examined (% incidence).
Statistically significantly different from the controls atp< 0.05, as calculated for this review (2-tailed, Fisher's
exact test).
eSee Footnote D in Table B-7 for TWA dose calculations for F0 females.
fl,2-DCP intakes for F1 males in the 0.024, 0.1, and 0.24% exposure groups were calculated by the study authors
using body weight and water consumption data for the premating time period (32.7, 128, and 250 mg/kg-day,
respectively) and postulating time period (19.4, 69.5, and 137 mg/kg-day, respectively). A TWA dose was
calculated for the entire study duration for this review using the following formula: ([premating dose x premating
duration] + [postulating dose x postulating duration]) total duration. Premating and postmating durations for the
F1 generation were 88 and 43 days, respectively.
gl,2-DCP intakes for F1 females in the 0.024, 0.1, and 0.24% exposure groups were calculated by the study authors
using body weight and water consumption data for the premating time period (40.6, 140.0, and 269 mg/kg-day,
respectively), gestation time period (37.9, 126, and 239 mg/kg-day, respectively), and lactation time period (26.4,
200.0, and 450.0 mg/kg-day, respectively). A TWA dose was calculated for the entire study duration for this
review using the following formula: ([premating dose x premating duration] + [gestation dose x gestation
duration] + [lactation dose x lactation duration]) total duration. Premating, gestation, and durations for the
F1 generation were 88, 21, and 21 days, respectively.
hNear-significant different from the controls at p = 0.0522, as calculated for this review (2-tailed, Fisher's exact
test).
S-D = Sprague-Dawley; TWA = time-weighted average.
100
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-ll. Body Weights and Water Intake for F1 Male and Female S-D Rats
Administered 1,2-Dichloropropane in Drinking Water for 21 Weeks11
F1 Males
Exposure Group, % in Drinking Water (TWA doses, mg/kg-d)b
0
0.024 (28.3)
0.10 (109)
0.24 (213)
Body weights (g)c
PND 21 (weaning)
118.6 ± 23.1
126.8 ± 17.6 (+7%)
121.0 ±21.0 (+2%)
105.2 ± 15.9* (-11%)
End of premating (Wk 11)
582.1 ±47.7
585.8 ± 53.2 (+1%)
578.1 ± 55.5 (-1%)
503.2 ±36.6* (-14%)
End of postmating (Wk 21)
666.8 ± 64.0
662.5 ±61.5 (-1%)
656.8 ± 68.2 (-1%)
572.2 ±43.6* (-14%)
Water intake (g/day)c
Wk 1
30.0 ±5.3
28.9 ± 7.0 (-4%)
27.3 ± 3.8d (-9%)
19.3 ± 3.2d (-36%)
End of premating (Wk 11)
66.8 ±21.8
54.0 ± 14.0d (-19%)
47.6 ± 17.0d (-29%)
33.9 ± 6.7d (-49%)
End of postmating (Wk 21)
54.4 ± 12.0
41.6 ± 9.9d (-24%)
39.8 ± 7.8d (-27%)
29.6 ± 7.7d (-46%)
F1 Females
Exposure Group, % in Drinking Water (TWA doses, mg/kg-d)e
0
0.024 (42.7)
0.10 (148)
0.24 (293)
Body weights (g)c
PND 21 (weaning)
112.1 ±23.4
119.2 ± 11.3 (+6%)
114.8 ± 17.5 (+2%)
96.4 ± 13.8* (-14%)
End of premating (Wk 11)
323.8 ±37.7
328.6 ± 25.4 (+1%)
313.6 ±32.5 (-3%)
293.6 ±32.0* (-9%)
End of gestation (Wk 18)
465.7 ±48.4
461.2 ±40.5 (-1%)
434.6 ±58.1 (-7%)
402.8 ± 44.0* (-14%)
End of lactation (Wk 21)
347.8 ±26.0
343.1 ± 20.5 (-1%)
337.6 ±31.0 (-3%)
306.3 ± 27.8* (-12%)
Water intake (g/day)c
Wk 1
32.6 ±8.5
27.3 ± 3.1d (-16%)
25.2 ± 4.8d (-23%)
17.8 ± 3.0d (-45%)
End of premating (Wk 11)
39.6 ±7.5
36.2 ± 6.3 (-9%)
39.6 ± 16.1 (0%)
26.0 ± 6.4d (-34%)
End of gestation (Wk 18)
67.8 ±21.5
69.6 ±30.1 (+3%)
44.9 ± ll.ld (-34%)
30.7 ± 8.2d (-55%)
End of lactation (Wk 21)
119.8 ±28.6
124.6 ±23.4 (+4%)
104.1 ± 13.7d (-13%)
85.8 ± 18.7d (-28%)
aDow Chemical Co (1990).
bSee Footnote F in Table B-10 for TWA dose calculations for F1 males.
°Values expressed as mean ± SD (percent change compared with control) for 21-30 rats/group; % change
control = ([treatment mean - control mean] control mean) x 100.
Statistically significantly different from the controls atp< 0.05, as calculated for this review (Student's /-test).
eSee Footnote G in Table B-10 for TWA dose calculations for F1 females.
* Statistically significantly different from control at p< 0.05, as reported by the study authors (Dunnett's test).
PND = postnatal day; S-D = Sprague-Dawley; TWA = time-weighted average; SD = standard deviation.
101
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-12. Body Weight and Food Consumption Data for Pregnant S-D Rats
Administered 1,2-Dichloropropane via Gavage on GDs 6-15a

Dose Group (mg/kg-d)
Parameterb
0
50
125
250
500
Number of pregnant animals0
4/10
9/10
8/10
6/9d
10/10
Body-weight gain (g):
GDs 6-9
GDs 6-16
GDs 0-16
9.6 ±2.7
56.1 ± 14.6
99.4 ± 13.4
6.9 ± 15.4
(-28%)
39.8 ±21.4
(-29%)
82.5 ± 17.9
(-17%)
-19.3 ± 15.7*
(-301%)
37.4 ± 10.5
(-33%)
88.1 ± 16.1
(-11%)
—25.9 ± 7.8*
(-370%)
49.9 ± 11.5
(-11%)
102.4 ± 16.8
(+3%)
-35.2 ± 11.2*
(-467%)
-7.0 ±34.1*
(-112%)
41.8 ± 33.3*
(-58%)
Terminal body weight (g)
339.9 ± 12.2
336.0 ± 11.7
(-1%)
341.8 ±25.4
(+1%)
355.1 ±24.5
(+4%)
297.1 ±31.7*
(-13%)
Food consumption (g/d):
GDs 6-9
GDs 9-12
GDs 12-16
22.0 ± 1.6
23.5 ± 1.3
24.5 ± 1.9
19.8 ±2.8
(-10%)
21.2 ±2.4
(-10%)
24.6 ±5.2
(0%)
15.2	± 5.6e
(-31%)
21.3	± 1.7e
(-9%)
24.2 ±2.3
(-1%)
12.6 ± 3.3e
(-43%)
22.9 ±5.1
(-3%)
23.6 ± 1.2
(-4%)
11.5 ± 5.7e
(-48%)
18.4 ±7.4
(-22%)
28.9 ± 11.2
(+18%)
aDow Chemical Co (1989c).
bValues are expressed as mean ± SD (percent change compared with control); % change control = ([treatment
mean - control mean] + control mean) x 100.
°Body weight and food consumption data were only reported for the females with confirmed pregnancies.
dOne dam died on GD 7 due to gavage error.
"Statistically significantly different from the controls at p< 0.05, as calculated for this review (2-tailed
Student's /-test).
* Statistically significantly different from the controls at p< 0.05, as reported by the study authors.
GD = gestation day; S-D = Sprague-Dawley; SD = standard deviation.
102
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-13. Maternal Body Weights and Body-Weight Gain in Pregnant S-D Rats
Administered 1,2-Dichloropropane via Gavage on GDs 6-15a
Parameterb
Dose Group (mg/kg-d)
0
10
30
125
Body weight (g)
GD 0
261.5 ± 14.8
268.1 ± 16.9 (+3%)
267.2 ± 15.8 (+2%)
268.2 ± 17.2 (+3%)
GD 6
302.3 ± 17.6
306.0 ± 17.6 (+1%)
304.6 ± 16.7 (+1%)
303.8 ± 17.9(0%)
GD 9
314.1 ± 19.8
318.4 ± 17.1 (+1%)
315.2 ± 17.0(0%)
301.2 ± 18.0* (-4%)
GD 12
332.4 ±22.4
335.3 ± 17.9 (+1%)
332.0 ± 18.7 (0%)
316.5 ± 19.2* (-5%)
GD 16
365.1 ±24.5
368.1 ±19.5 (+1%)
364.5 ± 22.0 (0%)
348.8 ± 19.3* (-4%)
GD 21
450.7 ±36.0
457.8 ± 27.6 (+2%)
456.1 ±30.7 (+1%)
438.7 ± 26.7° (-3%)
Body-weight gain (g)
GDs 0-6
40.8 ±8.4
37.9 ± 7.2 (-7%)
37.2 ± 8.0 (-9%)
35.6 ± 10.7 (-13%)
GDs 6-9
11.8 ± 5.1
12.4 ± 5.7 (+5%)
10.5 ±4.5 (-11%)
-2.6 ± 9.9* (-122%)
GDs 9-12
18.8 ±6.5
16.9 ±5.1 (-10%)
16.9 ±6.1 (-10%)
15.3 ± 8.3 (-19%)
GDs 12-16
32.2 ±7.5
32.7 ± 7.0 (+2%)
32.5 ± 6.0 (+1%)
32.4 ± 8.3 (+1%)
GDs 6-16
85.6 ± 14.6
88.3 ± 14.0 (+3%)
91.6 ± 14.4 (+7%)
89.8 ± 14.8 (+5%)
GDs16-21
62.9 ± 12.1
62.1 ± 9.7 (-1%)
59.9 ± 9.8 (-5%)
45.0 ± 8.6°* (-28%)
GDs0-21
189.2 ±30.0
188.8 ±23.7(0%)
188.7 ±23.5 (0%)
170.5 ±23.7C* (-10%)
"Kirk et al. (1995): Dow Chemical Co (1989d).
bValues are expressed as mean ± SD (percent change compared with control) of 25-30 dams/dose; % change
control = ([treatment mean - control mean] control mean) x 100.
Data from dam that delivered early were excluded from analysis.
* Statistically significantly different from control at p< 0.05, as reported by the study authors (Dunnett's or
Wilcoxon's test).
GD = gestation day; S-D = Sprague-Dawley; SD = standard deviation.
103
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-14. Skeletal Variations in Fetuses from S-D Dams Administered
1,2-Dichlropropane via Gavage on GDs 6-15a
Parameter
Dose Group (mg/kg-d)
0
10
30
125
Delayed ossification, skull:
Fetal incidence13
Litter incidence0
9/378 (2%)
8/25 (32%)
8/435 (2%)
8/28 (29%)
19/440 (4%)
10/28 (36%)
37/449* (8%)
16/30* (53%)
Delayed ossification, cervical centra:
Fetal incidence13
Litter incidence0
50/378 (13%)
21/25 (84%)
68/435 (16%)
22/28 (79%)
48/440 (11%)
18/28 (64%)
51/449 (11%)
22/30 (73%)
Delayed ossification, thoracic centra:
Fetal incidence13
Litter incidence0
8/378 (2%)
4/25 (16%)
14/435 (3%)
9/28 (32%)
13/440 (3%)
6/28 (21%)
21/449 (5%)
10/30 (33%)
"Kirk et al. (1995): Dow Chemical Co (1989d).
bNumber of fetuses affected/number of fetuses examined (% incidence).
°Number of litters affected/number of fetuses examined (% incidence).
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (censored
Wilcoxon's test).
GD = gestation day; S-D = Sprague-Dawley.
104
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-15. Reproductive Parameters of Pregnant NZW Rabbits Dosed via Gavage with
1,2-Dichloropropane on GDs 7-19a
Parameter
Dose Group (mg/kg-d)
0
25
100
250
Number pregnant (%)
4/7 (57%)
3/7 (43%)
5/7 (71%)
7/7 (100%)
Mortality (%)
0/7 (0%)
0/7 (0%)
0/7 (0%)
2/7 (29%)
Number of live litters (%)
4/4 (100%)
3/3 (100%)
5/5 (100%)
3/5 (60%)
Number of litters totally
resorbed (%)
0/4 (0%)
0/3 (0%)
0/5 (0%)
2/5b (40%)
Resorptions/litter°d
0.5 ±0.6
1.0 ± 0.0 (+2-fold)
1.6 ±2.6 (+3.2-fold)
2.0 ± 2.0 (+4-fold)
% Litters with resorptions
50
100
40
80
"Dow Chemical Co (1988d).
bBoth dams exhibited weight loss.
°Values expressed as mean ± SD (fold-change compared with control) for all dams (included dams with complete
litter resorption); fold-change control = treatment mean + control mean.
historical control values for this laboratory are 0.75 (range 0-2.2) resorptions/litter (data from 29 studies; average
of 7 control does/study).
Note: None of the findings were statistically significant (as reported by the study authors).
GD = gestation day; NZW = New Zealand white; SD = standard deviation.
Table B-16. Selected Hematology in Pregnant NZW Rabbits Dosed via Gavage with
1,2-Dichloropropane on GDs 7-19a
Parameter
Dose Group (mg/kg-d)
0
25
100
250
RBC (x 106/mm3)b
5.67 ±0.43
6.01 ±0.25 (+6%)
4.75 ±0.81 (-16%)
4.35 ± 0.44* (-23%)
Hb (g/dL)b
12.7 ± 1.1
12.9 ± 0.3 (+2%)
10.8 ± 1.7 (-15%)
9.7 ± 1.3* (-24%)
Hct (%)b
42.6 ±3.1
44.1 ± 1.7 (+4%)
36.1 ±5.8 (-15%)
33.4 ±4.2* (-22%)
Reticulocyte (%)b
2.1 ± 1.2
2.5 ± 0.4 (+19%)
4.5 ± 1.0* (+114%)
7.8 ± 1.5* (+271%)
Erythrocyte morphology0:
Polychromasia
Anisocytosis
0/7 (0%)
0/7 (0%)
1/7 (14%)
0/7 (0%)
4/7d (57%)
2/7 (29%)
3/5d (60%)
4/5d (80%)
aDow Chemical Co (1988d).
bValues expressed as mean ± SD (percent change compared with control) for 3-5 rats/group; % change
control = ([treatment mean - control mean] + control mean) x 100.
°Values expressed as number of animals with altered morphology/number of animals evaluated (% incidence).
Statistically significantly different from control at p< 0.05, as calculated for this review (Fisher's exact test).
* Statistically significantly different from control at p< 0.05, as reported by the study authors (Dunnett's test).
GD = gestation day; Hb = hemoglobin; Hct = hematocrit; NZW = New Zealand white; RBC = red blood cell;
SD = standard deviation.
105
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-17. Maternal Body Weights and Body-Weight Gain in Pregnant NZW Rabbits
Administered 1,2-Dichloropropane via Gavage on GDs 7-19a
Parameterb
Dose Group (mg/kg-d)
0
15
50
150
Body weight (g)
GD 0
3,764.5 ± 181.4
3,826.2 ± 187.2 (+2%)
3,849.1 + 283.5 (+2%)
3,860.9 + 233.6 (+3%)
GD 7
3,924.7 ± 199.6
3,962.4 ± 167.1 (+1%)
4,007.4 + 266.6 (+2%)
4,004.2+ 231.4 (+2%)
GD 10
3,930.7 ±201.9
4,014.0 ± 166.4 (+2%)
4,043.7 + 304.5 (+3%)
3,987.0 + 243.4 (+1%)
GD 13
3,960.6 ±214.3
4,043.8 ± 184.0 (+2%)
4,084.3 + 335.0 (+3%)
4,009.1 +254.5 (+1%)
GD 16
3,985.5 ±249.0
4,098.6 ± 196.6 (+3%)
4,125.0 + 346.6 (+4%)
3,947.1 +290.3 (-1%)
GD 20
3,973.3 ±243.3
4,079.6 ± 229.3 (+3%)
4,120.9 + 350.0 (+4%)
3,834.7 + 324.5 (-3%)
GD 28
4,104.9 ±298.2
4,173.8 ±215.2 (+2%)
4,144.6 + 250.4 (+1%)
4,065.1 +334.6 (-1%)
Body-weight gain (g)
GDs 0-7
160.2 ±64.5
136.2 ±93.7 (-15%)
158.3 + 84.3 (-1%)
143.3 + 59.9 (-11%)
GDs 7-10
6.0 ±51.7
51.6 ±54.0 (+760%)
36.3 + 60.0 (+505%)
-17.2 + 56.7 (-387%)
GDs 10-13
29.9 ±61.7
29.9 ±68.1 (0%)
40.6 + 79.6 (+36%)
22.1 + 70.0 (-26%)
GDs 13-16
24.9 ±70.3
54.7 ± 67.4 (+120%)
40.8 + 104.8 (+64%)
-53.3 + 100.5* (-314%)
GDs 16-20
-12.2 ± 107.8
-18.9 ± 105.6 (-55%)
-4.2+ 113.9 (+66%)
-112.4+ 130.6*° (-821%)
GDs 7-20
48.6 ± 151.5
117.2 ± 146.0 (+141%)
113.5 + 197.3 (+134%)
-165.1 + 234.4*c (-440%)
GDs 20-28
131.7 ± 139.4
94.2 ± 182.6 (-28%)
23.8+ 244.9 (-84%)
191.2+ 151.20d (+45%)
GDs 0-28
340.4 ±218.8
347.6 ± 153.2 (+2%)
295.5 + 192.2 (-13%)
194.7 + 211.0°-d (-43%)
aKirk et al (19951
bValues are expressed as mean ± SD (percent change compared with control) of 15-18 dams/dose; % change
control = ([treatment mean - control mean] + control mean) x 100.
Data from a dam that died on GD 17 was excluded from analysis.
dData from a dam that died on GD 22 was excluded from analysis.
* Statistically significantly different from control at p< 0.05, as reported by the study authors (Dunnett's test).
GD = gestation day; NZW = New Zealand white; SD = standard deviation.
106
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-18. Hematology in Pregnant NZW Rabbits Administered 1,2-Dichloropropane
via Gavage on GDs 7-19a
Parameterb
Dose Group (mg/kg-d)
0
15
50
150
RBC (x 106/mm3)
5.69 ±0.45
5.40 ± 0.39 (-5%)
5.46 ± 0.39 (-4%)
4.54 ± 0.57* (-20%)
Hb (g/dL)
12.5 ±0.8
12.2 ± 0.9 (-2%)
12.3 ± 0.8 (-2%)
10.2 ± 1.4* (-18%)
Hct (%)
42.9 ±3.2
41.2 ±2.3 (-4%)
41.9 ±2.9 (-2%)
34.9 ±4.3* (-19%)
Platelets (x 103/mm3)
427 ± 94
396 ± 93 (-7%)
468 ± 120 (+10%)
512 ± 103* (+20%)
WBC (x 103/mm3)
6.8 ± 1.5
7.2 ± 1.7 (+6%)
6.9 ± 1.6 (+1%)
8.6 ± 2.7* (+26%)
Reticulocyte (%)
3.2 ±0.6
3.6 ±0.7 (+13%)
3.8 ±0.9 (+19%)
6.7 ± 1.7* (+109%)
"Kirk ct al. (1995).
bValues are expressed as mean ± SD (percent change compared with control) of 15-18 does/dose; % change
control = ([treatment mean - control mean] + control mean) x 100.
* Statistically significantly different from control at p< 0.05, as reported by the study authors (Dunnett's or
Wilcoxon's test).
GD = gestation day; Hb = hemoglobin; Hct = hematocrit; NZW = New Zealand white; RBC = red blood cell;
SD = standard deviation; WBC = white blood cell.
107
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-19. Terminal Body Weights and Selected Hematology and Clinical Chemistry
Findings from Male F344 Rats Exposed to 1,2-Dichloropropane via Inhalation


for 13 Weeks3




Exposure Group, ppm (HECet, mg/m3)b

0
125.3
250.8
500.5
1,000.4
2,001.3
Parameters0
(0)
(13.63)
(27.28)
(54.42)
(108.79)
(217.62)
Terminal body weight (g)
307 ± 16
286 ±10d
292 ±14d
281±12d
257 ±19d
223 ±21d


(-7%)
(-5%)
(-8%)
(-16%)
(-27%)
Hematology:






RBC (106/|iL)
9.31 ±0.21
9.36 ±0.19
9.33 ±0.16
8.95 ±0.17**
8.00 ±0.22**
7.58 ±0.36**


(+1%)
(0%)
(-4%)
(-14%)
(-19%)
Hb (g/dL)
15.9 ±0.4
16.0 ±0.4
15.8 ±0.4
15.4 ±0.3*
14.7 ±0.2**
14.6 ±0.5**


(+1%)
(-1%)
(-3%)
(-8%)
(-8%)
Hct (%)
45.6 ± 1.2
46.1 ± 1.1
46.0 ±0.7
45.2 ±0.8
43.4 ±0.8**
43.7 ± 1.2**


(+1%)
(+1%)
(-1%)
(-5%)
(-4%)
Reticulocyte (%)
1.9 ±0.1
1.8 ±0.2
1.9 ±0.2
2.3 ±0.2
5.5 ±0.6**
10.5 ±3.0**


(-5%)
(0%)
(+21%)
(+189%)
(+453%)
Platelet (10''/|iL)
780 ± 57
804 ± 39
809 ± 53
816 ±67
925 ±59**
959 ±64**


(+3%)
(+4%)
(+5%)
(+19%)
(+23%)
Clinical chemistry






Total bilirubin (mg/dL)
0.13 ±0.02
0.13± 0.01
0.13± 0.01
0.13 ±0.01
0.14 ±0.01
0.18 ±0.02**


(0%)
(0%)
(0%)
(+8%)
(+38%)
GGT (IU/L)
2 ± 1
4 ± 5
3 ± 1
2 ± 1
2 ± 1
6 ± 10*


(+100%)
(+50%)
(0%)
(0%)
(+200%)
"Uiiieda et al. (2010).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects using the
following equation: HECet = (ppm x MW + 24.45) x (hours/day exposed + 24) x (days/week
exposed + 7) x RGDRet. RGDRet is the extrathoracic regional gas dose ratio (animal:human) (U.S. EPA. 1994b).
°Values are expressed as mean ± SD (percent change compared with control) for 9-10 rats/group; % change
control = ([treatment mean - control mean] + control mean) x 100.
Statistically significantly different from controls atp< 0.05, as calculated for this review (2-tailed Student's
/- test).
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Dunnett's test).
**Statistically significantly different from controls at p< 0.01, as reported by the study authors (Dunnett's test).
ET = extrathoracic respiratory effects; GGT = '/-glutamyl transferase; Hb = hemoglobin; Hct = hematocrit;
HEC = human equivalent concentration; MW = molecular weight; RBC = red blood cell; SD = standard deviation.
108
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-20. Terminal Body Weights and Selected Hematology and Clinical Chemistry
Findings from Female F344 Rats Exposed to 1,2-Dichloropropane via Inhalation


for 13 Weeks3



Exposure Group, ppm (HECet, mg/m3)b

0
125.3
250.8
500.5
1,000.4
2,001.3
Parameters0
(0)
(10.03)
(20.09)
(40.08)
(80.112)
(160.26)
Terminal body
173 ±9
167 ±7
166 ±9
164 ± 4d
157 ± 3d
142 ±12d
weight (g)

(-3%)
(-4%)
(-5%)
(-9%)
(-18%)
Hematology






RBC (106/|iL)
8.60 ±0.21
8.59 ±0.20
8.44 ± 0.24
8.13 ±0.27**
7.77 ±0.24**
7.18 ±0.39**


(0%)
(-2%)
(-5%)
(-10%)
(-17%)
Hb (g/dL)
15.9 ±0.5
15.8 ±0.4
15.7 ±0.4
15.4 ±0.6
15.1 ±0.4**
14.3 ±0.8**


(-1%)
(-1%)
(-3%)
(-5%)
(-10%)
Hct
44.3 ±0.9
44.4 ± 1.0
44.2 ± 1.0
43.7 ± 1.2
43.7 ± 1.1
42.5 ± 1.4**


(0%)
(0%)
(-1%)
(-1%)
(-4%)
Reticulocyte (%)
1.9 ±0.2
1.9 ±0.3
2.5 ±0.3
3.5 ±0.4*
6.4 ±2.7**
11.5 ±4.5**


(0%)
(+32%)
(+84%)
(+237%)
(+505%)
Platelet (10''/|iL)
817 ±64
783 ± 56
825 ± 58
863 ± 78
874 ± 54
932±114**


(-4%)
(+1%)
(+6)
(+7%)
(+14%)
Clinical chemistry






Total bilirubin
0.16 ±0.02
0.16± 0.03
0.15± 0.03
0.16 ±0.02
0.20 ±0.03*
0.25 ±0.06**
(mg/dL)

(0%)
(-6%)
(0%)
(+25%)
(+56%)

3 ± 1
2 ± 1
3 ± 1
3 ± 1
5 ± 2**
10 ±2**
GGT (IU/L)e

(-33%)
(0%)
(0%)
(+67%)
(+233%)
"Uiiieda et al. (2010).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects using the
following equation: HECet = (ppm x MW + 24.45) x (hours/day exposed + 24) x (days/week
exposed + 7) x RGDRet. RGDRet is the extrathoracic regional gas dose ratio (animal:human) (U.S. EPA. 1994b).
°Values are expressed as mean ± SD (percent change compared with control) for 9-10 rats/group; % change
control = ([treatment mean - control mean] + control mean) x 100.
Statistically significantly different from controls atp< 0.05, as calculated for this review (2-tailed Student's
/- test).
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Dunnett's test).
**Statistically significantly different from controls at p< 0.01, as reported by the study authors (Dunnett's test).
ET = extrathoracic respiratory effects; GGT = '/-glutamyl transferase; Hb = hemoglobin; Hct = hematocrit;
HEC = human equivalent concentration; MW = molecular weight; RBC = red blood cell; SD = standard deviation.
109
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-21. Selected Histopathological Lesions in Male F344 Rats Exposed to
1,2-Dichloropropane via Inhalation for 13 Weeks"
Parameters0
Exposure Group (ppm) (HECet, mg/m3)b
0
(0)
125.3
(13.63)
250.8
(27.28)
500.5
(54.42)
1,000.4
(108.79)
2,001.3
(217.62)
Spleen:
Hemosiderin deposits
Increased extramedullary
hematopoiesis
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
1/10 (10%)
0/10 (0%)
10/10*
(100%)
10/10*
(100%)
10/10*
(100%)
10/10*
(100%)
Bone marrow:
Increased hematopoiesis
0/10 (0%)
0/10 (0%)
0/10 (0%)
1/10 (10%)
10/10*
(100%)
10/10*
(100%)
Liver:
Centrilobular swelling
Severity1
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
9/10* (90%)
[1.0]
Adrenal gland:
Fatty change
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
1/10 (10%)
Nasal cavity:
Respiratory epithelium
Hyperplasia
Severityd
Inflammation
Olfactory epithelium
Atrophy
Severityd
0/10 (0%)
0/10 (0%)
0/10 (0%)
10/10*
(100%) [1.0]
0/10 (0%)
10/10*
(100%) [1.0]
10/10*
(100%) [1.3]
2/10 (20%)
10/10*
(100%) [1.2]
10/10*
(100%) [1.3]
4/10 (40%)
10/10*
(100%) [1.5]
10/10*
(100%) [2.0]
8/10* (80%)
10/10*
(100%) [2.2]
10/10*
(100%) [2.0]
8/10* (80%)
10/10*
(100%) [2.7]
aUmeda et al. (2010).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects using the
following equation: HECet = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week
exposed ^ 7) x RGDRet. RGDRet is the extrathoracic regional gas dose ratio (animal:human) (U.S. EPA. 1994b).
* Statistically significantly different from controls at p< 0.01, as reported by the study authors (Dunnett's test).
°Values are presented as number of animals with lesion/number of animals evaluated (% incidence).
dSeverity was graded as follows: 1 = slight, 2 = moderate, 3 = marked, 4 = severe.
ET = extrathoracic respiratory effects; HEC = human equivalent concentration; MW = molecular weight;
SD = standard deviation.
110
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-22. Selected Histopathological Lesions in Female F344 Rats Exposed to
1,2-Dichloropropane via Inhalation for 13 Weeks"
Parameters0
Exposure Group (ppm) (HECet, mg/m3)b
0
(0)
125.3
(10.03)
250.8
(20.09)
500.5
(40.08)
1,000.4
(80.112)
2,001.3
(160.26)
Spleen:
Hemosiderin deposits
Increased
extramedullary
hematopoiesis
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
4/10 (40%)
0/10 (0%)
10/10*
(100%)
1/10 (10%)
10/10*
(100%)
8/10* (80%)
9/9* (100%)
9/9* (100%)
Bone marrow:
Increased
hematopoiesis
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
10/10*
(100%)
9/9* (100%)
Liver:
Centrilobular swelling
Severity1
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
1/10 (10%)
[NR]
6/9 (67%)
[1.8]
Adrenal gland:
Fatty change
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
2/10 (20%)
9/9* (100%)
Nasal cavity:
Respiratory epithelium
Hyperplasia
Severityd
Inflammation
Olfactory epithelium
Atrophy
Severity1
0/10 (0%)
0/10 (0%)
0/10 (0%)
7/10* (70%)
[1.0]
0/10 (0%)
10/10*
(100%) [1.0]
10/10* (100%)
[1.0]
0/10 (0%)
10/10* (100%)
[1.0]
9/10* (90%)
[1.0]
0/10 (0%)
10/10*
(100%) [1.1]
10/10*
(100%) [1.2]
3/10 (30%)
10/10*
(100%) [1.0]
9/9* (100%)
[1.1]
4/9 (44%)
9/9* (100%)
[2.1]
"Unieda et al. (2010).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects using the
following equation: HECet = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week
exposed ^ 7) x RGDRet. RGDRet is the extrathoracic regional gas dose ratio (animal:human) (U.S. EPA. 1994b).
°Values are presented as number of animals with lesion/number of animals evaluated (% incidence).
dSeverity was graded as follows: 1 = slight, 2 = moderate, 3 = marked, 4 = severe.
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Dunnett's test).
ET = extrathoracic respiratory effects; HEC = human equivalent concentration; MW = molecular weight; NR = not
reported.
Ill
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-23. Terminal Body Weights and Upper Respiratory Lesion Incidence for F344
Rats Exposed to 1,2-Dichloropropane via Inhalation for 6 Hours/Day, 5 Days/Week
for 13 Weeks3
Parameter0
Exposure Group, ppm (HECet, mg/m3)b
0(0)
15 (1.6)
50 (5.4)
151 (16.5)
Males
Terminal body weight (g)d
295.3 ±23.1
289.3 ± 15.0
(-2%)
272.7 ± 27.0
(-8%)
264.6 ±24.6*
(-10%)
Nasal respiratory epithelium:
Hyperplasia (combined)
Very slight
Slight
0/10 (0%)
0/10 (0%)
0/10 (0%)
2/9 (22%)
2/9 (22%)
0/9 (0%)
5/10 (50%)e
4/10f (40%)
1/10 (10%)
9/10 (90%)e
5/10 (50%)e
4/10f (40%)
Nasal olfactory mucosa:
Degeneration of olfactory mucosa (combined)
Very slight
Slight
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/9 (0%)
0/9 (0%)
0/9 (0%)
10/10 (100%)e
10/10 (100%)e
0/10 (0%)
10/10 (100%)e
2/10 (20%)
8/10 (80%)e
Larynx (submucosa):
Inflammation, subacute, slight
0/10 (0%)
0/9 (0%)
0/10 (0/%)
4/10f (40%)
Females

0(0)
15 (1.2)
50 (4.0)
151 (12.1)
Terminal body weight (g)d
177.0 ± 13.0
172.8 ±9.1
(-2%)
169.6 ±5.2
(-4%)
164.3 ±5.0*
(-7%)
Nasal respiratory epithelium:
Hyperplasia (combined)
Very slight
Slight
0/10 (0%)
0/10 (0%)
0/10 (0%)
3/10 (30%)
3/10 (30%)
0/10 (0%)
7/10 (70%)e
5/10 (50%)e
2/10 (20%)
9/10 (90%)e
4/10f (40%)
5/10 (50%)e
Nasal olfactory mucosa:
Degeneration of olfactory mucosa (combined)
Very slight
Slight
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
10/10 (100%)e
9/10 (90%)e
1/10 (10%)
10/10 (100%)e
3/10 (30%)
7/10 (70%)e
Larynx (submucosa):
Inflammation, subacute, slight
0/10 (0%)
0/10 (0%)
0/10 (0/%)
0/10 (0%)
"Dow Chemical Co (1988a).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects using the
following equation: HECet = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week
exposed ^ 7) x RGDRet. RGDRet is the extrathoracic regional gas dose ratio (animal:human) (U.S. EPA. 1994b).
°Values are expressed as number of rats with lesion/number of rats evaluated (% incidence).
dValues are expressed as mean ± SD (percent change from control) for 9-10 animals/group; % change
control = ([treatment mean - control mean] control mean) x 100.
"Statistically significantly different from controls atp< 0.05, as calculated for this review (2-tailed Fisher's exact
test).
fMarginally significantly different from controls (0.05 
-------
FINAL
09-29-2016
Table B-24. Survival and Body and Selected Organ Weights in B6D2Fi/Crlj (SPF) Mice
Exposed to 1,2-Dichloropropane via Inhalation for 13 Weeks3
Parameter
Exposure Group, ppm (HECet, mg/m3)b
0(0)
50.0 (6.21)
100.1 (12.43)
200.0 (24.83)
300.2 (37.27)
399.9 (49.66)
Males
Survival
10/10
10/10
10/10
10/10
8/10
4/10d
Terminal body
weight (g)c
29.3 ± 1.7
29.5±3.1
(+1%)
28.1 ±2.1
(-4%)
26.6 ± 1.4*
(-9%)
25.6 ± 1.0**
(-13%)
24.1 + 0.8**
(-18%)
Liver weight0:
Absolute (g)
Relative (%BW)
1.17 ±0.05
3.99 ±0.23
1.21 ±0.10
(+3%)
4.11 ±0.27
(+3%)
1.19 ±0.06
(+2%)
4.25 ±0.28
(+7%)
1.15 ±0.09
(-2%)
4.33 ±0.21
(+9%)
1.33 ±0.13**
(+14%)
5.19 ± 0.41**
(+30%)
1.52 + 0.08**
(+30%)
6.29 + 0.38**
(+58%)
Spleen weight0:
Absolute (g)
Relative (%BW)
0.05 ±0.01
0.16 ±0.04
0.05 ±0.01
(0%)
0.16 ±0.02
(0%)
0.04 ±0.01
(-20%)
0.15 ±0.02
(-6%)
0.04 ±0.01
(-20%)
0.15 ±0.02
(-6%)
0.04 ± 0.00
(-20%)
0.17 ±0.02
(+6%)
0.05 + 0.01
(0%)
0.22 + 0.03**
(+38%)
Females

0(0)
50.0 (5.14)
100.1 (10.29)
200.0 (20.55)
300.2 (30.86)
399.9 (41.11)
Survival
10/10
10/10
10/10
10/10
10/10
9/10
Terminal BW (g)°
21.7 ± 1.1
22.1 ± 1.4
(+2%)
21.3 ±0.9
(-2%)
21.7 ± 1.9
(0%)
22.0±0.7
(+1%)
21.1 + 0.5
(-3%)
Liver weight0:
Absolute (g)
Relative (%BW)
0.95 ±0.08
4.38 ±0.25
1.01 ±0.08
(+6%)
4.58 ±0.26
(+5%)
0.98 ±0.05
(+3%)
4.62 ±0.23
(+5%)
1.03 ±0.08
(+8%)
4.76 ± 0.20
(+9%)
1.21 + 0.10**
(+27%)
5.48 + 0.34**
(+25%)
1.53 + 0.15**
(+61%)
7.29 + 0.78**
(+66%)
Spleen weight0:
Absolute (g)
Relative (%BW)
0.05 ±0.01
0.24 ±0.03
0.06 ± 0.02
(+20%)
0.25 ± 0.06
(+4%)
0.05 ±0.01
(0%)
0.24 ±0.03
(0%)
0.05 ±0.01
(0%)
0.22 ±0.02
(-8%)
0.05 + 0.01
(0%)
0.24 + 0.02
(0%)
0.06 + 0.01
(+20%)
0.29 + 0.03*
(+21%)
"Matsiiiiioto et al. (2013).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects using the
following equation: HECet = (ppm x MW + 24.45) x (hours/day exposed + 24) x (days/week
exposed + 7) x RGDRet. RGDRet is the extrathoracic regional gas dose ratio (animal:human) (U.S. EPA. 1994b).
cValues are expressed as mean ± SD (percent change compared with control) for surviving animals; % change
control = ([treatment mean - control mean] + control mean) x 100.
Statistically significantly different from controls atp< 0.01, as calculated for this study (2-tailed Fischer's exact
test).
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Dunnett's test).
**Statistically significantly different from controls at p< 0.01, as reported by the study authors (Dunnett's test).
BW = body weight; ET = extrathoracic respiratory effects; HEC = human equivalent concentration;
MW = molecular weight; SD = standard deviation.
113
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-25. Hematological Findings in B6D2Fi/Crlj (SPF) Mice Exposed to
1,2-Dichloropropane via Inhalation for 13 Weeks"
Parameter0
Exposure Group, ppm (HECet, mg/m3)b
0(0)
50.0 (6.21)
100.1 (12.43)
200.0 (24.83)
300.2 (37.27)
399.9 (49.66)
Males
RBC (106/nL)
10.94 ±0.29
10.36 ±0.38**
(-5%)
10.28 ±0.43**
(-6%)
10.26 ±0.39**
(-6%)
9.69 ±0.47
(-11%)
8.81 ±0.16**
(-19%)
Hb (g/dL)
15.7 ±0.3
15.1 ±0.6*
(-4%)
15.0 ±0.6*
(-4%)
14.9 ±0.6*
(-5%)
14.3 ±0.6**
(-9%)
13.4 ±0.3**
(-15%)
Hct (%)
50.4 ±0.9
48.6 ± 1.2*
(-4%)
48.6 ±2.0*
(-4%)
48.7 ± 1.4*
(-3%)
48.1 ± 1.5*
(-5%)
45.5 ±0.6**
(-10%)
MCV
46.0 ±0.8
46.9 ±0.7*
(+2%)
47.3 ±0.5**
(+3%)
47.5 ±0.7**
(+3%)
49.7 ± 1.1**
(+8%)
51.7 ±0.5**
(+12%)
Platelet (107|iL)
1,490 ±78
1,437 ±54
(-4%)
1,430 ±52
(-4%)
1,461 ±70
(-2%)
1,590 ±77*
(+7%)
1,772 ±99**
(+19%)
WBC (103/|iL)
2.52 ± 1.74
1.72 ± 1.06
(-32%)
1.49 ±0.93
(-41%)
1.95 ± 1.23
(-23%)
2.24 ± 1.23
(-11%)
1.68 ± 1.20
(-33%)
Females

0(0)
50.0 (5.14)
100.1 (10.29)
200.0 (20.55)
300.2 (30.86)
399.9 (41.11)
RBC (106/|iL)
10.63 ± 0.64
10.49 ±0.37
(-1%)
10.52 ±0.30
(-1%)
10.28 ±0.41
(-3%)
9.21 ±0.46**
(-13%)
8.79 ±0.44**
(-17%)
Hb (g/dL)
15.6 ± 1.2
15.5 ±0.6
(-1%)
15.5 ±0.4
(-1%)
15.2 ±0.7
(-3%)
14.1 ±0.7**
(-10%)
13.7 ±0.8**
(-12%)
Hct (%)
49.2 ±3.1
49.0 ± 1.2
(0%)
48.8 ± 1.1
(-1%)
48.9 ± 1.8
(-1%)
46.7 ±2.0*
(-5%)
45.2 ±2.2**
(-8%)
MCV
46.3 ±0.6
46.7 ±0.7
(+1%)
46.5 ±0.6
(0%)
47.6 ±0.7**
(+3%)
50.7 ±0.7**
(+10%)
51.5 ±0.9**
(+11%)
Platelet (103/jiL)
1,395 ±98
1,388 ± 172
(-1%)
1,300 ± 62
(-7%)
1,256 ±361
(-10%)
1,458 ±51
(+5%)
1,657 ± 149**
(+19%)
WBC (103/|iL)
1.76 ± 1.13
1.52 ±0.77
(-14%)
1.55 ± 1.07
(-12%)
1.66 ± 1.55
(-6%)
1.60 ± 1.12
(-9%)
2.54 ± 1.56
(+44%)
"Matsiiiiioto et al. (2013).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects using the
following equation: HECet = (ppm x MW + 24.45) x (hours/day exposed + 24) x (days/week
exposed + 7) x RGDRet. RGDRet is the extrathoracic regional gas dose ratio (animal:human) (U.S. EPA. 1994b).
°Values are expressed as mean ± SD (percent change compared with control) for 4-10 mice/group; % change
control = ([treatment mean - control mean] + control mean) x 100.
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Dunnett's test).
**Statistically significantly different from controls at p< 0.01, as reported by the study authors (Dunnett's test).
ET = extrathoracic respiratory effects; Hb = hemoglobin; Hct = hematocrit; HEC = human equivalent
concentration; MCV = mean corpuscular volume; MW = molecular weight; RBC = red blood cell; WBC = white
blood cell; SD = standard deviation.
114
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-26. Serum Biochemistry Findings in B6D2Fi/Crlj (SPF) Mice Exposed to
1,2-Dichloropropane via Inhalation for 13 Weeks"
Parameter0
Exposure Group, ppm (HECet, mg/m3)b
0
50.0 (6.21)
100.1 (12.43)
200.0 (24.83)
300.2 (37.27)
399.9 (49.66)
Males
T-bilirubin (mg/dL)
0.15 ±0.01
0.15 ±0.01
(0%)
0.15 ±0.01
(0%)
0.16 ±0.01
(+7%)
0.16 ±0.03
(+7%)
0.18 ±0.02*
(+20%)
Phospholipid
(mg/dL)
179 ±23
163 ± 13
(-9%)
155±18*
(-13%)
162 ± 25
(-9%)
206 ± 8*
(+15%)
213±17*
(+19%)
AST (U/L)
40 ±4
43 ±6
(+8%)
41 ±7
(+3%)
39 ±6
(-3%)
52 ± 12
(+30%)
139 ±24**
(+248%)
ALT (U/L)
17 ±2
16 ±3
(-6%)
17 ±3
(0%)
18 ±3
(+6%)
21 ± 5
(+24%)
95 ±37**
(+459%)
ALP (U/L)
141 ± 10
142 ± 15
(+1%)
134 ± 10
(-5%)
144 ± 12
(+2%)
174 ±8**
(+23%)
325 ±45**
(+130%)
LDH (U/L)
183 ±35
180 ± 27
(-2%)
218 ±118
(+19%)
171 ±30
(-7%)
212 ±50
(+16%)
397 ±64*
(+117%)
Females

0
50.0 (5.14)
100.1 (10.29)
200.0 (20.55)
300.2 (30.86)
399.9 (41.11)
T-bilirubin (mg/dL)
0.14 ±0.01
0.14 ±0.03
(0%)
0.14 ±0.02
(0%)
0.14 ± 0
(0%)
0.15 ±0.02
(+7%)
0.18 ±0.03**
(+29%)
Phospholipid
(mg/dL)
160 ± 20
156 ± 17
(-3%)
147 ± 19
(-8%)
158 ± 15
(-1%)
185 ± 16*
(+16%)
227 ±19**
(+42%)
AST (U/L)
53 ± 10
60 ±31
(+13%)
54 ± 13
(+2%)
45 ±9
(-15%)
75 ±45
(+42%)
206±173*
(+289%)
ALT (U/L)
21 ± 4
21 ±8
(0%)
20 ±3
(-5%)
18 ±3
(-14%)
27 ±25
(+29%)
95 ± 180
(+352%)
ALP (U/L)
237 ± 56
217 ±27
(-8%)
209 ± 20
(-12%)
201 ±28
(-15%)
195 ±29
(-18%)
197 ± 16
(-17%)
LDH (U/L)
201 ±21
233 ±93
(+16%)
207 ± 54
(+3%)
226 ± 96
(+12%)
276±119
(+37%)
568 ±364**
(+183%)
"Matsiiiiioto et al. (2013).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects using the
following equation: HECet = (ppm x MW + 24.45) x (hours/day exposed + 24) x (days/week
exposed + 7) x RGDRet. RGDRet is the extrathoracic regional gas dose ratio (animal:human) (U.S. EPA. 1994b).
°Values are expressed as mean ± SD (percent change compared with control) for 4-10 mice/group; % change
control = ([treatment mean - control mean] + control mean) x 100.
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Dunnett's test).
**Statistically significantly different from controls at p< 0.01, as reported by the study authors (Dunnett's test).
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase;
ET = extrathoracic respiratory effects; HEC = human equivalent concentration; LDH = lactate dehydrogenase;
MW = molecular weight; SD = standard deviation.
115
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-27. Selected Extrarespiratory Non-neoplastic Lesions in B6D2Fi/Crlj (SPF) Mice
Exposed to 1,2-Dichloropropane via Inhalation for 13 Weeks3
Parameter0
Exposure Group, ppm (HECet, mg/m3)b
0
(0)
50.0
(6.21)
100.1
(12.43)
200.0
(24.83)
300.2
(37.27)
399.9
(49.66)
Males
Stomach:
Hyperplasia: forestomach
0/10 (0%)
0/10 (0%)
0/10 (0%)
1/10 (0%)
2/10 (20%)
4/10* (40%)
Liver, central:
Swelling
Fatty change
Vacuolic change
Mineralization
Necrosis
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
8/10** (80%)
1/10 (10%)
0/10 (0%)
0/10 (0%)
1/10 (10%)
4/10* (40%)
5/10* (50%)
7/10** (70%)
4/10 (40%)
3/10 (30%)
Bone marrow:
Congestion
Increased erythropoiesis
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
1/10 (10%)
3/10 (30%)
6/10** (60%)
2/10 (20%)
Spleen:
Atrophy
Increased extramedullary
hematopoiesis
Hemosiderin deposits
Increased megakaryocyte
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
1/10 (10%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
1/10 (10%)
3/10 (30%)
0/10 (0%)
3/10 (30%)
5/10* (50%)
4/10* (40%)
4/10* (40%)
4/10* (40%)
Heart:
Ground glass appearance
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
3/10 (30%)
9/10** (90%)
Females

0
(0)
50.0
(5.14)
100.1
(10.29)
200.0
(20.55)
300.2
(30.86)
399.9
(41.11)
Stomach:
Hyperplasia: forestomach
0/10 (0%)
0/10 (0%)
0/10 (0%)
1/10 (0%)
10/10**
(100%)
10/10**
(100%)
Liver, central:
Swelling
Fatty change
Vacuolic change
Mineralization
Necrosis
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
7/10** (70%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
9/10** (90%)
0/10 (0%)
1/10 (10%)
9/10** (90%)
0/10 (0%)
Bone marrow:
Congestion
Increased erythropoiesis
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
4/10* (40%)
0/10 (0%)
4/10* (40%)
Spleen:
Atrophy
Increased extramedullary
hematopoiesis
Hemosiderin deposits
Increased megakaryocyte
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
1/10 (10%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
5/10* (50%)
0/10 (0%)
3/10 (30%)
0/10 (0%)
10/10**
(100%)
10/10**
(100%)
9/10** (90%)
116
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-27. Selected Extrarespiratory Non-neoplastic Lesions in
B6D2Fi/Crlj (SPF) Mice
Exposed to 1,2-Dichloropropane via Inhalation for 13 Weeks"

Parameter0
Exposure Group, ppm (HECet, mg/m3)b

0
50.0
100.1
200.0
300.2
399.9

(0)
(6.21)
(12.43)
(24.83)
(37.27)
(49.66)
Females
Heart:






Ground glass appearance
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
3/10 (30%)
9/10** (90%)
"Matsumoto et al. (2013).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects using the
following equation: HECet = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week
exposed ^ 7) x RGDRet. RGDRet is the extrathoracic regional gas dose ratio (animal:human) (U.S. EPA. 1994b).
°Values are presented as number of animals with lesion/number of animals evaluated (% incidence).
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Fischer's exact
test).
**Statistically significantly different from controls atp< 0.01, as reported by the study authors (Fischer's exact
test).
ET = extrathoracic respiratory effects; HEC = human equivalent concentration; MW = molecular weight.
117
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-28. Nasal Lesions in B6D2Fi/Crlj (SPF) Mice Exposed to 1,2-Dichloropropane via
Inhalation for 13 Weeks"
Parameter0
Exposure Group, ppm (HECet, mg/m3)b
0(0)
50.0 (6.21)
100.1 (12.43)
200.0 (24.83)
300.2 (37.27)
399.9 (49.66)
Males
Olfactory epithelium:
Respiratory metaplasia
Atrophy
Necrosis
Desquamation
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
3/10 (30%)
7/10** (70%)
4/10* (40%)
0/10 (0%)
3/10 (30%)
4/10* (40%)
1/10 (10%)
6/10** (60%)
Females

0(0)
50.0 (5.14)
100.1 (10.29)
200.0 (20.55)
300.2 (30.86)
399.9 (41.11)
Olfactory epithelium:
Respiratory metaplasia
Atrophy
Necrosis
Desquamation
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
4/10* (40%)
7/10** (70%)
4/10* (40%)
0/10 (0%)
3/10 (30%)
9/10** (90%)
2/10 (20%)
0/10 (0%)
aMatsumoto et al. (2013).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects using the
following equation: HECet = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week
exposed + 7) x RGDRet. RGDRet is the extrathoracic regional gas dose ratio (animal:human) (U.S. EPA. 1994b).
°Values are presented as number of animals with lesion/number of animals evaluated (% incidence).
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Fischer's exact test).
**Statistically significantly different from controls at p < 0.01, as reported by the study authors (Fischer's exact
test).
ET = extrathoracic respiratory effects; HEC = human equivalent concentration; MW = molecular weight.
118
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-29. Hematological Findings for NZW Rabbits Exposed to 1,2-Dichloropropane
via Inhalation for 6 Hours/Day, 5 Days/Week for 11 or 13 Weeks3

Exposure Group, ppm (HECet, mg/m3)b
Parameter0
0(0)
151 (71.0)
502 (236)
1,003 (471.8)
Males
Wk 11
Erythrocyte count (x 106/mm3)
Hb (g/dL)
Packed cell volume (%)
6.25 ±0.46
13.2 ±0.7
46.7 ±2.5
5.62 ±0.22*
(-10%)
12.8 ±0.5
(-3%)
44.0 ±2.1
(-6%)
4.94 ±0.12*
(-21%)
11.5 ± 0.5*
(-13%)
39.8 ± 1.4*
(-15%)
4.67 ±0.41*
(-25%)
11.3 ±0.9*
(-14%)
38.8 ±3.2*
(-17%)
Wk 13
Erythrocyte count (x 106/mm3)
Hb (g/dL)
Packed cell volume (%)
Reticulocytes (%)
Nucleated erythrocytes (per 100 WBC)
6.37 ±0.28
13.3 ±0.3
48.5 ± 1.1
1.2 ±0.4
1± 1
5.61 ±0.17*
(-12%)
12.5 ±0.5*
(-6%)
45.4 ± 1.9*
(-6%)
1.6 ±0.4
(+33%)
1± 1
(0%)
4.82 ±0.23*
(-24%)
11.2 ±0.4*
(-16%)
40.2 ± 1.8*
(-17%)
3.4 ± 1.0*
(+183%)
2 ± 2
(+100%)
4.51 ±0.36*
(-29%)
11.0 ±0.9*
(-17%)
39.0 ±3.3*
(-20%)
5.2 ± 1.1*
(+333%)
4 ± 6
(+300%)
Females

0(0)
151 (66.4)
502 (221)
1,003 (441.2)
Wk 11
Erythrocyte count (x 106/mm3)
Hb (g/dL)
Packed cell volume (%)
5.70 ±0.52
12.3	±0.6
44.4	±2.6
5.70 ±0.51
(0%)
12.5	±0.8
(+2%)
44.6	±3.2
(+0.5%)
4.86 ±0.43*
(-15%)
11.1 ± 0.7*
(-10%)
39.4 ±2.4*
("11%)
4.44 ±0.32*
(-22%)
10.4 ±0.5*
(-15%)
36.8 ± 1.8*
(-17%)
119
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-29. Hematological Findings for NZW Rabbits Exposed to 1,2-Dichloropropane
via Inhalation for 6 Hours/Day, 5 Days/Week for 11 or 13 Weeks3

Exposure Group, ppm (HECet, mg/m3)b
Parameter0
0(0)
151 (71.0)
502 (236)
1,003 (471.8)
Females
Wk 13




Erythrocyte count (x 106/mm3)
5.9 ±0.60
5.73 ±0.42
4.85 ±0.48*
4.47 ±0.32*


(-3%)
(-18%)
(-24%)
Hb (g/dL)
12.7 ±0.5
12.3 ±0.8
11.1 ± 0.8*
10.2 ±0.5*


(-3.1%)
(-13%)
(-20%)
Packed cell volume (%)
45.6 ±2.6
44.2 ±2.7
39.2 ±3.0*
36.7 ±2.1*


(-3.0%)
(-14%)
(-20%)
Reticulocytes
1.3 ±0.3
1.3 ±0.2
2.85 ±0.4*
3.95 ± 1.0*


(0%)
(+119%)
(+204%)
Nucleated erythrocytes
1± 1
0±0
0±0
1 ± 2


(-100%)
(-100%)
(0%)
"Dow Chemical Co (1988a).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects using the
following equation: HECet = (ppm x MW + 24.45) x (hours/day exposed + 24) x (days/week
exposed + 7) x RGDRet. RGDRet is the extrathoracic regional gas dose ratio (animal:human) (U.S. EPA. 1994b).
°Values are expressed as mean ± SD (percent change compared with control) for seven rabbits/group; % change
control = ([treatment mean - control mean] + control mean) x 100; rats were fasted for 24 hours prior to sacrifice.
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Dunnett's or
Wilcoxon's test).
ET = extrathoracic respiratory effects; Hb = hemoglobin; HEC = human equivalent concentration;
MW = molecular weight; NZW = New Zealand white; SD = standard deviation; WBC = white blood cell.
120
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-30. Selected Histopathology in NZW Rabbits Exposed to 1,2-Dichloropropane via
Inhalation for 6 Hours/Day, 5 Days/Week for 13 Weeks3
Parameter0
Exposure Group, ppm (HECet, mg/m3)b
0(0)
151 (71.0)
502 (236)
1,003 (471.8)
Bone marrow lesions
Males:
Hyperplasia
Slight
Moderate
Increased hematogenous pigment (macrophages)
0/7 (0%)
0/7 (0%)
0/7 (0%)
1/7 (14%)
2/7 (29%)
1/7 (14%)
1/7 (14%)
1/7 (14%)
6/7d (86%)
3/7 (43%)
3/7 (43%)
2/7 (29%)
7/7d(100%)
3/7 (43%)
4/7d (57%)
6/7d (86%)

0(0)
151 (66.4)
502 (221)
1,003 (441.2)
Females:
Hyperplasia
Slight
Moderate
Increased hematogenous pigment (macrophages)
2/7 (29%)
2/7 (29%)
0/7 (0%)
2/7 (29%)
0/7 (0%)
0/7 (0%)
0/7 (0%)
0/7 (0%)
5/7 (71%)
5/7 (71%)
0/7 (0%)
0/7 (0%)
7/7d (100%)
2/7 (29%)
3/7 (43%)
5/7 (71%)
Parameter0
Exposure Group, ppm (HECet, mg/m3)b
0(0)
151 (71.0)
502 (236)
1,003 (471.8)
Nasal lesions
Males:
Degeneration of olfactory epithelium
Very slight
Slight
2/7 (29%)
2/7 (29%)
0/7 (0%)
3/7 (43%)
3/7 (43%)
0/7 (0%)
2/7 (29%)
2/7 (29%)
0/7 (0%)
5/7 (71%)
1/7 (14%)
4/7e (57%)

0(0)
151 (66.4)
502 (221)
1,003 (441.2)
Females:
Degeneration of olfactory epithelium
Very slight
Slight
2/7 (29%)
2/7 (29%)
0/7 (0%)
2/7 (29%)
1/7 (14%)
1/7 (14%)
2/7 (29%)
0/7 (0%)
2/7 (29%)
2/7 (29%)
1/7 (14%)
1/7 (14%)
"Dow Chemical Co (1988a).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects using the
following equation: HECet = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week
exposed ^ 7) x RGDRet. RGDRet is the extrathoracic regional gas dose ratio (animal:human) (U.S. EPA. 1994b).
°Values are expressed as number of animals with lesions/number of animals examined (% incidence).
Statistically significantly different from controls atp< 0.05, as calculated for this review (2-tailed Fisher's exact
test).
"Marginally significantly different from controls (0.05 
-------
FINAL
09-29-2016
Table B-31. Selected Histopathological Lesions in Male F344 Rats Exposed to
1,2-Dichloropropane via Inhalation for up to 104 Weeks3
Parameter0
Exposure Group (ppm) (HECet, mg/m3)b
0(0)
80.2 (16.2)
200.5 (40.54)
500.2 (101.1)
Males
Non-neoplastic lesions: Respiratory epithelium:
Squamous cell metaplasia
Severity1
Inflammation
Severity
5/50 (10%)
[1.0]
20/50 (40%)
[1.0]
31/50** (62%)
[1.0]
35/50** (70%)
[1.0]
41/50** (82%)
[1.0]
47/50** (94%)
[1.0]
49/50** (98%)
[1.2]
47/50** (94%)
[1.2]
Non-neoplastic lesions: Olfactory epithelium:
Atrophy
Severity
0/50 (0%)
48/50** (96%)
[1.1]
50/50** (100%)
[1.9]
49/50** (98%)
[2.0]
Preneoplastic lesions (combined):
Transitional epithelium hyperplasia
Severity
Squamous hyperplasia
Severity
0/50 (0%)
0 (0%)
0 (0%)
31/50** (62%)
31/50** (62%)
[1.1]
2/50 (4%)
[1.0]
39/50** (78%)
39/50** (78%)
[1.1]
6/50* (12%)
[1.0]
50/50** (100%)
48/50** (96%)
[1.8]
27/50** (54%)
[1.1]
Neoplastic nasal lesions (combined):
Papilloma
Esthesioneuroepithelioma
0/50 (0%)f
0/50 (0%)f
0/50 (0%)
2/50 (4%)
0/50 (0%)
2/50 (4%)
4/50 (8%)
3/50 (6%)
1/50 (2%)
15/50** (30%)
15/50** (30%)
0/50 (0%)
aUmeda et al. (2010).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects using the
following equation: HECet = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week
exposed ^ 7) x RGDRet. RGDRet is the extrathoracic regional gas dose ratio (animal:human) (U.S. EPA. 1994b).
°Values are presented as number of animals with lesion/number of animals evaluated (% incidence).
dSeverity was graded as follows: 1 = slight, 2 = moderate, 3 = marked, 4 = severe.
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Fisher's exact test
or x2 test).
**Statistically significantly different from controls atp< 0.01, as reported by the study authors (Fisher's exact test
or x2 test).
f Statistically significantly dose-related trend at p< 0.01, as reported by the study authors (Peto test).
ET = extrathoracic respiratory effects; HEC = human equivalent concentration; MW = molecular weight.
122
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-32. Selected Histopathological Lesions in Female F344 Rats Exposed to
1,2-Dichloropropane via Inhalation for up to 104 Weeks"
Parameter0
Exposure Group (ppm) (HECet, mg/m3)b
0(0)
80.2 (10.7)
200.5 (26.75)
500.2 (66.71)
Non-neoplastic lesions: Respiratory epithelium:
Squamous cell metaplasia
Severity1
Inflammation
Severity
3/50 (6%)
[1.0]
10/50 (20%)
[1.0]
15/50** (30%)
[1.0]
30/50** (60%)
[1.0]
37/50** (74%)
[1.2]
39/50** (78%)
[1.0]
46/50** (92%)
[1.5]
40/50** (80%)
[1.1]
Non-neoplastic lesions: Olfactory epithelium:
Atrophy
Severity
0/50 (0%)
50/50** (100%)
[1.0]
50/50** (100%)
[1.9]
50/50** (100%)
[2.0]
Preneoplastic lesions (combined):
Transitional epithelium hyperplasia
Severity
Squamous hyperplasia
Severity
2/50 (10%)
2/50 (10%)
[1.0]
0/50 (0%)
21/50** (42%)
21/50** (42%)
[1.2]
0/50 (0%)
39/50** (78%)
39/50** (78%)
[1.1]
3/50 (6%)
[1.0]
48/50** (96%)
48/50** (96%)
[1.5]
20/50** (40%)
[1.3]
Neoplastic nasal lesions (combined):
Papilloma
Esthesioneuroepithelioma
0/50 (0%)f
0/50 (0%)f
0/50 (0%)
0/50 (0%)
0/50 (0%)
0/50 (0%)
0/50 (0%)
0/50 (0%)
0/50 (0%)
9/50** (18%)
9/50** (18%)
0/50 (0%)
aUmeda et al. (2010).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects using the
following equation: HECet = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week
exposed ^ 7) x RGDRet. RGDRet is the extrathoracic regional gas dose ratio (animal:human) (U.S. EPA. 1994b).
°Values are presented as number of animals with lesion/number of animals evaluated (% incidence).
dSeverity was graded as follows: 1 = slight, 2 = moderate, 3 = marked, 4 = severe.
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Fisher's exact test or
X2 test).
**Statistically significantly different from controls atp< 0.01, as reported by the study authors (Fisher's exact test
or x2 test).
f Statistically significantly dose-related trend at p< 0.01, as reported by the study authors (Peto test).
ET = extrathoracic respiratory effects; HEC = human equivalent concentration; MW = molecular weight.
123
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-33. Body and Selected Organ Weights in Male B6D2Fi/Crlj (SPF) Mice Exposed
to 1,2-Dichloropropane via Inhalation for 2 Years3
Parameter0
Exposure Group, ppm (HECet, mg/m3)b
0(0)
32.1 (4.73)
80.2 (11.8)
200.5 (29.55)
Terminal body weight (g)
41.9 ±7.5
46.8 ± 7.4 (+12%)
45.5 ± 8.0 (+9%)
44.0 + 8.1 (+5%)
Spleen weight:
Absolute (g)
Relative (g/g BW)
0.19 ±0.56
0.50 ± 1.46
0.16 ±0.35 (-16%)
0.42 ± 1.09 (-16%)
0.12 ±0.11 (-37%)
0.28 ± 0.29 (-44%)
0.15+ 0.11* (-21%)
0.34 + 0.26 (-32%)
Kidney weight:
Absolute (g)
Relative (g/g BW)
0.63 ±0.05
1.55 ±0.27
0.71 ±0.05** (+13%)
1.54 ±0.25 (-1%)
0.76 ±0.21** (+21%)
1.73±0.56 (+12%)
0.99+ 1.69** (+57%)
2.29+ 3.83* (+48%)
"Matsumoto et al. (2013).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects using the
following equation: HECet = (ppm x MW + 24.45) x (hours/day exposed + 24) x (days/week
exposed + 7) x RGDRet. RGDRet is the extrathoracic regional gas dose ratio (animal:human) (U.S. EPA. 1994b).
°Values are expressed as mean ± SD (percent change compared with control) for 26-41 mice; % change
control = ([treatment mean - control mean] + control mean) x 100.
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Dunnett's test).
**Statistically significantly different from controls at p< 0.01, as reported by the study authors (Dunnett's test).
BW = body weight; ET = extrathoracic respiratory effects; HEC = human equivalent concentration;
MW = molecular weight; SD = standard deviation.
124
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-34. Selected Non-neoplastic Lesions in B6D2Fi/Crlj (SPF) Mice Exposed to
1,2-Dichloropropane via Inhalation for 2 Years3
Parameter0
Exposure Group, ppm (HECet, mg/m3)b
0(0)
32.1 (4.73)
80.2 (11.8)
200.5 (29.55)
Nasal cavity, males
Olfactory epithelium:
Atrophy
Respiratory metaplasia
1/50 (2%)
19/50 (38%)
1/50 (2%)
27/50 (54%)
19/50** (38%)
23/50 (46%)
20/50** (40%)
21/50 (42%)
Submucosal gland:
Respiratory metaplasia
9/50 (18%)
13/50 (26%)
12/50 (24%)
18/50* (36%)
Nasal cavity, females
0(0)
32.1 (4.27)
80.2 (10.7)
200.5 (26.67)
Olfactory epithelium:
Atrophy
Respiratory metaplasia
8/50 (16%)
32/50 (64%)
8/50 (16%)
14/50 (28%)
19/50* (38%)
34/50 (68%)
16/50 (32%)
44/50* (88%)
Submucosal gland:
Respiratory metaplasia
16/50 (32%)
11/50 (22%)
13/50 (26%)
43/50** (86%)
Kidney, males
0(0)
32.1 (4.73)
80.2 (11.8)
200.5 (29.55)
Basophilic change
11/50 (22%)
30/50** (60%)
28/50** (56%)
33/50** (66%)
Cortical mineralization
7/50 (14%)
23/50** (46%)
30/50** (60%)
18/50** (36%)
Kidney, females
0(0)
32.1 (4.27)
80.2 (10.7)
200.5 (26.67)
Basophilic change
0/50 (0%)
0/50 (0%)
0/50 (0%)
0/50 (0%)
Cortical mineralization
0/50 (0%)
0/50 (0%)
0/50 (0%)
0/50 (0%)
aMatsumoto et al. (2013).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects using the
following equation: HECet = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week
exposed ^ 7) x RGDRet. RGDRet is the extrathoracic regional gas dose ratio (animal:human) (U.S. EPA. 1994b).
°Values are expressed as number of animals with lesion/number of animals evaluated (% incidence).
* Statistically significantly increased from controls at p< 0.05, as reported by the study authors (Fischer's exact
test).
**Statistically significantly increased from controls atp< 0.01, as reported by the study authors (Fischer's exact
test).
ET = extrathoracic respiratory effects; HEC = human equivalent concentration; MW = molecular weight.
125
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-35. Selected Neoplastic Lesions in B6D2Fi/Crlj (SPF) Mice Exposed to
1,2-Dichloropropane via Inhalation for 2 Years3
Parameter0
Exposure Group, ppm (HECpu, mg/m3)b
0(0)
32.1 (77.2)
80.2 (192)
200.5 (482.5)
Males
Lung:
Bronchiolo-alveolar adenoma and/or carcinoma
Bronchiolo-alveolar adenoma
Bronchiolo-alveolar carcinoma
9/50 (18%)
5/50 (10%)
4/50 (8%)
18/50* (36%)
14/50* (28%)
6/50 (12%)
14/50 (28%)
9/50 (18%)
6/50 (12%)
18/50* (36%)
12/50 (24%)
8/50 (16%)
Females

0(0)
32.1 (69.2)
80.2 (173)
200.5 (432.0)
Lung:
Bronchiolo-alveolar adenoma and/or carcinoma
Bronchiolo-alveolar adenoma
Bronchiolo-alveolar carcinoma
2/50 (4%)f
1/50 (2%)
1/50 (2%)f
4/50 (8%)
4/50 (8%)
1/50 (2%)
5/50 (10%)
4/50 (8%)
1/50 (2%)
8/50* (16%)
4/50 (8%)
4/50 (8%)
Males

0(0)
32.1 (77.2)
80.2 (192)
200.5 (482.5)
Harderian gland:
Adenoma
1/50 (2%)f
2/50 (4%)
3/50 (6%)
6/50 (12%)
Spleen:
Hemangioma and/or hemangiosarcoma
Hemangioma
Hemangio sarcoma
0/50 (0%)
0/50 (0%)
0/50 (0%)
4/50 (8%)
1/50 (2%)
3/50 (6%)
3/50 (6%)
0/50 (0%)
3/50 (6%)
6/50* (12%)
1/50 (2%)
5/50* (10%)
Females

0(0)
32.1 (69.2)
80.2 (173)
200.5 (432.0)
Harderian gland:
Adenoma
2/50 (4%)
2/50 (4%)
2/50 (4%)
2/50 (4%)
Spleen:
Hemangioma and/or hemangiosarcoma
Hemangioma
Hemangio sarcoma
2/50 (4%)
0/50 (0%)
2/50 (4%)
0/50 (0%)
0/50 (0%)
0/50 (0%)
1/50 (2%)
1/50 (2%)
0/50 (0%)
0/50 (0%)
0/50 (0%)
0/50 (0%)
"Matsiiiiioto et al. (2013).
bAnalytical exposure concentrations were converted to HECs for pulmonary respiratory effects using the following
equation: HECpu = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week exposed ^ 7) x RGDRPU.
RGDRi i is the pulmonary regional gas dose ratio (animal:human); see Equations 4-28 in U.S. EPA (1994b) for
calculation of RGDRPU and default values for variables.
cValues are expressed as number of animals with lesion/number of animals evaluated (% incidence).
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Fischer's exact
test).
f Statistically significant dose-related trend atp< 0.05, as reported by the study authors (Peto's test).
HEC = human equivalent concentration; MW = molecular weight; PU = pulmonary effects.
126
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table B-36. Estrous Cycle and Ovulation Parameters in Female F344 Rats Exposed to
1,2-Dichloropropane via Inhalation for 3 Weeks"
Endpoint
Exposure Group, ppm (HECet, mg/m3)b
0
50.7 (7.58)
99.9 (14.9)
200.7 (30.00)
Number of rats
8
6
6
9
Total number of cycles0
36
25
24
36
Number of cycles/ratd
4.50 ±0.76
4.17 ± 1.17 (-7%)
4.00 ±0.89 (-11%)
3.78 ±0.44 (-16%)
D/cycled
5.21 ±0.43
6.04 ± 2.43 (16%)
6.05 ± 1.08 (16%)
5.94 ± 0.56 (14%)
Number of rats with cycles lasting
>6 de
3/8 (38%)
2/6 (33%)
6/6 (100%)
9/9 (100%)
Number of total cycles lasting >6 df
3/36 (8.3%)
3/25 (12%)
13/24** (54%)
17/36** (47%)
Number of ovulated ova/ratd
8.83 ± 1.17
7.00 ±2.45 (-21%)
6.33 ± 2.52 (-28%)
5.75 ± 1.91* (-35%)
"Sekiguchi et al. (2002).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects using the
following equation: HECet = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week
exposed ^ 7) x RGDRet. RGDRet is the extrathoracic regional gas dose ratio (animal:human) (U.S. EPA. 1994b).
Total number of all estrous cycles observed in each group.
dValues are expressed as mean ± SD (percent change compared with control) for 6-9 rats/group; % change
control = ([treatment mean - control mean] control mean) x 100.
"Number presented as the number of animals showing at least one estrous cycle lasting >6 days/number of animals
in each group (% incidence).
fNumber presented as the number of estrous cycles observed lasting >6 days/number of estrous cycles observed in
each group (% incidence).
* Statistically significantly different from controls at p< 0.05, as reported by the study authors (Dunnett's multiple
comparison test).
**Statistically significantly different from controls atp< 0.01, as reported by the study authors (x2 test with Yate's
correction for continuity).
ET = extrathoracic respiratory effects; HEC = human equivalent concentration; MW = molecular weight;
SD = standard deviation.
127
1,2-Dichloropropane

-------
FINAL
09-29-2016
APPENDIX C. BENCHMARK DOSE MODELING RESULTS
MODELING PROCEDURE FOR DICHOTOMOUS DATA
The benchmark dose (BMD) modeling of dichotomous data was conducted with EPA's
Benchmark Dose Software (BMDS, Version 2.5). For these data, all of the dichotomous models
(i.e., Gamma, Multistage, Logistic, Log-Logistic, Probit, Log-Probit, and Weibull) available
within the software were fit using a default benchmark response (BMR) of 10% extra risk with
the exception of developmental/fetal effects, for which a BMR of 5% extra risk was used [as
outlined in the Benchmark Dose Technical Guidance; U.S. EPA (2012c) "I. Adequacy of model
fit was judged base on the %2 goodness-of-fit p-value {p > 0.1), magnitude of scaled residuals in
the vicinity of the BMR, and visual inspection of the model fit. Among all models providing
adequate fit, the lowest benchmark dose lower confidence limit/benchmark concentration lower
confidence limit (BMDL/BMCL) was selected if the BMDL/BMCL estimates from different
models varied >threefold; otherwise, the BMDL/BMCL from the model with the lowest
Akaike's information criterion (AIC) was selected as a potential point of departure (POD) from
which to derive the reference dose/reference concentration (RfD/RfC).
In addition, in the absence of a mechanistic understanding of the biological response to a
toxic agent, data from exposures much higher than the study lowest-observed-adverse-effect
level (LOAEL) do not provide reliable information regarding the shape of the response at low
doses. Such exposures, however, can have a strong effect on the shape of the fitted model in the
low-dose region of the dose-response curve. Thus, if lack of fit is due to characteristics of the
dose-response data for high doses, then the Benchmark Dose Technical Guidance document
allows for data to be adjusted by eliminating the high-dose group (U.S. LP A. 2012c). Because
the focus of BMD analysis is on the low-dose regions of the response curve, elimination of the
high-dose group is deemed reasonable.
MODELING PROCEDURE FOR CONTINUOUS DATA
The BMD modeling of continuous data was conducted with EPA's BMDS (Version 2.5).
For these data, all continuous models available within the software were fit using a default BMR
of 1 standard deviation (SD) relative risk unless a biologically determined BMR was available
(e.g., BMR 10% relative deviation for body weight based on a biologically significant weight
loss of 10%), as outlined in the Benchmark Dose Technical Guidance (U.S. LP A. 2012c). An
adequate fit was judged based on the %2 goodness-of-fit p-v alue (p > 0.1), magnitude of the
scaled residuals in the vicinity of the BMR, and visual inspection of the model fit. In addition to
these three criteria forjudging adequacy of model fit, a determination was made as to whether
the variance across dose groups was homogeneous. If a homogeneous variance model was
deemed appropriate based on the statistical test provided by BMDS (i.e., Test 2), the final BMD
results were estimated from a homogeneous variance model. If the test for homogeneity of
variance was rejected (p < 0.1), the model was run again while modeling the variance as a power
function of the mean to account for this nonhomogeneous variance. If this nonhomogeneous
variance model did not adequately fit the data (i.e., Test 3; p-v alue < 0.1), the data set was
considered unsuitable for BMD modeling. Among all models providing adequate fit, the lowest
BMDL/BMCL was selected if the BMDL/BMCL estimates from different models varied
>threefold; otherwise, the BMDL/BMCL from the model with the lowest AIC was selected as a
potential POD from which to derive the RfD/RfC.
128
1,2-Dichloropropane

-------
FINAL
09-29-2016
As described above for dichotomous data, if data did not fit any models due to
characteristics of the dose-response data for high doses, modeling was performed with
elimination of the high-dose group.
BMD MODELING TO IDENTIFY POTENTIAL PODs FOR THE DERIVATION OF A
SUBCHRONIC p-RfD
The following data sets were selected for BMD modeling:
•	Litter incidence data for delayed ossification in rat fetuses following maternal
administration of 1,2-dichloropropane (1,2-DCP) via gavage from Gestation Days
(GDs) 6-15 (Kirk et ai, 1995); selected as critical endpoint for subchrotticp-RfD
derivation.
•	Litter incidence data for delayed ossification in rabbit fetuses following maternal
administration of 1,2-DCP via gavage from GDs 7-19 (Kirk et aL 1995).
•	Continuous data for decreased body weight in male F344 rats administered 1,2-DCP
via gavage 5 days/week for 13 weeks (Dow Chemical Co. 1988b).
•	Continuous data for increased reticulocytes in pregnant New Zealand white (NZW)
rabbits administered 1,2-DCP via gavage from GDs 7-19 (Kirk et aL 1995).
Increased Litter Incidence of Delayed Skull Ossification in Rat Fetuses Exposed to 1,2-DCP
on GDs 6-15
The procedure outlined above was applied to the data for increased litter incidence of
delayed skull ossification in fetuses from Sprague Dawley (S-D) rat dams administered 1,2-DCP
via gavage from GDs 6-15 (Kirk et aL 1995) (see Table C-1). Table C-2 summarizes the BMD
modeling results. All models provided adequate fit to the data. BMDLs for models providing
adequate fit differed by >threefold, so the model with the lowest BMDL was selected
(LogLogistic). Thus, the BMDLos of 5.6 mg/kg-day from this model is selected for this endpoint
(see Figure C-l and the BMD text output for details).
Table C-l. Litter Incidence of Delayed Skull Ossification in Fetuses from S-D Rat Dams
Administered 1,2-Dichloropropane via Gavage on GDs 6-15a

Dose (mg/kg-d)
0
10
30
125
Sample size (number of litters)
25
28
28
30
Litter incidence
8
8
10
16
'Kirket ai H99TI
GD = gestation day; S-D = Sprague-Dawley.
129
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table C-2. BMD Modeling Results for Litter Incidence of Delayed Skull Ossification in
Fetuses from S-D Rat Dams Administered 1,2-Dichloropropane via Gavage on GDs 6-15
Model
DF
X2 Goodness-of-Fit
/>-Value"
AIC
BMDos
(mg/kg-d)
BMDLos
(mg/kg-d)
Gammab
1
0.70
148.95
26.10
8.00
Logistic
2
0.92
146.98
20.54
12.81
LogLogisticcd
1
0.71
148.95
25.33
5.63
LogProbit0
2
0.91
146.98
37.64
21.13
Multistage (1-degree)6
2
0.90
147.01
15.69
7.96
Multistage (2-degree)6
1
0.68
148.97
24.76
7.99
Multistage (3-dcgrcc)'le
1
0.68
148.97
24.76
7.99
Probit
2
0.92
146.98
20.12
12.52
Weibullb
1
0.70
148.95
25.74
8.00
aValues <0.1 fail to meet conventional goodness-of-fit criteria.
bPower restricted to >1.
°Slope restricted to >1.
dSelected model.
"Betas restricted to >0.
AIC = Akaike's information criterion; BMD = maximum likelihood estimate of the dose associated with the
selected BMR; BMDL = 95% lower confidence limit on the BMD (subscripts denote BMR: i.e., io = dose
associated with 10% extra risk); DF = degrees of freedom; GD = gestation day; S-D = Sprague-Dawley.
130
1,2-Dichloropropane

-------
FINAL
09-29-2016
Log-Logistic Model, with BMR of 5% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BM
0.7
0.6
"S	0.5
o
£
<
.2	0.4
"G
to
LL
0.3
0.2
0.1
0	20	40	60	80	100	120
dose
15:14 04/08 2015
Figure C-l. LogLogistic Model for Litter Incidence of Delayed Skull Ossification in Fetuses
from S-D Rat Dams Administered 1,2-Dichloropropane via Gavage on GDs 6-15 (Kirk et
al.. 1995)
Text Output for LogLogistic Model for Litter Incidence of Delayed Skull Ossification in
Fetuses from S-D Rat Dams Administered 1,2-Dichloropropane via Gavage on GDs 6-15
(Kirk et al.. 1995)
Logistic Model. (Version: 2.14; Date: 2/28/2013)
Input Data File:
C:/BMDS25 0_2014/Data/12-DCP/lnl_DelaySkullOss_Lnl-BMR05-Restrict.(d)
Gnuplot Plotting File:
C:/BMDS25 0_2014/Data/12-DCP/lnl_DelaySkullOss_Lnl-BMR05-Restrict.pit
Wed Apr 08 15:14:30 2015
BMDS Model Run
The form of the probability function is:
P[response] = background+(1-background)/[1+EXP(-intercept-siope*Log(dose))]
Dependent variable = Effect
Independent variable = Dose
Slope parameter is restricted as slope >= 1
Log-Logistic
- BMDL
BMD
131
1,2-Dichloropropane

-------
FINAL
09-29-2016
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial Parameter Values
background =	0.32
intercept =	-7.11782
slope =	1.29855
Asymptotic Correlation Matrix of Parameter Estimates
background
intercept
slope
background
1
-0. 64
0. 61
intercept
-0.64
1
-1
slope
0. 61
-1
1
Parameter Estimates
Interval
Variable
Limit
background
intercept
slope
Estimate
0.301998
-7.5024
1. 41029
Std. Err.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
* - Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)	# Param's	Deviance Test d.f.
-71.4002	4
-71.4723	3	0.144302 1
-73.6224	1	4.44442 3
P-value
0.704
0.2173
AIC:	148.945
Goodness of Fit
Dose	Est._Prob. Expected Observed	Size
Scaled
Residual
0.0000
10.0000
30.0000
125.0000
0.3020
0.3118
0.3457
0.5347
7.550	8.000
8.729	8.000
9.680	10.000
16.040	16.000
25
28
28
30
0.196
-0.298
0.127
-0.015
Chi^2 = 0.14	d.f. = 1
Benchmark Dose Computation
Specified effect =	0.05
Risk Type	=	Extra risk
Confidence level =	0.95
BMD =	25.3282
P-value = 0.7050
132
1,2-Dichloropropane

-------
FINAL
09-29-2016
BMDL =	5.62 668
Increased Litter Incidence of Delayed Skull Ossification in Rabbit Fetuses Exposed to
1,2-Dichloropropane on GDs 7-19
The procedure outlined above was applied to the data for increased litter incidence of
delayed skull ossification in fetuses from NZW rabbit does administered 1,2-DCP via gavage
from GDs 7-19 (Kirk et aL 1995) (see Table C-3). Table C-4 summarizes the BMD modeling
results. All models provided adequate fit to the data. BMDLs for models providing adequate fit
differed by >threefold, so the model with the lowest BMDL was selected (LogLogistic). Thus,
the BMDLos of 10 mg/kg-day from this model is selected for this endpoint (see Figure C-2 and
the BMD text output for details).
Table C-3. Litter Incidence of Delayed Skull Ossification in Fetuses from NZW Rabbit
Does Administered 1,2-Dichloropropane via Gavage on GDs 7-19a

Dose (mg/kg-d)

0
15
50
150
Sample size (number of litters)
18
16
17
15
Litter Incidence
0
0
2
6
"Kirk ct al. (1995).
GD = gestation day; NZW = New Zealand white.
133
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table C-4. BMD Modeling Results for Litter Incidence of Delayed Skull Ossification in
Fetuses from NZW Rabbit Does Administered 1,2-Dichloropropane via Gavage
on GDs 719
Model
DF
X2 Goodness-of-Fit
/>-Valuca
AIC
BMDos
(mg/kg-d)
BMDLos
(mg/kg-d)
Gammab
2
0.84
37.04
34.58
11.75
Logistic
2
0.39
38.86
56.17
35.26
LogLogisticcd
2
0.85
37.02
34.10
10.45
LogProbit0
3
0.98
34.81
35.57
23.83
Multistage (1-degree)6
3
0.82
36.08
18.00
10.55
Multistage (2-degree)6
2
0.77
37.28
34.26
11.43
Multistage (3-degree)6
2
0.77
37.28
34.26
11.43
Probit
2
0.45
38.48
50.97
31.92
Weibullb
2
0.82
37.11
33.76
11.64
"Values <0.1 fail to meet conventional goodness-of-fit criteria.
bPower restricted to > 1.
°Slope restricted to >1.
dSelected model.
"Betas restricted to >0.
AIC = Akaike's information criterion; BMD = maximum likelihood estimate of the dose associated with the
selected BMR; BMDL = 95% lower confidence limit on the BMD (subscripts denote BMR: i.e., 05 = dose
associated with 5% extra risk); DF = degrees of freedom; GD = gestation day; NZW = New Zealand white.
134
1,2-Dichloropropane

-------
FINAL
09-29-2016
Log-Logistic Model, with BMR of 5% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BM
Log-Logistic
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
BMDL
BMD
0
20
40
60
80
100
120
140
dose
16:05 04/10 2015
Figure C-2. LogLogistic Model for Litter Incidence of Delayed Skull Ossification in Fetuses
from NZW Rabbit Does Administered 1,2-Dichloropropane via Gavage on GDs 7-19 (Kirk
et al., 1995)
Text Output for LogLogistic Model for Litter Incidence of Delayed Skull Ossification in
Fetuses from NZW Rabbit Does Administered 1,2-Dichloropropane via Gavage on
GDs 7-19 (Kirk et al.. 1995)
Logistic Model. (Version: 2.14; Date: 2/28/2013)
Input Data File:
C:/BMDS25 0_2014/Data/12-DCP/Kirkl995_rabbit/lnl_skulloss_Lnl-BMR05-Restrict.(d)
Gnuplot Plotting File:
C:/BMDS25 0_2014/Data/12-DCP/Kirkl995_rabbit/lnl_skulloss_Lnl-BMR05-Restrict.pit
Fri Apr 10~ 16:05:12 2015
BMDS Model Run
The form of the probability function is:
P[response] = background+(1-background)/[1+EXP(-intercept-siope*Log(dose))]
Dependent variable = Effect
Independent variable = Dose
Slope parameter is restricted as slope >= 1
Total number of observations = 4
135
1,2-Dichloropropane

-------
FINAL
09-29-2016
Total number of records with missing values = 0
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial Parameter Values
background =	0
intercept =	-7.16982
slope =	1.34064
Asymptotic Correlation Matrix of Parameter Estimates
the user,
intercept
slope
( *** The model parameter(s) -background
have been estimated at a boundary point, or have been specified by
and do not appear in the correlation matrix )
intercept
1
-0. 99
slope
-0.99
1
Parameter Estimates
Interval
Variable
Limit
background
intercept
slope
Estimate
-9.13596
1.75429
Std. Err.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
* - Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)	# Param's	Deviance Test d.f.
-16.2528	4
-16.5124	2	0.519275 2
-24.376	1	16.2465 3
P-value
0.7713
0.001009
AIC:	37.0248
Goodness of Fit
Dose	Est._Prob. Expected Observed	Size
Scaled
Residual
0.0000
15.0000
50.0000
150.0000
0.0000
0.0123
0.0934
0.4144
0.000
0.197
1.587
6.216
0.000
0.000
2.000
6.000
18
16
17
15
0. 000
-0.446
0.344
-0.113
Chi^2 =0.33
d.f. = 2
P-value = 0.8477
Benchmark Dose Computation
136	1,2-Dichloropropane

-------
FINAL
09-29-2016
Specified effect
Risk Type
Confidence level
BMD
BMDL
0. 05
Extra risk
0. 95
34.1023
10.4498
Decreased Body Weight in Male Rats Exposed to 1,2-Dichloropropane via Gavage for
13 Weeks
The procedure outlined above was applied to the data for decreased body weight in male
F344 rats exposed to 1,2-DCP via gavage 5 days/week for 13 weeks (Dow Chemical Co. 1988b)
(see Table C-7). Table C-8 summarizes the BMD modeling results. Neither the constant nor the
nonconstant variance models provide adequate fit to the variance data using the full data set.
Table C-7. Body Weight in Male F344 Rats Exposed to 1,2-Dichloropropane via Gavage
5 Days/Week for 13 Weeks"

Dose (mg/kg-d)b
0
14
46
143
Sample size
15
15
15
15
Mean (g)
341.7
334.9
331
308
SD (g)
11.2
13.7
25.7
14.8
aDow Chemical Co (1988b).
bGavage doses were converted to ADDs by multiplying the administered gavage dose by (5/7) days/week.
ADD = adjusted daily dose; SD = standard deviation.
137
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table C-8. BMD Modeling Results for Body Weight in F344 Rats Exposed to
1,2-Dichloropropane via Gavage 5 Days/Week for 13 Weeks
Model
Test for Significant
Difference /j-Valuc"
Variance
/>-Valucb
Means
7?-Valueb
AIC
BMD io
(mg/kg-d, ADD)
BMDLio
(mg/kg-d, ADD)
Exponential
(Model 2)d
<0.0001
0.001889
0.5859
406.7058
-136.516
NA
Exponential
(Model 3)d
<0.0001
0.001889
0.5859
433.0087
-136.516
NA
Exponential
(Model 4)d
<0.0001
0.001889
<0.0001
409.276593
NA
NA
Exponential
(Model 5)d
<0.0001
0.001889
NA
431.008749
NA
NA
Hilld
<0.0001
0.001889
NA
431.008749
NA
NA
Linear0
<0.0001
0.001889
<0.0001
406.049023
-9,999
1,528.76
Polynomial
(2-degree)°
<0.0001
0.001889
<0.0001
406.7058
-9,999
491.02
Polynomial
(3-degree)0
<0.0001
0.001889
<0.0001
406.7058
-9,999
329.09
Power"1
<0.0001
0.001889
0.8137
433.0087
150.976
117.157
aValues >0.05 fail to meet conventional goodness-of-fit criteria.
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
"Coefficients restricted to be negative.
dPower restricted to > 1.
ADD = adjusted daily dose; AIC = Akaike's information criterion; BMD = maximum likelihood estimate of the
exposure dose associated with the selected BMR; BMDL = 95% lower confidence limit on the BMD (subscripts
denote BMR: i.e., io = exposure dose associated with 10% extra risk); NA = not applicable (BMDL computation
failed or the BMD was higher than the highest dose tested).
Increased Reticulocytes in Pregnant Rabbits Exposed to 1,2-Dichloropropane via Gavage
on GDs 7-19
The procedure outlined above was applied to the data for increased reticulocytes in
pregnant NZW rabbits administered 1,2-DCP via gavage on GDs 7-19 (Kirk et al.. 1995)
(see Table C-9). Table C-10 summarizes the BMD modeling results. Constant variance model
did not fit the variance data, but nonconstant variance model did. With nonconstant variance
model applied, all models except for Exponential Models 4 and 5 and the Hill Model provided
adequate fit to means. BMDLs for models providing adequate fit were sufficiently close
(differed by 
-------
FINAL
09-29-2016
Table C-9. Reticulocytes in Pregnant NZW Rabbits Administered 1,2-Dichloropropane via
Gavage on GDs 7-19a

Dose (mg/kg-d)
0
15
50
150
Sample size
18
16
17
15
Mean (%)
3.2
3.6
3.8
6.7
SD (%)
0.6
0.7
0.9
1.7
"Kirk ct al. (1995).
GD = gestation day; NZW = New Zealand white; SD = standard deviation.
Table C-10. BMD Modeling Results for Reticulocytes in Pregnant NZW Rabbits
Administered 1,2-Dichloropropane via Gavage on GDs 7-19
Model
Test for Significant
Difference /j-Valuc"
Variance
/>-Valucb
Means />-Valucb
AIC
BMDisd
(mg/kg-d)
BMDLisd
(mg/kg-d)
Constant Variance
Linear0
<0.0001
<0.0001
0.13
77.01
44.72
36.79
Nonconstant Variance
Exponential
(Model 2)^
<0.0001
0.73
0.35
55.14
37.17
29.92
Exponential
(Model 3)d
<0.0001
0.73
0.19
56.75
47.26
30.40
Exponential
(Model 4)d
<0.0001
0.73
0.04
59.30
28.90
22.02
Exponential
(Model 5)d
<0.0001
0.73
NA
59.18
50.04
25.39
Hilld
<0.0001
0.73
NA
59.18
50.06
NA
Linear0
<0.0001
0.73
0.12
57.30
28.90
22.02
Polynomial
(2-degree)°
<0.0001
0.73
0.21
56.63
47.95
26.81
Polynomial
(3-degree)0
<0.0001
0.73
0.28
56.22
48.93
27.45
Power"1
<0.0001
0.73
0.14
57.18
50.04
25.39
aValues >0.05 fail to meet conventional goodness-of-fit criteria.
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
Coefficients restricted to be positive.
dPower restricted to > 1.
"Selected model.
AIC = Akaike's information criterion; BMD = maximum likelihood estimate of the exposure dose associated with
the selected BMR; BMDL = 95% lower confidence limit on the BMD (subscripts denote BMR: i.e., io = exposure
dose associated with 10% extra risk); GD = gestation day; NA = not applicable (BMDL computation failed or the
BMD was higher than the highest dose tested); NZW = New Zealand white; SD = standard deviation.
139
1,2-Dichloropropane

-------
FINAL
09-29-2016
Exponential Model 2, with BMR of 1 Std. Dev. for the BMD and 0.95 Lower Confidence Level for BMDL
8
a)
CO
c
o
Q.
CO
a)
Q1
c
ro
a)
Exponential
BMDL BMD
dose
11:28 05/18 2015
Figure C-5. Exponential 2 Model for Percent Reticulocytes in Pregnant NZW Rabbits
Administered 1,2-Dichloropropane via Gavage on GDs 7-19 (Kirk et al., 1995)
Text Output for Exponential 2 Model for Percent Reticulocytes in Pregnant NZW Rabbits
Administered 1,2-Dichloropropane via Gavage on GDs 7-19 (Kirk et al., 1995)
Exponential Model. (Version: 1.9; Date: 01/29/2013)
Input Data File:
C:/BMDS25 0_2014/Data/12-DCP/Kirkl995_rabbit/exp_reticulocyte_Exp-ModelVariance-BMRlStd
-Up.(d)
Gnuplot Plotting File:
Mon May 18 11:28:21 2015
BMDS Model Run
The form of the response function by Model:
Model 2
Model 3
Model 4
Model 5
Y[dose]	= a	*	exp{sign *	b * dose}
Y[dose]	= a	*	exp{sign *	(b * dose)Ad}
Y[dose]	= a	*	[c-(c-l) *	exp{-b * dose}]
Y[dose]	= a	*	[c-(c-l) *	exp{-(b * dose)Ad}]
Note: Y[dose] is the median response for exposure = dose;
sign = +1 for increasing trend in data;
140
1,2-Dichloropropane

-------
FINAL
09-29-2016
sign = -1 for decreasing trend.
Model 2 is nested within Models 3 and 4.
Model 3 is nested within Model 5.
Model 4 is nested within Model 5.
Dependent variable = Mean
Independent variable = Dose
Data are assumed to be distributed: normally
Variance Model: exp(lnalpha +rho *ln(Y[dose]))
The variance is to be modeled as Var(i) = exp(lalpha + log(mean(i))
rho)
Total number of dose groups = 4
Total number of records with missing values = 0
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
MLE solution provided: Exact
Initial Parameter Values
Variable
lnalpha
rho
a
b
c
d
Model 2
-4.11723
2.74317
3.19097
0.00481343
0
1
Parameter Estimates
Variable
lnalpha
rho
a
b
c
d
Model 2
-4 .28274
2.84625
3.20531
0.00473261
0
1
Table of Stats From Input Data
Dose
0
15
50
150
18
16
17
15
Obs Mean
3.2
3.6
3.8
6.7
Obs Std Dev
0.6
0.7
0.9
1.7
Estimated Values of Interest
Dose
0
15
50
150
Est Mean
3.205
3.441
4.061
6.519
Est Std
0.6165
0.682
0.8633
1.693
Scaled Residual
-0. 03653
0.9318
-1.247
0.4144
Other models for which likelihoods are calculated:
Model A1:	Yij
Var{e(ij)}
Mu(i) + e(i j)
SigmaA2
141
1,2-Dichloropropane

-------
FINAL
09-29-2016
Model A2:	Yij
Var{e(ij)}
Model A3:
Model R:
Yij
Var{e(ij)}
Yij
Var{e(ij)}
Model
Mu(i) + e(i j)
Sigma(i)A2
Mu(i) + e(i j)
exp(lalpha + log(mean(i)) * rho)
Mu + e(i)
SigmaA2
Likelihoods of Interest
Log(likelihood)	DF
AIC
A1
A2
A3
R
2
-33. 44203
-22.20314
-22.51772
-67.36346
-23.5711
6
2
4
-60.65.
76.88405
60.40629
57.03545
138.7269
55.14221
This constant added to the
Additive constant for all log-likelihoods =
above values gives the log-likelihood including the term that does not
depend on the model parameters.
Explanation of Tests
Does response and/or variances differ among Dose levels? (A2 vs. R)
Are Variances Homogeneous? (A2 vs. Al)
Are variances adeguately modeled? (A2 vs. A3)
Does Model 2 fit the data? (A3 vs. 2)
Tests of Interest
-2*log(Likelihood Ratio)	D. F.
Test
1:
Test
2 :
Test
3:
Test
4 :
Test
Test 1
Test 2
Test 3
Test 4
p-value
90.32
22.48
0.6292
2.107
<0.0001
<0.0001
0.7301
0.3488
The p-value for Test 1 is less than .05. There appears to be a
difference between response and/or variances among the dose
levels, it seems appropriate to model the data.
The p-value for Test 2 is less than .1. A non-homogeneous
variance model appears to be appropriate.
The p-value for Test 3 is greater than .1.
variance appears to be appropriate here.
The p-value for Test 4 is greater than .1.
to adeguately describe the data.
The modeled
Model 2 seems
Benchmark Dose Computations:
Specified Effect = 1.000000
Risk Type = Estimated standard deviations from control
Confidence Level = 0.950000
BMD
BMDL
37.1709
29.9179
142
1,2-Dichloropropane

-------
FINAL
09-29-2016
BMD MODELING TO IDENTIFY POTENTIAL PODs FOR THE DERIVATION OF A
CHRONIC p-RfD
The following data sets were selected for BMD modeling:
•	Litter incidence data for delayed ossification in rat fetuses following maternal
administration of 1,2-DCP via gavage on GDs 6-15 (Kirk et aL 1995); selected as
critical endpoint for chronic p-RfD derivation.
•	Litter incidence data for delayed ossification in rabbit fetuses following maternal
administration of 1,2-DCP via gavage on GDs 7-19 (Kirk et aL 1995).
•	Incidence data for increased hepatocytomegaly in male B6C3Fi mice administered
1,2-DCP via gavage for 103 weeks (N I P. 1986).
Increased Litter Incidence of Delayed Skull Ossification in Rat Fetuses Exposed to
1,2-Dichloropropane on GDs 6-15
See BMD modeling results in the subchronic section above (Tables C-l-C-2, Figure C-l,
and associated BMD output text).
Increased Litter Incidence of Delayed Skull Ossification in Rabbit Fetuses Exposed to
1,2-Dichloropropane on GDs 7-19
See BMD modeling results in the subchronic section above (Tables C-3-C-4, Figure C-2,
and associated BMD output text).
Increased Incidence of Hepatocytomegaly in Male Mice Exposed to 1,2-Dichloropropane
via Gavage for 103 Weeks
The procedure outlined above was applied to the data for increased incidence of
hepatocytomegaly in male B6C3Fi mice administered 1,2-DCP via gavage 5 days/week for
103 weeks (NTP. 1986) (see Table C-l3). Table C-l4 summarizes the BMD modeling results.
The Logistic, Multistage 1-degree, and Probit models provided adequate fit to the data. The
BMDLs for models providing adequate fit are sufficiently close (differed by 
-------
FINAL
09-29-2016
Table C-14. BMD Output Data for Incidence of Hepatocytomegaly in Male B6C3Fi Mice
Administered 1,2-Dichloropropane via Gavage for 103 Weeks
Model
DF
X2 Goodness-of-Fit
/>-Value"
AIC
BMDio
(mg/kg-d)
BMDLio
(mg/kg-d)
Gammab
0
NA
122.079
119.845
60.1885
Logistic
1
0.5145
120.508
102.606
82.2716
LogLogistic0
0
NA
122.079
120.637
59.3308
LogProbit0
0
NA
122.079
117.866
76.9345
Multistage (1-degree)4"
1
0.654
120.285
108.35
58.46
Multistage (2-degree)d
1
NA
122.079
123.197
60.1885
Probit
1
0.4379
120.694
97.8117
77.136
Weibullb
0
NA
122.079
121.783
60.1885
"Values <0.1 fail to meet conventional goodness-of-fit criteria.
bPower restricted to > 1.
"Slope restricted to >1.
dBetas restricted to >0.
"Selected model.
AIC = Akaike's information criterion; BMD = maximum likelihood estimate of the dose associated with the selected
BMR; BMDL = 95% lower confidence limit on the BMD (subscripts denote BMR: i.e., io = dose associated with 10%
extra risk); DF = degrees of freedom; NA = not applicable (BMDL computation failed or the BMD was higher than
the highest dose tested).
144
1,2-Dichloropropane

-------
FINAL
09-29-2016
Multistage Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BM
Multistage
BMD Lower Bound
0.4
0.3
0.2
0.1
0
BMDL
BMD
0
20
40
60
80
100
120
140
160
180
dose
10:26 03/10 2016
Figure C-6. Multistage (2-degree) Model for Incidence of Hepatocytomegaly in Male
B6C3Fi Mice Administered 1,2-Dichloropropane via Gavage for 103 Weeks (NTP, 1986)
Text Output for Multistage (2-degree) Model for Incidence of Hepatocytomegaly in Male
B6C3Fi Mice Administered 1,2-Dichloropropane via Gavage for 103 Weeks (NTP, 1986)
Multistage Model. (Version: 3.3; Date: 02/28/2013)
Input Data File:
C:/Users/JKaiser/Desktop/BMDS240/Data/mst_hepatcyt_MM_ntp86_Mst2-BMR10-Restrict.(d)
Gnuplot Plotting File:
C:/Users/JKaiser/Desktop/BMDS24 0/Data/mst_hepatcyt_MM_ntp8 6_Ms12-BMRIO-Restrict.pit
Tue Mar 15 13:59:05 2016
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/s2) ]
The parameter betas are restricted to be positive
Dependent variable = Effect
Independent variable = Dose
Total number of observations = 3
145
1,2-Dichloropropane

-------
FINAL
09-29-2016
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
Degree of polynomial = 2
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0.0478073
Beta(l) =	0
Beta(2) = 9.51136e-006
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Beta(l)
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
Background	Beta (2)
Background	1	-0.66
Beta (2)	-0.66	1
Parameter Estimates
95.0% Wald Confidence
Interval
Variable	Estimate	Std. Err. Lower Conf. Limit Upper Conf.
Limit
Background	0.0541837	* * *
Beta(1)	0	* * *
Beta(2)	8.97479e-006	* * *
* - Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-58.0393
-58.1423
-64.1001
Param's
3
2
1
Deviance Test d.f.
0.206101
12.1217
P-value
0.6498
0.002332
AIC:
120.285
Goodness of Fit
Scaled
Dose	Est._Prob. Expected Observed	Size	Residual
0.0000	0.0542	2.709	3.000	50	0.182
89.2860	0.1195	5.855	5.000	49	-0.377
178.6000	0.2896	14.482 15.000	50	0.161
146
1,2-Dichloropropane

-------
FINAL
09-29-2016
Chi^2 = 0.20 d.f.	= 1 P-value = 0.6540
Benchmark Dose Computation
Specified effect =	0.1
Risk Type =	Extra risk
Confidence level =	0.95
BMD =	108.35
BMDL =	5 8.46
BMDU =	152.691
Taken together, (58.46	, 152.691) is a 90	% two-sided confidence
interval for the BMD
BMC MODELING TO IDENTIFY POTENTIAL PODs FOR THE DERIVATION OF A
SUBCHRONIC p-RfC
The following data sets were selected for BMD modeling:
•	Incidence data for nasal cavity lesions in male and female F344/DuCrj (SPF) rats
exposed to 1,2-DCP via inhalation for 6 hours/day, 5 days/week for 13 weeks (Dow
Chemical Co. 1988a); female POD selected as critical endpoint for subchronic
p-RfC derivation.
•	Incidence data for nasal cavity lesions in male and female B6D2Fi/Crlj (SPF) mice
exposed to 1,2-DCP via inhalation for 6 hours/day, 5 days/week for 13 weeks
(Nlatsumoto et al.. 2013).
Increased Incidence of Nasal Cavity Lesions in Male Rats Exposed to 1,2-Dichloropropane
via inhalation for 13 Weeks
The procedure outlined above was applied to the data for increased incidence of nasal
respiratory epithelium hyperplasia in male F344/DuCrj (SPF) rats administered 1,2-DCP via
inhalation for 6 hours/day, 5 days/week for 13 weeks (Dow Chemical Co. 1988a)
(see Table C-15). Table C-16 summarizes the BMC modeling results. All models provided
adequate fit to the data. BMCLs for models providing adequate fit were not sufficiently close
(differed by >threefold), so the model with the lowest BMCL was selected (LogLogistic). Thus,
the BMCLio (HEC) of 0.26 mg/m3 from this model is selected for this endpoint (see Figure C-7
and the BMC text output for details).
147
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table C-15. Incidence of Nasal Respiratory Epithelium Hyperplasia in Male F344 Rats
Exposed to 1,2-Dichloropropane via Inhalation for 6 Hours/Day, 5 Days/Week


for 13 Weeks3



HEC (mg/m3)b
0
1.6
5.4
16.5
Sample size
10
9
10
10
Incidence
0
2
5
9
"Dow Chemical Co (1988a).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects by treating
1,2-DCP as a Category 1 gas and using the following equation: HECet = (ppm x MW ^ 24.45) x (hours/day
exposed ^ 24) x (days/week exposed ^ 7) x RGDRet.
HEC = human equivalent concentration; MW = molecular weight.
Table C-16. BMC Modeling Results for Nasal Respiratory Epithelium Hyperplasia in Male
F344 Rats Exposed to 1,2-Dichloropropane via Inhalation for 6 Hours/Day, 5 Days/Week
for 13 Weeks
Model
DF
X2 Goodness-of-Fit
/j-Value"
AIC
BMC io
(mg/m3, HECet)
BMCLio
(mg/m3, HECet)
Gammab
3
0.9962
31.9576
0.766618
0.492999
Logistic
2
0.3154
37.286
2.30795
1.44566
LogLogisticcd
2
0.8374
34.2581
0.961257
0.262207
LogProbit0
3
0.9016
32.4352
1.25292
0.803737
Multistage (2-degree)6
2
0.9712
33.9564
0.774685
0.493044
Multistage (3-degree)6
2
0.3129
37.2675
2.27866
1.50938
Probit
2
0.9962
31.9576
0.766618
0.492999
Weibullb
3
0.9962
31.9576
0.766618
0.492999
aValues <0.1 fail to meet conventional goodness-of-fit criteria.
bPower restricted to > 1.
°Slope restricted to >1.
dSelected model.
"Betas restricted to >0.
AIC = Akaike's information criterion; BMC = maximum likelihood estimate of the concentration associated with the
selected BMR; BMCL = 95% lower confidence limit on the BMC (subscripts denote BMR: i.e., io = concentration
associated with 10% extra risk); DF = degrees of freedom; ET = extrathoracic respiratory effects; HEC = human
equivalent concentration.
148
1,2-Dichloropropane

-------
FINAL
09-29-2016
0	2	4	6	8	10 12 14 16
dose
13:22 04/19 2016
Figure C-7. LogLogistic Model for Incidence of Nasal Respiratory Epithelium Hyperplasia
in Male F344 Rats Exposed to 1,2-Dichloropropane via Inhalation for 6 Hours/Day,
5 Days/Week for 13 Weeks (Dow Chemical Co, 1988a)
Log-Logistic Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the B
Log-Logistic
BMD Lower Bound
Text Output for LogLogistic Model for Incidence of Nasal Respiratory Epithelium
Hyperplasia in Male F344 Rats Exposed to 1,2-Dichloropropane via Inhalation for
6 Hours/Day, 5 Days/Week for 13 Weeks (Dow Chemical Co, 1988a)
Logistic Model. (Version: 2.14; Date: 2/28/2013)
Input Data File:
C:/Users/JKaiser/Desktop/BMDS240/Data/lnl_nose_MR_DCC88a_Lnl-BMR10-Restrict.(d)
Gnuplot Plotting File:
C:/Users/JKaiser/Desktop/BMDS240/Data/lnl_nose_MR_DCC88a_Lnl-BMR10-Restrict.pit
Tue Apr 19 13:27:34 2016
BMDS Model Run
The form of the probability function is:
P[response] = background+(1-background)/[1+EXP(-intercept-siope*Log(dose))]
Dependent variable = Effect
Independent variable = Dose
Slope parameter is restricted as slope >= 1
149
1,2-Dichloropropane

-------
FINAL
09-29-2016
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial Parameter Values
background =	0
intercept =	-2.11862
slope =	1.47191
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -background
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
intercept	slope
intercept 1	-0.89
slope -0.89	1
Parameter Estimates
Interval
Variable
Limit
background
intercept
slope
Estimate
-2.14082
1. 42761
Std. Err.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-14.9497
-15.129
-26.4011
Param's
4
2
1
Deviance Test d.f.
0.358749
22.9029
P-value
0.835E
<.0001
AIC:
34.2581
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed	Size	Residual
0.0000 0.0000 0.000 0.000	10	0.000
1.6000 0.1870 1.683 2.000	9	0.271
5.4000 0.5663 5.663 5.000	10	-0.423
16.5000 0.8654 8.654 9.000	10	0.320
150
1,2-Dichloropropane

-------
FINAL
09-29-2016
Chi^2 = 0.35 d.f.	= 2 P-value = 0.8374
Benchmark Dose Computation
Specified effect =	0.1
Risk Type =	Extra risk
Confidence level =	0.95
BMD =	0.961257
BMDL =	0.2 622 07
Increased Incidence of Nasal Cavity Lesions in Female Rats Exposed to
1,2-Dichloropropane via Inhalation for 13 Weeks
The procedure outlined above was applied to the data for increased incidence of nasal
respiratory epithelium hyperplasia in female F344/DuCij (SPF) rats administered 1,2-DCP via
inhalation for 6 hours/day, 5 days/week for 13 weeks (Dow Chemical Co. 1988a)
(see Table C-17). Table C-18 summarizes the BMC modeling results. All models except the
Logistic and Probit models provided adequate fit to the data. BMCLs for models providing
adequate fit were not sufficiently close (differed by >threefold), so the model with the lowest
BMCL was selected (LogLogistic). Thus, the BMCLio (HEC) of 0.12 mg/m3 from this model is
selected for this endpoint (see Figure C-8 and the BMC text output for details).
Table C-17. Incidence of Nasal Respiratory Epithelium Hyperplasia in Female F344 Rats
Exposed to 1,2-Dichloropropane via Inhalation for 6 Hours/Day, 5 Days/Week


for 13 Weeks"



HEC (mg/m3)b
0
1.2
4.0
12.1
Sample size
10
10
10
10
Incidence
0
3
7
9
aDow Chemical Co (1988a).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects by treating
1,2-DCP as a Category 1 gas and using the following equation: HECet = (ppm x MW ^ 24.45) x (hours/day
exposed ^ 24) x (days/week exposed ^ 7) x RGDRet.
HEC = human equivalent concentration; MW = molecular weight.
151
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table C-18. BMC Modeling Results for Nasal Respiratory Epithelium Hyperplasia in
Female F344 Rats Exposed to 1,2-Dichloropropane via Inhalation for 6 Hours/Day,
5 Days/Week for 13 Weeks
Modelb
DF
X2 Goodness-of-Fit
/>-Valuca
AIC
BMC io
(mg/m3, HECet)
BMCio
(mg/m3, HECet)
Gamma0
3
0.8383
33.6682
0.424155
0.277086
Logistic
2
0.0836
41.1432
1.22889
0.773713
LogLogisticde
2
0.9934
34.9494
0.428241
0.117119
LogProbitd
3
0.893
33.455
0.665604
0.426139
Multistage
(2-degree)f
3
0.8383
33.6682
0.424155
0.277086
Multistage
(3-degree)f
3
0.8383
33.6682
0.424155
0.277086
Probit
2
0.0809
41.5273
1.29404
0.871488
Weibull0
3
0.8383
33.6682
0.424155
0.277086
aValues <0.1 fail to meet conventional goodness-of-fit criteria.
bScaled residuals for dose group above and below the BMC.
Tower restricted to >1.
dSlope restricted to >1.
Selected model.
fBetas restricted to >0.
AIC = Akaike's information criterion; BMC = maximum likelihood estimate of the concentration associated with
the selected BMR; BMCL = 95% lower confidence limit on the BMC (subscripts denote BMR:
i.e., io = concentration associated with 10% extra risk); DF = degrees of freedom; ET = extrathoracic respiratory
effects; HEC = human equivalent concentration.
152
1,2-Dichloropropane

-------
FINAL
09-29-2016
0	2	4	6	8	10	12
dose
13:29 04/19 2016
Figure C-8. LogLogistic Model for Incidence of Nasal Respiratory Epithelium Hyperplasia
in Female F344 Rats Exposed to 1,2-Dichloropropane via Inhalation for 6 Hours/Day,
5 Days/Week for 13 Weeks (Dow Chemical Co, 1988a)
Log-Logistic Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the B
Log-Logistic
BMD Lower Bound
Text Output for LogLogistic Model for Incidence of Nasal Respiratory Epithelium
Hyperplasia in Female F344 Rats Exposed to 1,2-Dichloropropane via Inhalation for
6 Hours/Day, 5 Days/Week for 13 Weeks (Dow Chemical Co, 1988a)
Logistic Model. (Version: 2.14; Date: 2/28/2013)
Input Data File:
C:/Users/JKaiser/Desktop/BMDS240/Data/lnl_nose_FR_DCC88a_Lnl-BMR10-Restrict.(d)
Gnuplot Plotting File:
C:/Users/JKaiser/Desktop/BMDS240/Data/lnl_nose_FR_DCC88a_Lnl-BMR10-Restrict.pit
Tue Apr 19 13:29:25 2016
BMDS Model Run
The form of the probability function is:
P[response] = background+(1-background)/[1+EXP(-intercept-siope*Log(dose))]
Dependent variable = Effect
Independent variable = Dose
Slope parameter is restricted as slope >= 1
153
1,2-Dichloropropane

-------
FINAL
09-29-2016
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial Parameter Values
background =	0
intercept =	-1.05315
slope =	1.31878
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -background
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
intercept	slope
intercept 1	-0.79
slope -0.79	1
Parameter Estimates
Interval
Variable
Limit
background
intercept
slope
Estimate
-1.06342
1.33692
Std. Err.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-15.4681
-15.4747
-27.6759
# Param's
4
2
1
Deviance Test d.f.
0. 013218
24.4155
P-value
0.9934
<.0001
AIC:
34.9494
Dose
Est. Prob.
Goodness of Fit
Expected Observed	Size
Scaled
Residual
0.0000
1.2000
4.0000
12.1000
0.0000
0.3058
0.6878
0.9063
0.000
3.058
6.878
9.063
0.000
3.000
7.000
9.000
10
10
10
10
0. 000
-0.040
0. 083
-0.069
154
1,2-Dichloropropane

-------
FINAL
09-29-2016
Chi^2 =0.01 d.f.	=2 P-value = 0.9934
Benchmark Dose Computation
Specified effect =	0.1
Risk Type =	Extra risk
Confidence level =	0.95
BMD =	0.428241
BMDL =	0.117119
Increased Incidence of Nasal Atrophy in Male Mice Exposed to 1,2-Dichloropropane via
Inhalation for 13 Weeks
The procedure outlined above was applied to the data for increased incidence of nasal
respiratory epithelium hyperplasia in male B6D2Fi/Crlj (SPF) mice administered 1,2-DCP via
inhalation for 6 hours/day, 5 days/week for 13 weeks (Nlatsumoto et aL 2013) (see Table C-19).
Table C-20 summarizes the BMC modeling results. Only the multistage (2-degree) model fit the
data. Thus, the BMCLio (HEC) of 11.6 mg/m3 from this model is selected for this endpoint
(see Figure C-9 and the BMC text output for details).
Table C-19. Incidence of Nasal Atrophy in Male B6D2Fi/Crlj (SPF) Mice Exposed to
1,2-Dichloropropane via Inhalation for 6 Hours/Day, 5 Days/Week for 13 Weeks"

HEC (mg/m3)b

0
6.21
12.43
24.83
37.27
49.66
Sample size
10
10
10
10
10
10
Incidence
0
0
0
0
7
4
aMatsimioto et al. (2013).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects by treating
1,2-DCP as a Category 1 gas and using the following equation: HECet = (ppm x MW ^ 24.45) x (hours/day
exposed ^ 24) x (days/week exposed ^ 7) x RGDRet.
HEC = human equivalent concentration; MW = molecular weight.
155
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table C-20. BMC Modeling Results for Nasal Atrophy in Male B6D2Fi/Crlj (SPF) Mice
Exposed to 1,2-Dichloropropane via Inhalation for 6 Hours/Day, 5 Days/Week
for 13 Weeks
Modelb
DF
X2 Goodness-of-Fit
/>-Value"
AIC
BMC io
(mg/m3, HECet)
BMCio
(mg/m3, HECet)
Gamma0
4
0.0739
39.0073
24.0954
14.2339
Logistic
4
0.0254
41.5701
24.9982
17.7041
LogLogisticd
4
0.0803
38.9623
23.6942
14.1415
LogProbitd
4
0.0922
38.4711
24.3111
14.802
Multistage (2-degree)e f
5
0.1141
38.4902
18.542
11.6023
Multistage (3-degree/
5
0.0888
37.9183
23.9897
12.8322
Probit
4
0.0348
40.6044
24.896
17.1826
Weibull0
4
0.0571
39.8494
22.7104
12.7051
aValues <0.1 fail to meet conventional goodness-of-fit criteria.
bScaled residuals for dose group above and below the BMC.
Tower restricted to >1.
dSlope restricted to >1.
Selected model.
fBetas restricted to >0.
AIC = Akaike's information criterion; BMC = maximum likelihood estimate of the concentration associated with
the selected BMR; BMCL = 95% lower confidence limit on the BMC (subscripts denote BMR:
i.e., io = concentration associated with 10% extra risk); DF = degrees of freedom; ET = extrathoracic respiratory
effects; HEC = human equivalent concentration.
156
1,2-Dichloropropane

-------
FINAL
09-29-2016
Multistage Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BM
1
Multistage
BMD Lower Bound
0.8
0.6
0.4
0.2
0
BMDL
BMD
0	10	20	30	40	50
dose
13:39 04/19 2016
Figure C-9. Multistage (2-degree) Model for Incidence of Nasal Atrophy in Male
B6D2Fi/Crlj (SPF) Mice Exposed to 1,2-Dichloropropane via Inhalation for 6 Hours/Day,
5 Days/Week for 13 Weeks (Matsumoto et al., 2013)
Text Output for Multistage (2-degree) Model for Incidence of Nasal Atrophy in Male
B6D2Fi/Crlj (SPF) Mice Exposed to 1,2-Dichloropropane via Inhalation for 6 Hours/Day,
5 Days/Week for 13 Weeks (Matsumoto et al., 2013)
Multistage Model. (Version: 3.3; Date: 02/28/2013)
Input Data File:
C:/Users/JKaiser/Desktop/BMDS24 0/Data/mst_nose_MM_Matsu_sc_Mst2-BMR10-Restrict. (d)
Gnuplot Plotting File:
C:/Users/JKaiser/Desktop/BMDS24 0/Data/mst_nose_MM_Matsu_sc_Mst2-BMR10-Restrict.pit
Tue Apr 19 13:39:56 2016
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/s2) ]
The parameter betas are restricted to be positive
Dependent variable = Effect
157
1,2-Dichloropropane

-------
FINAL
09-29-2016
Independent variable = Dose
Total number of observations = 6
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
Degree of polynomial = 2
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background =	0
Beta(1) = 0.0180099
Beta(2) =	0
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background -Beta(l)
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
Beta(2)
Beta (2)	1
Parameter Estimates
95.0% Wald Confidence
Interval
Variable	Estimate	Std. Err. Lower Conf. Limit Upper Conf.
Limit
Background	0	* * *
Beta(1)	0	* * *
Beta(2)	0.000306454	* * *
* - Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-12.8388
-18.2451
-28.5846
# Param's	Deviance	Test d.f.	P-value
6
1	10.8127	5	0.05522
1	31.4917	5	<.0001
AIC:
38.4902
Goodness of Fit
Scaled
Dose	Est._Prob. Expected Observed	Size	Residual
0.0000	0.0000	0.000	0.000	10	0.000
6.2100	0.0117	0.117	0.000	10	-0.345
158
1,2-Dichloropropane

-------
12.4300
0.0462
0.4 62
0.000
10
-0.696
24.8300
0.1722
1.722
0.000
10
-1.442
37.2700
0.3467
3.4 67
7.000
10
2.348
49.6600
0.5303
5 .303
4.000
10
-0.826
Chi^2 =
d.f. = 5
P-value = 0.1141
Benchmark Dose Computation
Specified effect
Risk Type
Confidence level
BMD
BMDL
BMDU
0.1
Extra risk
0. 95
18 .542
11.6023
24.3641
Taken together, (11.6023, 24.3641) is a 90
interval for the BMD
two-sided confidence
FINAL
09-29-2016
Increased Incidence of Nasal Atrophy in Female Mice Exposed to 1,2-Dichloropropane via
Inhalation for 13 Weeks
The procedure outlined above was applied to the data for increased incidence of nasal
respiratory epithelium hyperplasia in female B6D2Fi/Crlj (SPF) mice administered 1,2-DCP via
inhalation for 6 hours/day, 5 days/week for 13 weeks (Nlatsumoto et al, 2013) (see Table C-21).
Table C-22 summarizes the BMC modeling results. All models provided adequate fit to the data.
BMCLs for models providing adequate fit were sufficiently close (differed by 
-------
FINAL
09-29-2016
Table C-22. BMC Modeling Results for Nasal Atrophy in Female B6D2Fi/Crlj (SPF) Mice
Exposed to 1,2-Dichloropropane via Inhalation for 6 Hours/Day, 5 Days/Week for
13 Weeks
Modelb
DF
X2 Goodness-of-Fit
/j-Value"
AIC
BMCio
(mg/m3, HECet)
BMCio
(mg/m3, HECet)
Gamma06
5
0.9019
23.0732
21.4307
17.0653
Logistic
4
0.6171
25.5692
22.529
16.7963
LogLogisticd
4
0.8421
24.3627
23.0514
17.8769
LogProbitd
4
0.8356
24.408
22.9217
17.9987
Multistage
(2-degree)f
5
0.1934
32.2902
11.134
8.33021
Multistage
(3-degree)f
5
0.5497
27.2424
15.4578
12.0465
Probit
4
0.6303
25.697
22.2822
16.3196
Weibull0
4
0.5734
26.541
20.8038
15.0447
aValues <0.1 fail to meet conventional goodness-of-fit criteria.
bScaled residuals for dose group above and below the BMC.
Tower restricted to >1.
dSlope restricted to >1.
Selected model.
fBetas restricted to >0.
AIC = Akaike's information criterion; BMC = maximum likelihood estimate of the concentration associated with
the selected BMR; BMCL = 95% lower confidence limit on the BMC (subscripts denote BMR:
i.e., io = concentration associated with 10% extra risk); DF = degrees of freedom; ET = extrathoracic respiratory
effects; HEC = human equivalent concentration.
160
1,2-Dichloropropane

-------
FINAL
09-29-2016
Gamma Multi-Hit Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the
Gamma Multi-Hit
BMD Lower Bound
1
0.8
0.6
0.4
0.2
0
BMDL
BMD
0
5
10
15
20
25
30
35
40
dose
13:47 04/19 2016
Figure C-10. Gamma Model for Incidence of Nasal Atrophy in Female B6D2Fi/Crlj (SPF)
Mice Exposed to 1,2-Dichloropropane via Inhalation for 6 Hours/Day, 5 Days/Week for
13 Weeks (Matsumoto et al., 2013)
Text Output for Gamma Model for Incidence of Nasal Atrophy in Female B6D2Fi/Crlj
(SPF) Mice Exposed to 1,2-Dichloropropane via Inhalation for 6 Hours/Day, 5 Days/Week
for 13 Weeks (Matsumoto et al., 2013)
Gamma Model. (Version: 2.16; Date: 2/28/2013)
Input Data File:
C:/Users/JKaiser/Desktop/BMDS24 0/Data/gam_nose_FM_Matsu_sc_Gam-BMR10-Restrict.(d)
Gnuplot Plotting File:
C:/Users/JKaiser/Desktop/BMDS24 0/Data/gam_nose_FM_Matsu_sc_Gam-BMR10-Restrict.pit
Tue Apr 19 13:47:28 2016
BMDS Model Run
The form of the probability function is:
P[response]= background+(1-background)*CumGamma[siope*dose,power],
where CumGamma(.) is the cummulative Gamma distribution function
Dependent variable = Effect
Independent variable = Dose
Power parameter is restricted as power >=1
Total number of observations = 6
161
1,2-Dichloropropane

-------
FINAL
09-29-2016
Total number of records with missing values = 0
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial	(and Specified) Parameter Values
Background =	0.0833333
Slope =	0.232975
Power =	7.24694
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background -Power
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
Slope
Slope	1
Parameter Estimates
Interval
Variable
Limit
Background
Slope
0.678667
Power
Estimate
0
0.598283
18
Std. Err.
NA
0.041013
NA
NA - Indicates that this parameter has hit a bound
implied by some ineguality constraint and thus
has no standard error.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
0.517899
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-9.35947
-10.5366
-34.7949
# Param's
6
1
1
Deviance Test d.f.
2.3543
50.8709
P-value
0.7983
<.0001
AIC:
23.0732
Goodness of Fit
Scaled
Dose	Est._Prob. Expected Observed	Size	Residual
0.0000
0.0000
0.000
0.000
10
0. 000
5.1400
0.0000
0.000
0.000
10
-0.000
10.2900
0.0001
0.001
0.000
10
-0.028
20.5500
0. 0750
0.750
0.000
10
-0.900
30.8600
0.5741
5.741
7.000
10
0. 805
41.1100
0.9297
9.297
9.000
10
-0.368
162
1,2-Dichloropropane

-------
FINAL
09-29-2016
Chi^2 = 1.59 d.f.	= 5 P-value = 0.9019
Benchmark Dose Computation
Specified effect =	0.1
Risk Type =	Extra risk
Confidence level =	0.95
BMD =	21.4307
BMDL =	17.0 653
163
1,2-Dichloropropane

-------
FINAL
09-29-2016
APPENDIX D. BENCHMARK DOSE CALCULATIONS
FOR PROVISIONAL CANCER POTENCY VALUES
MODEL-FITTING PROCEDURE FOR CANCER INCIDENCE DATA
The model-fitting procedure for dichotomous cancer incidence is as follows. The
Multistage-Cancer model in the EPA's Benchmark Dose Software (BMDS, Version 2.5) is fit to
the incidence data using the extra risk option. The Multistage-Cancer model is run for all
polynomial degrees up to n - 1 (where n is the number of dose groups including control). An
adequate model fit is judged by three criteria: (1) goodness-of-fit p-value (p < 0.1); (2) visual
inspection of the dose-response curve; and (3) scaled residual at the data point (except the
control) closest to the predefined benchmark response (BMR). Among all of the models
providing adequate fit to the data, the benchmark dose lower confidence limit/benchmark
concentration level (BMDL/BMCL) for the model with the lowest Akaike's information
criterion (AIC) is selected as the point of departure (POD). In accordance with U.S. EPA
(2012c) guidance, benchmark dose/benchmark concentration (BMD/BMC) and BMDL/BMCL
values associated with an extra risk of 10% are calculated.
BMD MODELING TO IDENTIFY POTENTIAL PODs FOR p-OSF DERIVATION
The following data sets were selected for BMD modeling:
•	Incidence data for combined hepatocellular adenoma or carcinoma in male mice
exposed to 1,2-dichloropropane (1,2-DCP) via gavage for 2 years (N I P. 1986);
selected as critical endpoint for provisional oral slope factor (p-OSF) derivation
•	Incidence data for combined hepatocellular adenoma or carcinoma in female mice
exposed to 1,2-DCP via gavage for 2 years (N'l'P. 1986):
•	Incidence data for mammary gland tumor in female mice exposed to 1,2-DCP via
gavage for 2 years (N I P. 1986)
Increased Combined Incidence of Hepatocellular Adenoma or Carcinoma in Male Mice
Exposed to 1,2-Dichloropropane for 2 Years
The procedure outlined above was applied to the data for increased combined incidence
of hepatocellular adenoma or carcinoma in male mice exposed to 1,2-DCP via gavage
5 days/week for 2 years (N I P. 1986) (see Table D-1). Table D-2 summarizes the BMD
modeling results. Only the 1-degree Multistage cancer model provided adequate fit to the data.
Thus, the BMDLio (HED) of 2.71 mg/kg-day from this model is selected for this endpoint
(see Figure D-l and the BMD text output for details).
164
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table D-l. Combined Incidence of Hepatocellular Adenoma or Carcinoma in Male
B6C3Fi Mice Administered 1,2-Dichloropropane via Gavage 5 Days/Week

for 103 Weeks"


HED (mg/kg-d)b
0
12.5
25.1
Sample size
50
50
50
Incidence
18
26
33
aNTP (1986).
bGavage doses were converted to ADDs by multiplying the administered gavage dose by (5/7) days/week and
converted into HEDs using BW3/4 scaling.
ADD = adjusted daily dose; BW = body weight; HED = human equivalent dose.
Table D-2. BMD Modeling Results for Combined Incidence of Hepatocellular Adenoma
or Carcinoma in Male B6C3Fi Mice Administered 1,2-Dichloropropane via Gavage

5 Days/Week for 103 Weeks




X2 Goodness-of-Fit

BMDio
BMDLio
Model
DF
/>-Valuca
AIC
(mg/kg-d, HED)
(mg/kg-d, HED)
Multistage cancer (l-degree)b c
1
0.8829
202.702
4.25256
2.71195
Multistage cancer (2-degree)b
0
NA
204.68
4.85779
2.71604
aValues <0.1 fail to meet conventional goodness-of-fit criteria.
bPower restricted to > 1.
°Selected model.
AIC = Akaike's information criterion; BMD = maximum likelihood estimate of the dose associated with the
selected BMR; BMDL = 95% lower confidence limit on the BMD (subscripts denote BMR: i.e., io = dose
associated with 10% extra risk); DF = degrees of freedom; HED = human equivalent dose; NA = not applicable.
165
1,2-Dichloropropane

-------
FINAL
09-29-2016
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit forth
Multistage Cancer
Linear extrapolation
BMD Lower Bound
0.8
0.7
0.6
0.5
0.4
0.3
0.2
BMDL
BMD
0
5
10
15
20
25
dose
08:45 04/14 2016
Figure D-l. Multistage (1-degree) Model for Combined Incidence of Hepatocellular
Adenoma or Carcinoma in Male B6C3Fi Mice Administered 1,2-Dichloropropane via
Gavage 5 Days/Week for 103 Weeks (NTP, 1986)
Text Output for Multistage (1-degree) Model for Combined Incidence of Hepatocellular
Adenoma or Carcinoma in Male B6C3Fi Mice Administered 1,2-Dichloropropane via
Gavage 5 Days/Week for 103 Weeks (NTP, 1986)
Multistage Cancer Model. (Version: 1.10; Date: 02/28/2013)
Input Data File:
C:/Users/JKaiser/Desktop/BMDS24 0/Data/msc_livercancer_MM_NTP8 6_Mscl-BMR10.(d)
Gnuplot Plotting File:
C:/Users/JKaiser/Desktop/BMDS24 0/Data/msc_livercancer_MM_NTP8 6_Mscl-BMR10.pit
Thu Apr 14 08:45:17 2016
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*doseAl) ]
The parameter betas are restricted to be positive
Dependent variable = Effect
166
1,2-Dichloropropane

-------
FINAL
09-29-2016
Independent variable = Dose
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 2
Total number of specified parameters = 0
Degree of polynomial = 1
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background =	0.354122
Beta(l) =	0.025203
Asymptotic Correlation Matrix of Parameter Estimates
Background	Beta(l)
Background	1	-0.7
Beta (1)	-0.7	1
Parameter Estimates
95.0% Wald Confidence
Interval
Variable	Estimate	Std. Err.	Lower Conf. Limit Upper Conf.
Limit
Background	0.35716	*	*	*
Beta(1)	0.0247758	*	*	*
* - Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-99.34
-99.3509
-103.919
Param's
3
2
1
Deviance Test d.f.
0.0217131
9.15741
P-value
0.8829
0. 01027
AIC:
202.702
Dose
Goodness of Fit
Est._Prob. Expected Observed	Size
Scaled
Residual
0.0000
12.5000
25.1000
0.3572
0.5284
0.6548
17.858
26.418
32 .742
18.000
26.000
33.000
50
50
50
0. 042
-0.119
0. 077
Chi^2 =0.02
d.f. = 1
P-value = 0.8829
167
1,2-Dichloropropane

-------
FINAL
09-29-2016
Benchmark Dose Computation
Specified effect =	0.1
Risk Type =	Extra risk
Confidence level =	0.95
BMD =	4.25256
BMDL =	2.71195
BMDU =	9.34791
Taken together, (2.71195, 9.34791) is a 90	% two-sided confidence
interval for the BMD
Multistage Cancer Slope Factor =	0.0368738
Increased Combined Incidence of Hepatocellular Adenoma or Carcinoma in Female Mice
Exposed to 1,2-Dichloropropane For 2 Years
The procedure outlined above was applied to the data for increased combined incidence
of hepatocellular adenoma or carcinoma in female mice exposed to 1,2-DCP via gavage
5 days/week for 2 years (N I P. 1986) (see Table D-3). Table D-4 summarizes the BMD
modeling results. Both models provided adequate fit; the 2-degree Multistage model converged
to the 1-degree Multistage cancer model. Thus, the BMDLio (HED) of 8.51 mg/kg-day from this
model is selected for this endpoint (see Figure D-2 and the BMD text output for details).
Table D-3. Combined Incidence of Hepatocellular Adenoma or Carcinoma in Female
B6C3Fi Mice Administered 1,2-Dichloropropane via Gavage 5 Days/Week for 103 Weeks"

HED (mg/kg-d)b
0
12.5
25.1
Sample size
50
50
50
Incidence
2
8
9
"NTP (1986).
bGavage doses were converted to ADDs by multiplying the administered gavage dose by (5/7) days/week and
converted into HEDs using BW3'4 scaling.
ADD = adjusted daily dose; BW = body weight; HED = human equivalent dose.
168
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table D-4. BMD Results for Combined Incidence of Hepatocellular Adenoma or
Carcinoma in Female B6C3Fi Mice Administered 1,2-Dichloropropane via Gavage

5 Days/Week for 103 Weeks




X2 Goodness-of-Fit

BMD io
BMDLio
Model
DF
/>-Valuca
AIC
(mg/kg-d, HED)
(mg/kg-d, HED)
Multistage cancer (1-degree)1, 0
1
0.414
112.548
14.4772
8.51111
Multistage cancer (2-degree)b
1
0.414
112.548
14.4773
8.51111
aValues <0.1 fail to meet conventional goodness-of-fit criteria.
bPower restricted to >1.
°Selected model.
AIC = Akaike's information criterion; BMD = maximum likelihood estimate of the dose associated with the
selected BMR; BMDL = 95% lower confidence limit on the BMD (subscripts denote BMR: i.e., io = dose
associated with 10% extra risk); DF = degrees of freedom.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit fort
0.35
Multistage Cancer
Linear extrapolation
BMD Lower Bound
0.3
0.25
0.2
0.15
0.05
BMDL
BMD
0
5
10
15
20
25
dose
09:01 04/14 2016
Figure D-2. Multistage (1-degree) Model for Combined Incidence of Hepatocellular
Adenoma or Carcinoma in Female B6C3Fi Mice Administered 1,2-Dicloropropane via
Gavage 5 Days/Week for 103 Weeks (NTP, 1986)
169
1,2-Dichloropropane

-------
FINAL
09-29-2016
Text Output for Multistage (1-degree) Model for Combined Incidence of Hepatocellular
Adenoma or Carcinoma in Female B6C3Fi Mice Administered 1,2-Dichloropropane via
Gavage 5 Days/Week for 103 Weeks (N TP. 1986)
Multistage Cancer Model. (Version: 1.10; Date: 02/28/2013)
Input Data File:
C:/Users/JKaiser/Desktop/BMDS24 0/Data/msc_livercancer_FM_NTP8 6_Mscl-BMR10.(d)
Gnuplot Plotting File:
C:/Users/JKaiser/Desktop/BMDS24 0/Data/msc_livercancer_FM_NTP8 6_Mscl-BMR10.pit
Thu Apr 14 09:01:29 2016
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*doseAl) ]
The parameter betas are restricted to be positive
Dependent variable = Effect
Independent variable = Dose
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 2
Total number of specified parameters = 0
Degree of polynomial = 1
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0.0575182
Beta(1) = 0.00627421
Asymptotic Correlation Matrix of Parameter Estimates
Background	Beta(l)
Background	1	-0.78
Beta (1)	-0.78	1
Parameter Estimates
Interval
Variable
Limit
Background
Beta(1)
Estimate
0.045592
0.00727766
Std. Err.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
170
1,2-Dichloropropane

-------
FINAL
09-29-2016
* - Indicates that this value is not calculated.
Model
Full model
Fitted model
Reduced model
AIC:
Analysis of Deviance Table
Deviance Test d.f.
Log(likelihood)
-53.9504
-54.2742
-57.0001
112 .548
# Param's
3
2
1
P-value
0.647608
6.09946
0. 421
0.04737


Goodness of Fit







Scaled
Dose
Est. Prob.
Expected
Observed
Size
Residual
0.0000
0. 0456
2.280
2.000
50
-0.190
12 .5000
0.1286
6.429
8.000
50
0. 664
25.1000
0.2049
10.247
9.000
50
-0.437
Chi^2 =0.67
d.f. = 1
P-value = 0.4140
Benchmark Dose Computation
Specified effect
Risk Type
Confidence level
BMD
BMDL
BMDU
0.1
Extra risk
0. 95
14.4772
8 .51111
46.5151
Taken together, (8.51111, 46.5151) is a 90
interval for the BMD
two-sided confidence
Multistage Cancer Slope Factor =
0.0117494
Increased Incidence of Mammary Gland Adenocarcinomas in Female Rats Exposed to
1,2-Dichloropropane for 2 Years
The procedure outlined above was applied to the data for increased incidence of
mammary gland adenocarcinomas in female rats exposed to 1,2-DCP via gavage 5 days/week for
2 years (N I P. 1986) (see Table D-5). Table D-6 summarizes the BMD modeling results. The
2-degree Multistage cancer model provided the best fit to the data. Thus, the BMDLio (HED) of
30.4 mg/kg-day from this model is selected for this endpoint (see Figure D-3 and the BMD text
output for details).
171
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table D-5. Incidence of Mammary Gland Adenocarcinomas in Female F344 Rats
Administered 1,2-Dichloropropane via Gavage 5 Days/Week for 103 Weeks"

HED (mg/kg-d)b

0
21.4
43.0
Sample size
50
50
50
Incidence
1
2
5
"NTP (1986).
bGavage doses were converted to ADDs by multiplying the administered gavage dose by (5/7) days/week and
converted into HEDs using BW3'4 scaling.
ADD = adjusted daily dose; BW = body weight; HED = human equivalent dose.
Table D-6. BMD Modeling Results for Incidence of Mammary Gland Adenocarcinomas
in Female F344 Rats Administered 1,2-Dichloropropane via Gavage 5 Days/Week


for 103 Weeks




X2 Goodness-of-Fit

BMD io
BMDLio
Model
DF
/>-Value"
AIC
(mg/kg-d, HED)
(mg/kg-d, HED)
Multistage cancer (l-degree)b
1
0.5948
0.5948
60.2832
29.4027
Multistage cancer (2-degree)b c
0
0.9847
0.9847
47.7125
30.3983
aValues <0.1 fail to meet conventional goodness-of-fit criteria.
bPower restricted to > 1.
°Selected model.
AIC = Akaike's information criterion; BMD = maximum likelihood estimate of the dose associated with the
selected BMR; BMDL = 95% lower confidence limit on the BMD (subscripts denote BMR: i.e., io = dose
associated with 10% extra risk); DF = degrees of freedom; HED = human equivalent dose; NA = not applicable.
172
1,2-Dichloropropane

-------
FINAL
09-29-2016
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit fort
Multistage Cancer
Linear extrapolation
BMD Lower Bound
0.2
0.15
0.05
BMD
BMDL
0
10
20
30
40
50
dose
07:46 03/16 2016
Figure D-3. Multistage (1-degree) Model for Incidence of Mammary Gland
Adenocarcinomas in Female F344 Rats Administered 1,2-Dichloropropane via Gavage
5 Days/Week for 103 Weeks (NTP. 1986)
Text Output for Multistage (1-degree) Model for Incidence of Mammary Gland
Adenocarcinomas in Female F344 Rats Administered 1,2-Dichloropropane via Gavage
5 Days/Week for 103 Weeks (NTP. 1986)
Multistage Cancer Model. (Version: 1.10; Date: 02/28/2013)
Input Data File: C:/Users/JKaiser/Desktop/BMDS240/Data/msc_mgland_ntp86_Msc2-
BMR10.(d)
Gnuplot Plotting File:
C:/Users/JKaiser/Desktop/BMDS24 0/Data/msc_mgland_ntp8 6_Msc2-BMR10.pit
Wed Mar 16 08:46:10 2016
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/s2) ]
The parameter betas are restricted to be positive
Dependent variable = Effect
Independent variable = Dose
173
1,2-Dichloropropane

-------
FINAL
09-29-2016
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
Degree of polynomial = 2
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0.0196977
Beta(l) =	0
Beta(2) = 4.64694e-005
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Beta(l)
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
Background	Beta (2)
Background	1	-0.69
Beta (2)	-0.69	1
Parameter Estimates
Interval
Variable
Limit
Background
Beta(1)
Beta(2)
Estimate
0.0198356
0
4.62822e-005
Std. Err.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
Indicates that this value is not calculated.
Model
Full model
Fitted model
Reduced model
Analysis of Deviance Table
#
Log(likelihood)
-29.5533
-29.5535
-31.2323
Param's
3
2
1
Deviance Test d.f.
0.000370021
3.35802
P-value
0.9847
0.1866
AIC:
63.107
Goodness of Fit
Scaled
Dose	Est._Prob. Expected Observed	Size	Residual
0.0000	0.0198	0.992	1.000	50	0.008
21.4290	0.0404	2.022	2.000	50	-0.016
174
1,2-Dichloropropane

-------
FINAL
09-29-2016
42.8600	0.0997	4.986	5.000	50	0.007
Chi^2 = 0.00	d.f. = 1	P-value = 0.9847
Benchmark Dose Computation
Specified effect =	0.1
Risk Type =	Extra risk
Confidence level =	0.95
BMD =	47.7125
BMDL =	30.3983
BMDU =	4 97.5 62
Taken together, (30.3983, 497.562) is a 90	% two-sided confidence
interval for the BMD
Multistage Cancer Slope Factor = 0.00328965
BMD MODELING TO IDENTIFY POTENTIAL PODs FOR p-IUR DERIVATION
The following data sets were selected for BMD modeling:
•	Incidence data for nasal tumors (papilloma or esthesioneuropeithelima) in male rats
exposed to 1,2-DCP via inhalation for 2 years (limeda et al.. 2010); selected as
critical endpoint for provisional inhalation unit risk (p-IUR) derivation.
•	Incidence data for nasal tumors (only papillomas were observed) in female rats
exposed to 1,2-DCP via inhalation for 2 years (TJnieda et al.. 2010).
•	Incidence data for Harderian gland adenoma in male mice exposed to 1,2-DCP via
inhalation for 2 years (Nlatsumoto et al.. 2013).
•	Incidence data for combined bronchiolo-alveolar adenoma or carcinoma in female
mice exposed to 1,2-DCP via inhalation for 2 years (Nlatsumoto et al.. 2013).
Increased Incidence of Nasal Tumors in Male Rats Exposed to 1,2-Dichloropropane for
2 Years
The procedure outlined above was applied to the data for increased incidence of nasal
tumors (papilloma or esthesioneuroepithelioma) in male rats exposed to 1,2-DCP via inhalation
for 6 hours/day, 5 days/week for 104 weeks (Umeda et al.. 2010) (see Table D-7). Table D-8
summarizes the BMD modeling results. The 3-degree Multistage Cancer Model provided the
best fit to the data. Thus, the BMCLio (HEC) of 26.7 mg/m3 from this model is selected for this
endpoint (see Figure D-4 and the BMD text output for details).
175
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table D-7. Incidence of Nasal Tumors (Papilloma or Estheioneuroepithelioma) in Male
F344 Rats Exposed to 1,2-Dichloropropane via Inhalation for 6 Hours/Day, 5 Days/Week


for 104 Weeks"



HEC (mg/m3)b
0
16.2
40.54
101.1
Sample size
50
50
50
50
Incidence
0
2
4
15
"Uiiieda et al. (2010).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects by treating
1,2-DCP as a Category 1 gas and using the following equation: HECet = (ppm x MW ^ 24.45) x (hours/day
exposed ^ 24) x (days/week exposed ^ 7) x RGDRet.
HEC = human equivalent concentration; MW = molecular weight.
Table D-8. BMC Modeling Results for Incidence of Nasal Tumors (Papilloma or
Estheioneuroepithelioma) in Male F344 Rats Exposed to 1,2-Dichloropropane via
Inhalation for 6 Hours/Day, 5 Days/Week for 104 Weeks



X2 Goodness-of-Fit

BMCio
BMCLio
Model
DF
/j-Valuc11
AIC
(mg/m3, HECet)
(mg/m3, HECet)
Multistage cancer (l-degree)b
3
0.7941
108.841
35.1022
24.9885
Multistage cancer (2-degree)b
2
0.8965
109.973
42.8701
26.4536
Multistage cancer (3-degree)b c
2
0.9438
109.871
45.072
26.6569
aValues <0.1 fail to meet conventional goodness-of-fit criteria.
bPower restricted to > 1.
°Selected model.
AIC = Akaike's information criterion; BMC = maximum likelihood estimate of the concentration associated with
the selected BMR; BMCL = 95% lower confidence limit on the BMC (subscripts denote BMR:
i.e., io = concentration associated with 10% extra risk); DF = degrees of freedom; ET = extrathoracic respiratory
effects; HEC = human equivalent concentration.
176
1,2-Dichloropropane

-------
FINAL
09-29-2016
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit forth
Multistage Cancer
Linear extrapolation
BMD Lower Bound
0.4
0.3
0.2
0.1
0
BMDL
BMD
0
20
40
60
80
100
dose
14:09 04/19 2016
Figure D-4. Multistage (1-degree) Model for Incidence of Nasal Tumors (Papilloma or
Estheioneuroepithelioma) in Male F344 Rats Exposed to 1,2-Dichloropropane via
Inhalation for 6 Hours/Day, 5 Days/Week for 104 Weeks (Umeda et al., 2010)
Text Output for Multistage (1-degree) Model for Incidence of Nasal Tumors (Papilloma or
Estheioneuroepithelioma) in Male F344 Rats Exposed to 1,2-Dichloropropane via
Inhalation for 6 Hours/Day, 5 Days/Week for 104 Weeks (Umeda et al., 2010)
Multistage Cancer Model. (Version: 1.10; Date: 02/28/2013)
Input Data File:
C:/Users/JKaiser/Desktop/BMDS240/Data/msc_nosetumors_MR_Umedal0_Msc3-BMR10.(d)
Gnuplot Plotting File:
C:/Users/JKaiser/Desktop/BMDS24 0/Data/msc_nosetumors_MR_Umedal0_Msc3-BMR10.pit
Tue Apr 19 14:09:58 2016
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/s2-beta3* doseA3)]
The parameter betas are restricted to be positive
Dependent variable = Effect
Independent variable = Dose
177
1,2-Dichloropropane

-------
FINAL
09-29-2016
Total number of observations = 4
Total number of records with missing values = 0
Total number of parameters in model = 4
Total number of specified parameters = 0
Degree of polynomial = 3
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0.00415118
Beta(1) = 0.00176184
Beta(2) =	0
Beta(3) = 1.68578e-007
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background -Beta(2)
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
Beta(1)	Beta(3)
Beta (1)	1	-0.93
Beta (3)	-0.93	1
Parameter Estimates
Interval
Variable
Limit
Background
Beta(1)
Beta(2)
Beta(3)
Estimate
0
0.00204785
0
1.42636e-007
Std. Err.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-52.8789
-52.9353
-67.1864
# Param's	Deviance	Test d.f.	P-value
4
2	0.112741	2	0.9452
1	28.6151	3	<.0001
AIC:
109.871
Goodness of Fit
Scaled
Dose	Est._Prob. Expected Observed	Size	Residual
178
1,2-Dichloropropane

-------
FINAL
09-29-2016
0.0000
0.0000
0.000
0.000
50
0. 000
16.2000
0.0332
1.661
2.000
50
0.268
40.5400
0. 0884
4.419
4.000
50
-0.209
101.1000
0.2984
14.921
15.000
50
0. 024
Chi^2 = 0.12	d.f. = 2	P-value = 0.9438
Benchmark Dose Computation
Specified effect =	0.1
Risk Type =	Extra risk
Confidence level =	0.95
BMD =	45.072
BMDL =	2 6.65 69
BMDU =	66.4762
Taken together, (26.6569, 66.4762) is a 90	% two-sided confidence
interval for the BMD
Multistage Cancer Slope Factor = 0.00375138
Increased Incidence of Nasal Tumors in Female Rats Exposed to 1,2-Dichloropropane for
2 Years
The procedure outlined above was applied to the data for increased incidence of nasal
tumors (only papillomas were observed) in female rats exposed to 1,2-DCP via inhalation for
6 hours/day, 5 days/week for 104 weeks (TJmeda et aL 2010) (see Table D-9). Table D-10
summarizes the BMD modeling results. All models provided adequate fit to the data, so the
model with the lowest AIC was selected (Multistage Cancer, 3-degree). Thus, the BMCLio
(HEC) of 46.2 mg/m3 from this model is selected for this endpoint (see Figure D-5 and the BMD
text output for details).
Table D-9. Incidence of Nasal Tumors (Only Papillomas were Observed) in Female F344
Rats Exposed to 1,2-Dichloropropane via Inhalation for 6 Hours/Day, 5 Days/Week


for 104 Weeks"



HEC (mg/m3)b
0
10.7
26.75
66.71
Sample size
50
50
50
50
Incidence
0
0
0
9
"Uiiieda et al. (2010).
bAnalytical exposure concentrations were converted to HECs for extrathoracic respiratory effects by treating
1,2-DCP as a Category 1 gas and using the following equation: HECet = (ppm x MW ^ 24.45) x (hours/day
exposed ^ 24) x (days/week exposed ^ 7) x RGDRet.
HEC = human equivalent concentration; MW = molecular weight.
179
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table D-10. BMC Modeling Results for Incidence of Nasal Tumors (only Papillomas were
observed) in Female F344 Rats Exposed to 1,2-Dichloropropane via Inhalation for
6 Hours/Day, 5 Days/Week for 104 Weeks


X2 Goodness-of-Fit

BMCio
BMCLio
Model
DF
/>-Value"
AIC
(mg/m3, HECet)
(mg/m3, HECet)
Multistage cancer (l-degree)b
3
0.135
57.8068
57.3825
34.7054
Multistage cancer (2-degree)b
3
0.6012
52.5047
53.3842
41.5097
Multistage cancer (3-dcgrcc)li C
3
0.877
50.4516
55.3501
46.1932
aValues <0.1 fail to meet conventional goodness-of-fit criteria.
bPower restricted to > 1.
°Selected model.
AIC = Akaike's information criterion; BMC = maximum likelihood estimate of the concentration associated with
the selected BMR; BMCL = 95% lower confidence limit on the BMC (subscripts denote BMR:
i.e., io = concentration associated with 10% extra risk); DF = degrees of freedom; ET = extrathoracic respiratory
effects; HEC = human equivalent concentration.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for t
0.35
Multistage Cancer
Linear extrapolation
BMD Lower Bound
0.3
0.25
0.2
0.15
0.1
0.05
0
BMDL
BMD
0
10
20
30
40
50
60
70
dose
14:15 04/19 2016
Figure D-5. Multistage (3-degree) Model for Incidence of Nasal Tumors (only Papillomas
were observed) in Female F344 Rats Exposed to 1,2-Dichloropropane via Inhalation for
6 Hours/Day, 5 Days/Week for 104 Weeks (Umeda et al., 2010)
180
1,2-Dichloropropane

-------
FINAL
09-29-2016
Text Output for Multistage (3-degree) Model for Incidence of Nasal Tumors (only
Papillomas were observed) in Female F344 Rats Exposed to 1,2-Dichloropropane via
Inhalation for 6 Hours/Day, 5 Days/Week for 104 Weeks (Unieda et al., 2010)
Multistage Cancer Model. (Version: 1.10; Date: 02/28/2013)
Input Data File:
C:/Users/JKaiser/Desktop/BMDS240/Data/msc_nosetumors_FR_Umedal0_Msc3-BMR10.(d)
Gnuplot Plotting File:
C:/Users/JKaiser/Desktop/BMDS24 0/Data/msc_nosetumors_FR_Umedal0_Msc3-BMR10.pit
Tue Apr 19 14:15:18 2016
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/s2-beta3* doseA3)]
The parameter betas are restricted to be positive
Dependent variable = Effect
Independent variable = Dose
Total number of observations = 4
Total number of records with missing values = 0
Total number of parameters in model = 4
Total number of specified parameters = 0
Degree of polynomial = 3
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background =	0
Beta(l) =	0
Beta(2) =	0
Beta(3) = 6.81631e-007
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background -Beta(l) -Beta(2)
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
Beta(3)
Beta (3)	1
Parameter Estimates
181
1,2-Dichloropropane

-------
FINAL
09-29-2016
95.0% Wald Confidence
Interval
Variable	Estimate	Std. Err.	Lower Conf. Limit Upper Conf.
Limit
Background
0
k
k
k
Beta(1)
0
k
k
k
Beta(2)
0
k
k
k
Beta(3)
6.21329e-007
-k
k
k
* - Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-23.5697
-24.2258
-36.7042
# Param's
4
1
1
Deviance Test d.f.
1.31225
26.2691
P-value
0.7262
<.0001
AIC:
50.4516
Dose
Goodness of Fit
Est._Prob. Expected Observed	Size
Scaled
Residual
0.0000
10.7000
26.7500
66.7100
Chi^2 =0.(
0.0000
0.0008
0.0118
0.1684
d.f. = 3
0.000	0.000	50
0.038	0.000	50
0.591	0.000	50
8.422	9.000	50
P-value = 0.8770
0. 000
-0.195
-0.773
0.218
Benchmark Dose Computation
Specified effect =	0.1
Risk Type	=	Extra risk
Confidence level =	0.95
BMD =	55.3501
BMDL =	4 6.1932
BMDU =	67.6939
Taken together, (46.1932, 67.6939) is a 90	% two-sided confidence
interval for the BMD
Multistage Cancer Slope Factor = 0.00216482
182	1,2-Dichloropropane

-------
FINAL
09-29-2016
Increased Incidence of Harderian Gland Adenomas in Male Mice Exposed to
1,2-Dichloropropane for 2 Years
The procedure outlined above was applied to the data for increased incidence of
Harderian gland adenomas in male mice exposed to 1,2-DCP via inhalation for 6 hours/day,
5 days/week for 104 weeks (Nlatsumoto et aL 2013) (see Table D-l 1). Table D-12 summarizes
the BMD modeling results. All models provided adequate fit to the data, and converged to the
1-degree model. Thus, the BMCLio (HEC) of 251 mg/m3 from this model is selected for this
endpoint (see Figure D-6 and the BMD text output for details).
Table D-ll. Incidence of Harderian Gland Adenoma in Male B6D2Fi/Crlj (SPF) Mice
Exposed to 1,2-Dichloropropane via Inhalation for 6 Hours/Day, 5 Days/Week

for 104 Weeks"



HEC (mg/m3)b
0
77.2
192
482.5
Sample size
50
50
50
50
Incidence
1
2
3
6
"Matsiiiiioto et at (2013).
bAnalytical exposure concentrations were converted to HECs for pulmonary respiratory effects using the following
equation: HECpu = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week exposed ^ 7) x RGDRPU.
RGDRi i is the pulmonary regional gas dose ratio (animal:human); see Equations 4-28 in U.S. EPA (1994b) for
calculation of RGDRPU and default values for variables.
HEC = human equivalent concentration; MW = molecular weight.
Table D-12. BMC Modeling Results for Incidence of Harderian Gland Adenoma in Male
B6D2Fi/Crlj (SPF) Mice Exposed to 1,2-Dichloropropane via Inhalation for 6 Hours/Day,
5 Days/Week for 104 Weeks


X2 Goodness-of-Fit

BMCio
BMCLio
Model
DF
/>-Valuca
AIC
(mg/m3, HECpu)
(mg/m3, HECpu)
Multistage cancer (l-degree)b c
2
0.9935
90.001
475.928
251.121
Multistage cancer (2-degree)b
2
0.9935
90.001
475.928
251.121
Multistage cancer (3-degree)b
2
0.9935
90.001
475.928
251.121
aValues <0.1 fail to meet conventional goodness-of-fit criteria.
bPower restricted to > 1.
°Selected model.
AIC = Akaike's information criterion; BMC = maximum likelihood estimate of the concentration associated with
the selected BMR; BMCL = 95% lower confidence limit on the BMC (subscripts denote BMR:
i.e., io = concentration associated with 10% extra risk); DF = degrees of freedom; HEC = human equivalent
concentration; PU = pulmonary effects.
183
1,2-Dichloropropane

-------
FINAL
09-29-2016
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for t
Multistage Cancer
Linear extrapolation
BMD Lower Bound
0.25
0.2
0.05
BMDL
BMG
0
100
200
300
400
500
dose
10:28 09/08 2016
Figure D-6. Multistage (1-degree) Model for Incidence of Harderian Gland Adenoma in
Male B6D2Fi/Crlj (SPF) Mice Exposed to 1,2-Dichloropropane via Inhalation for
6 Hours/Day, 5 Days/Week for 104 Weeks (Matsumoto et al., 2013)
Text Output for Multistage (1-degree) Model for Incidence of Harderian Gland Adenoma
in Male B6D2Fi/Crlj (SPF) Mice Exposed to 1,2-Dichloropropane via Inhalation for
6 Hours/Day, 5 Days/Week for 104 Weeks (Matsumoto et al., 2013)
Multistage Cancer Model. (Version: 1.10; Date: 02/28/2013)
Input Data File:
C:/Users/JKaiser/Desktop/BMDS240/Data/msc_hardgland_MM_Matsul3_Mscl-BMR10.(d)
Gnuplot Plotting File:
C:/Users/JKaiser/Desktop/BMDS240/Data/msc_hardgland_MM_Matsul3_Mscl-BMR10.pit
Thu Sep 08 10:28:32 2016
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*doseAl) ]
184
1,2-Dichloropropane

-------
FINAL
09-29-2016
The parameter betas are restricted to be positive
Dependent variable = Effect
Independent variable = Dose
Total number of observations = 4
Total number of records with missing values = 0
Total number of parameters in model = 2
Total number of specified parameters = 0
Degree of polynomial = 1
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0.0210709
Beta(1) = 0.000220233
Asymptotic Correlation Matrix of Parameter Estimates
Background	Beta(l)
Background	1	-0.71
Beta (1)	-0.71	1
Parameter Estimates
95.0% Wald Confidence
Interval
Variable	Estimate	Std. Err.	Lower Conf. Limit Upper Conf.
Limit
Background	0.02 08 62 9	*	*	*
Beta(1)	0.000221379	*	*	*
* - Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-42.9938
-43.0002
-45.3935
# Param's
4
2
1
Deviance Test d.f.
0.0129026
4 .79943
P-value
0.9936
0.1871
AIC:
90.0005
Goodness of Fit
Scaled
Dose	Est._Prob. Expected Observed	Size	Residual
0.0000	0.0209	1.043	1.000	50	-0.043
77.2000	0.0375	1.873	2.000	50	0.095
185
1,2-Dichloropropane

-------
FINAL
09-29-2016
192.0000	0.0616	3.080	3.000	50	-0.047
482.5000	0.1201	6.003	6.000	50	-0.001
Chi^2 =0.01	d.f. = 2	P-value = 0.9935
Benchmark Dose Computation
Specified effect =	0.1
Risk Type =	Extra risk
Confidence level =	0.95
BMD =	475.928
BMDL =	251.121
BMDU =	2014 . 42
Taken together, (251.121, 2014.42) is a 90	% two-sided confidence
interval for the BMD
Multistage Cancer Slope Factor = 0.000398215
Increased Combined Incidence of Bronchiolo-Alveolar Adenoma or Carcinoma in Female
Mice Exposed to 1,2-DCP for 2 Years
The procedure outlined above was applied to the data for increased combined incidence
of bronchiolo-alveolar adenoma or carcinoma in female mice exposed to 1,2-DCP via inhalation
for 6 hours/day, 5 days/week for 104 weeks (Nlatsumoto et ai, 2013) (see Table D-13).
Table D-14 summarizes the BMD modeling results. All models provided adequate fit to the
data, and converged to the 1-degree model. Thus, the BMCLio (HEC) of 177 mg/m3 from this
model is selected for this endpoint (see Figure D-7 and the BMD text output for details).
Table D-13. Combined Incidence of Bronchiolo-alveolar Adenoma or Carcinoma in
Female B6D2Fi/Crlj (SPF) Mice Exposed to 1,2-Dichloropropane via Inhalation for
6 Hours/Day, 5 Days/Week for 104 Weeks"

HEC (mg/m3)b
0
69.2
173
432.0
Sample size
50
50
50
50
Incidence
2
4
5
8
aMatsimioto et at (2013).
bAnalytical exposure concentrations were converted to HECs for pulmonary respiratory effects using the following
equation: HECpu = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week exposed ^ 7) x RGDRPU.
RGDRi i is the pulmonary regional gas dose ratio (animal:human); see Equations 4-28 in U.S. EPA (1994b) for
calculation of RGDRPU and default values for variables.
HEC = human equivalent concentration; MW = molecular weight.
186
1,2-Dichloropropane

-------
FINAL
09-29-2016
Table D-14. BMC Modeling Results for Combined Incidence of Bronchiolo-Alveolar
Adenoma or Carcinoma in Female B6D2Fi/Crlj (SPF) Mice Exposed to
1,2-Dichloropropane via Inhalation for 6 Hours/Day, 5 Days/Week for 104 Weeks


X2 Goodness-of-Fit

BMCio
BMCLio
Model
DF
/>-Valuca
AIC
(mg/m3, HECpu)
(mg/m3, HECpu)
Multistage cancer (1-degree)1, 0
2.00
0.904
125.347
341.97
177.213
Multistage cancer (2-degree)b
2.00
0.904
125.347
341.97
177.213
Multistage cancer (3-degree)b
2.00
0.904
125.347
341.97
177.213
aValues <0.1 fail to meet conventional goodness-of-fit criteria.
bPower restricted to > 1.
°Selected model.
AIC = Akaike's information criterion; BMC = maximum likelihood estimate of the concentration associated with
the selected BMR; BMCL = 95% lower confidence limit on the BMC (subscripts denote BMR:
i.e., io = concentration associated with 10% extra risk); DF = degrees of freedom; HEC = human equivalent
concentration; PU = pulmonary effects.
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for t
Multistage Cancer
Linear extrapolation
BMD Lower Bound
0.3
0.25
0.2
0.15
0.1
0.05
0
BMDL
BMD
0
50
100
150
200
250
300
350
400
450
dose
14:23 04/19 2016
Figure D-7. Multistage (1-degree) Model for Combined Incidence of Bronchiolo-Alveolar
Adenoma or Carcinoma in Female B6D2Fi/Crlj (SPF) Mice Exposed to
1,2-Dichloropropane via Inhalation for 6 Hours/Day, 5 Days/Week for 104 Weeks
(Matsumoto et al., 2013)
187
1,2-Dichloropropane

-------
FINAL
09-29-2016
Text Output for Multistage (1-degree) Model for Combined Incidence of
Bronchiolo-Alveolar Adenoma or Carcinoma in Female B6D2Fi/Crlj (SPF) Mice Exposed
to 1,2-Dichloropropane via Inhalation for 6 Hours/Day, 5 Days/Week for 104 Weeks
(Matsumoto et al., 2013)
Multistage Cancer Model. (Version: 1.10; Date: 02/28/2013)
Input Data File:
C:/Users/JKaiser/Desktop/BMDS240/Data/msc_broncho_FM_Matsul3_Mscl-BMR10.(d)
Gnuplot Plotting File:
C:/Users/JKaiser/Desktop/BMDS240/Data/msc_broncho_FM_Matsul3_Mscl-BMR10.pit
Tue Apr 19 14:23:18 2016
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*doseAl) ]
The parameter betas are restricted to be positive
Dependent variable = Effect
Independent variable = Dose
Total number of observations = 4
Total number of records with missing values = 0
Total number of parameters in model = 2
Total number of specified parameters = 0
Degree of polynomial = 1
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0.0507611
Beta(1) = 0.00029003
Asymptotic Correlation Matrix of Parameter Estimates
Background	Beta(l)
Background	1	-0.72
Beta (1)	-0.72	1
Parameter Estimates
95.0% Wald Confidence
Interval
188
1,2-Dichloropropane

-------
FINAL
09-29-2016
Variable	Estimate	Std. Err. Lower Conf.	Limit Upper Conf.
Limit
Background	0.0479005	* *	*
Beta(1)	0.000308099	* *	*
* - Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-60.5733
-60.6734
-62.7912
# Param's
4
2
1
Deviance Test d.f.
0.200217
4.4357
P-value
0.9047
0.2181
AIC:
125 .347
Dose
Est. Prob.
Goodness of Fit
Expected
Observed
Size
Scaled
Residual
0.0000
69.2000
173.0000
432.0000
0.0479
0.0680
0.0973
0.1666
2 .395
3.399
4.866
8 .328
2.000
4.000
5.000
8.000
50
50
50
50
-0.262
0.338
0. 064
-0.124
Chi^2 = 0.20
d.f. = 2
P-value = 0.9040
Benchmark Dose Computation
Specified effect =	0.1
Risk Type	=	Extra risk
Confidence level =	0.95
BMD =	341.97
BMDL =	177.213
BMDU =	1802.72
Taken together, (177.213, 1802.72) is a 90	% two-sided confidence
interval for the BMD
Multistage Cancer Slope Factor = 0.000564294
189	1,2-Dichloropropane

-------
FINAL
09-29-2016
APPENDIX E. REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). (2014a). Propylene
dichloride. Documentation of the threshold limit values for chemical substances, 7th
edition [TLV/BEI], Cincinatti, OH.
ACGIH (American Conference of Governmental Industrial Hygienists). (2014b). Propylene
dichloride. TLVs and BEIs based on the documentation of the threshold limit values for
chemical substances and physical agents and biological exposure indices [TLV/BEI], In
ACGIH Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs)
Appendix B (pp. 51). Cincinnati, OH.
AT SDR (Agency for Toxic Substances and Disease Registry). (1989). Toxicological profile for
1,2-dichloropropane [ATSDR Tox Profile], (RISKLINE/1991090047). Atlanta, GA: U.S.
Department of Health and Human Services, Public Health Service.
http://www.atsdr.cdc. gov/toxprofiles/tp.asp?id=831&tid=162
AT SDR (Agency for Toxic Substances and Disease Registry). (2016). Minimal risk levels
(MRLs). March 2016. Atlanta, GA: Agency for Toxic Substances and Disease Registry
(ATSDR). Retrieved from http://www.atsdr.cdc.gov/mrls/index.asp
Battels. MJ; Timchalk. C. (1990). 1,2-Dichloropropane: Investigation of the mechanism of
mercapturic acid formation in the rat. Xenobiotica 20: 1035-1042.
Baruffmi. A; Cirla. AM: Pisati. G; Ratti. R; Zedda. S. (1989). Allergic contact dermatitis from
1.2-dichloropropane.	Contact Demi 20: 379-380. http://dx.doi.Org/10.l 11 l/i.1600-
0536.1989.tb03178.x
Belyaeva, NN; Bonashevskaya, TI; Marshak, TL; Brodskii, VY. (1977). Investigation of the
effect of certain chlorinated hydrocarbons on the composition of the hepatocyte
population of the rat liver. Bull Exp Biol Med 83: 396-400.
http://dx.doi.org/10.1007/BF0Q799375
Benbrahim-Tallaa. L; Lauby-Secretan. B; Loom is. D; Guvton. KZ; Grosse. Y; El Ghissassi. F;
Bouvard. V; Guha. N; Mattock. H; Strait'. K. (2014). Carcinogenicity of
perfluorooctanoic acid, tetrafluoroethylene, dichloromethane, 1,2-dichloropropane, and
1.3-propane	sultone. Lancet Oncol 15: 924-925. http://dx.doi.org/10.1016/S147Q-
2045(14)70316-X
Bio Dynamics (Bio/dynamics Inc.). (1981). Acute oral toxicity study in rats. (TSCATS/017993.
OTS84003A. EPA I.D. 878211460). East Millstone, NJ: Exxon Corporation.
Bruckner. IV; Mackenzie. WF; Ramanathan. R; Muralidhara. S: Kim. HI: Dallas. CE. (1989).
Oral toxicity of 1,2-dichloropropane: acute, short-term, and long-term studies in rats.
Toxicol Sci 12: 713-730. http://dx.doi.org/10.1016/0272-0590C89)90003-l
Cat/EPA (California Environmental Protection Agency). (1999). Public health goal for 1,2-
dichloropropane in drinking water. Sacramento, CA: Office of Environmental Health
Hazard Assessment, http://oehha.ca.gov/water/phg/pdf/12dcp f.pdf
Cal/EPA (California Environmental Protection Agency). (2004). No significant risk level
(NSRL) for the proposition 65 carcinogen 1,2-dichloropropane. Sacramento, CA: Office
of Environmental Health Hazard Assessment.
http://oehha.ca.gov/prop65/law/pdf zip/oehha2004a.pdf
Cal/EPA (California Environmental Protection Agency). (2014). All OEHHA acute, 8-hour and
chronic reference exposure levels (chRELs) as of June 2014. Sacramento, CA: Office of
Health Hazard Assessment, http://www.oehha.ca.gov/air/allrels.html
190
1,2-Dichloropropane

-------
FINAL
09-29-2016
Cal/EPA (California Environmental Protection Agency). (2016a). Chemicals known to the state
to cause cancer or reproductive toxicity July 15, 2016. (Proposition 65 list). Sacramento,
CA: California Environmental Protection Agency, Office of Environmental Health
Hazard Assessment, http://oehha.ca.eov/proposition-65/proposition-65-list
Cal/EPA (California Environmental Protection Agency). (2016b). OEHHA toxicity criteria
database [Database], Sacramento, CA: Office of Environmental Health Hazard
Assessment. Retrieved from http://www.oehha.ca.eov/tcdb/index.asp
Carers. A; Morpurgo. G. (1981). Comparison of the mutagenic activity of pesticides in vitro in
various short-term assays. In Progress in environmental mutagenesis and carcinogenesis:
Proceedings of the 10th annual meeting of the European Environmental Mutagen Society
(EEMS), Athens, Greece, 14-19 September 1980. New York, NY: Elsevier/North-
Holland Biomedical Press.
Chiappino. G: Secchi. GC. (1968). [Description of a case of acute intoxication from accidental
ingestion of 1,2-dichloropropane sold as trilene], G Ital Med Lav Ergon 59: 334-341.
Chroust K; Pavlova. M; Prokop. Z; Mendel. J; Bozkova, K; Kubat. Z; /aii. CV; Damborskv. J.
(2006). Quantitative structure-activity relationships for toxicity and genotoxicity of
halogenated aliphatic compounds: Wing spot test of Drosophila melanogaster.
Chemosphere 67: 152-159. http://dx.doi.Org/10.1016/i.chemosphere.2006.09.020
De Lorenzo. F; Deglinnocenti. S; Ruocco. A; Silengo. L; Cortese. R. (1977). Mutagenicity of
pesticides containing 1,3-dichloropropene. Cancer Res 37: 1915-1917.
Di Nucci. A; Gregotti. C; Manzo. L; Imbriani. M; Ghittori. S; Bianco. L; Maestri. L; Capodaglio.
K (1990). 1,2-dichloropropane hepatotoxicity in rats after inhalation exposure. J Appl
Toxicol 10: 391-394. http://dx.doi.org/10.1002/iat.25501006Q2
Di Nucci, A; Imbriani, M; Ghittori, S; Gregotti, C; Baldi, C; Locatelli. C; Manzo, L; Capodaglio,
K (1988). 1,2-Dichloropropane-induced liver toxicity: Clinical data and preliminary
studies in rats. Arch Toxicol 12: 370-374.
Dow Chemical Co (Dow Chemical Company). (1968). Hepatotoxic potency of propylene
dichloride vapors relative to their narcotic and lethal potencies in mice with cover letter.
(OTS0206134. TSCATS/017436. EPA Doc #878210624). Washington, D.C.: U.S.
Environmental Protection Agency.
Dow Chemical Co (Dow Chemical Company). (1988a). Final report on propylene dichloride 13-
week inhalation toxicity study with rats, mice and rabbits with cover letter dated 032888.
(FYIOTS04880399). Midland, MI.
Dow Chemical Co (Dow Chemical Company). (1988b). N eurotox i col ogi c examination of rats
exposed to 1,2-dichloropropane (PDC) via gavage for 13 weeks. In Letter from Dow
Chemical Company to US EPA regarding submission of final study reports for 1,2-
dichloropropane with attachments. (OTS0527733 (STUDY ID: K-002127-013)).
Midland, MI.
Dow Chemical Co (Dow Chemical Company). (1988c). Propylene dichloride: a 13-day repeated
oral gavage study in New Zealand white rabbits with attached appendix and cover letter
dated 011389. (OTS0516642. Doc I.D. 86890000079). Midland, MI.
Dow Chemical Co (Dow Chemical Company). (1988d). Propylene dichloride: Oral teratology
probe study in New Zealand white rabbits with cover letter dated 100188.
(TSCATS/401132. OTS0516583. EPA I.D. 86-890000004). Midland, MI.
Dow Chemical Co (Dow Chemical Company). (1989a). N eurotoxi col ogi c examination of
Fischer 344 rats exposed to 1,2-dichloropropane via gavage for 2 weeks with cover letter
dated 022389. (TSCATS/311076. OTS0517725. EPA I.D. 86890000125).
191
1,2-Dichloropropane

-------
FINAL
09-29-2016
Dow Chemical Co (Dow Chemical Company). (1989b). Propylene dichloride: dominant lethal
study in Sprague-Dawley rats (final) with cover letters. (OTS0527736. EPA I.D.
408967206).
https://ntrl.ntis. eov/NTRL/dashboard/searchResults.xhtml?searchOuerv=OTS0527736
Dow Chemical Co (Dow Chemical Company). (1989c). Propylene dichloride: Oral teratology
probe study in Sprague-Dawley rats with cover letter. (OTS0527712). Midland, MI.
Dow Chemical Co (Dow Chemical Company). (1989d). Propylene dichloride: oral teratology
probe study in Sprague-Dawley rats with cover letter dated 041389. Washington, D.C.:
U.S. Environmental Protection Agency.
Dow Chemical Co (Dow Chemical Company). (1990). Propylene dichloride: two-generation
reproduction study in sprague-dawley rats (final) with cover letter. (TSCATS/411990.
OTS0527738. EPA Doc. ID 40-9067215). Midland, MI: Dow Chemical.
Fiaccadori. E; Maggiore. U; Rotelli. C; Giacosa. R; Ardissino. D; De Pal ma. G; Bergamaschi. E;
Mutti. A. (2003). Acute renal and hepatic failure due to accidental percutaneous
absorption of 1,2-dichlorpropane contained in a commercial paint fixative [Letter],
Nephrol Dial Transplant 18: 219-220. http://dx.doi.org/10.1093/ndt/18.L219
Fiserova-Bergerova. ¥; Pierce. IT; Pro/.. PO. (1990). Dermal absorption potential of industrial
chemicals: Criteria for skin notation. Am J Ind Med 17: 617-635.
http://dx.doi.org/10.1002/aiim.47001705Q7
Galloway. SM; Armstrong. MJ; Reuben. C; Col man. S; Brown. B; Cannon. C; Bloom. AD;
Nakamura. F; Ahmed. M; Duk. S; Rimpo. J; Margolin. BH; Resnick. MA: Anderson. B;
Zeiger. E. (1987). Chromosome aberrations and sister chromatid exchanges in Chinese
hamster ovary cells: Evaluations of 108 chemicals [Review], Environ Mol Mutagen 10:
1-175. http://dx.doi.org/10.1002/em.28501005Q2
Gargas. ML: Burgess. RJ; Voisard. DE; Cason. GH; Andersen. ME. (1989). Partition
coefficients of low-molecular-weight volatile chemicals in various liquids and tissues.
Toxicol Appl Pharmacol 98: 87-99.
Gi. M; Fuiioka. M; Yamano. S; Shimomura. E; Ishii. N; Kakehashi. A; Takeshita. M;
Wanibuchi. H. (2015a). Determination of hepatotoxicity and its underlying metabolic
basis of 1,2-dichloropropane in male Syrian hamsters and B6C3F1 mice. Toxicol Sci
145: 196-208. http://dx.doi.org/10.1093/toxsci/kfv045
Gi. M; Fuiioka. M; Yamano. S; Shimomura. E; Kanki. M; Kawachi. S; Tachibana. H: Tatsumi.
K; Fang. H; Ishii. N; Kakehashi. A; Wanibuchi. H. (2015b). Modifying effects of 1,2-
dichloropropane on N-nitrosobis(2-oxopropyl)amine-induced cholangiocarcinogenesis in
male Syrian hamsters. J Toxicol Sci 40: 647-656. http://dx.doi.org/10.2131/its.40.647
Grzywa, Z; Rudzki, E. (1981). Dermatitis from dichloropropane. Contact Demi 7: 15 1-152.
http://dx.doi.Org/lQ.llll/i.16QQ-Q536.1981.tbQ4589.x
Guengerich. FP; Kim. DH; Iwasaki. M. (1991). Role of human cytochrome P-450 I1E1 in the
oxidation of many low molecular weight cancer suspects. Chem Res Toxicol 4: 168-179.
http://dx.doi.org/10.1021/tx00020a0Q8
Haworth. S; Lawlor. T; Mortelmans. K: Speck. W; Zeiger. E. (1983). Salmonella mutagenicity
test results for 250 chemicals. Environ Mutagen 5: 3-142.
http://dx.doi.org/10.1002/em.28600507Q3
Heppel. LA; Highman. B; Peake. EG. (1948). Toxicology of 1,2-dichloropropane (propylene
dichloride): IV. Effects of repeated exposures to a low concentration of the vapor. J Ind
Hyg Toxicol 30: 189-191.
192
1,2-Dichloropropane

-------
FINAL
09-29-2016
Heppel. LA; Neal. PA. (1946). Toxicology of 1,2-dichloropropane (propylene dichloride) studies
on effects of daily inhalations. J Ind Hyg Toxicol 28: 1-8.
Highman. B; Heppel. LA. (1946). Toxicology of 1,2-dichloropropane (propylene dichloride);
pathologic changes produced by a short series of daily exposures. Arch Pathol 42: 525-
534.
HSDB (Hazardous Substances Data Bank). (2014). 1,2-Dichloropropane (CASRN: 78-87-5).
Bethesda, MD: U.S. National Library of Medcine. http://toxnet.nlm.nih.gov/cgi-
bin/sis/search2/f?./temp/ cGOoI.f:3
I ARC (International Agency for Research on Cancer). (2015). I ARC Monographs on the
evaluation of carcinogenic risk to humans. Geneva, Switzerland: International Agency for
Research on Cancer, WHO. http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php
Imberti. R; Calabrese, SR; Emilio, G; Marchi, L; Giuffrida, L. (1987). [Acute poisoning with
solvents: chlorinated aliphatic hydrocarbons], Minerva Anestesiol 53: 399-403.
Imberti. R: Nlapelli. A; Colombo. P; Richelmi. P; Berte. F; Bellomo. G. (1990). 1,2-
dichloropropane (DCP) toxicity is correlated with DCP-induced glutathione (GSH)
depletion and is modulated by factors affecting intracellular GSH. Arch Toxicol 64: 459-
465. http://dx.doi.org/10.1007/BFQ1977627
IPCS (Intemational Programme on Chemical Safety). (2016). INCHEM: Chemical safety
information from intergovernmental organizations [Database]: World Health
Organization. Canadian Centre for Occupational Health and Safety. Inter-Organization
Programme for the Sound Management of Chemicals. Retrieved from
http://www.inchem.org/
Jones. AR; Gibson. J. (1980). 1,2-dichloropropane: metabolism and fate in the rat. Xenobiotica
10: 835-846. http://dx.doi.org/10.3109/00498258009Q33814
Kennedy. GL. Jr; Graepel. GJ. (1991). Acute toxicity in the rat following either oral or inhalation
exposure. Toxicol Lett 56: 317-326. http://dx.doi.org/10.1016/0378-4274(91)90160-8
Kirk. HP; Berdasco. NM: Breslin. WJ; Hanlev. TRJ. (1995). Developmental toxicity of 1,2-
dichloropropane (PDC) in rats and rabbits following oral gavage. Fundam Appl Toxicol
28: 18-26. http://dx.doi.org/10.1006/faat. 1995.1141
Kramers, PGN; Mout, HCA; Bissumbhar, B; Mulder, CR. (1991). Inhalation exposure in
Drosophila mutagenesis assays: Experiments with aliphatic halogenated hydrocarbons,
with emphasis on the genetic activity profile of 1,2-dichloroethane. Mutat Res 252: 17-
33. http://dx.doi.org/10.1016/0165-1161(91)90248-7
Kubo. S; Kinoshita. M; Takemura. S; Tanaka. S; Shinkawa. H; Nishioka. T: Hamano. G: I to. T:
Abue. M; Aoki. M; Nakagawa. K; Unno. M; Hijioka. S; Fuiivoshi. T; Shimizu. Y;
Mizuguchi, T; Shirabe, K; Nishie, A; Oda, Y; Takenaka, K; Kobarai, T; Hisano, T;
Saiura. A; Numao. H; Toda. M; Kuwae. Y; Nakanuma. Y; Endo. G. (2014a).
Characteristics of printing company workers newly diagnosed with occupational
cholangiocarcinoma. J Hepatobiliary Pancreat Sci 21: 809-817.
http://dx.doi.org/10.1002/ihbp.137
Kubo. S; Matsuzaki. K; Seki. T; Ohsawa. M; Kumagai. S; Endo. G. (2014b). Severe acute
hepatitis in a printing company worker: a case study. J Occup Health 57: 87-90.
http://dx.doi.org/10.1539/ioh.14-0122-CS
193
1,2-Dichloropropane

-------
FINAL
09-29-2016
Kubo. S; Nakanuma. Y; Takemura. S; Sakata. C; Urata. Y; Nozawa. A; Nishioka. T; Kinoshita.
M; Hamano. G; Teraiima. H; Tachiyama. G; Mat sum lira. Y; Yamada. T; Tanaka. H;
Nakamori, S; Arimoto, A; Kawada. N; Fujikawa. M; Fuiishima. H; Sugawara. Y;
Tanaka. S; Tovokawa. H; Kuwae. Y; Ohsawa. M; Uehara- S; Sato. KK; Havashi. T;
Endo. G. (2014c). Case series of 17 patients with cholangiocarcinoma among young adult
workers of a printing company in Japan. J Hepatobiliary Pancreat Sci 21: 479-488.
http://dx.doi.org/10.1002/ihbp.86
Kumagai. S; Kurumatani. N; Arimoto. A; Ichihara. G. (2013). Cholangiocarcinoma among offset
colour proof-printing workers exposed to 1,2-dichloropropane and/or dichloromethane.
Occup Environ Med 70: 508-510. http://dx.doi.Org/10.l 136/oemed-2012-101246
Kumagai. S; Kurumatani. N; Arimoto. A; Ichihara. G. (2014). Time course of blood parameters
in printing workers with cholangiocarcinoma. J Occup Health 56: 279-284.
http://dx.doi. org/ 10.1539/i oh. 13-0263 -OA
Kumagai. S; Sobue. T; Makiuchi. T; Kubo. S; Uehara. S; Havashi. T; Sato. KK; Endo. G.
(2016). Relationship between cumulative exposure to 1,2-dichloropropane and incidence
risk of cholangiocarcinoma among offset printing workers. Occup Environ Med 73: 545-
552. http://dx.doi.org/10.1136/oemed-2015-103427
Lucantoni, C; Grottoli, S; Gaetti. R. (1992). 1,2-Dichloropropane is a renal and liver toxicant
[Letter], Toxicol Appl Pharmacol 117: 133.
Matsumoto. M; Umeda. Y; Take. M; Nishizawa. T; Fukushima. S. (2013). Sub chronic toxicity
and carcinogenicity studies of 1,2-dichloropropane inhalation to mice. Inhal Toxicol 25:
435-443. http://dx.doi.org/10.3109/08958378.2013.80Q618
Matsumoto. T; Okura. Y; Okawa. Y; Mikami. T; Nagase. T; Hashimoto. K; Suzuki. M; Sugai.
N; Suzuki, S. (1982). Acute toxicity testing of some chlorinated lower hydro carbons
dichloromethane 1 2 dichloropropane and 1 3 dichloropropane [Abstract], JJTHE 28: P-
31.
Matsumoto. T; Okura. Y; Okawa. Y; Mikami. T; Nagase. T; Hashimoto. K; Suzuki. S; Suzuki.
M; Sugai. N, (1983). Toxicity test of dichloromethane and 1,2-dichloropropane and 1,3-
dichloropropane. JJTHE 29: P38-P38.
Mellon Institute of Industrial Research. (1947a). Recalculation of liver and kidney weights
previously reported with revised conclusions on the toxicity of eight chlorinated
hydrocarbons. (TSCATS/308694. OTS0515561. EPA Doc I.D.86-870001399). Houston,
TX: Union Carbide Corporation.
Mellon Institute of Industrial Research. (1947b). Repeated exposure of rats and dogs to vapors of
eight chlorinated hydrocarbons. (TSCATS/308690. OTS0515559. EPA Doc ID.86-
870001397). Pittsburgh, PA: Carbide and Carbon Chemicals Corporation.
Myhr. BC; Caspary. WJ. (1991). Chemical mutagenesis at the thymidine kinase locus in L5 178Y
mouse lymphoma cells: Results for 31 coded compounds in the National Toxicology
Program. Environ Mol Mutagen 18: 51-83. http://dx.doi.org/10.1002/em.28501801Q9
NIOSH (National Institute for Occupational Safety and Health). (1994). Immediately dangerous
to life or health concentrations (IDHL). Propylene dichloride. Atlanta, GA: Centers for
Disease Control and Prevention, http://www.cdc.gov/niosh/idlh/78875.html
NIOSH (National Institute for Occupational Safety and Health). (2011). NIOSH Pocket guide to
chemical hazards. Propylene dichloride. Atlanta, GA: Centers for Disease Control and
Prevention, http://www.cdc. gov/niosh/npg/npgdO534.html
194
1,2-Dichloropropane

-------
FINAL
09-29-2016
NIOSH (National Institute for Occupational Safety and Health). (2015). NIOSH pocket guide to
chemical hazards. Introduction. Atlanta, GA: Center for Disease Control and Prevention.
http://www.cdc.gov/niosh/npg/pgintrod.html
NTP (National Toxicology Program). (1986). Toxicology and carcinogenesis studies of 1,2-
dichloropropane (propylene dichloride) (CAS no. 78-87-5) in F344/N rats and B6C3F1
mice (gavage studies) (pp. 182 PP). (NTP TR 263). Research Triangle Park, NC: U.S.
Department of Health and Human Services, Public Health Service.
NTP (National Toxicology Program). (2014). Report on carcinogens. Thirteenth edition.
Research Triangle Park, NC: U.S. Department of Health and Human Services, Public
Health Service, http://ntp.niehs.nih.gov/pubhealth/roc/rocl3/index.html
OECD (Organisation for Economic Co-operation and Development). (2003). S1DS Initial
Assessment Report from SIAM 17. Arona, Italy, 11-15 November 2003. 1,2-
dichloropropane. http://www.chem.unep.ch/irptc/sids/OECDSIDS/78875.pdf
OSHA (Occupational Safety & Health Administration). (2006a). Safety and health regulations
for construction: Occupational health and environmental controls - Gases, vapors, fumes,
dusts, and mists. (1926.55 App A). Washington, DC: U.S. Department of Labor.
http://www.osha.gov/pls/oshaweb/owadisp.show document?p table STAND A R1) S & p
id=10629
OSHA (Occupational Safety & Health Administration). (2006b). Table Z-l: Limits for air
contaminants. Occupational safety and health standards, subpart Z, toxic and hazardous
substances. (OSHA standard 1910.1000, 29 CFR). Washington, DC: U.S. Department of
Labor.
http://www.osha.gov/pls/oshaweb/owadisp.show document?p table STAND A R D S & p
id=9992
OSHA (Occupational Safety & Health Administration). (201 1). Air contaminants: Occupational
safety and health standards for shipyard employment, subpart Z, toxic and hazardous
substances. (OSHA Standard 1915.1000). Washington, DC: U.S. Department of Labor.
https://www.osha.gov/pls/oshaweb/owadisp.show document?p table STANDARDS&P
id10286
Perbellini, L; Zedde, A; Schiavon. R; Franchi, GL. (1985). [Disseminated intravascular
coagulation (DIC) caused by 1,2-dichloropropane (commercial trielin). Description of 2
cases], Med Lav 76: 412-417.
Perocco. P; Bolognesi. S; Alberghini W. (1983). Toxic activity of seventeen industrial solvents
and halogenated compounds on human lymphocytes cultured in vitro. Toxicol Lett 16:
69-75. http://dx.doi.org/10.1016/0378-4274(83)90012-7
Pozzi, C; Marai, P; Ponti, R; DeH'Oro, C; Sal a. C; Zedda, S; Locatelli, F. (1985). Toxicity in
man due to stain removers containing 1,2-dichloropropane. Br J Ind Med 42: 770-772.
http://dx.doi.Org/10.l 136/oem.42.11.770
Principe. P; Dogliotti, E; Bignami, M; Crebetti. R; Falcone. E; Fabrizi. M; Conti. G; Comba. P.
(1981). Mutagenicity of chemicals of industry and agricultural relevance in Salmonella,
Streptomyces and Aspergillus. J Sci Food Agric 32: 826-832.
http://dx.doi.org/10.1002/isfa.274032Q812
Prival. MJ; Dunkel. VC. (1989). Reevaluation of the mutagenicity and carcinogenicity of
chemicals previously identified as "false positives" in the Salmonella typhimurium
mutagenicity assay. Environ Mol Mutagen 13: 1-24.
http://dx.doi.org/10.1002/em.28501301Q2
195
1,2-Dichloropropane

-------
FINAL
09-29-2016
Sato. Y; Kubo. S; Takemura. S; Sugawara. Y; Tanaka. S; Fujikawa. M; Arimoto. A; Harada. K;
Sasaki. M; Nakanuma. Y. (2014). Different carcinogenic process in cholangiocarcinoma
cases epidemically developing among workers of a printing company in Japan. Int J Clin
Exp Pathol 7: 4745-4754.
Sekiguchi. S; Suda. M; Zhai. YL; Honma. T. (2002). Effects of 1 -bromopropane, 2-
bromopropane, and 1,2-dichloropropane on the estrous cycle and ovulation in F344 rats.
Toxicol Lett 126: 41-49.
Shell Oil Co (Shell Oil Company). (1982). Toxicology of fine chemicals: The acute oral and
percutaneous toxicity, skin and eye irritancy and skin sensitizing potential of 1,2-
dichloropropane (light ends). (TSCATS/016752. OTS0205965. EPA I.D. 878212009).
Houston, TX.
Sidorenko, GI; Tsulaya, VR; Bonashevskaya, TI; Shaipak, VM. (1979). Study of the combined
action of a group of chlorine derivatives of hydrocarbons entering the organism by
inhalation. Environ Health Perspect 30: 13-18.
Sobue. T; Utada. M; Makiuchi. T; Ohno. Y; Uehara. S; Hayashi. T; Sato. KK; Endo. G. (2015).
Risk of bile duct cancer among printing workers exposed to 1,2-dichloropropane and/or
dichloromethane. J Occup Health 57: 230-236. http://dx.doi.org/10.1539/ioh.14-0116-0A
SRI (Stanford Research Institute). (1975). In vitro microbiological mutagenicity studies of ethyl
compounds. (86870001694). Midland, MI: Dow Chemical Company.
Stolzenberg. SJ; Hine. CH. (1980). Mutagenicity of 2- and 3-carbon halogenated compounds in
the Salmonella/mammalian-microsome test. Environ Mutagen 2: 59-66.
http://dx.doi.org/10.1002/em.28600201Q9
Suzuki. T; Yanagiba. Y; Suda. M; Wang. RS. (2014). Assessment of the genotoxicity of 1,2-
dichloropropane and dichloromethane after individual and co-exposure by inhalation in
mice. J Occup Health 56: 205-214.
Take. M; Matsumoto. M; Takeuchi. T; Haresaku. M; Kondo. H; Senoh. H; Umeda. Y;
Takamura-Enya. T; Fukushima. S. (2014). Inhalation exposure to 1,2-dichloropropane:
Distribution of blood and tissue concentrations of 1,2-dichloropropane in rats during and
after exposure. J Environ Sci Health A Tox Hazard Subst Environ Eng 49: 1341-1348.
http://dx.doi.org/10.1080/10934529.2Q14.928193
Thorel. JM; Bercoff. E; Massari. P; Drov. JM; Chassagne. P; Proust. B; Hemet. J; Bourreille. J.
(1986). [Toxicity of 1,2 dichloropropane. A case with portal hypertension], J Toxicol
Clin Exp 6: 247-252.
Timchalk. C; Dryzga. MP; Smith. FA; Bartels. MJ. (1991). Disposition and metabolism of
[14C] 1,2-dichloropropane following oral and inhalation exposure in Fischer 344 rats.
Toxicology 68: 291-306. http://dx.doi.org/10.1016/0300-483Xf91 )90076-D
Tomimaru. Y; Kobayashi. S; Wada. H; Hama. N; Kawamoto. K; Eguchi. H; Kira. T; Morii. E;
Doki. Y; Mori. M; Nagano. H. (2014). Intrahepatic cholangiocarcinoma in a worker at an
offset color proof-printing company: An autopsy case report. Hepatology Research Jun:
488-493. http://dx.doi.org/10.1111/hepr. 12363
Trevisan. A; Rizzi. E; Bungaro. A; Pozzobon. L; Gioffre. F; Scapinello. A; Valeri. A; Chiesura.
P. (1988). Proximal tubule brush border angiotensin converting enzyme behaviour and
nephrotoxicity due to 1,2-dichloropropane. Arch Toxicol 12: 190-192.
http://dx.doi.org/10.1007/978-3-642-73113-6 31
Trevisan. A; Rizzi. E; Scapinello. A: Gioffre. F; Chiesura. P. (1989). Liver toxicity due to 1,2-
dichloropropane in the rat. Arch Toxicol 63: 445-449.
http://dx.doi.org/10.1007/BF0Q316446
196
1,2-Dichloropropane

-------
FINAL
09-29-2016
Trevisan. A; Troso. O; Maso. S. (1991). Recovery of biochemical changes induced by 1, 2-
dichloro propane in rat liver and kidney. Hum Exp Toxicol 10: 241-244.
U.S. Congress. (1990). Clean Air Act as amended in 1990, Sect. 112 (b) (1) Hazardous air
pollutants. Public Law 101-549 Nov. 15, 1990.
U.S. EPA (U.S. Environmental Protection Agency). (1987). Health effects assessment for 1,2-
dichloropropane [EPA Report], (EPA/600/8-88/029). Cincinnati, OH: Environmental
Criteria and Assessment Ofiice.
U.S. EPA (U.S. Environmental Protection Agency). (1988). Recommendations for and
documentation of biological values for use in risk assessment (pp. 1-395). (EPA/600/6-
87/008). Cincinnati, OH: U.S. Environmental Protection Agency, Office of Research and
Development, Office of Health and Environmental Assessment.
http://cfpub.epa. goy/ncea/cfm/recordisplay.cfm?deid=34855
U.S. EPA (U.S. Environmental Protection Agency). (1991). Guidelines for developmental
toxicity risk assessment (pp. 1-71). (EPA/600/FR-91/001). Washington, DC: U.S.
Environmental Protection Agency, Risk Assessment Forum.
http://cfpub.epa.gov/ncea/cfm/recordisplav.cfm?deid=23162
U.S. EPA (U.S. Environmental Protection Agency). (1992). Dermal exposure assessment:
Principles and applications (interim report) [EPA Report], (EPA/600/8-91/01 IB).
Washington, DC: Office of Health and Environmental Assessment.
http://cfpub.epa.gov/ncea/cfm/recordisplav.cfm?deid=12188
U.S. EPA (U.S. Environmental Protection Agency). (1994a). Chemical assessments and related
activities (CARA) [EPA Report], (600/R-94/904; OHEA-I-127). Washington, DC: U.S.
Environmental Protection Agency, Office of Health and Environmental Assessment.
http://nepis.epa. gov/Exe/ZvPURL.cgi?Dockev=6000 lG8L.txt
U.S. EPA (U.S. Environmental Protection Agency). (1994b). Methods for derivation of
inhalation reference concentrations and application of inhalation dosimetry [EPA Report]
(pp. 1-409). (EPA/600/8-90/066F). Research Triangle Park, NC: U.S. Environmental
Protection Agency, Office of Research and Development, Office of Health and
Environmental Assessment, Environmental Criteria and Assessment Office.
https://cfpub. epa.gov/ncea/risk/recordisplay. cfm?deid=71993&CFID=51174829&CFTO
KEN 25006317
U.S. EPA (U.S. Environmental Protection Agency). (1998). Reregi strati on eligibility decision
(RED). 1,3-Dichloropropene. Washington, DC: Office Prevention, Pesticides and Toxic
Substances.
http://www.epa.gov/pesticides/chem search/reg acti on s/rer e gi strati on/red PC-
029001 l-Sep-98.pdf
U.S. EPA (U.S. Environmental Protection Agency). (2002a). IRIS summary for 1,2-
dichloropropane; CASRN 78-87-5. Washington, DC: U.S. Environmental Protection
Agency, Integrated Risk Information System, http://www.epa.gov/iris/subst/0601.htm
U.S. EPA (U.S. Environmental Protection Agency). (2002b). A review of the reference dose and
reference concentration processes (pp. 1-192). (EPA/630/P-02/002F). Washington, DC:
U.S. Environmental Protection Agency, Risk Assessment Forum.
http://www.epa.gov/osa/review-reference-dose-and-reference-concentration-processes
U.S. EPA (U.S. Environmental Protection Agency). (2005). Guidelines for carcinogen risk
assessment [EPA Report] (pp. 1-166). (EPA/630/P-03/001F). Washington, DC: U.S.
Environmental Protection Agency, Risk Assessment Forum.
http://www2.epa.gov/osa/guidelines-carcinogen-risk-assessment
197
1,2-Dichloropropane

-------
FINAL
09-29-2016
U.S. EPA (U.S. Environmental Protection Agency). (201 la). Dichloropropane, 1,2- (CASRN 78-
87-5). Health Effects Assessment Summary Tables for Superfund (HEAST). Washington,
DC: Prepared by the Office of Research and Development, National Center for
Environmental Assessment, Cincinnati OH for the Office of Emergency and Remedial
Response, http://epa-heast.ornl.eov/heast.php?chemical=Dichloropropane%2C+l%2C2-
U.S. EPA (U.S. Environmental Protection Agency). (201 lb). Recommended use of body weight
3/4 as the default method in derivation of the oral reference dose (pp. 1-50).
(EPA/100/R11/0001). Washington, DC: U.S. Environmental Protection Agency, Risk
Assessment Forum, Office of the Science Advisor.
https://www.epa.gov/risk/recommended-use-bodv-weight-34-default-method-derivation-
oral-reference-dose
U.S. EPA (U.S. Environmental Protection Agency). (2012a). 1,2-Dichloropropane. Exposure
assessment tools and models: Estimation program interface (EPI) suite. Version 4.11
[Fact Sheet], Washington, DC: Office of Prevention, Pesticides and Toxic Substances.
http ://www. epa. gov/oppt/exposure/pub s/epi suite.htm
U.S. EPA (U.S. Environmental Protection Agency). (2012b). 2012 Edition of the drinking water
standards and health advisories [EPA Report], (EPA/822/S-12/001). Washington, DC:
Office of Water, http://www.epa.gov/sites/production/files/2015-
09/documents/dwstandards2012.pdf
U.S. EPA (U.S. Environmental Protection Agency). (2012c). Benchmark dose technical
guidance (pp. 1-99). (EPA/100/R-12/001). Washington, DC: U.S. Environmental
Protection Agency, Risk Assessment Forum, https://www.epa.gov/risk/benchmark-dose-
techni cal - gui dance
U.S. EPA (U.S. Environmental Protection Agency). (2012d). Chemical data access toll (CDAT).
2012 Chemical data reporting (CDR). CAS 78-87-5, propane, 1,2-dichloro. Available
online at http://www.epa.gov/oppt/cdr/index.html
Umeda. Y; Matsumoto. M; Aiso. S; Nishizawa. T; Nagano. K; Arito. H; Fukushima. S. (2010).
Inhalation carcinogenicity and toxicity of 1,2-dichloropropane in rats. Inhal Toxicol 22:
1116-1126. http://dx.doi.org/10.3109/08958378.201Q.526973
Utsumi, H; Hakoda, M; Kiyoshige, K; Manabe, H; Mitade, C; Murayama, J; Han, SK; Hamada,
A. (1992). Cytotoxicity and mutagenicity of micropollutants in drinking water. Water Sci
Technol 25: 325-332.
von der Hude. W; Behm. C; Gurtler. R; Easier. A. (1988). Evaluation of the SOS chromotest.
MutatRes 203: 81-94. http://dx.doi.org/10.1016/0165-1161(88)90023-4
Von Der Hude. W; Scheutwinkel, M; Gramlich. U; Fissler. B; Easier. A. (1987). Genotoxicity of
three-carbon compounds evaluated in the SCE test in vitro. Environ Mol Mutagen 9: 401-
410. http://dx.doi.org/10.1002/em.28600904Q6
WHO (World Health Organization). (2016). Online catalog for the Environmental Health
Criteria (EHC) monographs. Available online at
http://www.who.int/ipcs/publications/ehc/en/
Woodruff. RC: Mason. JM; Valencia. R; Zimmering. S. (1985). Chemical mutagenesis testing in
Drosophila. V. Results of 53 coded compounds tested for the National Toxicology
Program. Environ Mutagen 7: 677-702. http://dx.doi.org/10.1002/em.28600705Q7
Yamada. K; Kumagai. S; Nagova. T; Endo. G. (2014). Chemical exposure levels in printing
workers with cholangiocarcinoma. J Occup Health 56: 332-338.
http://dx.doi.org/10.1539/ioh.14-0073-OA
198
1,2-Dichloropropane

-------
FINAL
09-29-2016
Zedda. S; Sal a. C; Po/./.i. C; Locatelli. F. (1900). Human acute poisoning due to 1,2-
dichloropropane. (NIOSH/00145827). Zedda, S; Sala, C; Pozzi, C; Locatelli, F.
Zhang. L; Zone. C; Ichihara- S; Naito. H: Tovokuni S; Kumauai. S; Ichihara. G. (2015). Atrial
to find appropriate animal models of dichloropropane-induced cholangiocarcinoma based
on the hepatic distribution of glutathione S-transferases. J Occup Health 57: 548-554.
http://dx.doi.org/10.1539/ioh.15-0085-QA
199
1,2-Dichloropropane

-------